Minimal inhibiting concentration

Clin Ther, 2001 Apr, 23(4), 578 - 84
The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate; Kaye CM et al.; BACKGROUND: A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing . OBJECTIVE: This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects . METHODS: A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg; 16:1 ratio) was administered to subjects at the start of a meal . After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures . The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 microg/mL, the time above the MIC (T >MIC) would be approximately > or = 40% over a 12-hour dosing interval . RESULTS: The study enrolled 24 and 31 healthy male and female subjects, respectively . Their mean age was 35 years (range, 18-58 years) and mean body weight was 69 kg (range, 51-86 kg) . After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase . The mean T >MIC for an amoxicillin MIC of 4 microg/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate . By 12 hours, plasma amoxicillin concentrations were very low (approximately 0.05 microg/mL), suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen . The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate . No deaths or serious adverse events were reported . CONCLUSIONS: The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria--including beta-lactamase-producing organisms--and strains with amoxicillin MICs < or = 4 microg/mL.

Antimicrob Agents Chemother, 2001 Jun, 45(6), 1937 - 8
Sputum itraconazole concentrations in cystic fibrosis patients; Sermet-Gaudelus I et al.; Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis . There was a high interindividual variability in sputum itraconazole concentration and sputum/serum drug concentration ratio . Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.

Antimicrob Agents Chemother, 2001 Jun, 45(6), 1908 - 10
In vitro activities of moxifloxacin and other fluoroquinolones against Mycoplasma pneumoniae; Hamamoto K et al.; A total of 105 isolates of Mycoplasma pneumoniae were evaluated for susceptibility to moxifloxacin, sparfloxacin, levofloxacin, and ciprofloxacin . Moxifloxacin, a newly synthesized compound, showed the greatest activity . The MICs and MBCs at which 50 and 90% of isolates were affected were 0.15 (MIC(50) and MBC(50)) and 0.3 microg/ml (MIC(90) and MBC(90)) respectively . The results indicate that moxifloxacin might be promising an antimycoplasmal agent.

Antimicrob Agents Chemother, 2001 Jun, 45(6), 1882 - 5
In vitro activities of terbinafine against Aspergillus species in comparison with those of itraconazole and amphotericin B; Moore CB et al.; Compared with the in vitro activities of itraconazole (geometric mean MIC {GM}, 0.56 microg/ml) and amphotericin B (GM, 0.66 microg/ml), the in vitro activity of terbinafine was inferior against Aspergillus fumigatus (GM, 19.03 microg/ml) (P < 0.05) and superior against A . flavus (GM, 0.10 microg/ml), A . terreus (GM, 0.16 microg/ml), and A . niger (GM, 0.19 microg/ml) . Clinical correlation is required, as trailing endpoints are problematic.

Antimicrob Agents Chemother, 2001 Jun, 45(6), 1854 - 9
Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model; Gonzalez GM et al.; Caspofungin (Merck Pharmaceuticals) was tested in vitro against 25 clinical isolates of Coccidoides immitis . In vitro susceptibility testing was performed in accordance with the National Committee for Clinical Laboratory Standards document M38-P guidelines . Two C . immitis isolates for which the caspofungin MICs were different were selected for determination of the minimum effective concentration (MEC), and these same strains were used for animal studies . Survival and tissue burdens of the spleens, livers, and lungs were used as antifungal response markers . Mice infected with strain 98-449 (48-h MIC, 8 microg/ml; 48-h MEC, 0.125 microg/ml) showed 100% survival to day 50 when treated with caspofungin at > or =1 mg/kg . Mice infected with strain 98-571 (48-h MIC, 64 microg/ml; 48-h MEC, 0.125 microg/ml) displayed > or =80% survival when the treatment was caspofungin at > or =5 mg/kg . Treatment with caspofungin at 0.5, 1, 5, or 10 mg/kg was effective in reducing the tissue fungal burdens of mice infected with either isolate . When tissue fungal burden study results were compared between strains, caspofungin showed no statistically significant difference in efficacy in the organs of the mice treated with both strains . A better in vitro-in vivo correlation was noted when we used the MEC instead of the MIC as the endpoint for antifungal susceptibility testing . Caspofungin may have a role in the treatment of coccidioidomycosis.

Antimicrob Agents Chemother, 2001 Jun, 45(6), 1828 - 35
Optimal susceptibility testing conditions for detection of azole resistance in Aspergillus spp.: NCCLS collaborative evaluation . National Committee for Clinical Laboratory Standards; Espinel-Ingroff A et al.; The most important role of susceptibility testing is to identify potentially resistant isolates for the agent being evaluated . Standard testing guidelines recently have been proposed for antifungal susceptibility testing of filamentous fungi (molds) . This collaborative (eight centers) study evaluated further newly proposed guidelines (NCCLS, proposed standard M38-P, 1998) and other testing conditions for antifungal susceptibility testing of Aspergillus spp . to itraconazole and three new triazoles, posaconazole (SCH56592), ravuconazole (BMS-207147), and voriconazole . MICs of itraconazole, posaconazole, ravuconazole, and voriconazole for 15 selected isolates of three species of Aspergillus (A . fumigatus, A . flavus, and A . terreus) with well documented in vitro, clinical, or animal data were determined in each center by using four medium formulations (standard RPMI-1640 {RPMI}, RPMI with 2% dextrose, antibiotic medium 3 {M3}, and M3 with 2% dextrose) and two criteria of MIC determination (complete {MIC-0s} and prominent {MIC-2s} growth inhibition) at 24, 48, and 72 h . The highest reproducibility (92 to 99%) was seen with the standard RPMI and M3 media . Moreover, the distinction between itraconazole-resistant (MICs of >8 microg/ml for clinically resistant strains) and -susceptible (MICs of 0.03 to 1 microg/ml) isolates, as well as between a voriconazole-resistant laboratory mutant and other isolates (voriconazole MICs of 2 to >8 versus 0.12 to 2 microg/ml), was more consistently evident with the standard RPMI medium and when MIC-0s were determined at 48 h . These results provide further refinement of the testing guidelines for susceptibility testing of Aspergillus spp . and warrant consideration for inclusion in the future NCCLS document M38-A.

J Clin Oncol, 2001 May 15, 19(10), 2616 - 25
Hürthle cell carcinoma: a critical histopathologic appraisal; Stojadinovic A et al.; PURPOSE: Controversy exists over the ability of morphology to predict the biologic behavior of Hurthle cell carcinoma . The aim of this study was to conduct a critical histopathologic review of Hurthle cell carcinoma and to correlate morphologic parameters with clinical outcome . PATIENTS AND METHODS: Patients with histologically confirmed Hurthle cell carcinoma treated between 1940 and 2000 form the basis of this study . Adenomas were excluded . Tumors of unknown malignant behavior ({UMB} n = 17) had solid growth pattern, incomplete capsular invasion (Ci), or both but no vascular invasion (Vi) . Minimally invasive carcinomas ({MIC} n = 23) had one focus of intra- or extracapsular Vi, one focus of complete Ci, or both . Widely invasive carcinomas ({WIC} n = 33) demonstrated more than one focus of Vi, more than one focus of Ci, or both . The primary end points were relapse-free survival (RFS) and disease-specific survival (DSS) . Rates of recurrence/death were estimated by Kaplan-Meier method . The univariate influence of prognostic factors on end points was analyzed by log-rank test, and multivariate analysis was performed by Cox regression . RESULTS: Median follow-up was 8 years . No patients with UMB or MIC relapsed or died of disease . Of WIC, 73% relapsed and 55% died of disease . Age, size, and extent of resection did not influence outcome . Adverse predictors of RFS and DSS among WIC were extrathyroidal extension, nodal metastasis, positive margin, and solid growth pattern (P <.05) . Both Ci and Vi were associated with worse DSS (P <.05) . On multivariate analysis, extrathyroidal extension and nodal metastases were independent predictors of outcome (P <.05) . CONCLUSION: Patients with Hurthle cell carcinoma have a prognosis that is predicted by well-defined histomorphologic characteristics . Unlike differentiated thyroid cancer, nodal metastases predict a worse outcome in widely invasive Hurthle cell carcinoma, as does extrathyroidal extension.

J Investig Med, 2001 May, 49(3), 292 - 6
Use of potassium tellurite for rapid-drug susceptibility testing of Mycobacterium avium complex; Afghani B et al.; BACKGROUND: Mycobacterium avium complex (MAC) is a major cause of infection in immunocompromised patients . MAC possesses an enzyme that reduces potassium tellurite in less than 3 days and results in formation of a black precipitate . The objective of this study was to determine whether reduction of potassium tellurite by mycobacteria can be used as a means of testing the susceptibility of MAC to clarithromycin . METHODS: Minimum inhibitory concentrations (MICs) for 104 clinical isolates of MAC were determined by the tellurite method and compared with those tested by a recommended microdilution method . Microdilution breakpoints were used for interpretation of susceptibility . MIC of less than 8 microg/mL was considered as susceptible, and MIC of greater than or equal to 8 microg/mL was resistant . RESULTS: There was agreement within a 2-fold dilution between MICs for 89% of isolates . Of the 53 isolates that had discrepant MICs by the two methods, 70% had higher MICs by the tellurite method . When the MICs were classified into interpretive categories, there was 100% agreement by the two methods . The MIC tested by the tellurite method was available within 5 days . CONCLUSIONS: These data suggest that use of potassium tellurite is a more rapid, reliable, and inexpensive method of testing the susceptibility of MAC to clarithromycin.

Trop Med Int Health, 2001 May, 6(5), 407 - 11
Melarsoprol refractory T . b . gambiense from Omugo, north-western Uganda; Matovu E et al.; Culture adapted T . b . gambiense isolated from Northwest Uganda were exposed to 0.001-0.14 microg/ml melarsoprol or 1.56-100 microg/ml DL-alpha-difluoromethylornithine (DFMO) . Minimum inhibitory concentrations (MICs) of each drug were scored for each isolate after a period of 10 days drug exposure . The results indicate that T . b . gambiense isolates from Northwest Uganda had elevated MIC values for melarsoprol ranging from 0.009 to 0.072 microg/ml as compared with T . b . gambiense isolates from Cote d'Ivoire with MIC values ranging from 0.001 to 0.018 microg/ml or with T . b . rhodesiense from Southeast Uganda with MIC values from 0.001 to 0.009 microg/ml . All MIC values obtained fell below expected peak melarsoprol concentrations in serum of treated patients . However, it may not be possible to maintain constant drug concentrations in serum of patients as was the case in our in vitro experiments . Importantly, the MIC of 0.072 microg/ml exhibited by one of the isolates from Northwest Uganda was above levels attainable in CSF indicating that this isolate would probably not be eliminated from CSF of treated patients . PCR amplification of the gene encoding the P2-like adenosine transporter followed by restriction digestion with Sfa NI enzyme revealed presence of fragments previously observed in a trypanosome clone with laboratory-induced arsenic resistance . From our findings it appears that reduced drug susceptibility may be one factor for the frequent relapses of sleeping sickness after melarsoprol treatment occurring in Northwest Uganda.

New Microbiol, 2001 Apr, 24(2), 193 - 6
Sensitivity of Borrelia and Leptospira to Quinupristin-dalfopristin (Synercid) in vitro; Murgia R et al.; In vitro activity of Quinupristin-dalfopristin (Synercid) against seventeen isolates of Borrelia burgdorferi and two representatives of Leptospira spp . was investigated . MICs ranged from 0.03 to 0.125 for B . burgdorferi and 0.125-0.25 microg/ml for Leptospires . Time killing studies carried out with 2 MIC demonstrated U 3 log(10)-unit killing after 72 h, showing a significant activity against spirochetes, though at a lower level than other antibiotics in use in the therapy of Lyme disease and leptospirosis.

Planta Med, 2001 Apr, 67(3), 279 - 81
A new antimycobacterial, 3 beta-acetoxy-15 alpha,22-dihydroxyhopane, from the insect pathogenic fungus Aschersonia tubulata; Boonphong S et al.; Bioassay-guided fractionation of the cell extract of the insect pathogenic fungus Aschersonia tubulata BCC 1785 led to the isolation of dustanin (1), 3 beta,15 alpha,22-trihydroxyhopane (3), 5 alpha,8 alpha-epidioxy-24(R)-methylcholesta-6,22-diene-3 beta-ol (6), together with the new 3 beta-acetoxy-15 alpha,22-dihydroxyhopane (4) . Chemical structures of these compounds were elucidated by spectral analyses as well as chemical transformation . Compounds 1 and 4 exhibited antimycobacterial activity with the minimum inhibitory concentration (MIC) of 12.5 micrograms/ml.

Clin Infect Dis, 2001 Jun 1, 32(11), 1554 - 61 Epub 2001 May 04.
Oropharyngeal candidiasis in patients with human immunodeficiency virus: correlation of clinical outcome with in vitro resistance, serum azole levels, and immunosuppression; Walmsley S et al.; Azole-resistant thrush has emerged as a problem in people who are infected with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), especially those who have low CD4 cell counts who have had a previous relapse of oral candidiasis, and in those who require long-term suppressive antifungal therapy . Because of the development of a standardized methodology for antifungal susceptibility testing and interpretive criteria for resistance testing, studies of the clinical predictive value of in vitro results are possible . In this study, 61% of organisms isolated from patients who were receiving azole therapy and who had clinically resistant thrush had minimal inhibitory concentration values that would classify the isolate as "resistant" or "susceptible dose dependent." In contrast, 86% of isolates from patients with thrush that was clinically responsive to an azole were classified in vitro as "susceptible" or "susceptible dose dependent." No resistant isolates were detected in samples obtained from asymptomatic control patients who were not exposed to azole drugs . Serum levels of azole and CD4 cell counts were also important parameters with regard to prediction of response . We conclude that in vivo and in vitro correlations compare favorably to studies of susceptibility testing in bacteria.

Diagn Microbiol Infect Dis, 2001 Mar, 39(3), 177 - 9
In vitro susceptibility of recent clinical isolates of Chlamydia trachomatis to macrolides and tetracyclines; Samra Z et al.; We tested the in vitro activity of clarithromycin, azithromycin, roxithromycin, erythromycin, doxycycline, and tetracycline against 50 clinical isolates of Chlamydia trachomatis . The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) were determined in a tissue culture system using cycloheximide treated McCoy cells . MIC values for all the isolates were < or =0.015 microg/ml for clarithromycin, < or =0.125 microg/ml for roxithromycin and azithromycin, and < or =0.25 microg/ml for erythromycin and doxycycline . Almost half of the isolates (44%) were inhibited only by a concentration of 0.5 microg/ml of tetracycline . MBC as high as 4 microg/ml was displayed by doxycycline and tetracycline against 8% and 4% of the isolates respectively of the agents recommended by the Center for Disease Control as drugs of choice for the treatment of chlamydial infections, azithromycin exhibited a markedly better in-vitro activity than did erythromycin and doxycycline.

J Clin Pathol, 2001 May, 54(5), 408 - 11
Role of screening agar plates for in vitro susceptibility testing of Helicobacter pylori in a routine laboratory setting; Warburton-Timms VJ et al.; BACKGROUND: Resistance of Helicobacter pylori to the more frequently used antibiotics (metronidazole and clarithromycin) reduces eradication rates even with triple treatment . Determining the antibiogram profile of H pylori can take up to 14 days and delays appropriate treatment . AIMS: To determine the role of screening agar plates for more rapid in vitro susceptibility of H pylori to metronidazole, amoxicillin, and clarithromycin . METHODS: Routine gastric biopsy specimens from 507 dyspeptic patients were inoculated on to 10% lysed blood agar plates containing metronidazole (8 microg/ml), clarithromycin (2 microg/ml), or amoxicillin (0.5 microg/ml) . The minimum inhibitory concentration (MIC) of the 90 isolates was determined using the E test . RESULTS: Metronidazole resistance was detected in 28 of 90 isolates by E test and nine of 98 by screening agar . The screening agar detected none of the four clarithromycin resistant isolates detected by the E test . CONCLUSIONS: The screening agar method is not sufficiently sensitive to be used alone.

J Antimicrob Chemother, 2001 May, 47(5), 521 - 6
Comparison of Etest and a tablet diffusion test with the NCCLS broth microdilution method for fluconazole and amphotericin B susceptibility testing of Candida isolates; Arendrup M et al.; Three methods were compared for the susceptibility testing of yeast isolates to fluconazole and amphotericin B: two fagar diffusion methods (Etest and a tablet diffusion test) and the National Committee for Clinical Laboratory Standards (NCCLS) broth microdilution method . Given as MIC(50)s (range), fluconazole endpoints were: for the 24 h broth microdilution test, 0.25 mg/L (0.06-32 mg/L); for the Etest, 0.38 mg/L (0.064-24 mg/L); and for the NCCLS broth microdilution test, 2 mg/L (0.06->or=64 mg/L) . With breakpoints of <3 mg/L for susceptible and >16 mg/L for resistant, the Etest and the 24 h microdilution test classified the isolates in agreement with the classification obtained by the NCCLS method . Results obtained by Etest were in closer NCCLS method than those obtained with the tablet test . Amphotericin B endpoints were lower for the 24 h microdilution and Etests than MICs obtained by the NCCLS broth microdilution method . Reproducibility was high for all tests; however, disadvantages of both diffusion tests were microcolonies in the inhibition zone and dependence on stringent standardization of inoculum.

Microbios, 2001, 104(409), 149 - 58
A simple classification method for residual antibiotics using E . coli cells transformed by the calcium chloride method and drug resistance plasmid DNA; Lin SY et al.; Using three different plasmid DNA codings for kanamycin (KM), chloramphenicol (CP), and ampicillin- (AMP) and tetracycline- (TC) resistance, four different competent Escherichia coli strains were transformed by the calcium chloride method to produce KM-, CP- and AMP- and TC-resistant strains . Evaluation of minimum inhibitory concentrations (MIC) of 22 antibiotics, showed KM-resistant E . coli to be cross resistant only to fradiomycin (FRM); CP-resistant E . coli, especially HB101 and JM109 strains, exhibited cross-resistance only to thiamphenicol (TP) . On the other hand, AMP- and TC-resistant E . coli showed cross resistance to several penicillins, tetracyclines and erythromycin . E . coli ATCC-27166, the strain most sensitive to all drugs in this experiment, was employed for disc diffusion experiments and from the pattern of appearance of the inhibition zone, eight major antibiotics were divided into three groups depending on their activity against containing each of the three plasmids . Only gentamicin (GM) activity was not affected by any of the drug resistant strains . Assay techniques utilizing three resistant strains may be the technique for screening foods for antibiotic residues in the future.

Mol Cell Endocrinol, 2001 Apr 25, 175(1-2), 5 - 13
CCK expression in enteroendocrine cell is regulated by soluble factor(s) from underlying fibroblasts; Ratineau C et al.; Studies on the cross-talk between the intestinal epithelium and the underlying connective tissue have concentrated on enterocytes . In contrast, little is known about the interactions between the mesenchymal compartment and the enteroendocrine cells, scattered among the other cell types of the epithelium . To address this question, a panel of coculture systems between the enteroendocrine STC-1 cell line and three intestinal myofibroblastic cell lines (MIC) was used in order to assess different levels of regulation, namely cell-cell and cell-matrix interactions, and the role of diffusible factors . We demonstrate that the expression of cholecystokinin, a typical intestinal hormone produced by STC-1 cells, is up-regulated in the presence of a fibroblastic environment through a paracrine pathway involving FGF2 . Concomitantly, STC-1 cell morphology and proliferation were also modulated, but through distinct mechanisms according to the origin of fibroblasts . The results reveal definite epithelio-mesenchymal interactions that may be critical for the maintenance of phenotype and function of enteroendocrine cells.

Clin Microbiol Infect, 2001 Mar, 7(3), 130 - 7
Isolation and in vitro susceptibility to amphotericin B, itraconazole and posaconazole of voriconazole-resistant laboratory isolates of Aspergillus fumigatus; Manavathu EK et al.; OBJECTIVES: To select voriconazole-resistant mutants of Aspergillus fumigatus in the laboratory from drug-susceptible clinical isolates and examine their in vitro susceptibility to amphotericin B and investigational azoles, and to compare the intramycelial accumulation of voriconazole in the resistant isolates with that in the susceptible parent . METHODS: Voriconazole-resistant Aspergillus fumigatus isolates were selected in the laboratory from three highly susceptible (MIC < or = 0.5 mg/L) clinical isolates by stepwise selection on peptone yeast extract glucose (PYG) agar containing 0.5 mg and 4 mg voriconazole/L . Twenty-three colonies that grew in the presence of 4 mg voriconazole/L on PYG agar (frequency 1.9 x 10(-8)) were tested for their in vitro susceptibility to amphotericin B, itraconazole, voriconazole and posaconazole by a broth macrodilution technique . The accumulation of voriconazole in the mycelia of two representative resistant isolates (VCZ-W42 and VCZ-W45) was determined by a previously described bioassay . RESULTS: The geometric mean MICs (mg/L) of amphotericin B, itraconazole, voriconazole and posaconazole for these isolates were 0.45 +/- 0.19, 0.69 +/- 0.45, 5.24 +/- 3.74 and 0.27 +/- 0.18, respectively . A comparison of the geometric mean MICs of the antifungals obtained for the resistant isolates to those of the susceptible parents showed 1.15-, 2.76-, 16.90- and 1.42-fold increases, respectively, for amphotericin B, itraconazole, voriconazole and posaconazole, suggesting that low-level cross-resistance exists between the azole antifungals . The susceptible parent and the resistant isolates accumulated similar amounts of voriconazole . CONCLUSIONS: These results suggest that spontaneous mutants of Aspergillus fumigatus resistant to voriconazole could emerge among clinical isolates under selection pressure and that the observed reduced in vitro susceptibility to voriconazole may not be due to reduced accumulation of the drug in the mycelia.

Mycopathologia, 2001, 149(3), 117 - 21
Electrophoretic karyotyping and antifungal susceptibility patterns of Candida parapsilosis clinical isolates causing deep and superficial fungal infections; Barchiesi F et al.; Forty-six isolates of Candida parapsilosis, each from a single patient, were collected from July 1993 through March 1999 at the University of Ancona Hospitals and Clinics . Twenty-eight strains were isolated from superficial lesioned sites, including skin, nails and other sources while 18 strains were isolated from blood . The isolates were typed by electrophoretic karyotyping (EK) and tested for their susceptibility to fluconazole (FLC), itraconazole (ITC), flucytosine (5-FC), and amphotericin B (AMB) . Our data confirmed that EK is a useful technique for DNA typing of isolates of Candida parapsilosis and showed that the source of isolation is not associated with a given DNA type . Although strains belonging to this species of Candida are susceptible to the most common antifungals, including the triazoles, the degree of ITC susceptibility was dose dependent (MIC ranging from 0.25-0.5 microgram/ml) for 98% of the isolates.

Mycopathologia, 2001, 149(3), 109 - 15
Penicillium marneffei: types and drug susceptibility; Imwidthaya P et al.; The PCR fingerprints of 30 Penicillium marneffei isolates from Chiang Rai in Northern Thailand and Bangkok in central Thailand were studied through use of single-nucleotide primers (GACA)4 and the phage M13 core sequence . Discrimination of fingerprint patterns was based on differences in the number of major bands . The P . marneffei isolates were divided into four types, i.e., A, B, C, and D . Type A was found in two isolates from Chiang Rai (6.7%) . Types B and C respectively were found in two (6.7%) and one (3.3%) isolates from Bangkok . The predominate type D (83.3%) was found in isolates obtained from Chiang Rai and Bangkok . The PCR fingerprinting method was found to be useful for the epidemiological study of P . marneffei, a dimorphic opportunistic fungus and an emerging pathogen in the HIV pandemic . In vitro drug susceptibility testing by broth macrodilution to four antifungal agents against the yeast form of P . marneffei was performed . The MIC ranges for amphotericin B, fluconazole, itraconazole, and ketoconazole were 0.125-0.5, 4.0-8.0, < 0.032, and < 0.125 microgram/ml respectively.

Scand J Infect Dis, 2001, 33(3), 222 - 6
Pharmacokinetics of ceftazidime in febrile neutropenic patients; Nyhlen A et al.; Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v . as a bolus injection over the course of 3 min . The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients . The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2lambda(z)) significantly shorter, compared with elderly, healthy subjects (p < 0.005) . Three patients survived long enough to be assayed after normalization of temperature and neutrophil counts . Glomerular filtration rates and clearances tended to be higher and the area under the curve and half-life lower on the day of fever and neutropenia . When considering our data in relation to known MIC values for common pathogens, ceftazidime administered intermittently every 6 h seems an appropriate regimen in patients with febrile neutropenia . Larger studies are needed to confirm this.

Antimicrob Agents Chemother, 2001 May, 45(5), 1568 - 71
In vitro activity of clarithromycin against intracellular Helicobacter pylori; Piccolomini R et al.; The in vitro intracellular effect of clarithromycin, amoxicillin, metronidazole, lansoprazole, and rifabutin, tested at concentrations corresponding to one times the MIC, two times the MIC, and four times the MIC, was evaluated against an invasive Helicobacter pylori strain . At four times the MIC, clarithromycin showed an early bactericidal effect within 4 h of incubation and, in determining the complete killing within a 16 h-incubation period, lansoprazole and rifabutin showed comparable activity, yielding bactericidal activities within 4 and 8 h of incubation, respectively . Amoxicillin and metronidazole showed bacteriostatic activity only.

Antimicrob Agents Chemother, 2001 May, 45(5), 1500 - 4
Accurate prediction of macrolide resistance in Helicobacter pylori by a PCR line probe assay for detection of mutations in the 23S rRNA gene: multicenter validation study; van Doorn LJ et al.; Helicobacter pylori strains from 299 patients were tested in six laboratories in different countries . Macrolide susceptibility of the strains was determined by agar dilution (17.4%) or the epsilometer test (82.6%) . Mutations in the 23S ribosomal DNA (rDNA) that are associated with macrolide resistance were analyzed by PCR and reverse hybridization (PCR-line probe assay {LiPA}) . This method identifies A2115G, G2141A, A2142G, A2142C, A2142T, A2143G, and A2143C mutations in the 23S rDNA . vacA s-region (s1a, s1b, s1c, and s2) and m-region (m1, m2a, and m2b) genotypes and cagA status were also determined using another PCR-LiPA system . Of the 299 strains investigated by MIC testing, 130 (43.5%) were resistant and 169 (56.5%) were susceptible to clarithromycin . Of the 130 resistant strains, 127 (97.7%) contained 23S rDNA mutations, whereas 167 (98.8%) of the 169 susceptible strains contained wild-type sequences . The predominant mutations were A2143G (45.2%) and A2142G (33.3%) . Twenty-eight (19.8%) strains contained multiple 23S rDNA mutations . Only five resistant strains contained the A2142C mutation (three of these in combination with the A2142G mutation), and the A2115G, G2141A, A2142T, and A2143C mutations were not found . MICs of clarithromycin for the A2142G mutant strains were significantly higher than MICs for the A2143G strains . Although there was no significant association between 23S rDNA mutations and the vacA and cagA status, clarithromycin-susceptible strains more often contained mixed vacA genotypes, indicating the presence of multiple H . pylori strains . In conclusion, our data confirmed the very strong association between 23S rDNA mutations and macrolide resistance and showed that the PCR-LiPA permits accurate and reliable diagnosis of macrolide resistance in H . pylori.

Ann Pharmacother, 2001 Apr, 35(4), 409 - 13
Serum concentrations of cefuroxime after continuous infusion in coronary bypass graft patients; Pass SE et al.; OBJECTIVE: To describe the serum concentrations of continuous infusion of cefuroxime for postsurgical prophylaxis of sternal wound infection in patients undergoing coronary artery bypass graft (CABG), and to assess the incidence of sternal wound infection in this population . METHODS: This was a prospective, noncomparative trial involving 54 patients undergoing elective CABG surgery . All patients enrolled in the study received cefuroxime 1.5 g as a single intravenous dose 30 minutes preoperatively, followed by a continuous infusion of 3 g every 24 hours until removal of all central venous catheters . RESULTS: Of the 53 evaluable patients, the mean steady-state cefuroxime serum concentration was 21.6 +/- 14.2 microg/mL (range 6.56-59.5) . No patient developed a sternal wound infection . The mean treatment duration was 2.58 +/- 2.13 days (range 1-13) . The median hospital and intensive care unit lengths of stay were six days and 46 hours, respectively . The average antibiotic cost per day was $32.76 . CONCLUSIONS: These preliminary results of continuous infusion of cefuroxime 3 g/d for prophylaxis of sternal wound infections in CABG patients indicate that serum concentrations are highly variable, but reliably above the minimum inhibitory concentration for the common anticipated pathogens in this setting . Further comparative trials in a larger number of patients are necessary before this mode of administration can be routinely advocated for prophylaxis.

Planta Med, 2001 Mar, 67(2), 161 - 3
In vitro anti-Helicobacter pylori activity of irisolidone isolated from the flowers and rhizomes of Pueraria thunbergiana; Bae EA et al.; The inhibitory effect of isoflavones isolated from the flowers and rhizomes of Pueraria thunbergiana (Leguminosae) on the growth of Helicobacter pylori (HP) was investigated . Isoflavone glycosides did not inhibit the growth of HP . However, their aglycones, irisolidone, tectorigenin and genistein, inhibited HP growth . Among them, irisolidone had the most potent inhibitory activity against HP and its MIC was 12.5-25 micrograms/ml . Genistein only weakly inhibited the urease of HP and H+/K(+)-ATPase of rat stomach: its IC50 were 0.43 and 0.89 mg/ml, respectively.

J Ethnopharmacol, 2001 May, 75(2-3), 203 - 5
Anti-Helicobacter pylori activity of Aristolochia paucinervis Pomel extracts; Gadhi CA et al.; The anti-Helicobacter pylori effect of the extracts and the fractions obtained from Aristolochia paucinervis rhizome and leaves were studied against a reference strain of H . pylori by using the agar dilution method . Only the methanol extracts and the hexane fractions of either the rhizome or the leaves exhibited an inhibitory activity at a concentration of < or =128 microg/ml . The leaf hexane fraction APLH demonstrated a higher inhibitory activity (MIC: 4 microg/ml) than the rhizome hexane fraction APRH (MIC: 16 microg/ml), the leaf methanol extract APLM (MIC: 32 microg/ml) and the rhizome methanol extract APRM (MIC: 128 microg/ml) . This inhibitory activity was confirmed for the active extracts and fractions against clinical isolates of H . pylori (n = 20) for which MIC50) and MIC90 were determined.

Chest, 2001 Apr, 119(4), 1001 - 10
Comparisons of peak diurnal expiratory flow variation, postbronchodilator FEV(1) responses, and methacholine inhalation challenges in the evaluation of suspected asthma; Goldstein MF et al.; STUDY OBJECTIVES: The validity of peak expiratory flow variation (PEFvar) as defined by National Heart, Lung, and Blood Institute (NHLBI) guidelines as a diagnostic tool for suspected asthma or its comparative value to methacholine inhalation challenge (MIC) or postbronchodilator (BD) FEV(1) responses has not been formally assessed . We prospectively analyzed the correlation of 28 different PEFvar indexes (including 4 NHLBI-compatible indexes) with MIC and pre-BD and post-BD FEV(1) responses in suspected asthmatic subjects with normal findings on lung examination, chest radiography, and baseline spirometry . DESIGN: Participants were asked to record peak expiratory flow four times daily for 2 to 3 weeks, followed by an MIC . During a minimum 6-month follow-up period, a clinical diagnosis of asthma was made or ruled out based on testing results and response to antiasthma therapy . SETTING: Medical school-affiliated subspecialty private practice of allergy, asthma, and immunology . PARTICIPANTS: One hundred twenty-one suspected asthmatic patients with normal findings on lung examination, chest radiography, and baseline spirometry . MEASUREMENTS AND RESULTS: Fifty-seven subjects completed both the peak flow diary and the MIC and were accepted for statistical analysis . There were no statistically significant correlations between any peak expiratory flow index and MIC . Among the three diagnostic tools evaluated, MIC had the highest sensitivity (85.71%) . All the PEFvar indexes and post-BD responses had low sensitivity and high false-negative rates . CONCLUSIONS: PEFvar and post-BD FEV(1) responses are poor substitutes for MIC in the assessment of patients with suspected asthma with normal findings on lung examination, chest radiography, and spirometry . Our findings warrant a reconsideration of the NHLBI guidelines recommendation of the utility of PEFvar as a diagnostic tool for asthma in clinical practice.

Ther Drug Monit, 2001 Apr, 23(2), 93 - 9
Inhibition of thrombin by iopromide in vitro; Graf LL et al.; Iopromide is a nonionic, iodinated, monomeric, radiographic contrast agent used in various indications, including coronary angiography and visceral and peripheral arteriography . Nonionic contrast media have been postulated to increase thrombogenicity when compared with ionic contrast media . The goal of this study was to characterize the interaction of iopromide with thrombin, specifically to determine the rate, extent, specificity, and reversibility of the thrombin inhibition by iopromide, the integrity of the thrombin-iopromide complex, and the inhibitory potency of iopromide using a validated assay methodology . Iopromide was mixed with purified thrombin or pooled serum from healthy male and female donors . The final concentrations of iopromide in the presence of estimated physiologic concentrations of thrombin (1 nmol/L) were 0-184 mmol/L . After incubation for defined time intervals, the activity of thrombin was determined by adding substrate and measuring the absorbance of the generated chromophores at 405 nm . The possible inhibition of the protease trypsin by iopromide was investigated to evaluate the specificity of thrombin inhibition by iopromide . Iopromide was compared with Thromstop, a known thrombin inhibitor, to assess the relative potency of iopromide . The inhibition of thrombin by iopromide was immediate, rapidly reversible, and proportionate to the iopromide concentrations . The minimum inhibitory concentration of iopromide was 50 mmol/L . At the highest iopromide concentration tested, 184 mmol/L, the mean inhibition of thrombin activity was 44.5% . The mean concentration of iopromide associated with a 50% inhibition was 206 mmol/L . The inhibitory potency of iopromide was 4 x 10(6) times smaller than that of Thromstop . The inhibition of thrombin by iopromide is specific, because trypsin was not inhibited by iopromide . The results indicate that in vitro iopromide at clinically relevant concentrations partially inhibits thrombin activity . However, the in vitro model used does not consider other factors that may be relevant for the overall coagulation response in vivo.

Mycoses, 2000, 43 Suppl 2, 45 - 50
{Antifungal susceptibility testing in chronically recurrent vaginal candidosis as basis for effective therapy}; Czaika V et al.; The chronically recidivist vulvo-vaginal candidiasis is one of the most stubborn problematic diagnosis in the dermatology and gynaecology ward . Prognosis and therapy are primarily determined by the causative micro-organism and the interaction of the fungal species with the currently available antifungal agents . Objective of the study was the investigation of vaginal yeast isolates from patients with chronically recidivist vaginal candidiasis against 8 antifungal agents with the aim of optimising the standard therapy with azole antifungal agents and assessment of alternative therapy schemes . 55 clinical isolates (Dermatology, Charite) of 40 patients were tested by microdilution according to DIN 58940-84 . Species differentiation and identification was performed by Fourier-Transform Infrared Spectroscopy (FTIR) . In the result Candida glabrata was the predominant causative agent for the recidivist vaginal candidiasis . MIC-mode values for C . glabrata were: fluconacole 32 micrograms/ml, itraconacole 1 microgram/ml, ketoconacole 1 microgram/ml, amphotericine B, voriconacole 0.03 microgram/ml, amphotericin B 0.5 microgram/ml, terbinafine 128 micrograms/ml, cicloproxolamine 4 micrograms/ml, 5-fluorocytosine 0.03 microgram/ml . Some strains of Patients with suboptimal introductory low doses of fluconacole showed increasing of MIC in course of therapy . Parallel resistance with itraconacole was observed in all these cases . Consecutively isolated strains could be clearly and reliably identified by FTIR . In conclusion of most importance is the initial dose adapatation of the drug used, e.g . for fluconacole 800/d p.o., when C . glabrata is the causative agent . Low dose fluconacole therapy is always unsuccessful in recurrent vaginal candidiasis and induces secondary resistance . Demonstrated high susceptibility of voriconacole, amphotericine B an 5-fluorocytosine particularly for C . glabrata may indicate of an anitmycotic therapy potential unconsidered regarding to dermatological indication up to now.

J Med Microbiol, 2001 Apr, 50(4), 375 - 82
Susceptibility to fluconazole of Candida clinical isolates determined by FUN-1 staining with flow cytometry and epifluorescence microscopy; Pina-Vaz C et al.; The susceptibility of clinical Candida isolates to fluconazole was assayed by flow cytometry (FCM) and epifluorescence microscopy (EFM), with FUN-1 staining . In all, 25 clinical isolates of Candida spp . (12 sensitive, 3 dose-dependently sensitive and 10 resistant to fluconazole according to the NCCLS M27-A protocol) were treated with increasing concentrations of fluconazole during 1 or 2 h staining with FUN-1 for 30 min and analysed, respectively, by FCM at 575 nm (FL2) and by EFM . Fluconazole-susceptible strains showed an increased accumulation of FUN-1 in comparison with controls as determined by FCM and a reduced metabolic processing of the probe, confirmed by EFM . Conversely, resistant strains showed decreased FUN-1 staining and were able to process the probe . The fluconazole minimal inhibitory concentrations (MICs) determined by FCM or EFM after FUN-1 staining compared very well with the corresponding values determined by the M27-A protocol, indicating that FUN-1 staining can be used as an alternative to the conventional method . MIC values of resistant strains, with the exception of C . krusei, were lower when treatment with fluconazole followed pre-incubation with 0.1 mM sodium azide, a concentration known to inhibit the activity of efflux pumps . These results show that FUN-1 staining can be used as an alternative and rapid method for the assessment of susceptibility of Candida clinical isolates to fluconazole . Furthermore, the results suggest that resistance of Candida cells to fluconazole, with the exception of C . krusei strains, is likely to be due to the activity of efflux pumps.

Diagn Cytopathol, 2001 Apr, 24(4), 233 - 9
Role of immunocytochemistry and DNA flow cytometry in the fine-needle aspiration diagnosis of malignant small round-cell tumors; Brahmi U et al.; In the present study, DNA flow cytometry (FCM) and immunocytochemistry (ICC) with a selected panel of antibodies were performed on 51 cases of malignant tumors which were referred for fine-needle aspiration biopsy (FNAB) to our Department of Cytology for the last 2 yr . Twelve cases were diagnosed as neuroblastoma, 16 as Ewing's sarcoma, 2 as retinoblastoma, 5 as non-Hodgkin's lymphoma (NHL), 5 as rhabdomyosarcoma, 2 as peripheral neuroectodermal tumors (PNETs), and 8 as Wilms' tumor . Eleven of 12 neuroblastomas were diploid by FCM, and 1 was aneuploid, with an S-phase fraction (SPF) of 8.3% . Neuron-specific enolase (NSE) was negative in 3 and positive in 8 cases of neuroblastoma, whereas neuroblastoma marker was positive in 3/11 . Sixteen of 17 Ewing's sarcomas were diploid, and 1 showed tetraploid aneuploidy, with an SPF of 10.06% . Eight of 13 Ewing's sarcomas were positive for Mic-2 gene product (Ewing's marker) . All 5 NHL were positive for leukocyte-common antigen (LCA) . Three of 5 rhabdomyosarcomas were diploid, and 2 cases showed aneuploidy . Rhabdomyosarcoma showed muscle-specific actin positivity in 4 and desmin positivity in 3 cases . All 3 cases of PNET were diploid and positive for the Mic-2 gene product, whereas NSE and vimentin were positive in 2 cases . Both cases of retinoblastoma were diploid . Immunostaining was noncontributory in 1 case, and the other showed positivity for the retinoblastoma gene product, NSE, and chromogranin . Seven of 8 Wilms' tumors were diploid, and 1 showed aneuploid, with an SPF of 11.13% . Seven of 8 Wilms' tumors were positive for cytokeratin (CK), 5 were positive for NSE, 6 were positive for epithelial membrane antigen (EMA), and 5 were positive for vimentin . FNAB diagnosis of malignant round-cell tumors is difficult only by light microscopy . Due to the availability of specific markers for subgrouping tumors, ICC has proved to be more useful these days, while DNA FCM has little diagnostic value, as most of them are diploid . Further ancillary studies, e.g., electron microscopy, image analysis, and other molecular investigations, are required to further categorize these tumors more precisely for better clinical management of these cases .

Clin Microbiol Infect, 2001 Jan, 7(1), 11 - 6
In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species; Moore CB et al.; OBJECTIVE: To investigate the in vitro activity of LY303366 (LY) against Candida isolates comprising nine different species and comparison with fluconazole (FLU), flucytosine (5FC) and amphotericin B (AMB) . METHODS: The method used was a microtitre modification of the NCCLS M27-A accepted standard using either RPMI-1640 with 2% glucose (5FC and FLU) or antibiotic medium 3 with 2% glucose (LY and AMB) . The minimum inhibitory concentration (MIC) was the lowest drug concentration that reduced growth by 80% compared with the drug-free control . Minimum fungicidal concentrations (MFCs; 99% kill) were also determined for all isolates for LY and AMB . RESULTS: Overall, 58 of 105 (55.2%) isolates were resistant to FLU (MIC < or = 16 mg/L) . There was no relationship between FLU and LY MICs for C . albicans or non-albicans species . For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: LY 0.011 and < or = 0.001-16, FLU 8.72 and < or = 0.125- > 128, 5FC 0.393 and < or = 0.03- > 32, AMB 0.046 and 0.008-0.125 . Differences in susceptibility to LY were seen: C . parapsilosis (n = 12, GM 0.4 and range 0.125-16) and C . guilliermondii (n = 8, GM 0.46 and range 0.25-1) were both found to be significantly less susceptible to LY than all other species (P < or = 0.05) . For all isolates, geometric mean MFC values and ranges (in mg/L) were: LY 0.032 and 0.002-16, AMB 0.143 and 0.03-2 . The MFC value was the same as or only one drug dilution higher than the MIC value for 69.5% and 48.6% of isolates tested for LY and AMB, respectively . Tolerance was described in 13.3% and 5.7% of isolates for LY and AMB, respectively . A reproducibility study performed on 20% of the isolates showed that 90.5%, 100%, 95.2% and 100% of isolates retested were the same or within one well of the original MIC value for LY, FLU, 5FC and AMB, respectively . CONCLUSIONS: LY303366 shows promising antifungal activity in vitro and warrants further in vivo investigation.

Int J Antimicrob Agents, 2001 Mar, 17(3), 229 - 31
In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis; Rodriguez JC et al.; The in vitro activity of ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin against strains of Mycobacterium tuberculosis was studied . Moxifloxacin and levofloxacin showed the greatest activity having an MIC(90) of 1 mg/l . The MIC(90) for ofloxacin was 2 mg/l and for ciprofloxacin 4 mg/l . Further studies should be made to determine the role played by these compounds in the treatment of tuberculosis.

Int J Antimicrob Agents, 2001 Mar, 17(3), 203 - 8
In vitro activity of mezlocillin, meropenem, aztreonam, vancomycin, teicoplanin, ribostamycin and fusidic acid against Borrelia burgdorferi; Hunfeld KP et al.; The in vitro susceptibility profile of Borrelia burgdorferi is not yet well defined for several antibiotics . Our study explored the in vitro susceptibility of B . burgdorferi to mezlocillin, meropenem, aztreonam, vancomycin, teicoplanin, ribostamycin and fusidic acid . Minimal inhibitory concentrations (MICs) and minimal borreliacidal concentrations (MBCs) were measured using a standardised colorimetric microdilution method and conventional subculture experiments . MIC values were lowest for mezlocillin (MIC(90), < or =0.06 mg/l) and meropenem (MIC(90), 0.33 mg/l) . Vancomycin (MIC(90), 0.83 mg/l) was less effective in vitro . Borreliae proved to be resistant to aztreonam (MIC(90), >32 mg/l), teicoplanin (MIC(90), 6.6 mg/l), ribostamycin (MIC(90), 32 mg/l), and fusidic acid (MIC(90), >4 mg/l) . The mean MBCs resulting in 100% killing of the final inoculum after 72 h of incubation were lowest for mezlocillin (MBC, 0.83 mg/l) . This study gathered further data on the in vitro susceptibility patterns of the B . burgdorferi complex . The excellent in vitro effectiveness of acylamino-penicillin derivatives and their suitability for the therapy of Lyme disease is emphasised.

J Biol Chem, 2001 May 18, 276(20), 16911 - 8 Epub 2001 Feb 26.
The propeptide of the transforming growth factor-beta superfamily member, macrophage inhibitory cytokine-1 (MIC-1), is a multifunctional domain that can facilitate protein folding and secretion; Fairlie WD et al.; Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily . While it is synthesized in a pre-pro form, it is unique among superfamily members because it does not require its propeptide for correct folding or secretion of the mature peptide . To investigate factors that enable these propeptide independent events to occur, we constructed MIC-1/TGF-beta1 chimeras, both with and without a propeptide . All chimeras without a propeptide secreted less efficiently compared with the corresponding constructs with propeptide . Folding and secretion were most affected after replacement of the predicted major alpha-helix in the mature protein, residues 56-68 . Exchanging the human propeptide in this chimera with either the murine MIC-1 or TGF-beta1 propeptide resulted in secretion of the unprocessed, monomeric chimera, suggesting a specific interaction between the human MIC-1 propeptide and mature peptide . Propeptide deletion mutants enabled identification of a region between residues 56 and 78, which is important for the interaction between the propeptide and the mature peptide . Cotransfection experiments demonstrated that the propeptide must be in cis with the mature peptide for this phenomenon to occur . These results suggest a model for TGF-beta superfamily protein folding.

Zhongguo Yao Li Xue Bao, 1999 Nov, 20(11), 1031 - 4
Antimycoplasmal activities of (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10 -{4-(2-pyridyl)-1-piperazinyl}-7-oxo-7H-pyrido{1,2,3-de}{1,4}benzoxazine -6-carboxylic acid (YH-6) in comparison with other antibiotics in vitro; Ye H et al.; AIM: To determine the susceptibilities of Mycoplasma and Ureaplasma to (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10 -{4-(2-pyridyl)-1-piperazinyl}-7-oxo-7H-pyrido{1,2,3-de}{1,4}benzoxazine -6-carboxylic acid (YH-6) and to compare it with those referential quinolones, macrolides, and tetracyclines . METHODS: The minimum inhibitory concentration (MIC) were determined by microdilution method in vitro . RESULTS: The MIC of YH-6 for Ureaplasma urealyticum (Uu: 250 micrograms.L-1), Mycoplasma hominis (Mh: 500 micrograms.L-1), M orale (Mo: 125 micrograms.L-1) and M salivarium (Ms: 125 micrograms.L-1) were closely similar to those of macrolides (erythromycin and leucomycin) and were 2-8 folds greater than those of ofloxacin (Ofl) . Uu and Mh easily induced resistance to erythromycin and tetracycline . They did not easily form resistance to quinolone (YH-6, Ofl), josamycin and tylosin . Tetracycline-resistance (Tcr) or erythromycin-resistance (EMr) strains of Uu (or Mh) had cross-resistance to erythromycin or tetracycline . However, they had no cross-resistance to quinolone, josamycin and tylosin . CONCLUSION: YH-6 was a highly active quinolone against Mycoplasma, but could hardly induce resistance to Uu . EMr- or Tcr- strains of Uu (or Mh) had no cross-resistance to YH-6.

Med Mycol, 2001 Feb, 39(1), 91 - 5
Synergistic interaction of terbinafine with triazoles or amphotericin B against Aspergillus species; Ryder NS et al.; The in vitro activity of terbinafine alone and in combination with other antifungal agents was tested against isolates of Aspergillus fumigatus, A . flavus and A . niger . Testing was performed in a modified National Committee for Clinical Laboratory Standards (NCCLS) macrodilution broth assay, and interactions were examined using a checkerboard design . Terbinafine was highly active against Aspergillus isolates (minimum inhibitory concentration {MIC} 0.01 to 2 microg ml(-1)) with a primary fungicidal action (minimum fungicidal concentration {MFC} 0.02 to 4 microg ml(-1)) . Amphotericin B was also highly active and cidal as expected (MIC 1 microg ml(-1), MFC 1 to 4 microg ml(-1)) . The triazoles itraconazole and voriconazole were highly active but showed a variable degree of cidal activity against the different strains, voriconazole having the more potent cidal activity . Fluconazole had no significant activity (MIC > 128 microg ml(-1)) . Drug combinations were tested in the A . fumigatus and A . niger strains . Terbinafine and amphotericin showed an additive to synergistic interaction depending on the isolate . Combinations of terbinafine with itraconazole or voriconazole displayed a potent synergistic interaction and fungicidal activity against all isolates . Surprisingly, fluconazole also potentiated the activity of terbinafine in an additive to synergistic fashion, despite its lack of activity alone . The results suggest potential clinical application of terbinafine in aspergillosis, either alone or in combination with amphotericin or triazoles.

Med Mycol, 2001 Feb, 39(1), 129 - 33
Effect of sub-MICs of antimycotics on expression of intracellular esterase of Trichophyton rubrum; Fachin AL et al.; The electrophoretic pattern of the intracellular esterase of the dermatophyte Trichophyton rubrum was altered when this fungus was grown in the presence of subinhibitory concentrations of the antimycotics tioconazole or griseofulvin . All strains (original isolate and antimycotic resistant mutants) presented five clearly visible bands when cultivated on medium containing below-minimum inhibitory concentrations (sub-MICs) of tioconazole or griseofulvin, and only two clearly visible bands when cultivated in medium without antimycotics . No extra bands were detected in the electrophoretic patterns of the extracellular esterase of these fungi (mutants or the original isolate) when cultivated with or without tioconazole or griseofulvin (sub-MIC values) . These results suggest that additional forms of esterase are produced inside the cell and may be a nonspecific response to cellular stress, or may participate in cellular detoxification processes in the presence of these antimycotics.

Salud Publica Mex, 2001 Jan-Feb, 43(1), 27 - 31
{Prevalence of Moraxella catarrhalis colonization in asymptomatic carriers under 6 years of age}; Leanos-Miranda B et al.; OBJECTIVE: To determine the prevalence of upper respiratory tract colonization by Moraxella catarrhalis in children under six years of age . MATERIAL AND METHODS: A survey was conducted between January and December 1998 in Mexico City, among children aged 2 months to 5 years, selected through cluster sampling . Pharyngeal samples were taken for M . catarrhalis identification . The minimal inhibitory concentration to different antibiotics was obtained and beta-lactamases were determined by the iodometric test . Statistical analysis consisted of frequency distributions, odds ratios, 95% confidence intervals, and Mantel-Haenszel chi 2 . Statistical significance was set at p < 0.05 . RESULTS: After excluding 37 children, the study population was 604 children from Mexico City; M . catarrhalis was present in 130 pharyngeal specimens (22.9%) . Most of the strains were positive for beta-lactamase production (75.4%) . Eighty percent of the strains was resistant to penicillin and 70% to ampicillin and amoxicillin . None were resistant to cefotaxime, imipenem, meropenem and erythromycin . CONCLUSIONS: Prevalence of M . catarrhalis upper respiratory tract colonization is similar to that of other respiratory pathogens . These findings warrant future research on the role of M . catarrhalis as an etiologic agent in acute and chronic respiratory infections in Mexico.

Pathol Biol (Paris), 2001 Feb, 49(1), 53 - 6
{In vitro inhibition of Chlamydia trachomatis growth by liposome-encapsulated cyclines}; Sangare L et al.; The antichlamydial activity of tetracycline (Tet) and doxycycline (Dox) encapsulated in cationic (CaL), anionic (AnL) and neutral (NtL) liposomes has been evaluated in vitro by adding serial dilutions of antibiotics (minimum inhibitory concentration, MIC: 0.12-0.007 microgram/ml; MBC: 4 to 0.25 micrograms/ml) to HeLa 229 cell monolayers inoculated with Chlamydia trachomatis L2/434/Bu (10(3) ufi/ml) . Following 72 h incubation at 37 degrees C under a 5% CO2 atmosphere, the chlamydial inclusions were stained by the May-Giemsa method to determine the MICs . After a second and third passage, the MBC1 and MBC2 were determined in antibiotic-free medium . The chlamydial inclusions were then counted to assess the degree of growth inhibition at each antibiotic dilution tested for MBC1 and MBC2 determinations . The MIC, MBC1 and MBC2 of the various antichlamydial agents were as follows: Tet (0.12; 4; 4), AnL-Tet (0.01; 1; 1), NtL-Tet (0.03; 1; 2), Dox (0.06; 1; 2), CaL-Dox (0.03; 0.5; 2), AnL-Dox (0.01; 1; 2), and NtL-Dox (0.03; 0.5; 0.5) . It was found that Tet and Dox liposome-encapsulated antibiotics were more active than their non-encapsulated counterparts, and the inclusion count showed a higher inhibitory activity of the former antibiotics on chlamydial growth . The inhibition of chlamydial growth by AnL-Tet may be of bactericidal nature . In conclusion, liposome-encapsulated drugs could be of value in the treatment of chlamydial infections.

Zhonghua Jie He He Hu Xi Za Zhi, 1998 Mar, 21(3), 174 - 7
{Relationship between catalase activity, KatG gene and isoniazid-resistance in M . tuberculosis}; Wang X et al.; OBJECTIVE: To investigate the relationship between catalase activity, KatG gene, gene mutation and INH-resistance in M . tuberculosis . METHOD: Catalase activities in 58 M . tuberculosis isolates were tested, and KatG gene mutations were detected further by PCR-SSCP . RESULT: None of INH-sensitive isolates lacked KatG sequences and all expressed catalase . 8(25%) INH-resistant isolates did not express catalase and 3(10%) lacked KatG gene, most of which were strains of high levels of resistance (MIC > 50 micrograms/ml) . 8 INH-resistant isolates were analyzed further by PCR-SSCP and all were found to have KatG gene mutation . CONCLUSION: These findings indicated that lacking of catalase activity and KatG gene deletion occurred mainly in those highly INH-resistant strains, gene mutation other than complete deletion of KatG gene may be the major mechanism of INH-resistance.

Antimicrob Agents Chemother, 2001 Apr, 45(4), 1143 - 50
In vitro activity of a novel antimycobacterial compound, N-octanesulfonylacetamide, and its effects on lipid and mycolic acid synthesis; Parrish NM et al.; beta-Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the beta-ketoacyl synthase reaction involved in fatty acid elongation . We tested the efficacy of N-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria . Using the BACTEC radiometric growth system, we observed that OSA inhibits the growth of several species of slow-growing mycobacteria, including Mycobacterium tuberculosis (H37Rv and clinical isolates), the Mycobacterium avium complex (MAC), Mycobacterium bovis BCG, Mycobacterium kansasii, and others . Nearly all species and strains tested, including isoniazid and multidrug resistant isolates of M . tuberculosis, were susceptible to OSA, with MICs ranging from 6.25 to 12.5 microg/ml . Only three clinical isolates of M . tuberculosis (CSU93, OT2724, and 401296), MAC, and Mycobacterium paratuberculosis required an OSA MIC higher than 25.0 microg/ml . Rapid-growing mycobacterial species, such as Mycobacterium smegmatis, Mycobacterium fortuitum, and others, were not susceptible at concentrations of up to 100 microg/ml . A 2-dimensional thin-layer chromatography system showed that OSA treatment resulted in a significant decrease in all species of mycolic acids present in BCG . In contrast, mycolic acids in M . smegmatis were relatively unaffected following exposure to OSA . Other lipids, including polar and nonpolar extractable classes, were unchanged following exposure to OSA in both BCG and M . smegmatis . Transmission electron microscopy of OSA-treated BCG cells revealed a disruption in cell wall synthesis and incomplete septum formation . Our results indicate that OSA inhibits the growth of several species of mycobacteria, including both isoniazid-resistant and multidrug resistant strains of M . tuberculosis . This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescribed mechanism . Our results indicate that OSA may serve as a promising lead compound for future antituberculous drug development.

J Assoc Physicians India, 1995 Mar, 43(3), 167 - 9, 172
Efficacy of standard ten millicurie dose of radio-iodine in management of autonomously functioning toxic thyroid nodules; Sharma R et al.; Therapeutic effect of radio-iodine treatment on thyroid patients with autonomously functioning toxic thyroid nodule was evaluated . Fifty one patients were given a standard dose of 10 mci of radioiodine (I-131) and were followed up for 2-3 years . The failure rate (relapse after 10 mci of radioiodine) of this regime was 10% . It was found that the nodules less than or equal to 3 cms . in size were completely cured after a dose of 10 mic . of radio-iodine therapy, over a follow up period of next 6 months . Patients having nodules larger than 3 cms . relapsed after first dose of 10 mci of radio-iodine, but were cured completely after the second dose of 10 mci of radio-iodine therapy . Tri-iodothyronine (T3) and thyroxine (T4) values were both found to be high before giving treatment in all the cases . Only one case developed hypothyroidism after radioiodine therapy.

Saudi Med J, 2001 Jan, 22(1), 53 - 7
Antibiotic susceptibilities of Helicobacter pylori; Bindayna KM; OBJECTIVE: The aim of this study was to evaluate the prevalence of resistance among 83 Helicobacter pylori isolates cultured from biopsies taken during routine endoscopies in 1998-1999 . METHODS: Minimum Inhibitory Concentration of amoxicillin, tetracycline, clarithromycin and metronidazole were determined by Epsilometer test . RESULTS: Forty-seven strains (57%) were resistant to metronidazole, and 27 (32.5%) were resistant to clarithromycin . Twenty of the 27 strains resistant to clarithromycin were also resistant to metronidazole . None of the strains were resistant to amoxicillin or tetracycline . CONCLUSION: A high percentage of patients from Bahrain were infected with resistant strains of Helicobacter pylori . Antibiotic resistance monitoring is very important and unified national treatment policies are needed.

J Environ Monit, 2000 Oct, 2(5), 462 - 9
Airborne thermal degradation products of polyurethene coatings in car repair shops; Karlsson D et al.; A methodology for workplace air monitoring of aromatic and aliphatic, mono- and polyisocyanates by derivatisation with di-n-butylamine (DBA) is presented . Air sampling was performed using midget impinger flasks containing 10 ml of 0.01 mol l(-1) DBA in toluene and a glass-fibre filter in series after the impinger flask, thereby providing the possibility of collecting and derivatising isocyanates in both the gas and particle phases . Quantification was made by LC-MS, monitoring the molecular ions {MH}+ . Air samples taken with this method in car repair shops showed that many different isocyanates are formed during thermal decomposition of polyurethane (PUR) coatings . In addition to isocyanates such as hexamethylene (HDI), isophorone (IPDI), toluene (TDI) and methylenediphenyl diisocyanate (MDI), monoisocyanates such as methyl (MIC), ethyl (EIC), propyl (PIC), butyl (BIC) and phenyl isocyanate (PhI) were found . In many air samples the aliphatic monoisocyanates dominated . During cutting and welding operations, the highest levels of isocyanates were observed . In a single air sample from a welding operation in a car repair shop, the highest concentrations found were: MIC, 290; EIC, 60; PIC, 20; BIC, 9; PhI, 27; HDI, 105; IPDI, 39; MDI, 4; and 2,4-TDI and 2,6-TDI 140 microg m(-3) . Monitoring the particle size distribution and concentration during grinding, welding and cutting operations showed that ultrafine particles (< 0.1 microm) were formed at high concentrations . Isocyanates with low volatility were mainly found in the particle phase, but isocyanates with a relatively high volatility such as TDI, were found in both the particle and gas phases.

Int J Pharm, 2001 Mar 14, 215(1-2), 101 - 11
Gel-forming erodible inserts for ocular controlled delivery of ofloxacin; Di Colo G et al.; A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo . Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression . The in vitro drug release from inserts was mainly controlled by insert erosion . The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71) . The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds . Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded . The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17 . Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type . On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs . 1.39 +/- 0.05 microg ml(-1); 693.6 vs . 62.7 microg ml(-1) min; and 290 vs . 148 min, respectively) . Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.

Hum Immunol, 2001 Mar, 62(3), 279 - 85
Sequence analysis of the MHC class I region reveals the basis of the genomic matching technique; Gaudieri S et al.; The genomic matching technique (GMT) improves survival following bone marrow transplantation (BMT) between unrelated donor and recipient pairs correlating with a decrease in incidence and severity of graft-versus-host disease (GvHD) . The principles of this technique are based on the duplication and polymorphic characteristics of the major histocompatibility complex (MHC) . Specifically, the beta block GMT matches for a 300 kb region that contains the human leukocyte antigen (HLA-B and -C) genes as well as other non-HLA genes such as the natural killer cell receptor ligand PERB11 (MIC) . The block contains two large segmental duplications . One results in two PERB11 genes (11.1 and 11.2), the other in two class I genes (HLA-B and -C) . With the complete sequencing of the class I region of the MHC in different haplotypes, we can now show that the beta block GMT profiles reflect amplification of the duplicated PERB11 segments and not the duplicated segments containing HLA-B and -C, and yet provide a signature that characterizes the entire block rather than individual loci.

Yao Xue Xue Bao, 1997, 32(1), 15 - 8
{Effect of berberine on intracellular free CA2+ concentration in cultured brain cells}; Wu JF et al.; Intracellular free calcium concentration ({Ca2+}i) was measured with Ca(2+)-sensitive fluorescent indicator, Fura-2/AM, in cultured brain cells using AR-CM-MIC cation measurement system, and the effects of berberine (Ber) on the changes in {Ca2+}i induced by CaCl2, norepinephrine, KCl and H2O2 were studied . The results indicate that the resting {Ca2+}i was 35 +/- 8 nmol.L-1 in Ca(2+)-free Hank's solution . Ber showed no effect on the resting {Ca2+}i when the extracellular Ca2+ were 0.01-10 mmol.L-1 . Ber 1-100 mumol.L-1 dose-dependently inhibited norepinephrine and H2O2 induced {Ca2+}i elevation . Ber at high concentration (10-100 mumol.L-1) inhibited K(+)-induced {Ca2+}i elevation . This suggests that the inhibitory effects of Ber on norepinephrine, K(+)-, and H2O2-induced {Ca2+}i elevation may be one of the mechanisms against cerebral ischemia.

Immunity, 2001 Feb, 14(2), 123 - 33
ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor; Cosman D et al.; The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB . The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB . The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16 . The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell-resistant target cells confers susceptibility to NK cell cytotoxicity . Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus-infected cells might evade attack by the immune system.

Zhonghua Zhong Liu Za Zhi, 2000 Nov, 22(6), 480 - 2
{Apoptosis and uterine cervical carcinogenesis}; Yao J et al.; OBJECTIVE: To investigate the possible role of apoptosis in the development of uterine cervical carcinoma . METHODS: Formalin-fixed, paraffin-embedded samples from 190 patients {41 patients with severe dysplasia (SD); 37 with carcinoma in situ(CIS); 31 with microinvasive carcinoma (MIC), 40 with fran invasive large cell non-keratinizing epidermoid carcinoma (IC)}, and 41 samples from normal cervical squamous epithelium (NE) were studied . The number of apoptotic cells was assessed in situ by the TDT-mediated dUTP-biotin nick end labeling (TUNEL) method . PCNA, p53 and bcl-2 were demonstrated immunohistochemically . RESULTS: (1) In NE, TUNEL-positive cells were found in the superficial layer and PCNA-positive cells were confined in the lamina profunda, while in cervical neoplasia these cells were irregulasly scattered throughout the cervical lesions . (2) The TUNEL staining index decreased while PCNA increased with progression of the neoplasm, showing a significant negative correlation between apoptosis and proliferation . (3) In patients with SD and CIS who had overexpression of p53 and bcl-2 proteins, the cells positively stained by TUNEL were significantly less in number than in these with negative p53 and bcl-2 expression . No such observation for PCNA expression . CONCLUSION: These results suggest that apoptosis is associated with the early process of cervical carcinogenesis and apoptosis is closely correlated with overexpression of p53 and bcl-2 proteins.

J Chemother, 2001 Feb, 13(1), 24 - 33
Comparison of five different methods for detection of SHV extended-spectrum beta-lactamases; Bedenic B et al.; Five different methods for detection of different types of SHV extended-spectrum beta-lactamases (ESBL) were compared: minimum inhibitory concentration (MIC) determination of beta-lactam with and without clavulanic acid, double-disk synergy test (DDST), inhibitor potentiated disk diffusion test (IPDDT), three-dimensional test (TDT) and PCR/Nhe I test . MIC determination of beta-lactam with and without clavulanic acid was the most sensitive method regardless of the type of beta-lactamase . However the specificity of this method was a little above 90% . IPDDT turned out to be a very sensitive method too but it lacks specificity because 26.9% of ceftazidime sensitive strains (putative ESBL negative), gave a positive result . It is important to put all four disks on the plate because ceftazidime and aztreonam were more sensitive indicators for SHV-5 and SHV-12 beta-lactamase producers while cefotaxime and ceftriaxone were more reliable in detecting SHV-2 beta-lactamase producers . The DDST detected all SHV-5 and SHV-12 beta-lactamase producers and 95.2% of SHV-2, so it was less sensitive than MIC determination but was highly specific, since there were no false negative results observed . The sensitivity of DDST can be improved by using all four disks and placing them at the smaller distance from the central disk (2.5 cm) . The TDT was the least sensitive method, particularly for SHV-5 and SHV-12 beta-lactamase producers . The PCR/Nhe I test for detection of ESBL blaSHV genes is a highly sensitive and specific method but it is rather laborious and thus not very practical for use in routine clinical laboratories . Nevertheless it has potential to serve as the gold standard in epidemiological investigations on ESBLs . According to the results of this investigation MIC determination of beta-lactam with and without clavulanic acid, even if only one antibiotic is used and the PCR/Nhe I tests are the most reliable methods for detection of SHV ESBLs.

Eur J Med Chem, 2001 Jan, 36(1), 75 - 80
Synthesis and mycological activity of the compounds obtained in the reaction of N(3)-substituted amidrazones with sulphinyl-bis-2,4-dihydroxybenzenethioyl; Modzelewska-Banachiewicz B et al.; 2-Phenyl-5-(2,4-dihydroxybenzene)-1,3,4-thiadiazole (4), 2-(2-pyridyl)-2,4-dihydroxybenzene-1,3,4-thiadiazole (5), N(1)-2,4-dihydroxybenzenecarbothio-N(3)-phenyl-benzamidrazone (6) and N(1)-2,4-dihydroxybenzenecarbothio-N(3)-phenyl-2-picoline-amidrazone (7) were prepared and tested for their antimycotic activity . The chemical structures were confirmed by IR, 1H-NMR, EI-MS and elemental analysis . The minimal inhibitory concentration (MIC) values against dermatophytes, yeasts and moulds were determined for the estimation of potential activity in vitro . The strongest fungistatic activity for compound 5 in relation to dermatophytes was found with MIC 0.48-0.99 microg mL(-1).

Can J Vet Res, 2001 Jan, 65(1), 64 - 7
Pharmacokinetics of enrofloxacin after intravenous and intramuscular administration in Angora goats; Elmas M et al.; Pharmacokinetics and bioavailability of enrofloxacin were determined after single intravenous (IV) and intramuscular (IM) administrations of 5 mg/kg body weight (BW) to 5 healthy adult Angora goats . Plasma enrofloxacin concentrations were measured by high performance liquid chromatography . Pharmacokinetics were best described by a 2-compartment open model . The elimination half-life and volume of distribution after IV and IM administrations were similar (t1/2beta, 4.0 to 4.7 h and Vd(ss),1.2 to 1.5 L/kg, respectively) . Enrofloxacin was rapidly (t1/2a, 0.25 h) and almost completely absorbed (F, 90%) after IM administration . Mean plasma concentrations of enrofloxacin at 24 h after IV and IM administration (0.07 and 0.09 microg/mL, respectively) were higher than the minimal inhibitory concentration (MIC) values for most pathogens . In conclusion, once-daily IV and IM administration of enrofloxacin (5 mg/kg BW) in Angora goats may be useful in treatment of infectious diseases caused by sensitive pathogens.

Berl Munch Tierarztl Wochenschr, 2001 Jan-Feb, 114(1-2), 57 - 60
{Pharmacokinetics of kanamycin after subcutaneous and intravenous administration in dogs}; Calvo Wieland A et al.; Six beagle dogs were treated with kanamycin subcutaneously or intravenously in a dosage of 5 mg/kg . The plasma kanamycin concentration was measured over 24 hours by high pressure liquid chromatography with UV detection after derivatization and solid phase extraction . After subcutaneous application, kanamycin was absorbed quickly, and maximum plasma levels of 18.9 micrograms/ml in average after ca . 1 hour were measured . With complete systemic availability, the minimal inhibitory concentration of 4 micrograms/ml was maintained for 4 hours . After subcutaneous administration, kanamycin was terminally eliminated with a mean half life period of 2 hours.

Nat Immunol, 2001 Mar, 2(3), 255 - 60
Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells; Groh V et al.; NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress . Because NKG2D is also present on most CD8alphabeta T cells, it may modulate antigen-specific T cell responses, depending on whether MIC molecules--distant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentation--are induced on the surface of pathogen-infected cells.We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia . MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28- CD8alphabeta T cells . This function overcame viral interference with MHC class I antigen presentation . Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation.Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.

Ann Pathol, 2001 Feb, 21(1), 76 - 80
{Congenital fetal neuroblastoma}; Rivasi F et al.; Neuroblastoma are pediatric tumors of neural crest origin, most often localized in adrenal glands and infrequently congenital . We report two fetal cases found at autopsy, performed at 24 and 28 weeks of gestation, respectively . The 24 week old fetus did not show any malformation; systematic histological analysis found neuroblastoma cells in both the adrenal glands and the retroperitoneal fat tissue . The 28 week old fetus was hydropic and exhibited a nodule (3 cm) in the posterior mediastinum, next to the thoracic spinal cord . This tumor responded to a neuroblastoma associated with small metastatic foci in the adrenal glands, the liver and the frontal brain cortex . The placenta was abnormally heavy and showed hemorrhagic and necrotic areas . Microscopically plugged clumps of neuroblastoma cells were found inside fetal vessels . Immunohistochemistry was employed in both cases and the cells showed immunoreactivity for NSE, NB 84, chromogranin, synaptophysin and neurofilaments, while desmin, MIC 2, and protein S-100 were negative . Congenital neuroblastomas are rare and, to our knowledge this is the thirteenth report of congenital neuroblastoma associated with placental metastasis.

J Antimicrob Chemother, 2001 Mar, 47(3), 341 - 3
Characterization of high-level fluoroquinolone resistance in Escherichia coli O78:K80 isolated from turkeys; Giraud E et al.; Fluoroquinolone resistance was characterized in Escherichia coli O78:K80 isolated from diseased turkeys . The level of resistance to fluoroquinolones of the isolates appeared closely correlated with substitutions in GyrA and ParC, but not with the production of the AcrAB efflux pump . Among isolates highly resistant to ciprofloxacin (MIC 8 mg/L) and harbouring identical substitutions (two in GyrA and one in ParC), two close but distinguishable ribotypes were identified . This indicated that at least two independent selection events may have occurred.

Drugs, 2001, 61(1), 9 - 18
The role of fluoroquinolones in tuberculosis today; Berning SE; Tuberculosis is a growing international health concern; it is the leading infectious cause of death in the world today . The fluoroquinolones are the most recent class of drugs offering hope in the fight against this disease . Ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin are currently the most commonly used agents used against Mycobacterium tuberculosis (TB), with in vitro minimum inhibitory concentrations (MICs) of 0.1 to 4 mcg/ml . Resistance in TB to fluoroquinolones may occur spontaneously or may be acquired, especially when these agents are used inappropriately . Cross-resistance among the fluoroquinolones has been shown in TB . The fluoroquinolones offer a favourable pharmacokinetic profile for the treatment of TB . Most demonstrate excellent oral bioavailability and achieve maximum (peak) serum concentrations well above the MIC . They are also distributed widely, including intracellularly . The fluoroquinolones are cleared renally and/or hepatically, with varying serum half-lives . Fluoroquinolones are most effective when the peak concentration (Cmax) to MIC ratio is maximised . Fluoroquinolones such as ciprofloxacin and ofloxacin have been used in regimens for the prevention of TB, but have been poorly tolerated when used in combination with pyrazinamide . Favourable responses with fluoroquinolones in regimens used in the treatment of clinical TB disease have been seen . They, however, are not to be considered as equal replacements for isoniazid or rifampicin (rifampin) and should be used with at least 2 other antituberculous agents . Therapeutic drug monitoring of fluoroquinolones is beneficial in assuring that maximum Cmax to MIC ratios are being achieved, especially in patients at risk for malabsorption, such as those infected with HIV . Higher, once-daily doses of most fluoroquinolones are becoming more common in treating TB . Fluoroquinolones are generally well tolerated with long term use in treating TB, but rare, serious adverse effects have been reported with general fluoroquinolone use . The most common drug interactions with fluoroquinolones in TB therapy include the malabsorption interactions associated with multivalent cations and cytochrome P450 interactions with ciprofloxacin . An increased risk of central nervous system effects with concomitant cycloserine has been reported and seen clinically . When using fluoroquinolones to treat TB, careful consideration of individual susceptibility patterns, pharmacokinetic and toxicity profiles should be taken . The aid of a TB expert may also be warranted . The exact role of the fluoroquinolones in treating TB remains to be determined.

Dig Liver Dis, 2000 Dec, 32(9), 763 - 8
Prevalence of Helicobacter pylori resistance to antibiotics in Northeast Italy: a multicentre study . GISU . Interdisciplinary Group for the Study of Ulcer; Pilotto A et al.; AIMS: To evaluate prevalence of primary Helicobacter pylori antibiotic resistances in Northeast Italy and to identify risk factors associated with this resistance . MATERIALS AND METHODS: A total of 248 patients undergoing upper gastrointestinal endoscopy were enrolled from 19 Endoscopy Units over a 6-month period . From each patient, 4 gastric biopsies were taken for histology and 2 were sent to the Central Referral Microbiological Laboratory for culture and determination of antibiotic activity against Helicobacter pylori by means of E-test . Strains were considered resistant when minimum inhibitory concentration was >8 microg/ml for metronidazole and >1 microg/ml for clarithromycin . No cut-off value was predefined for amoxycillin . RESULTS: Culture of Helicobacter pylori was successfully performed in 167 patients . Primary resistance to metronidazole, clarithromycin or amoxycillin was 14.9%, 1.8% and 0%, respectively Patients infected with Helicobacter pylori strains resistant to antibiotics were more frequently females than males (70.3% vs 41.4%), had a significantly lower coffee intake (66.6% vs 86.6%) and lower body mass index (23.7+/-2.6 vs 25.3+/-3.6) than patients with susceptible Helicobacter pylori strains . Age, smoking, alcohol use, family history of Helicobacter pylori infection, concomitant diseases and treatments, endoscopic diagnoses, Helicobacter pylori density and histological activity of chronic gastritis were not associated with antibiotic resistance . Multivariate analysis confirmed that female gender (odds ratio = 2.74, 95% confidence interval = 1.03-7.27) was the only significant risk factor associated with antibiotic resistance . CONCLUSIONS: In this population, primary Helicobacter pylori resistance to metronidazole was higher than resistance to clarithromycin, and female gender was significantly associated with this resistance . The low prevalence of resistance to metronidazole, clarithromycin and amoxycillin identified in this geographical area suggests that proton pump inhibitor-based triple regimens including these antibiotics may still be used as first line therapies against Helicobacter pylori infection.

Eur J Surg, 2001 Jan, 167(1), 46 - 9
Trimethoprim-sulphamethoxazole and metronidazole as prophylaxis in colorectal surgery: a study of bioavailability after an oral single dose; Raab Y et al.; OBJECTIVE: To evaluate oral single dose prophylaxis in colorectal surgery . DESIGN: Prospective study . SETTING: University hospital, Sweden . SUBJECTS: 24 patients (13 women; 11 men; mean age 57 years, range 27-81) listed for elective colorectal operations . INTERVENTION: At 0630 on the day of the operation all patients were given an oral dose of trimethoprim-sulphamethoxazole (TMP 160 mg and SMZ 800 mg) and metronidazole (2 g) . The serum concentrations of TMP and SMZ were analysed in venous samples taken at the start and end of each operation . RESULTS: The earliest operation started at 0830 and the last finished at 1700 . The median (range) serum concentrations of TMP were 1.4 (0.7-2.6) mg/L (start) and 1.3 (1.0-2.8) mg/L (end), and of SMZ 35 (15-65) mg/L (start) and 33 mg (13-70) mg/L (end) . The individual values were above or equal to the minimal inhibitory concentration (TMP 0.8 mg/L; SMZ 15.2 mg/L) for relevant gram-negative species . CONCLUSION: Oral TMP/SMZ in the morning gives satisfactory serum concentrations independently of when the operation is done during the day . The regimen is simple and has the potential for being an effective alternative to intravenous prophylaxis.

Bioorg Med Chem Lett, 2001 Feb 12, 11(3), 301 - 3
Antimycobacterial in vitro activity of cobalt(II) isonicotinoylhydrazone complexes . Part 10; Bottari B et al.; Octahedral cobalt(II) complexes of isonicotinoylhydrazones, which were obtained from the primary antituberculous agent isoniazid, have been synthesised and characterised . Their antimycobacterial in vitro activity has been evaluated against Mycobacterium tuberculosis H37Rv: they exhibit MIC values ranging from < 0.1 to 0.39 microg/mL, showing them to be generally more active than previously reported analogous Cu(II) and Ni(II) complexes.

J Neural Transm Suppl, 2000, (60), 273 - 6
GDF-15/MIC-1 a novel member of the TGF-beta superfamily; Strelau J et al.; We have cloned, expressed, and raised antibodies against a novel member of the TGF-beta superfamily, growth/differentiation factor-15 (GDF-15) . The predicted protein is identical to macrophage inhibitory cytokine-1 (MIC-1), which was discovered simultaneously . GDF-15 is a more distant member of the TGF-beta superfamily and does not belong to one of the known TGF-beta subfamilies . In the CNS, GDF-15/MIC-1 mRNA is abundantly expressed by the choroid plexus . In addition we have preliminary evidence that GDF-15/MIC-1 is a potent trophic factor for selected classes of neurons in vitro and in vivo . Thus, GDF-15 is a novel neurotrophic factor with prospects for the treatment of disorders of the CNS.

Scand J Infect Dis, 2000, 32(6), 669 - 73
Influence of pH and concentration on the postantifungal effect and on the effects of sub-MIC concentrations of 4 antifungal agents on previously treated Candida spp; Garcia MT et al.; This study investigates the impact of different pH values (5.5 and 7.4) on the postantifungal effect (PAFE) and the effect of sub-MIC concentrations (1/4 x MIC) on C . albicans and C . glabrata in the PAFE stage (PAFSE) . The PAFE stage was induced by a 1.5 h pretreatment with different doses (1, 4 and 8 x MIC) of 4 antifungal agents . An increase in the pH and/or an increase in the dose of the antimycotic prolonged the duration of the PAFE induced by amphotericin B or 5-fluorocytosine and the PAFSE induced by all 4 antifungal agents in both species . 5-Fluorocytosine and amphotericin B (except for treatment with 1 x MIC at pH 5.5) induced significant PAFEs (0.5-3.0 h and 1.4-4.8 h, respectively), which were increased (to 0.9-3.2 h and 0.8-3.4 h, respectively) by posterior (PLEASE EXPLAIN WHAT YOU MEAN BY THE WORD "POSTERIOR" HERE) exposure to 1/4 X MIC of the respective antifungal agent . Although ketoconazole and fluconazole were not able to induce significant PAFEs, posterior exposure to 1/4 x MIC of each of these 2 azoles led to significant PAFSEs of up to 2.6 h in both yeast species when the concentrations and pH were high enough.

Ophthalmic Surg Lasers, 2001 Jan-Feb, 32(1), 25 - 9
Ocular penetration of cefepime following systemic administration in humans; Ozdamar A et al.; OBJECTIVE: To investigate the penetration of cefepime (a fourth generation cephalosporin) into the aqueous humor after single-dose intravenous administration in humans . PATIENTS AND METHODS: Before receiving cataract surgery, 30 patients received randomly 1 g (group 1, 15 patients) and 2 g (group 2, 15 patients) single intravenous injection of cefepime before surgery . Samples of aqueous humor and serum were obtained at 0.5, 1, 2, 4, and 12 hours after injection . Three patients were sampled each time for 1 g and 2 g of cefepime . Samples were assayed for cefepime concentrations with high performance liquid chromatography (HPLC) . RESULTS: All the patients had detectable cefepime in their aqueous humor and serum measurable by HPLC . A mean peak aqueous humor level was 5.16 +/- 0.88 microg/mL in group 1 and 5.87 +/- 1.64 microg/mL in group 2 at 0.5 hour after injection . The mean level of cefepime in aqueous humor decreased after 0.5-hour measurements in both groups and was measured as 0.82 +/- 0.21 microg/mL in group 1 and 2.04 +/- 0.30 microg/mL in group 2 at 12 hours after injection . CONCLUSION: Aqueous humor levels of cefepime after single IV injection were above the minimum inhibitory concentration (MIC90) for most ocular pathogens, but the duration of exposure to an antibiotic was not sufficient for therapeutic effect.

Acta Paediatr Suppl, 2000 Dec, 89(435), 35 - 9
Epidemiology of pneumococcal infections in Swedish children; Eriksson M et al.; OBJECTIVE: This paper provides an overview of pneumococcal infections in Swedish children . METHOD: Data supplied by the Swedish Institute for Infectious Disease Control (SMI) provided information on invasive pneumococcal isolates and on isolates with reduced susceptibility to penicillin . Disease burden was estimated from data collected in northern Stockholm and Malmohus County . Results: Only 3-6% of the total number of invasive pneumococcal isolates came from children 0-15 years of age . Predominant serotypes in descending frequency were 7, 6, 14, and 23 . Strains from all sources with reduced sensitivity to penicillin (MIC > or = 0.5 mg/l) were found in 3% of children and varied between 0.2% and 11%, with the highest value found in Southern Sweden (predominating strains were 9, 19, 15, 6, and 23) . A 10-year review of all cases of meningitis in Northern Stockholm reflected an incidence of 10/100,000 (0-2 years) or 5.8/100,000 (0-5 years), with severe sequelae occurring in 20% of children . This information can be used to predict an annual incidence of 30 cases of meningitis in Sweden . CONCLUSION: The large proportion of serotype 7 among invasive isolates is distressing since this serotype is not represented in the present 7- and 9-valent protein-conjugated vaccines under development . However, the heptavalent vaccine, including serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F would (at a serotype level) provide coverage against 83% of the resistant isolates in Southern Sweden.

Analyst, 2000 Nov, 125(11), 1949 - 54
Determination of airborne methyl isocyanate as dibutylamine or 1-(2-methoxyphenyl)piperazine derivatives by liquid and gas chromatography; Henriks-Eckerman ML et al.; The usefulness of a glass fibre filter method to collect airborne methyl isocyanate (MIC) was studied in laboratory experiments and in a workplace during manufacture of mineral wool insulation material . Filter collection was based on derivatisation in situ with 1-(2-methoxyphenyl)piperazine (2MP) . 2MP impinger sampling was also evaluated in the workplace . Impinger sampling with dibutylamine (DBA) was used as an independent method . The samples were analysed by liquid and gas chromatography using various detection techniques: mass spectrometry, ultraviolet and electrochemical detection (LC-MS, LC-UV, LC-EchD and GC-MS) . The sampling efficiency of 2MP filters for MIC varied with the origin of the glass fibre filter . Two Whatman filters (diameter 25 mm) with altogether 21 mumol of 2MP collected 100% of 9.8 micrograms of MIC during 30 min at an airflow rate of 1 l min-1 . The workplace measurements were performed at two concentration levels, 0.003 and 0.09 mg m-3 . The theoretical amounts of derivatisation reagent were 42 mumol (2MP filter), 52 mumol (2MP impinger) and 100 mumol (DBA) . MIC concentrations were 20% lower by the 2MP methods compared with the DBA method (statistically significant difference) . Breakthrough was 6% for the DBA method and 9% for the 2MP impinger method . To trap both MIC and isocyanic acid, which was also present in the workplace samples, a tenfold molar amount of 2MP reagent was used . The precision of sample preparation, expressed as relative standard deviation, was 3.5% (0.17 microgram ml-1, n = 6) . The precision of sampling in the workplace was 15% (0.002 mg m-3, n = 6) . The limit of quantification was 0.0006 mg m-3 for 30 l of air by the 2MP impinger method and 0.03-0.05 mg m-3 by the 2MP filter method . Hence, airborne MIC can be determined using 2MP as derivatisation reagent . Impinger sampling is preferable when low concentration levels are expected.

Zhonghua Kou Qiang Yi Xue Za Zhi, 1997 Nov, 32(6), 369 - 71
{Bianticollagen membrane: preparation and analysis of properties}; Li C et al.; This study was undertaken to assess the antiplaque and anticollagenase properties of bianticollagen membrane (BACM) for use in the guided tissue regeneration (GTR) . First, preparing cross-linked collagen membrane (GLCM) from bone collagen by glutaraldehyde and ultraviolet irradiation . Then, the GLCM was coated with tetracycline (TC) delivery device, which is BACM . BACM's properties are as follows: under scan electron microscope (SEM), it is a three dimensional structure with small pores; the modulus of elasticity in low strain regions and swelling ratio are 20.4 g/mm2 and 0.141 respectively; immediate type and delayed type hypersensitivity are negative; BACM with TC 150 micrograms placed into pockets, the average intrasulcular TC concentration measured at the end of the 7-days is 46.76 +/- 5.69 micromol/L, which is 2 times higher than MIC of TC; the period against collagenase (100 u) digestion is over 30 days in vitro; 1 mg GLCM and BACM implanted in mice may maintain about 4 weeks and 7 weeks respectively, and BACM and GLCM placed onto patient's root surface in flap operation and taken at 7th day the bacteria on BACM are significantly less than that on GLCM under SEM . These results indicate that BACM has antiplaque and stronger antidegradation effects than GLCM.

Can J Gastroenterol, 2000 Nov, 14(10), 891 - 4
Pathophysiology of antibiotic resistance: clarithromycin; Taylor DE; Resistance of Helicobacter pylori to antibiotics ranges from 3% to 10% and may exceed these levels in some countries . The pathophysiology of clarithromycin resistance is reviewed, including the mode of action by which the antibiotic inhibits protein synthesis and the mechanism of resistance, which involves a mutation at position 2142 or 2143 in the V loop domain of the 23SrRNA genes . Mutations of A2142G confer a higher minimum inhibitory concentration than mutations of A2143G . The former demonstrate cross-resistance to macrolide, lincosamide and streptogramin antibiotics, whereas the latter are susceptible to streptogramin B . In vitro mutagenesis combined with natural transformation were used to create several types of clarithromycin-resistant mutants . H pylori strains with A2142G and A2143G mutations had a higher growth rate than those with A2142C, A2143 or A2142T mutations . Data from this study indicate why clarithromycin-resistant clinical isolates of H pylori are more likely to have A2142G or A2143G mutations and only occassionally A2142C mutations.

Int J Antimicrob Agents, 2000 Sep, 16(1), 69 - 71
Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis; Bettencourt MV et al.; The comparative activity of five phenothiazines against multidrug-resistant strains of Mycobacterium tuberculosis (MDRTB) was studied using the Bactec 460 system . The order of antimycobacterial activity of the phenothiazines was: chlorpromazine = thioridazine > promethazine > promazine = desipramine . However, the levels required for an MIC 50 exceeded 1 mg/l and are beyond those that are clinically achievable . As phenothiazines are concentrated by macrophages that phagocytose and have in situ activity against mycobacteria, these agents may be considered for use as adjuvants for the management of freshly diagnosed tuberculosis in patients from populations with a high prevalence of MDRTB.

Antimicrob Agents Chemother, 2001 Mar, 45(3), 764 - 7
Activities of linezolid against rapidly growing mycobacteria; Wallace RJ Jr et al.; Linezolid is an oxazolidinone available as an oral drug which has activity against most gram-positive bacteria . However, few species of the genus Mycobacterium have been studied . We tested 249 clinical isolates and 10 reference strains of rapidly growing mycobacteria for susceptibility to linezolid by broth microdilution . Clinical species included the Mycobacterium fortuitum group (n = 74), M . abscessus (n = 98), M . chelonae (n = 50), M . mucogenicum (n = 10), and M . fortuitum third biovariant complex (10) . The modal MIC for M . mucogenicum was 1.0 microg/ml, and the MIC at which 90% of the isolates tested are inhibited (MIC(90)) was 4 microg/ml; the modal MIC for the M . fortuitum group was 4 microg/ml, and the MIC(90) was 16 microg/ml; the modal MIC for the M . fortuitum third biovariant complex was 4 microg/ml, and the MIC(90) was 8 microg/ml; the modal MIC for M . chelonae was 8 microg/ml, and the MIC(90) was 16 microg/ml; and the modal MIC for M . abscessus was 32 microg/ml, and the MIC(90) was 64 microg/ml . Based on peak levels of linezolid in serum of 15 to 20 microg/ml, we propose the following broth MIC breakpoints for these species: susceptible, < or = 8 microg/ml; moderately susceptible, 16 microg/ml; and resistant, > or =32 microg/ml) . These studies demonstrate the excellent potential of linezolid for therapy of rapidly growing mycobacteria.

Phytother Res, 2001 Feb, 15(1), 79 - 81
Antidermatophytic properties of extracts from the leaves of Aristolochia paucinervis Pomel; Gadhi CA et al.; Several fractions of a methanol extract from the leaves of Aristolochia paucinervis Pomel (Aristolochiaceae) were screened for their antidermatophytic efficiency against different human pathogenic fungi responsible for tinea and other skin infections . The antifungal study was carried out by the macrodilution agar method and the results showed that, with the exception of the aqueous fraction, all the fractions exhibited antifungal activities against the dermatophytic fungi tested . The hexane fraction was found to be the most effective (MIC range: 64-2048 microg/mL), whereas the butanol fraction was the least active (MIC range: 1024 microg/mL to more than 2048 microg/mL) . The most susceptible fungi were Epidermophyton floccosum and Trichophyton violaceum in contrast to Trichophyton mentagrophytes and Trychophyton rubrum which were less sensitive to the fractions tested . The effects were compared with those of ketoconazole, amphotericin B and griseofulvin, for which MIC ranges were, respectively, 0.12-4 microg/mL, 0.5-4 microg/mL and 0.5-2 microg/mL .

Int J Infect Dis, 2000, 4(3), 118 - 22
Lincomycin-induced endotoxin release in Escherichia coli sepsis: evidence for release in vitro and in vivo; Horii T et al.; OBJECTIVE: To evaluate the propensity of lincomycin and clindamycin to induce release of endotoxin, the authors investigated endotoxin release in Escherichia coli isolated from a patient who developed septic shock following lincomycin treatment . METHODS: Endotoxin release from the E . coli isolate exposed to lincomycin, clindamycin, and ceftazidime were determined in vitro and in vivo . RESULTS: In vitro, this E . coli released significantly larger amounts of endotoxin after exposure for 6 hours to lincomycin or clindamycin versus no antibiotic; however, endotoxin release with these antibiotics was significantly less than with ceftazidime . There was no significant difference in in vitro endotoxin release between small (8 mg/L) and large (0.5 minimum inhibitory concentration {MIC}) doses of these antibiotics, and 0.5 MICs of lincomycin and clindamycin were 1024 and 256 mg/L, respectively . These results were supported by scanning electron microscopic observations, which demonstrated that lincomycin, clindamycin, and ceftazidime induced formation of filamentous cells . In addition, plasma endotoxin concentrations after treatment for 4 hours with lincomycin, clindamycin, and ceftazidime (5 mg/kg) were at least 20-fold higher than with no antibiotic in an E . coli sepsis rat model . CONCLUSION: Results of this study suggest that the bacteriostatic antibiotics, lincomycin and clindamycin, induce endotoxin release in the treatment of E . coli infections.

Curr Infect Dis Rep, 2001 Feb, 3(1), 29 - 34
Influence of Pharmacokinetic and Pharmacodynamic Principles on Antibiotic Selection; Zhanel GG; When evaluating the efficacy of antibiotics for the treatment of respiratory tract infections, such as community acquired pneumonia and acute exacerbations of chronic bronchitis, assessment of clinical cure may not be the most relevant parameter, as it may not be related to microbiological eradication or to the minimum inhibitory concentration (MIC) of the infecting pathogen . It is more relevant to study the efficacy of the antibiotic in eradicating the bacterial pathogen, because this is frequently related to both the MIC of the pathogen and the antibiotic dosage regimen . Pharmacodynamics correlates the concentration of antibiotic in the blood or at the infection site with its biological effect against the organism (bacteriological eradication) . For beta-lactams, the pharmacodynamic parameter that best correlates with eradication is time (T) above MIC (T > MIC); for aminoglycosides and fluoroquinolones, it is the area under the curve at 24 hours (AUC(24))-to-MIC ratio (AUC(24)/MIC) . Knowledge of pharmacodynamics allows optimum use of antibiotics; in vitro models, animal models, and retrospective and prospective clinical trials have shown that the use of such knowledge optimizes bacteriological eradication and enhances patient outcome . In the future, pharmacodynamic studies will be used not only to assess optimal ways for antibiotics to eradicate resistant pathogens, but also to investigate the ability of antibiotics to prevent the development of resistance on therapy and to eradicate pathogens from colonizing sites.

Eur J Dermatol, 2001 Jan-Feb, 11(1), 58 - 62
Recalcitrant trichophytic granuloma associated with NK-cell deficiency in a SLE patient treated with corticosteroid; Akiba H et al.; Although deep trichophytic infection often occurs in immunocompromised patients, the immune deficiency in such patients has not been clarified . A 28-year-old man who suffered from recalcitrant trichophytic granuloma and tinea universalis during treatment for SLE with corticosteroid is described here to define the immunological abnormalities . In addition to routine immunological tests, we evaluated the patient's innate and specific immune functions to dermatophytes, including T cell, natural killer (NK) cell and neutrophil functions and activation of the complement cascade . We measured the minimum inhibitory concentration (MIC) of itraconazole for the isolated fungus and its concentrations in the patient's serum and pus . Trichophyton (T.) rubrum was constantly isolated from the exudates of the patient's skin lesions, although the concentrations of itraconazole in his serum (198 ng/ml) and lesions (210 ng/ml) were sufficient to inhibit the growth of the isolated fungus in vitro . Specific cell-mediated immune responses, determined by T cell stimulation and IFN-gamma production, were evoked following stimulation with trichophytic antigens . The patient's innate immunity, assessed by activation of the complement cascade and neutrophil-mediated phagocytosis, was not impaired . The number of circulating NK cells was markedly decreased (0.2% of the peripheral blood mononuclear cells), and was associated with low NK cell activity against K-562 cells even though lymphopenia had improved . The deficiency of innate immunity mediated by NK cells might be responsible for a part of the persistence of trichophytic granuloma in our case . Dermatophytes usually affect the horny layer of the skin and do not invade the living layers because the host immune system uses various mechanisms to eliminate the fungi . Both specific T cell-mediated immunity and nonspecific immunological mechanisms provide host defense against fungal infections . An adaptive immune response is usually preceded by innate immune responses mediated by neutrophils, NK cells, and circulating proteins such as complement components and anti-microbial peptides . However, in patients with localized or systemic immunological defects, granulomatous cutaneous infection of dermatophytes mostly caused by trichophytic fungi may occur {1} . Trichophytic granuloma includes Majocchi's granuloma {2} and disseminated trichophytic granuloma {3} . Recently, we experienced a patient with trichophytic granuloma and tinea universalis caused by Trichophyton (T.) rubrum infection during treatment with corticosteroid for systemic lupus erythematosus (SLE) . We describe the clinical details of this patient, focusing on his immunological defects which led to the persistence of the fungal infection.

Chemotherapy, 2001 Mar-Apr, 47(2), 123 - 7
Experimental in vitro efficacy study on the interaction of epiroprim plus isoniazid against Mycobacterium tuberculosis; Dosso M et al.; Thirty Mycobacterium tuberculosis strains (8: INH(R)/INH(R), 12: INH(R)/RIF(S), 10: INH(S)/RIF(S)) were examined against MICs of epiroprim (EPM) and isoniazid (INH) separately or in association . EPM alone proved to be insufficiently active against the various mycobacterial isolates (MIC > or =256 microg/ml) . The observed average sensitivity to the association of EPM plus INH was, in contrast, considerably increased, as reflected by reduced MICs and lower percentages of resistant strains . MICs ranged between 16 and 32 microg/ml EPM and 2 and 4 microg/ml INH for INH(R) strains . All INH(S) isolates were inhibited by a concentration of 0.125 microg/ml EPM and 0.06 microg/ml INH . The fractional inhibitory concentration indices indicated an additive activity on INH(R)/RIF(R) strains and a synergistic activity on INH(R)/RIF(S) and INH(S)/RIF(S) strains . The synergistic activity of this drug association needs to be confirmed in an animal model .

J Nat Prod, 2001 Jan, 64(1), 37 - 41
Antitubercular activity of triterpenoids from Lippia turbinata; Wachter GA et al.; Assay-guided fractionation of the antitubercular MeOH-CH(2)Cl(2) extract obtained from Lippia turbinata led to the isolation of four novel triterpenoids-3beta,25-epoxy-3alpha,21alpha-dihydroxy-22beta-(3-methylbut-2-en-1-oyloxy)olean-12-ene-28-oic acid (1); 3beta,25-epoxy-3alpha,21alpha-dihydroxy-22beta-angeloyloxyolean-12-ene-28-oic acid (2); 3beta,25-epoxy-3alpha,21alpha-dihydroxy-22beta-tigloyloxyolean-12-ene-28-oic acid (3); and 3beta,25-epoxy-3alpha-hydroxy-22beta-(2-methylbutan-1-oyloxy)olean-12-ene-28-oic acid (4)-together with the known triterpenoids lantanilic acid (5), camaric acid (6), lantanolic acid (7), and rehmannic acid (8) . The MIC values of 1-8 for growth inhibition of Mycobacterium tuberculosis were determined in the radiorespirometric BACTEC system.

Tissue Antigens, 2001 Jan, 57(1), 55 - 65
Sequence of the swine major histocompatibility complex region containing all non-classical class I genes; Chardon P et al.; A segment of 158,063 nucleotides of the pig major histocompatibility complex (SLA) and corresponding to the junction of the class I and class III regions was sequenced entirely . The centromeric part of the segment contained six class III genes including the three tumor necrosis factor genes, while the telomeric part contained three genes belonging to the class I region . The order and the molecular organization of these genes were exactly conserved in the SLA and HLA complexes, except for the SC1 gene which displayed a shift of the reading frame in swine . The cluster of the three SLA class I-related genes (Ib) and the MIC1 and MIC2 genes were located in the middle of the segment, in the following order from the centromeric side onwards, SLA-6, SLA-7, SLA-8, MIC-1 and MIC-2 . All three SLA Ib genes displayed an overall molecular structure compatible with the expression of membrane-anchored glycoproteins . The SLA-7 and SLA-8 genes bear greater resemblance than to the SLA-6 gene . Six SLA-6 alleles have been previously defined differing each from the other by unique point mutations . One of them, appeared to have arisen through the occurrence of a gene conversion event in which the SLA-7 gene served as template . Only MIC-2 gene might be functional, the second MIC-1 gene being truncated . In all, the 14 genes characterized spans 37% of the total sequence . The remaining 63% nucleotides comprised a number of repeat DNA motives, including LINE fragments, SINEs, microsatellites, and also numerous nucleotide stretches not yet defined in swine.

J Vet Pharmacol Ther, 2000 Dec, 23(6), 373 - 8
Administration of ticarcillin in combination with clavulanic acid intravenously and intrauterinely to clinically normal oestrous mares; Van Camp SD et al.; Ticarcillin and clavulanic acid (potassium clavulanate) were administered to normal oestrous mares intravenously (i.v.) at a dose of 50 and 1.67 mg/kg for ticarcillin and clavulanate, respectively . In a crossover design, the same drugs were administered intrauterine (i.u.) at a dose of 12.4 and 0.4 mg/kg for ticarcillin and clavulanate, respectively . The i.u . dose was administered in 100 mL of saline solution . Endometrial tissue biopsies and plasma samples were collected after drug administration for the determination of ticarcillin and clavulanate concentrations by high-pressure liquid chromatography and pharmacokinetic calculations . After i.u . administration both drugs were poorly absorbed into the plasma . The ticarcillin half-life from tissue and plasma was short after i.v . administration . Although concentrations in tissue were higher after i.u . administration than i.v., concentrations of ticarcillin declined rapidly, which would necessitate frequent treatment in order to maintain drug concentrations above the minimum inhibitory concentrations (MIC) throughout the treatment period . Clavulanate concentrations in tissue were either low or persisted for only a short time after administration via either route . It appears that addition of clavulanate to the formulation for treatment of i.u . infections in mares is of questionable value based on these concentrations.

Clin Microbiol Infect, 2000 Feb, 6(2), 74 - 81
Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release; Sjolin J et al.; OBJECTIVE: To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein (PBP) 3-specific beta-lactam antibiotic cefuroxime, the aminoglycoside tobramycin, and a combination of the two, and to test the relationship between bacterial killing rate and endotoxin release . METHODS: A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two . Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h . All experiments were performed in triplicate . For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used . RESULTS: Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size . At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001) . With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin . When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01) . This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin . CONCLUSIONS: Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate . Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.

Int J Antimicrob Agents, 2001 Feb, 17(2), 115 - 22
Sustained release of isoniazid from a single injectable dose of poly (DL-lactide-co-glycolide) microparticles as a therapeutic approach towards tuberculosis; Dutt M et al.; Drug delivery strategies to achieve a sustained drug release and increased bioavailability involve the use of biodegradable polymeric drug carriers . Poly (DL-lactide-co-glycolide) (PLG) microparticles were investigated as carriers for isoniazid (INH) . In vitro and in vivo release of INH from different formulations of PLG microparticles was examined . In vitro experiments showed a sustained release of INH up to 6 days from non-porous microparticles while porous microparticles released INH over 3 days . Both porous and non-porous microparticles released INH in plasma for up to 2 days . Hardened PLG microparticles sustained release of INH for up to 7 weeks both in vitro and in vivo . The concentrations of INH obtained at all times were much higher than the minimum inhibitory concentration (MIC) of INH . Controls injected with free INH showed release of INH in plasma for up to 12 h and in organs for up to 24 h . There was no hepatotoxicity induced as compared with control animals . Taken together these results suggest that PLG-based antitubercular drugs may serve as ideal therapeutic agents for the treatment of tuberculous infections.

Gynecol Oncol, 2001 Feb, 80(2), 201 - 6
K-ras mutations in Müllerian inclusion cysts associated with serous borderline tumors of the ovary; Alvarez AA et al.; OBJECTIVE: Mullerian inclusion cysts (MIC) are small benign appearing glands that are occasionally noted in lymph nodes and peritoneal biopsies . They occur most frequently in women with serous ovarian tumors, with borderline tumors (SBOT) having a higher incidence than invasive cancers . The aim of this study was to examine whether MIC and SBOT have identical K-ras mutations, which would suggest that they are related . Methods . Six patients in whom adequate tissue was available from SBOT, MIC, and normal tissue were identified from a consecutive series of patients with SBOT who underwent lymph node sampling from 1992 to 1997 at Duke University Medical Center . DNA extraction was performed using laser capture microdissection . Exon 1 of the K-ras gene was amplified using PCR and subjected to single-strand conformation analysis to screen for mutations . Shifted bands were sequenced to confirm the presence of mutations . RESULTS: Mutations in codon 12 of K-ras were found in three of six (50%) SBOT . In two of these three cases, the identical mutation was found in the SBOT and the MIC (gly to val in both cases), but not in the corresponding normal DNA . In one case, a mutation was seen in the ovarian tumor (gly to asp), but not in the corresponding MIC . CONCLUSIONS: Mutations in codon 12 of the K-ras gene are a hallmark of serous borderline tumors . The presence of identical K-ras mutations in some SBOT and their associated MIC suggests that they are related processes . Both may arise due to a field effect, or alternatively some MIC may represent metastases from the primary ovarian tumor.

J Antimicrob Chemother, 2001 Feb, 47(2), 203 - 6
Synergic activity of D-cycloserine and beta-chloro-D-alanine against Mycobacterium tuberculosis; David S; D-Cycloserine (DCS) is a peptidoglycan inhibitor . Although very effective against Mycobacterium tuberculosis, it is seldom employed in the management of this infection due to its high toxicity . beta-Chloro-D-alanine (another peptidoglycan inhibitor) reduces the MIC of DCS from 50 to 2.5 mg/L at a concentration significantly below its MIC for this organism . A reduction in bacterial viability and significant growth inhibition (as quantified by the X/Y quotient for the Bactec radiometric procedure) were observed with subinhibitory concentrations of both drugs . It is suggested that this powerful synergic effect should be the object of in vivo and eventually clinical trials.

J Urol, 2000 May, 163(5), 1560 - 4
Concentration of ofloxacin in canine prostate tissue and prostate fluid after intraprostatic injection of biodegradable sustained-releasing microspheres containing ofloxacin; Bahk JY et al.; PURPOSE: Excellent treatment results in chronic prostatitis by direct intra-prostatic injection of antibiotic were reported several decades ago with only minimal scientific background . We examined the distribution, in prostatic tissue and fluid, of the antibiotic in canines after intra-prostatic injection of biodegradable sustained-releasing microspheres containing 12 mg . of ofloxacin . MATERIALS AND METHODS: A total of 36 male dogs, 12 controls and 24 experimental, older than 2 years, were used . Experimental dogs were given biodegradable sustained releasing microspheres containing ofloxacin 12 mg . and poly(D,L-lactic) acid 28 mg., designed to release over more than a 4 week period . The 12 control animals were divided into 2 groups, and oral ofloxacin 100 mg . was given twice a day for 2 and 4 weeks . The 24 experimental animals were divided into 4 subgroups of 6 dogs each, 4 for prostatic tissue and 2 for prostatic fluid level of ofloxacin determination . Anesthesia was initiated with ketamine HCl and xylazine, and maintained with intermittent ketamine HCl . In the experimental groups, 1 ml . of resolved formula was injected into one lobe of surgically exposed prostates . The concentration of ofloxacin was measured by high performance liquid chromatography (HPLC) of blood, prostatic tissue and prostatic fluid . Pilocarpine 0.5 mg./kg . was used for the collection of the prostatic fluid . RESULTS: The total ofloxacin of controls were 2,800 (2 weeks) and 5,600 (4 weeks) mg . In control groups, tissue concentrations of ofloxacin were relatively even at all segments of prostate, 7.4 +/- 0.8 (2 weeks) and 9.2 +/- 1.1 microg./ml . (4 weeks) . The blood level ranged between 3.6 to 5.1 microg./ml . The prostatic fluid level ranged from 3.1 to 5.7 microg . /ml . In the experimental groups, the tissue levels of ofloxacin were 10.5 +/- 3.0 (1 week), 13.8 +/- 4.5 (2 weeks), 7.1 +/- 0.9 (3 weeks) and 7.7 +/- 3.0 microg./ml . (4 weeks) in the injected lobe . The opposite lobes were 8.0 +/- 1.1 (1 week), 10.2 +/- 4.2 (2 weeks), 5 . 1 +/- 1.4 (3 weeks) and 7.6 +/- 0.8 (4 weeks) microg./ml . The blood level in the experimental groups ranged between 0.16 to 0.59 microg./ml . The prostate fluid level ranged from 2.9 to 6.1 microg./ml . in 8 dogs . Upon pathologic examination, the microspheres were interposed between prostate stroma and their size was reduced over time . CONCLUSIONS: Our study indicates that there is communication between the right and left prostate lobes . Direct injection of biodegradable sustained releasing ofloxacin formula into the prostate may be a substitute for long term antibiotic medication in humans for chronic prostatitis in the future without hurting the minimal inhibitory concentration(MIC)90.

Med Dosw Mikrobiol, 2000, 52(3), 223 - 8
{Characteristics of the MRSA clone with reduced susceptibility to vancomycin}; Mlynarczyk G et al.; The MIC of vancomycin was determined for all S . aureus strains isolated during 1997 in one hospital . MIC values for most isolates were in the range of 0.5-2 mg/l . In 18 strains, MIC was = 6 mg/L . All these strains were MRSA . Recently described VISA strains possessed MIC values for vancomycin equal or higher than 8 mg/l and such strains were not detected in the investigated group . Although strains with MIC = 6 mg/l are not VISA, but they are candidate for reduced vancomycin susceptibility, e.g . during therapy in compromised patients . Analysis of DNA of these strains by pulsed-field gel electrophoresis (PFGE) revealed that 15 of them shared a significant similarity, allowing to place them in the same group . The comparison data of phage patterns as well as antibiotic resistance patterns strongly suggest that all these strains were derivatives of a single clone.

Biochemistry, 2001 Jan 9, 40(1), 65 - 73
Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities; Fairlie WD et al.; Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily whose increased expression is associated with macrophage activation and which is expressed highly in placenta as compared to other tissues . There are two known allelic forms of human MIC-1 due an amino acid substitution at position 6 of the mature protein . We have raised four monoclonal antibodies (MAbs) and one polyclonal antiserum to the mature protein region of human MIC-1 and have used an extensive panel of MIC-1 relatives, mutants, and chimeras to map their epitopes . None of the MAbs were able to cross-react with either the murine homologue of MIC-1 or with hTGF-beta1, and all of the MAb epitopes were conformation-dependent . A distinct cross-reactivity pattern with the various antigens was observed for each of the monoclonal and polyclonal antibodies suggesting the presence of at least five immunogenic regions on the MIC-1 surface . One of the MAbs is directed against the amino terminus of the protein and can distinguish between the two allelic forms of MIC-1 . The epitopes for the other three MAbs were located near the tips of the so-called "fingers" of the protein and appeared to be partially overlapping as each involved amino acids in the region 24-37 . In one case, it was possible to mutate murine MIC-1 so that it could be recognized by one of the MAbs . Finally, the use of another mutant in which Cys 77 was replaced by serine enabled confirmation of the location of the MIC-1 interchain disulfide bond.

Pancreas, 2001 Jan, 22(1), 28 - 31
Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis: a meta-analysis; Sharma VK et al.; Severe acute pancreatitis is frequently complicated by local and systemic infections resulting in substantial morbidity, mortality, and health care costs . Antibiotic prophylaxis may prevent some infections . We searched for randomized, controlled trials comparing antibiotic prophylaxis with no prophylaxis in patients with acute necrotizing pancreatitis (ANP) . Only trials that used antibiotics that reach minimum inhibitory concentration (MIC) in necrotic pancreatic tissue were included . We calculated relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT) for individual trials and pooled data . Antibiotic prophylaxis significantly reduced sepsis by 21.1% (NNT = 5) and mortality by 12.3% (NNT = 8) compared with no prophylaxis . There was also a nonsignificant trend toward a decrease in local pancreatic infections (ARR = 12%; NNT = 8) . Antibiotic prophylaxis decreases sepsis and mortality in patients with ANP . All patients with ANP should be given prophylaxis with an antibiotic with proven efficacy in necrotic pancreatic tissue.

Int J Antimicrob Agents, 2001 Jan, 17(1), 51 - 5
In vitro, ex-vivo and in vivo activities of ethambutol and sparfloxacin alone and in combination against mycobacteria; Kaur D et al.; The MIC of ethambutol and sparfloxacin for Mycobacterium smegmatis and M . avium was determined using a broth dilution method . The MICs of sparfloxacin and ethambutol were lower for M . smegmatis than M . avium . The combination of ethambutol and sparfloxacin was additive against M . smegmatis but synergistic for M . avium . The effect of these drugs alone and in combination used at C(max) levels was screened against M . avium and M . tuberculosis H(37)Rv growing intracellularly in murine macrophage cell lines . In vivo studies using this combination given at 100 mg/kg of body weight once weekly showed greater activity than the drugs used singly . These results suggest that combination of ethambutol and sparfloxacin has significant activity intracellularly and in animal models against M . avium and M . tuberculosis.

J Clin Microbiol, 2001 Jan, 39(1), 339 - 42
Improved detection of amphotericin B-resistant isolates of Candida lusitaniae by Etest; Peyron F et al.; Both intrinsic and acquired resistance to amphotericin B have been documented for Candida lusitaniae . Amphotericin B remains the drug of choice for many critical fungal infections, and the detection of resistance is essential to monitor treatment effectively . The limitations of the National Committee for Clinical Laboratory Standards (NCCLS) reference methodology for detection of amphotericin B resistance are well documented, and several alternative methods have been proposed . Etest assays with RPMI and antibiotic medium 3 (AM3) agar were compared to the NCCLS M27-A broth macrodilution method using AM3 for amphotericin B resistance testing with 49 clinical isolates of C . lusitaniae . The panel included nine isolates with known or presumed resistance to amphotericin B on the basis of in vivo and/or in vitro data . The distribution of amphotericin B MICs by Etest with RPMI ranged from 0 . 032 to 16 microg/ml and was bimodal . All of the putatively resistant isolates were inhibited by amphotericin B at >/=0.38 microg/ml and could be categorized as resistant using this breakpoint . Etest with AM3 yielded a broader amphotericin B MIC range (0.047 to 32 microg/ml), and there were six putatively resistant isolates for which MICs were >1 microg/ml . The separation of putatively susceptible and resistant isolates was less obvious . Broth macrodilution with AM3 generated a unimodal distribution of MICs (ranging from 0.032 to 2 microg/ml) and failed to discriminate most of the putatively resistant isolates at both 24 and 48 h . Etest using RPMI and, to a lesser extent, using AM3 provided better discrimination between amphotericin B-resistant and -susceptible isolates of C . lusitaniae.

J Clin Endocrinol Metab, 2000 Dec, 85(12), 4781 - 8
The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women; Moore AG et al.; Macrophage inhibitory cytokine-1 (MIC-1) is a recently described divergent member of the transforming growth factor-ss superfamily . MIC-1 transcription up-regulation is associated with macrophage activation, and this observation led to its cloning . Northern blots indicate that MIC-1 is also present in human placenta . A sensitive sandwich enzyme-linked immunosorbent assay for the quantification of MIC-1 was developed and used to examine the role of this cytokine in pregnancy . High levels of MIC-1 are present in the sera of pregnant women . The level rises substantially with progress of gestation . MIC-1 can also be detected, in large amounts, in amniotic fluid and placental extracts . In addition, the BeWo placental trophoblastic cell line was found to constitutively express the MIC-1 transcript and secrete large amounts of MIC-1 . These findings suggest that the placental trophoblast is a major source of the MIC-1 present in maternal serum and amniotic fluid . We suggest that MIC-1 may promote fetal survival by suppressing the production of maternally derived proinflammatory cytokines within the uterus.

J Antibiot (Tokyo), 2000 Oct, 53(10), 1182 - 90
On the mechanism of action of the myxobacterial fungicide ambruticin; Knauth P et al.; The myxobacterial fungicide, ambruticin, kills the yeast, Hansenula anomala, with high efficacy (MIC 0.05 microg/ml), but only when the cells are growing . The earliest effect, observed almost immediately after the addition of the antibiotic, is a transient but substantial increase of intracellular glycerol, followed by an accumulation of triacylglycerols and free fatty acids . At about the time when free fatty acids accumulate, the cells become leaky to low molecular weight compounds . We assume that this leakage kills the cells . The mechanism of action of ambruticin thus appears to be the same as that of the phenylpyrroles, e.g., pyrrolnitrin, viz., interference with osmoregulation.

Acta Pol Pharm, 2000 Jul-Aug, 57(4), 307 - 10
Studies on pyrazine derivatives--XXXIV . Synthesis and tuberculostatic activity of alpha-oxo ketene dithioacetals pyrazine derivatives; Milczarska B et al.; The alpha-oxo ketene dithioacetalic derivatives (2a-e) were obtained by the reaction of 2-acetylpyrazine (1) with CS2 and appropriate mono- or dihalogeno-compound . An action of the primary amines and diamines upon 3,3-di(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-one (2a) yielded 3-(alkylamino)-3-(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-on e (3a-g), 1-(2-pyrazinyl)-2-tetrahydro-1H-2-imidazolyliden-1-ethanone (3h) and the 2-hexahydro-2-pyrimidinyliden-1-(2-pyrazinyl)-1-ethanone derivatives (3i-j), respectively . Tuberculostatic activity of the studied compounds was found to be low except the compound 2b (MIC 192-62 micrograms/cm3; MIC 210-31 micrograms/cm3).

J Urol, 2001 Jan, 165(1), 97 - 9
Pharmacokinetics of clarithromycin in the prostate: implications for the treatment of chronic abacterial prostatitis; Giannopoulos A et al.; PURPOSE: We studied the pharmacokinetics of orally administered clarithromycin in prostatic tissue to define its role in the treatment of chronic abacterial prostatitis caused by intracellular pathogens . MATERIALS AND METHODS: A total of 45 men receiving 3 oral doses of 750 mg . clarithromycin at 12-hour intervals underwent suprapubic prostatectomy for benign prostate hyperplasia 4, 5, 6 and 7 hours after the last drug dose in 13, 12, 10 and 10 patients, respectively . Concentrations were determined in the prostate tissue and in plasma by an agar diffusion assay . RESULTS: A mean peak level of clarithromycin of 3.22 and 3.08 microg./gm . of tissue was achieved 4 hours after the third drug dose at the center and periphery of the adenoma, respectively . Tissue levels remained statistically superior to plasma levels at all intervals . CONCLUSIONS: The oral administration of clarithromycin achieved a prostate level much higher than the minimal inhibitory concentration of clarithromycin for the intracellular pathogens of chronic prostatitis . Thus, clarithromycin may be considered for treating chronic abacterial prostatitis.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 353 - 5
In vitro pharmacodynamic studies of activities of ketolides HMR 3647 (Telithromycin) and HMR 3004 against extracellular or intracellular Helicobacter pylori; Gustafsson I et al.; The pharmacodynamic properties of the ketolides HMR 3647 (telithromycin) and HMR 3004 were studied against Helicobacter pylori . Both ketolides showed a pronounced concentration-dependent killing, a significant postantibiotic effect, a long postantibiotic sub-MIC effect, and a reduction of intracellular H . pylori.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 327 - 30
In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates; Arikan S et al.; We investigated the relevance of prominent reduction in turbidity macroscopically (MIC) and formation of aberrant hyphal tips microscopically (minimum effective concentration; MEC) in measuring the in vitro activity of caspofungin against Aspergillus and Fusarium . Caspofungin generated low MICs and MECs against Aspergillus, but not for Fusarium . While MICs increased inconsistently when the incubation time was prolonged, MEC appeared as a stable and potentially relevant endpoint in testing in vitro caspofungin activity.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 312 - 5
In vitro and in vivo efficacies of T-3811ME (BMS-284756) against Mycoplasma pneumoniae; Takahata M et al.; T-3811, the free base of T-3811ME (BMS-284756), a new des-F(6)-quinolone, showed a potent in vitro activity (MIC at which 90% of the isolates tested are inhibited {MIC(90)}, 0.0313 microg/ml) against Mycoplasma pneumoniae . The MIC(90) of T-3811 was 4-fold higher than that of clarithromycin but was 4- to 8-fold lower than those of trovafloxacin, gatifloxacin, gemifloxacin, and moxifloxacin and was 16- to 32-fold lower than those of levofloxacin, ciprofloxacin, and minocycline . In an experimental M . pneumoniae pneumonia model in hamsters, after the administration of T-3811ME (20 mg/kg of body weight as T-3811, once daily, orally) for 5 days, the reduction of viable cells of M . pneumoniae in bronchoalveolar lavage fluid was greater than those of trovafloxacin, levofloxacin, and clarithromycin (20 and 40 mg/kg, orally) (P < 0.05).

Antimicrob Agents Chemother, 2001 Jan, 45(1), 303 - 5
Affinities of beta-lactams for penicillin binding proteins of Chlamydia trachomatis and their antichlamydial activities; Storey C et al.; Binding affinities of beta-lactam antibiotics for the three penicillin binding proteins (PBPs) from Chlamydia trachomatis were determined in vitro and compared with their antichlamydial activities . Mecillinam selectively inhibited PBP1, with a 50% inhibitory concentration for PBP1 binding (0.2 microg/ml) similar to the MIC (0.1 microg/ml) and minimum bactericidal concentration (0.25 microg/ml) . Although the other beta-lactams inhibited a wider range of PBPs than mecillinam, their antichlamydial activities were inferior to that of mecillinam.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 217 - 22
Activity of moxifloxacin by itself and in combination with ethambutol, rifabutin, and azithromycin in vitro and in vivo against Mycobacterium avium; Bermudez LE et al.; Moxifloxacin activity against Mycobacterium avium complex (MAC) was evaluated in vitro against 25 strains . The MIC was determined to range from 0.125 to 2.0 microg/ml . In addition, U937 macrophage monolayers infected with MAC strain 101 (serovar 1) were treated with moxifloxacin (0.25 to 8 microg/ml) daily, and the number of intracellular bacteria was quantitated after 4 days . Moxifloxacin showed inhibitory activity at 0.5 microg/ml and higher . To assess the activity of moxifloxacin containing regimens in vivo, we infected C57BL bg(+)/bg(+) mice with 3 x 10(7) MAC strain 101 bacteria intravenously . One week later treatment was begun with the following: (i) moxifloxacin (50 mg/kg/day or 100 mg/kg/day), ethambutol (100 mg/kg/day), or a combination of moxifloxacin and ethambutol; or (ii) moxifloxacin (100 mg/kg/day), azithromycin (200 mg/kg/day), or rifabutin (40 mg/kg/day) as oral monotherapy; or (iii) all permutations of two-drug therapy or all three drugs in combination . All groups contained at least 14 animals, and the control group received the drug vehicle . After 4 weeks, quantitative blood cultures were obtained and the number of bacteria in liver and spleen was quantitated . Moxifloxacin, ethambutol, and azithromycin were active as single agents in liver, spleen, and blood . Rifabutin showed inhibitory activity only in the blood . Two-drug combinations containing azithromycin were no more active than azithromycin alone . Similarly, the three-drug combination was not more active than azithromycin alone in the spleen . Rifabutin did not add to the activity of any other single agent or two-drug combination . Moxifloxacin at both concentrations in combination with ethambutol was significantly more active than each drug alone.

J Appl Microbiol, 2000 Nov, 89(5), 778 - 84
Effect of antibiotics on viability staining of Escherichia coli in solid phase cytometry; D'Haese E et al.; Solid phase cytometry (SPC) has been investigated as a tool to assess the effect of antibiotics on the viability of Escherichia coli . After exposure of the cells to the antibiotic, they are retained on a polyester membrane filter and labelled using a fluorescein derivative as a substrate for intracellular esterases . The number of fluorescent bacteria is automatically counted in an Ar laser scanning device . In the presence of nutrients, all antibiotics tested in concentrations exceeding the MIC inhibited the multiplication of cells but not the labelling per se . However, when no nutrients were added, the cells did not multiply, and inhibition of the fluorescent staining was only observed for membrane permeabilizing antibiotics, even at sub-MIC concentrations . The selective detection by SPC of membrane-permeabilizing antibiotics corroborates the requirement of membrane integrity for viability labelling of bacteria . This selectivity has been exploited to develop a method for the detection of colistin residues in milk.

Eur J Drug Metab Pharmacokinet, 2000 Apr-Jun, 25(2), 121 - 6
Effects of imidazole antimycotics on the liver microsomal cytochrome P450 isoforms in rats: comparison of in vitro and ex vivo studies; Suzuki S et al.; We have studied the effects of three imidazole derivatives, clotrimazole (CLO), ketoconazole (KET) and miconazole (MIC) on the liver microsomal diazepam (DZ) metabolism . In in vitro experiments using rats and human liver microsomes, significant inhibition of CYP3A in terms of DZ-3-hydroxylase activity was observed . The inhibition of DZ metabolism was seen 1 h after CLO dosing . On the other hand, the induction of certain cytochrome P450 (CYP) isozymes was observed in in vivo studies 24 h after dosing . That is, CYP1A, CYP2B and CYP3A2, but not CYP2E, were observed 24 h after CLO or KET or MIC treatment . Under these conditions, CLO was the most potent inducer of CYP3A and MIC was a more potent inducer of CYP1A and CYP2B . KET induced CYP1A and CYP2B whereas the inducibility of KET was less than those of CLO and MIC . All of the imidazole derivatives tested here showed significant inhibition of CYP isozymes which overcame the induction of the CYP isozymes by those drugs in the data of Western blot analysis.

Can J Urol, 2000 Aug, 7(4), 1081 - 4
A para-testicular primitive neuroectodermal tumor in an adult: a case report and literature review; Cohen DD et al.; OBJECTIVE: The authors describe the salient clinical, radiologic and histopathologic features of an extremely rare para-testicular primitive neuroectodermal tumor in a 25 year-old man . INTERVENTION: Excisional biopsy of the tumor en bloc was performed . Adjuvant VAdriaC-based chemotherapy (Vincristine, Doxorubicin, and Cyclophosphamide) was given post-operatively . MAIN OUTCOME MEASURES: Histopathologic examination and immunohistochemical studies were performed on formaldehyde-fixed, paraffin-embedded tumor tissue . RESULTS: Histologic examination showed an undifferentiated small cell tumor . The tumor cells stained positively with MIC-2, a marker specific for primitive neuroectodermal tumors . The patient is 12 months post surgery and has completed adjuvant chemotherapy with no evidence of recurrent disease . CONCLUSIONS: This highly unusual, peripheral primitive neuroectodermal tumor should be considered in the differential diagnosis of undifferentiated small cell neoplasms of the genitourinary system in adults, from the kidney to the testicle . We present a patient with a PNET treated based on a Ewing's family of tumors protocol.

J Antimicrob Chemother, 2000 Dec, 46(6), 981 - 5
Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model; Cottagnoud P et al.; Linezolid, a new oxazolidinone antibiotic, showed good penetration (38+/-4%) into the meninges of rabbits with levels in the CSF ranging from 9.5 to 1.8 mg/L after two i.v . injections (20 mg/kg) . Linezolid was clearly less effective than ceftriaxone against a penicillin-sensitive pneumococcal strain . Against a penicillin-resistant strain, linezolid had slightly inferior killing rates compared with the standard regimen (ceftriaxone combined with vancomycin) . In vitro, linezolid was marginally bactericidal at concentrations above the MIC (5 x and 10 x MIC).

Int J Antimicrob Agents, 2000 Nov, 16(3), 273 - 80
Pharmacokinetic/pharmacodynamic predictors of time to clinical resolution in patients with acute bacterial exacerbations of chronic bronchitis treated with a fluoroquinolone; Meinl B et al.; Forty nine subjects with acute bacterial exacerbations of chronic bronchitis (ABECB) treated with grepafloxacin were evaluated for parameters predictive of clinical outcome . Signs and symptoms associated with ABECB were serially collected and evaluated for changes . Coughs per day, sputum volume and the percentage of sputum neutrophils were associated with clinical outcome . A by groups analysis, based on clinical success was performed using Cox regression analysis to determine factors associated with time to clinical success and time to reduction in sputum volume, coughs per day and sputum neutrophil percent . Factors evaluated included AUIC (AUC/MIC), isolate species, years and type of underlying lung disease, alcohol use, smoking history and number of ABECB within the previous 12 months . AUIC<276 (mg h/l)/mg/l (P<0.03) and or the presence of mild bronchiectasis (P<0.01) were associated with longer time to clinical success . In addition a relationship was found between AUIC>212 (mg h/l)/mg/l (P<0.01) and AUIC>576 (mg h/l)/mg/l (P<0.02) and decreasing days to sputum volume reduction and coughs per day, respectively . A diagnosis of mild bronchiectasis prolonged the time to reduce coughs per day (P<0.03) and neutrophil percentage (P<0.01) . Patients with mild bronchiectasis were found to have an increase in the time to clinical success, coughs per day improvement and sputum neutrophil percent improvement . AUIC is an important PK/PD parameter predictive of successful outcome in ABECB, even in subjects with mild bronchiectasis . Grepafloxicin has been withdrawn from sale since these studies were carried out . This work is published to illustrate the relationship between pharmacodynamics and clinical efficacy and the use of AUIC as a valuable predictive parameter for fluoroquinolones.

Int J Antimicrob Agents, 2000 Nov, 16(3), 233 - 8
Outer membrane changes in Pseudomonas stutzeri resistant to chlorhexidine diacetate and cetylpyridinium chloride; Tattawasart U et al.; Changes in outer membrane proteins (OMP) and lipopolysaccharide (LPS) in cells of strains of Pseudomonas stutzeri sensitive and resistant to chlorhexidine diacetate (CHA) or cetylpyridinium chloride (CPC) have been examined . Four of five CHA-resistant strains had alterations in OMP profiles, including the expression of two additional protein bands . All the CPC-resistant strains had altered OMP profiles but the changes varied from strain to strain . Loss of the fastest-migrating bands was observed in the LPS from CHX-resistant strains . In strain JM 302R with high-level CHX resistance (minimal inhibitory concentration 100 mg/l as opposed to 2.5 mg/l in the parent-strain, JM 302), all the fast-migrating bands were lost and the strain showed 'cross-resistance' to polymyxin, gentamicin and ethylenediamine tetraacetic acid . It is however, possible that the altered LPS patterns reflect a response to alterations in other components rather than being directly associated per se with the enhanced resistance.

Med Pregl, 2000 May-Jun, 53(5-6), 266 - 71
{Clinical use of tetracyclines in the treatment of periodontal diseases}; Bokor-Bratic M et al.; INTRODUCTION: There are a number of chemically different tetracycline homologues . The older group of tetracyclines, which was introduced in the 1950-60s, includes tetracycline, oxytetracycline, chlortetracycline and demeclocycline . The newer group of tetracyclines includes doxycycline, methacycline and minocycline . PHARMACOKINETICS: Elevated concentration of tetracycline in gingival fluid with respect to blood levels was an unexpected phenomenon . Patients given 250 mg every 6 hours had average crevicular fluid concentrations between 4 to 8 g/ml and blood concentrations between 2 to 2.5 g/ml after 48 hours . The levels in crevicular fluid and blood of volunteers who received 250 mg every 12 hours were 2 to 4 g/ml and 0.3 to 1.4 g/ml respectively after 48 hours . The concentration of doxycycline in gingival fluid after administration of 200 mg/1st day and then 100 mg/day achieved average level of 6 g/ml . Minocycline, a semisynthetic derivate of tetracycline, has shown to yield gingival fluid levels 5 times as high as serum levels after administration of 100 mg every 12 hours . MECHANISMS OF ACTION: Tetracycline and its derivates demonstrate high in vitro activity against most periodontal bacteria, including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Eikenella corrodens, Wolinella recta and Fusobacterium nucleatum . The study of in vitro susceptibility of these 6 bacterial strains showed that, in regard to blood level, minimal inhibitory concentration is higher and it is the concentration of the drug that can be expected in gingival fluid following oral administration of 100 mg per day (doxycycline) (Table 1) . The anti-inflammatory effect of tetracyclines was demonstrated histologically not only by reducing the size of the infiltrated connective tissue, but qualitative changes were also observed . Golub and associates have presented evidence that tetracyclines inhibit collagenase activity in gingival fluid and in tissue cultures . Therapeutic concentrations of tetracycline inhibit chemotaxis, phagocytosis and random migration of neutrophils in vitro . ADVERSE EFFECTS: Great amounts of tetracyclines cause gastrointestinal disorders, nausea, vomiting and diarrhea . Tetracyclines suppress activity of the enzymes in the bowel and pancreas . During longlasting administration they can damage the liver and kidneys . Tetracyclines can cause photo-sensibilization . They make deposits with calcium in bones, specially during prenatal period and during growth, so they can cause permanent teeth discoloration and hypoplasia . INTERACTIONS: The most important interaction is with penicillin . These two kinds of antibiotics antagonize and decrease the therapeutic effect of each other, so their administration at the same time should be avoided . A significant interaction occurs between tetracyclines and metal ions . This interaction often has been observed in conjunction with use of various antacids . Tetracyclines can also influence the production and absorption of vitamin K . Nephrotoxicity has been reported when tetracyclines have been administrated in conjunction with methoxyflurane . INDICATIONS: Doxycycline, due to its advantages over tetracycline (Table 2), is indicated in treating destructive periodontal diseases including: juvenile periodontitis and refractory marginal periodontitis . Doxycycline therapy may be used for acute periodontal abscess and if the conditions are accompanied by general symptoms . Prophylactic application is recommended for implant placement procedures including membranes in guided tissue regeneration . RESULTS OF CLINICAL STUDY: ORAL APPLICATION: In spite of great number of published investigations this paper presents only the results of placebo-controlled, double-blind studies . There is evidence that therapy in localized juvenile periodontitis should eliminate Actinobacillus actinomycetemcomitans, since 95% of patients harbored this bacteria . (ABSTRACT TRUNCATED)

Chem Pharm Bull (Tokyo), 2000 Nov, 48(11), 1805 - 6
Isolation of a potent anti-MRSA sesquiterpenoid quinone from Ulmus davidiana var . japonica; Shin DY et al.; A highly potent anti-MRSA sesquiterpenoid has been isolated from Ulmus davidiana var . japonica, which has been traditionally used to treat infectious diseases in Korea . This naturally occurring antibiotic was identified as mansonone F (1) . This compound has been found to be highly active specifically against MRSA and showed an MIC range of 0.39-3.13 microg/ml which is comparable to that of vancomycin.

Antimicrob Agents Chemother, 2000 Dec, 44(12), 3441 - 3
High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA; Mazzariol A et al.; Immunoblotting with antibody against AcrA, an obligatory component of the AcrAB multidrug efflux system, showed that this protein was overexpressed by >/=170% in 9 of 10 clinical isolates of Esherichia coli with high-level ciprofloxacin resistance (MICs, >/=32 microg/ml) but not in any of the 15 isolates for which the MIC was </=1 microg/ml.

Antimicrob Agents Chemother, 2000 Dec, 44(12), 3428 - 31
Bactericidal activities of antibiotics against intracellular Francisella tularensis; Maurin M et al.; MICs of many antibiotics for Francisella tularensis are low in axenic medium, whereas only aminoglycosides, tetracyclines, and fluoroquinolones are useful in treating tularemic patients . In an in vitro cell system, only these antibiotics, rifampin, and telithromycin were bactericidal against intracellular F . tularensis . These results correlate better with clinical data than MIC data do.

Antimicrob Agents Chemother, 2000 Dec, 44(12), 3368 - 73
Characterization of an In vitro-selected amoxicillin-resistant strain of Helicobacter pylori; DeLoney CR et al.; An amoxicillin-resistant (Amox(r)) strain of Helicobacter pylori was selected for by culturing an amoxicillin-sensitive (Amox(s)) strain in increasingly higher concentrations of amoxicillin, resulting in a 133-fold increase in MIC, from 0.03 to 0.06 microg/ml to 4 to 8 microg/ml . This resistance was stable upon freezing for at least 6 months and conferred cross-resistance to seven other beta-lactam antibiotics . beta-Lactamase activity was not detected in this Amox(r) strain; however, analysis of the penicillin-binding protein (PBP) profiles generated from isolated bacterial membranes of the Amox(s) parental strain and the Amox(r) strain revealed a significant decrease in labeling of PBP 1 by biotinylated amoxicillin (bio-Amox) in the Amox(r) strain . Comparative binding studies of PBP 1 for several beta-lactams demonstrated that PBP 1 in the Amox(r) strain had decreased affinity for mezlocillin but not significantly decreased affinity for penicillin G . In addition, PBP profiles prepared from whole bacterial cells showed decreased labeling of PBP 1 and PBP 2 in the Amox(r) strain at all bio-Amox concentrations tested, suggesting a diffusional barrier to bio-Amox or a possible antibiotic efflux mechanism . Uptake analysis of (14)C-labeled penicillin G showed a significant decrease in uptake of the labeled antibiotic by the Amox(r) strain compared to the Amox(s) strain, which was not affected by pretreatment with carbonyl cyanide m-chlorophenylhydrazone, eliminating the possibility of an efflux mechanism in the resistant strain . These results demonstrate that alterations in PBP 1 and in the uptake of beta-lactam antibiotics in H . pylori can be selected for by prolonged exposure to amoxicillin, resulting in increased resistance to this antibiotic.

Antimicrob Agents Chemother, 2000 Dec, 44(12), 3337 - 43
Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria; Sindelar G et al.; Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated . To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations . Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring . When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells . For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs . Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not . With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.

J Antimicrob Chemother, 2000 Sep, 46 Suppl T2, 9 - 23
MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview; Turner PJ; The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) is a global, multicentre surveillance study that compares the activity of meropenem in centres that are prescribers with that of imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin . Of the 46 centres (intensive care units, cystic fibrosis units, neutropenia units and general wards) contributing to this study, 29 were in Europe, 14 in the Americas and three in the Middle East and Asia . The results for the most common isolates obtained in the first year of the study from these three regions show that meropenem has a broad spectrum of activity and potency in these centres, with 89% of the 6890 strains tested having an MIC < or = 4 mg/L . The overall susceptibility was lower for the comparator antibiotics . There was evidence in all regions of strains producing beta-lactamases and other resistance mechanisms against the other beta-lactams tested, fluoroquinolones and aminoglycosides . Future years' results from this surveillance study will show whether meropenem will continue to exhibit such activity.

J Antimicrob Chemother, 2000 Nov, 46(5), 793 - 6
Frameshift mutations in rdxA and metronidazole resistance in North American Helicobacter pylori isolates; Kwon DH et al.; In Helicobacter pylori, the oxygen-insensitive nitroreductase RdxA is likely to activate metronidazole (Mtz) by reduction and formation of cytotoxic intermediates . Mutations in rdxA have been associated with Mtz resistance in H . pylori . In vitro Mtz susceptibilities of 17 randomly selected H . pylori isolates were determined by the agar dilution method . DNA sequence analysis of rdxA alleles of eight susceptible isolates (MIC range: 0.25-1.0 mg/L) and nine resistant isolates (MIC range: 16-256 mg/L) showed that six of nine Mtz-resistant H . pylori isolates contained insertion or deletion mutations ('indel' mutations) . One isolate contained a substitution mutation at codon position 148 that resulted in the introduction of a premature stop codon . Creation of stop codons within the rdxA coding sequence by either frameshift or substitution mutations resulted in premature translation termination and expression of putatively truncated RdxA polypeptides.

New Microbiol, 2000 Oct, 23(4), 415 - 21
Influence of an extended incubation period on values of minimum inhibitory concentrations of antibiotics in Stenotrophomonas maltophilia clinical strains; Hejnar P et al.; In 106 Stenotrophomonas maltophilia clinical strains the susceptibility to 19 kinds of antibiotics was tested by the broth dilution micromethod at 24 h and 48 h incubation . Isolated strains demonstrated the lowest frequency of resistance to cotrimoxazole (7.5% of resistant strains at 24 h incubation and 18.9% at 48 h), ofloxacin (13.2% and 30.2%), ciprofloxacin (19.8% and 50.9%) and to cefoperazone/sulbactam (20.8% and 37.7%) . The smallest growth of the number of resistant strains after extended incubation was recorded in gentamicin (by 10.4%), ceftazidime (by 11.3%) and cotrimoxazole (by 11.4%) . On the contrary, the largest growth of resistance was demonstrated in cefoperazone and ciprofloxacin (by 31.1%) . Average values of the growth of minimum inhibitory concentrations (MICs) were lowest in ciprofloxacin and ofloxacin (2.3 times) and highest in piperacillin/tazobactam (4.5 times) and piperacillin (5.0 times) . As far as the stability of MIC is concerned, the largest occurrence of strains with the MIC growth doubled as a maximum was found in ceftazidime (78.4%), ofloxacin (76.1%) and ciprofloxacin (75.3%), the smallest in piperacillin/tazobactam (43.2%) and piperacillin (38.9%) . The importance of incubation extended to 48 h during the testing of S . maltophilia strains was noted for correctly setting their susceptibility to antibiotics.

Chemotherapy, 2000 Nov-Dec, 46(6), 390 - 4
In vitro susceptibility to itraconazole, clotrimazole, ketoconazole and terbinafine of 100 isolates of Trichophyton rubrum; Fernandez-Torres B et al.; BACKGROUND: A reference method for dermatophyte in vitro susceptibility testing is lacking . With the advent of new antimycotics, susceptibility testing has received increasing attention as an important laboratory tool for aiding the selection of appropriate drug therapy . METHODS: One hundred strains of Trichophyton rubrum were tested against four antifungal agents, itraconazole, clotrimazole, ketoconazole and terbinafine, by using a modification of the proposed standard M38-P of the National Committee for Clinical Laboratory Standards and two types of standardized inocula, 1.4 x 10(4) and 5 x 10(3) CFU/ml . RESULTS: Terbinafine was revealed to be the most effective antifungal drug . Of the three azole derivatives tested, clotrimazole showed the highest antifungal activity, while the minimum inhibitory concentrations (MICs) of itraconazole and ketoconazole were similar . Inoculum size did not affect the MIC of any of the antifungal agents tested . CONCLUSION: Our preliminary data provide promising results for the development of a reference method for dermatophyte susceptibility testing based on the microdilution technique, although more dermatophytes should be tested and the method evaluated in different laboratories .

J Bacteriol, 2000 Nov, 182(22), 6509 - 13
Escherichia coli TehB requires S-adenosylmethionine as a cofactor to mediate tellurite resistance; Liu M et al.; The Escherichia coli chromosomal determinant for tellurite resistance consists of two genes (tehA and tehB) which, when expressed on a multicopy plasmid, confer resistance to K(2)TeO(3) at 128 microg/ml, compared to the MIC of 2 microg/ml for the wild type . TehB is a cytoplasmic protein which possesses three conserved motifs (I, II, and III) found in S-adenosyl-L-methionine (SAM)-dependent non-nucleic acid methyltransferases . Replacement of the conserved aspartate residue in motif I by asparagine or alanine, or of the conserved phenylalanine in motif II by tyrosine or alanine, decreased resistance to background levels . Our results are consistent with motifs I and II in TehB being involved in SAM binding . Additionally, conformational changes in TehB are observed upon binding of both tellurite and SAM . The hydrodynamic radius of TehB measured by dynamic light scattering showed a approximately 20% decrease upon binding of both tellurite and SAM . These data suggest that TehB utilizes a methyltransferase activity in the detoxification of tellurite.

Genome Res, 2000 Oct, 10(10), 1579 - 86
SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity; Gaudieri S et al.; The human major histocompatibility complex (MHC) is characterized by polymorphic multicopy gene families, such as HLA and MIC (PERB11); duplications; insertions and deletions (indels); and uneven rates of recombination . Polymorphisms at the antigen recognition sites of the HLA class I and II genes and at associated neutral sites have been attributed to balancing selection and a hitchhiking effect, respectively . We, and others, have previously shown that nucleotide diversity between MHC haplotypes at non-HLA sites is unusually high (>10%) and up to several times greater than elsewhere in the genome (0.08%-0.2%) . We report here the most extensive analysis of nucleotide diversity within a continuous sequence in the genome . We constructed a single nucleotide polymorphism (SNP) profile that reveals a pattern of extreme but interrupted levels of nucleotide diversity by comparing a continuous sequence within haplotypes in three genomic subregions of the MHC . A comparison of several haplotypes within one of the genomic subregions containing the HLA-B and -C loci suggests that positive selection is operating over the whole subgenomic region, including HLA and non-HLA genes . {The sequence data for the multiple haplotype comparisons within the class I region have been submitted to DDBJ/EMBL/GenBank under accession nos . AF029061, AF029062, and AB031005-AB031010 . Additional sequence data have been submitted to the DDBJ data library under accession nos . AB031005-AB03101 and AF029061-AF029062.}

Bratisl Lek Listy, 2000, 101(2), 78 - 84
{Continuous flow ventilatory support using a multijet insufflation catheter . Physical, mathematical and clinical prerequisites and principles}; Torok P et al.; The authors present theoretical principles of a new ventilatory support continuous flow ventilatory support (CFVS) with multijet insufflation catheter (MIC) . Theoretical part of the presented work reasons the need of this type of ventilatory support and explains basic mathematical and physiologic principles of described mechanical ventilation method and reveals the advantages of continuous flow ventilatory support with multijet insufflation catheter in comparison with terminal eye catheter . Physical and mathematical analysis on a model of lungs in static and dynamic conditions revealed that the difference in the value of maximal inspiratory pressure is significantly higher in the system with terminal eye catheter and confirmed that the CFVS application with multijet insufflation catheter is connected with minimal risk of barotrauma by gas flow up to 20-26 l/min . The paper concludes that continuous flow ventilatory support with multijet insufflation catheter is more efficient with the possibility of significantly higher gas flow application than with terminal eye catheter and without the risk of pressure rise in the airways and without rise of breathing work . (Fig . 10, Ref . 11.)

Arch Pharm (Weinheim), 2000 Sep, 333(9), 293 - 8
Evaluation of methylthio-, methylsulfinyl-, and methylsulfonyl-analogs of alkanes and alkanoic acids as cardiac inotropic and antifungal agents; Iqbal N et al.; A group of alkane and alkanoic acid compounds of general formula MeS(O)m(CH2)nR {m = 0-2; n = 1, 5, 13; R = Me, CO2H(Na)} were synthesized for evaluation as cardiac inotropic and antifungal agents . Inotropic activity was determined as the ability of the test compound to modulate in vitro guinea pig atrium contractility . The oxidation state of the S-atom was an important determinant of inotropic modulation since the thio (m = 0) analogs exhibited a positive inotropic effect . In contrast, the sulfinyl (m = 1) and sulfonyl (m = 2) analogs exhibited a negative inotropic effect . A pentyl spacer (n = 5) provided the largest positive or negative inotropic effect . The relative positive, and negative, inotropic potency orders with respect to the R-substituent were Me > or = CO2H, and CO2Na > or = Me, respectively . The most potent positive inotrope MeS(CH2)5Me (EC50 = 4.49 x 10(-6) M) could serve as a useful lead-compound for the design of a new class of positive inotropic agents . In a broad spectrum antifungal screen, the minimal inhibitory concentration (MIC) range for the five most active compounds was MeSO2(CH2)5Me (0.46-1.83 mM), MeS(CH2)13Me (0.31-1.23 mM), MeSO(CH2)13Me (< 0.009-1.87 mM), MeSO2(CH2)13Me (0.27-1.09 mM), and MeS(CH2)13CO2H (0.27-1.09 mM), relative to the reference drug Ampotericin B (< 0.0002-0.002 mM) . The most active antifungal agent MeSO(CH2)13Me was selective against C . guillermondi, C . neoformans, S . cerevisiae, and A . fumigatus (strain TIMM 1776).

J Biol Chem, 2001 Jan 19, 276(3), 1772 - 9 Epub 2000 Oct 18.
Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity; Wiedemann I et al.; Unlike numerous pore-forming amphiphilic peptide antibiotics, the lantibiotic nisin is active in nanomolar concentrations, which results from its ability to use the lipid-bound cell wall precursor lipid II as a docking molecule for subsequent pore formation . Here we use genetically engineered nisin variants to identify the structural requirements for the interaction of the peptide with lipid II . Mutations affecting the conformation of the N-terminal part of nisin comprising rings A through C, e.g . {S3T}nisin, led to reduced binding and increased the peptide concentration necessary for pore formation . The binding constant for the S3T mutant was 0.043 x 10(7) m(-1) compared with 2 x 10(7) m(-1) for the wild-type peptide, and the minimum concentration for pore formation increased from the 1 nm to the 50 nm range . In contrast, peptides mutated in the flexible hinge region, e.g . {DeltaN20/DeltaM21}nisin, were completely inactive in the pore formation assay, but were reduced to some extent in their in vivo activity . We found the remaining in vivo activity to result from the unaltered capacity of the mutated peptide to bind to lipid II and thus to inhibit its incorporation into the peptidoglycan network . Therefore, through interaction with the membrane-bound cell wall precursor lipid II, nisin inhibits peptidoglycan synthesis and forms highly specific pores . The combination of two killing mechanisms in one molecule potentiates antibiotic activity and results in nanomolar MIC values, a strategy that may well be worth considering for the construction of novel antibiotics.

Mycoses, 2000 Sep, 43(7-8), 309 - 12
In vitro susceptibilities of 11 clinical isolates of Exophiala species to six antifungal drugs; Meletiadis J et al.; The antifungal activities of miconazole, terbinafine, itraconazole, UR 9825, voriconazole and amphotericin B against 11 clinical isolates of Exophiala spp . were tested by the broth microdilution method . All drugs were very active against Exophiala spp. . The 90% minimal inhibitory concentration (MIC90) ranged from 0.125 to 1 microgram ml-1 . Terbinafine was the most active drug against Exophiala spinifera, Exophiala dermatitidis and Exophiala castellanii and seems to be a promising agent in the treatment of infections caused by these fungi.

Antimicrob Agents Chemother, 2000 Nov, 44(11), 3174 - 6
Postantibiotic leukocyte enhancement of meropenem against gram-positive and gram-negative strains; Novelli A et al.; The postantibiotic leukocyte enhancement (PALE) of meropenem in vitro in comparison with that of imipenem was evaluated with 24 recently isolated gram-positive and gram-negative strains . In general, pre-exposure to carbapenems (at four times the MIC for 2 h) led to increased polymorphonuclear cell phagocytic killing . The PALE of imipenem was generally significantly less than that observed with meropenem.

Antimicrob Agents Chemother, 2000 Nov, 44(11), 3133 - 6
Antibiotic susceptibility pattern of Mycobacterium marinum; Aubry A et al.; In vitro activities of 17 antibiotics against 53 clinical strains of Mycobacterium marinum, an atypical mycobacterium responsible for cutaneous infections, were determined using the reference agar dilution method . Rifampin and rifabutin were the most active drugs (MICs at which 90% of the isolates tested were inhibited {MIC(90)s}, 0.5 and 0.6 microgram/ml, respectively) . MICs of minocycline (MIC(90), 4 microgram/ml), doxycycline (MIC(90), 16 microgram/ml), clarithromycin (MIC(90), 4 microgram/ml), sparfloxacin (MIC(90), 2 microgram/ml), moxifloxacin (MIC(90), 1 microgram/ml), imipenem (MIC(90), 8 microgram/ml), sulfamethoxazole (MIC(90), 8 microgram/ml) and amikacin (MIC(90), 4 microgram/ml) were close to the susceptibility breakpoints . MICs of isoniazid, ethambutol, trimethoprim, azithromycin, ciprofloxacin, ofloxacin, and levofloxacin were above the concentrations usually obtained in vivo . For each drug, the MIC(50), geometric mean MIC, and modal MIC were very close, showing that all the strains had a similar susceptibility pattern . Percent agreement (within +/-1 log(2) dilution) between MICs yielded by the Etest method and by the agar dilution method used as reference were 83, 59, 43, and 24% for minocycline, rifampin, clarithromycin, and sparfloxacin, respectively . Reproducibility with the Etest was low, in contrast to that with the agar dilution method . In conclusion, M . marinum is a naturally multidrug-resistant species for which the agar dilution method is more accurate than the Etest for antibiotic susceptibility testing.

Diagn Microbiol Infect Dis, 2000 Oct, 38(2), 101 - 7
Susceptibility testing of voriconazole, fluconazole, itraconazole and amphotericin B against yeast isolates in a Turkish University Hospital and effect of time of reading; Uzun O et al.; Voriconazole is a promising azole effective against a variety of fungi, including yeasts . In this study, we tested in vitro activities of voriconazole, fluconazole, itraconazole and amphotericin B against some ATCC and reference strains and 250 clinical yeast isolates . We also evaluated the effect of time of reading on MIC results . Voriconazole was the most active agent against Candida and Trichosporon isolates, including the putatively fluconazole-resistant C . krusei (MIC(90) 0.25 microg/ml) and C . glabrata (MIC(90) 0.5 microg/ml) . Amphotericin B MICs were scattered in a considerably narrow range in both RPMI 1640 and Antibiotic Medium 3 . MICs at 24 hours and 48 hours were similar in general for all antifungals tested . The highest percentage of strains that showed 24-hour and 48-hour MICs within +/-1-log(2) dilution was observed for amphotericin B tested in RPMI (99%), and the lowest for amphotericin B tested in Antibiotic Medium 3 (80%) . In conclusion, voriconazole is very effective against a wide spectrum of Candida species and 24-hour readings could substitute 48-hour MIC evaluation.

Biochem Biophys Res Commun, 2000 Oct 22, 277(2), 394 - 400
The role of cysteine residues in tellurite resistance mediated by the TehAB determinant; Dyllick-Brenzinger M et al.; TehATehB is a tellurite (TeO(2-)(3)) resistance determinant found on the Escherichia coli chromosome . Normally silent, it specifies a minimal inhibitory concentration (MIC) of 2 microg K(2)TeO(3)/ml unless upregulated or present on a multicopy plasmid which results in an MIC of 128 microg/ml . Both TehA and TehB have three cysteine residues . Oligonucleotide site-directed mutagenesis was carried out to systematically replace all six cysteine residues by alaninies . The results showed that cysteine residues in both TehA and TehB play a role in tellurite resistance: A single cysteine change had no effect, however increasing combinations of two or three cysteine substitutions demonstrated strong phenotypic effects with minimal inhibitory concentrations ranging from 16-64 microg K(2)TeO(3)/ml . A cysteine-free mutant in which all six cysteine residues were replaced by alanines maintained a MIC of 16 microg/ml . Further investigations on the role of cysteines in resistance were studied using thiol reactive reagents on the soluble subunit TehB . These studies confirmed that TehB is a dimer and undergoes a conformational change with tellurite and S-adenosyl-l-methionine binding . Studies using native and SDS denaturing PAGE under reducing and oxidizing conditions suggested that a cysteine in TehB is involved in binding tellurite .

J Antimicrob Chemother, 2000 Oct, 46(4), 613 - 6
Clarithromycin resistance stability in Helicobacter pylori: influence of the MIC and type of mutation in the 23S rRNA; Alarcon T et al.; Thirty clarithromycin-resistant Helicobacter pylori strains (MIC range 8-64 mg/L) were subcultured in a drug-free medium and the MIC was determined every five passages to detect in vitro stability of resistance . Three out of the 30 (10%) lost their resistance after 10, 13 or 18 subcultures (MIC decrease from 8 to 0.008, from 16 to 0 . 064 and from 32 to 0.016 mg/L) . The effect of four macrolides at subinhibitory concentrations on the development of resistance was studied in H . pylori NCTC 11638 and TIGR 26695 . A change in the MIC was observed only when NCTC11638 was exposed to 0.5 x MIC of erythromycin for 20 days.

J Antimicrob Chemother, 2000 Oct, 46(4), 565 - 70
Activity of rifapentine and its metabolite 25-O-desacetylrifapentine compared with rifampicin and rifabutin against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M . bovis BCG; Rastogi N et al.; The in vitro activity of rifapentine and its metabolite, 25-O:-desacetylrifapentine, as compared with that of rifampicin and rifabutin, was determined against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M . bovis BCG . MICs were determined radiometrically and by the 1% proportional method using Middlebrook 7H11 agar . The bactericidal effect of the drugs was determined in parallel at selected concentrations . For drugsusceptible isolates of M . tuberculosis, the Bactec MICs of rifapentine and 25-O:-desacetylrifapentine were 0.03-0.06 mg/L and 0 . 125-0.25 mg/L, respectively . Similar MICs were obtained for M . africanum (0.03-0.125 and 0.125-0.50 mg/L, respectively), and M . bovis (0.063-0.25 and 0.125-1.0 mg/L, respectively), but MICs were considerably lower for M . bovis BCG (0.008-0.063 mg/L for rifapentine and 0.016-0.125 mg/L for its metabolite) . In general, MICs determined using 7H11 agar medium were usually one or two dilutions higher than those obtained using Bactec broth . When compared with rifampicin and rifabutin, the inhibitory activity of rifapentine for drug-susceptible isolates was roughly equal to that of rifabutin, and the inhibitory activity of 25-O:-desacetylrifapentine was comparable to that of rifampicin; however, rifapentine was somewhat more bactericidal than rifabutin at equal concentrations . Clinical isolates of M . tuberculosis with a high degree of resistance to rifampicin (MIC >/= 32 mg/L) were also highly resistant to rifabutin, rifapentine and 25-O:-desacetylrifapentine, although the MICs of rifabutin in this case were somewhat lower than the MICs of rifapentine.

Int J Food Microbiol, 2000 Sep 25, 60(2-3), 219 - 29
Inhibition of fungal growth on bread by volatile components from spices and herbs, and the possible application in active packaging, with special emphasis on mustard essential oil; Nielsen PV et al.; The effect of modified atmosphere packaging (MAP) on the most important spoilage fungi of bread was investigated . Penicillium commune, P . roqueforti, Aspergillus flavus and Endomyces fibuliger were able to grow at oxygen levels down to 0.03%, while the chalk mould E . fibuliger was capable of growing even in the presence of an oxygen absorber . High levels of carbon dioxide retarded growth but not completely . As an alternative to MAP active packaging (AP) using volatile essential oils (EO) and oleoresins (OL) from spices and herbs were tested against a range of fungi commonly found on bread . Concentrations of 1, 10 or 100 microl EO or OL were added to a filter paper placed in the lid of a Petri dish inoculated with one of the test fungi . The Petri dish was sealed hermetically to avoid the exchange of gases . Mustard essential oil showed the strongest effect . Cinnamon, garlic and clove also had high activity, while oregano oleoresin only inhibited growth weakly . Vanilla showed no inhibitory effect towards the tested microorganisms at the applied concentrations . A . flavus was more resistant than the other microorganisms while P . roqueforti was the most sensitive . Mustard essential oil was investigated in greater detail . The minimal inhibitory concentration (MIC) for the active component, allyl isothiocyanate (AITC), was determined for the same species and an additional three moulds and one yeast . MIC values ranged from 1.8 to 3.5 microg/ml gas phase . Results showed that whether AITC was fungistatic or fungicidal depended on its concentration, and the concentration of spores . When the gas phase contained at least 3.5 microg/ml, AITC was fungicidal to all tested fungi . Results of sensory evaluation showed, that hot-dog bread was more sensitive to AITC than rye bread . The minimal recognisable concentration of AITC was 2.4 microg/ml gas phase for rye bread and between 1.8 and 3.5 microg/ml gas phase for hot-dog bread . These findings showed that the required shelf-life of rye bread could be achieved by active packaging with AITC . Active packaging of hot-dog bread, may nevertheless require the additional effect of other preserving factors to avoid off-flavour formation

Eur J Clin Microbiol Infect Dis, 2000 Aug, 19(8), 593 - 601
Determinants for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients; Masia Canuto M et al.; A point prevalence study to document oral yeast carriage was undertaken . Risk factors for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients were investigated with a case-control design . Cases included all patients with fluconazole-resistant strains (MIC> or =64 microg/ml), and controls were those with susceptible (MIC< or =8 microg/ml) or susceptible-dependent-upon-dose (MIC 16-32 microg/ml) strains . One hundred sixty-eight Candida strains were isolated from 153 (88%) patients, 28 (16%) of whom had oropharyngeal candidiasis . Overall, 19 (12%) of the patients harbored at least one resistant organism (MIC > or = 64 microg/ml) . Among patients with resistant strains, tuberculosis (P<0.001), esophageal candidiasis (P = 0.001), clinical thrush (P<0.001), and a CD4 + cell count < 200/mm3 (P = 0.03) were more frequent . These patients had also been treated more commonly with antituberculous drugs (adjusted odds ratio {OR} 6.13; 95% confidence interval {CI} 2.11-17.80), ciprofloxacin (OR 6.0; 95% CI 1.23-29.26), fluconazole (OR 4.59; 95% CI 1.55-13.52), and steroids (OR 4.13; 95% CI 1.11-15.39) . Multivariate analysis showed that the determinants for fluconazole resistance were therapy with antituberculous drugs (OR 3.61; 95% CI 1.08-12.07; P=0.03) and one of the following: previous tuberculosis (OR 3.53; 95% CI 1.08-14.57; P=0.03) or fluconazole exposure (OR 3.41; 95% CI 1.10-10.54) . Findings from this study indicate that treatment with antituberculous drugs, previous tuberculosis, and fluconazole exposure are the strongest determinants for development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients.

Braz J Infect Dis, 2000 Apr, 4(2), 55 - 60
Antifungal susceptibility testing: progress and future developments; Pfaller MA; The establishment of a standardized broth reference method for antifungal susceptibility testing of yeasts has opened the door to a number of interesting and useful developments . The adaptation of the reference macrodilution method to a microdilution method has significantly increased the clinical utility of antifungal susceptibility testing, and both methods are now included in the NCCLS document M27-A . The publication of quality control limits for five antifungal agents, coupled with the establishment of interpretive MIC breakpoints for three agents, provides useful parameters to survey clinical isolates of Candida and other yeast species . Adaptations of the M27 microdilution method for testing molds has also proved feasible . These developments have made it possible for a number of recent studies designed to expand the capabilities of laboratories to perform antifungal susceptibility testing and to enhance our understanding of trends in antifungal susceptibility . The availability of reference methods also provides a useful touchstone for the development of commercial products that promise to be more user friendly and to further improve test standardization . Products in varying stages of development include two colorimetric microdilution methods (Sensititre and KPI) and the Etest stable gradient MIC method . Preliminary data indicate that these methods are viable alternatives to the reference method for testing of yeasts . Furthermore, Etest may also prove useful for testing molds . Future expectations for antifungal susceptibility testing includes improved ability to detect amphotericin B resistance, development of an NCCLS document for susceptibility testing of molds, and application of these methods for testing dermatophytes . Incorporation of antifungal susceptibility testing methods into the clinical trials of new antifungal agents will facilitate the establishment of clinical correlates and further enhance the clinical utility of antifungal susceptibility testing.

Avian Dis, 2000 Jul-Sep, 44(3), 490 - 7
The antifungal activity of natamycin toward molds isolated from commercially manufactured poultry feed; Brothers AM et al.; The antifungal activity of natamycin, a polyene antifungal compound, was evaluated on molds isolated from commercial poultry feed . The antifungal activity was measured by determination of the minimal inhibitory concentration (MIC) for natamycin on molds growing on semisolid microbiological medium (potato dextrose agar) containing pure natamycin at concentrations ranging from 0 to 200 mg/liter . Natamycin exhibited a high degree of antifungal activity against the 191 isolates of aspergilli used in this study, with average MIC values ranging from 5.08 to 40.1 mg/liter for Aspergillus fumigatus and Aspergillus parasiticus, respectively . Natamycin was also equally effective in inhibiting the growth of nonaflatoxigenic compared with aflatoxigenic isolates of Aspergillus flavus and A . parasiticus . Natamycin was also efficacious against molds other than aspergilli, with MIC values ranging from 2.15 to 5.80 mg/liter for Paecilomyces and Rhizopus spp., respectively . Natamycin exhibited apparent sporicidal activity against spores of toxigenic strains of Fusarium moniliforme and A . parasiticus but not Penicillium rubrum . This sporicidal activity was evident only when spores were exposed to an in vitro concentration of natamycin of 25 mg/liter or higher for a period of time of at least 12 hr . The growth inhibiting activity of natamycin was more pronounced compared with the sporicidal activity.

Indian J Med Res, 2000 Jul, 112, 15 - 20
The effects of clofazimine, niclosamide & amphotericin B, on electron transport of Leishmania donovani promastigotes; Datta G et al.; BACKGROUND & OBJECTIVES: The study was undertaken to explore the locus of interaction of clofazimine and niclosamide which showed substantial growth inhibition property in Leishmania donovani promastigotes . METHODS: The uptake of final electron acceptor oxygen and 2,6-dichlorophenolindophenol (DCPIP) reduction in the electron transport chain were measured by constant volume Warburg respirometer and monitoring absorbance at 600 nm, respectively . Irreversibility of O2 uptake inhibition by clofazimine and niclosamide was determined by dilution of cell suspension followed by centrifugation . RESULTS: Clofazimine and niclosamide showed their minimum inhibitory concentration (MIC) at 33 and 150 micrograms/ml, respectively . Oxygen uptake inhibition by clofazimine and niclosamide was not reversed by removal of the drug by centrifugation . Rotenone, a potent inhibitor of mammalian electron transport chain showed no inhibition on the electron transport chain of L . donovani promastigotes . Cyanide at 1 mM concentration showed partial inhibition in L . donovani promastigotes . Oxygen uptake and DCPIP reduction by L . donovani promastigotes were highly sensitive to sulphhydryl group inhibitors . Strong inhibition of oxygen uptake (80-100%) by L . donovani promastigotes was achieved by clofazimine, niclosamide and amphotericin B . Amphotericin B failed to inhibit DCPIP reduction by L . donovani promastigotes, whereas DCPIP reduction was inhibited by clofazimine and niclosamide, respectively . INTERPRETATION & CONCLUSION: DCPIP reduction was mediated by transplasma membrane electron transport as evidenced by its inhibition with membrane impermeable quinone 1,2-naphthoquinone-4-sulphonic acid (NQSA) . Transplasma membrane electron transport requires b-cytochromes and sulphhydryl groups for its function and was inhibited by clofazimine and niclosamide.

Am J Surg, 2000 Jun, 179(6), 436 - 40
Intermittent and continuous ceftazidime infusion for critically ill trauma patients; Hanes SD et al.; BACKGROUND: The adequacy of intermittent and continuous infusion ceftazidime for the treatment of nosocomial pneumonia in critically ill trauma patients was assessed by analyzing ceftazidime pharmacokinetics in relation to the minimum inhibitory concentration (MIC) and treatment outcome . METHODS: Serial blood samples were obtained during ceftazidime therapy in 31 trauma patients . Ceftazidime pharmacokinetics were compared with that of previously studied healthy volunteers . Ceftazidime pharmacokinetics were analyzed according to the time above the MIC and treatment outcome . RESULTS: Critically ill trauma patients had a significantly increased volume of distribution and clearance (0.32 +/- 0.14 L/kg and 2.35 +/- 0.89 mL . min(-1) . kg(-1), respectively) compared with healthy volunteers (0.21 +/- 0.03 and 1.58 +/- 0.23 mL . min(-1) . kg(-1)) . The time above the MIC was >/=92% of the dosing interval for all patients and treatment outcomes were similar between the two treatment groups . CONCLUSIONS: Ceftazidime pharmacokinetics are significantly altered in critically ill trauma patients . Both intermittent and continuous ceftazidime regimens were equally effective for the treatment of nosocomial pneumonia caused by less virulent bacteria.

J Nat Prod, 2000 Sep, 63(9), 1210 - 3
Known and novel terpenes from Buddleja globosa displaying selective antifungal activity against dermatophytes; Mensah AY et al.; Lipophilic extracts of the stembark of Buddleja globosa were found to have antifungal activity at 125 microg/mL against three dermatophytic fungal species but had no activity at 1000 microg/mL against four other fungal species or two yeast species . Bioassay-guided fractionation of Si gel column eluates using the sensitive fungal species resulted in active fractions from which were isolated five compounds that were characterized by spectroscopic methods as one novel and four known compounds . The known compounds were the diterpene buddlejone (1), the bisditerpene maytenone, and the two sesquiterpenes buddledin A and buddledin B, while the novel compound was characterized as the diterpene deoxybuddlejone (2) . The minimum inhibitory concentration of all the compounds was determined against all the microorganisms under test, and buddledins A and B were shown to exhibit the greatest antifungal activity, with values of 43 microM and 51 microM, respectively, against the sensitive fungi Trichophyton rubrum, Tricophyton interdigitale, and Epidermophyton floccosum.

Klin Padiatr, 2000 Jul-Aug, 212(4), 185 - 8
Primitive neuroectodermal tumor of the pancreas . An extremely rare tumor . Case report and review of the literature; Bulchmann G et al.; Peripheral primitive neuroectodermal tumor (PPNET) is a malignant neoplasm of the peripheral nervous system and soft tissues . Representing the fourth case published we herein report a PPNET arising in the pancreas of a six year old girl . She presented with severe anemia due to ulcerative tumor growth and hemorrhage into the duodenum . From the first biopsy pancreatoblastoma was considered as histological diagnosis . Therefore pancreato-duodenectomy was successfully performed . Immunohistochemically, the tumor cells were positive for cytokeratines and several neuronal markers . Due to focal membranous staining for MIC-2 gene product and rosettes in one lymph node metastasis the diagnosis had to be altered into PPNET . This was confirmed by cytogenetic analysis . We conclude that the interpretation of histologic sample excisions from pediatric pancreatic neoplasms may be difficult and that PPNET should be included in the differential diagnosis.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2709 - 14
Epidemiological survey of amoxicillin-clavulanate resistance and corresponding molecular mechanisms in Escherichia coli isolates in France: new genetic features of bla(TEM) genes; Leflon-Guibout V et al.; Amoxicillin-clavulanate resistance (MIC >16 microg/ml) and the corresponding molecular mechanisms were prospectively studied in Escherichia coli over a 3-year period (1996 to 1998) in 14 French hospitals . The overall frequency of resistant E . coli isolates remained stable at about 5% over this period . The highest frequency of resistant isolates (10 to 15%) was observed, independently of the year, among E . coli isolated from lower respiratory tract samples, and the isolation rate of resistant strains was significantly higher in surgical wards than in medical wards in 1998 (7.8 versus 2.8%) . The two most frequent mechanisms of resistance for the 3 years were the hyperproduction of the chromosomal class C beta-lactamase (48, 38.4, and 39.7%) and the production of inhibitor-resistant TEM (IRT) enzymes (30.4, 37.2, and 41.2%) . By using the single-strand conformational polymorphism-PCR technique and sequencing methods, we determined that 59 IRT enzymes corresponded to previously described IRT enzymes whereas 8 were new . Three of these new enzymes derived from TEM-1 by only one amino acid substitution (Ser130Gly, Arg244Gly, and Asn276Asp), whereas three others derived by two amino acid substitutions (Met69Leu and Arg244Ser, Met69Leu and Ile127Val, and Met69Val and Arg275Gln) . The two remaining new IRTs showed three amino acid substitutions (Met69Val, Trp165Arg, and Asn276Asp and Met69Ile, Trp165Cys, and Arg275Gln) . New genetic features were also found in bla(TEM) genes, namely, bla(TEM-1B) with either the promoters Pa and Pb, P4, or a promoter displaying a C-->G transversion at position 3 of the -35 consensus sequence and new bla(TEM) genes, notably one encoding TEM-1 but possessing the silent mutations originally described in bla(TEM-2) and then in some bla(TEM)-encoding IRT enzymes.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2623 - 9
Evaluation of nitrofurantoin combination therapy of metronidazole-sensitive and -resistant Helicobacter pylori infections in mice; Jenks PJ et al.; The main objectives of this study were to determine whether the nitroreductase enzyme encoded by the rdxA gene of Helicobacter pylori was responsible for reductive activation of nitrofurantoin and whether a triple-therapy regimen with nitrofurantoin was able to eradicate metronidazole-sensitive and -resistant H . pylori infections from mice . The susceptibilities to nitrofurantoin of parent and isogenic rdxA mutant strains (three pairs), as well as a series of matched metronidazole-sensitive and -resistant strains isolated from mice (30) and patients (20), were assessed by agar dilution determination of the MIC . Groups of mice colonized with the metronidazole-sensitive H . pylori SS1 strain or a metronidazole-resistant rdxA SS1 mutant were treated with either metronidazole or nitrofurantoin as part of a triple-therapy regimen . One month after the completion of treatment the mice were sacrificed and their stomachs were cultured for H . pylori . The nitrofurantoin MICs for all strains tested were between 0.5 and 4.0 microg/ml . There was no significant difference between the susceptibility to nitrofurantoin of the parental strains and those of respective rdxA mutants or between those of matched metronidazole-sensitive and -resistant H . pylori isolates . The regimen with metronidazole eradicated infection from all eight SS1-infected mice and from one of eight mice inoculated with the rdxA mutant (P < or =0.001) . The regimen with nitrofurantoin failed to eradicate infection from any of the six SS1-infected mice (P < or =0.001) and cleared infection from one of seven mice inoculated with the rdxA mutant . These results demonstrate that, despite the good in vitro activity of nitrofurantoin against H . pylori and the lack of cross-resistance between metronidazole and nitrofurantoin, eradication regimens involving nitrofurantoin are unable to eradicate either metronidazole-sensitive or -resistant H . pylori infections from mice.

Antimicrob Agents Chemother, 2000 Oct, 44(10), 2619 - 22
Clarithromycin-resistant mycobacterium avium is still susceptible to treatment with clarithromycin and is virulent in mice; Bermudez LE et al.; Resistance to clarithromycin in breakthrough Mycobacterium avium complex (MAC) isolates typically occurs 3 to 4 months after the initiation of monotherapy in bacteremic AIDS patients . It has been suggested that continuation of clarithromycin therapy still results in clinical and microbiological improvement . To study this paradox, C57BL/6 beige mice were infected with a clarithromycin-resistant (MIC, > or =128 microg/ml) strain of MAC 101 (CLA-R MAC 101) and treated with 200 mg of clarithromycin per kg of body weight/day alone or in combination with ethambutol (100 mg/kg/day) for 2 weeks . Mice infected with a clarithromycin-susceptible strain of MAC 101 had bacterial loads reduced by 90% in the liver and 91% in the spleen (P<0.05, compared with the control) . Clarithromycin treatment of CLA-R MAC 101 resulted in a 65% reduction of bacterial loads in the liver (P = 0.009) and a 71% reduction in the spleen (P = 0.009), compared with the results for the untreated control . CLA-R MAC 101 and MAC 101 (isogenic strains) had comparable growth rates in murine tissue, ruling out a loss of virulence of CLA-R MAC 101 . Strains of MAC currently defined as macrolide resistant may still respond to treatment with an agent such as clarithromycin within infected tissues.

J Bacteriol, 2000 Oct, 182(19), 5479 - 85
Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides; Boshoff HI et al.; A pyrazinamidase (PZase)-deficient pncA mutant of Mycobacterium tuberculosis, constructed by allelic exchange, was used to investigate the effects of heterologous amidase gene expression on the susceptibility of this organism to pyrazinamide (PZA) and related amides . The mutant was highly resistant to PZA (MIC, >2,000 microg/ml), in accordance with the well-established role of pncA in the PZA susceptibility of M . tuberculosis (A . Scorpio and Y . Zhang, Nat . Med . 2:662-667, 1996) . Integration of the pzaA gene encoding the major PZase/nicotinamidase from Mycobacterium smegmatis (H . I . M . Boshoff and V . Mizrahi, J . Bacteriol . 180:5809-5814, 1998) or the M . tuberculosis pncA gene into the pncA mutant complemented its PZase/nicotinamidase defect . In both pzaA- and pncA-complemented mutant strains, the PZase activity was detected exclusively in the cytoplasm, suggesting an intracellular localization for PzaA and PncA . The pzaA-complemented strain was hypersensitive to PZA (MIC, </=10 microg/ml) and nicotinamide (MIC, >/=20 microg/ml) and was also sensitive to benzamide (MIC, 20 microg/ml), unlike the wild-type and pncA-complemented mutant strains, which were highly resistant to this amide (MIC, >500 microg/ml) . This finding was consistent with the observation that benzamide is hydrolyzed by PzaA but not by PncA . Overexpression of PzaA also conferred sensitivity to PZA, nicotinamide, and benzamide on M . smegmatis (MIC, 150 microg/ml in all cases) and rendered Escherichia coli hypersensitive for growth at low pH.

Clin Infect Dis, 2000 Aug, 31 Suppl 2, S40 - 4
Clinical pharmacology of the fluoroquinolones: studies in human dynamic/kinetic models; Schentag JJ; Traditional antibiotic dosage adjustments, compensate only for disease-induced changes in the serum concentration profile . Dosage adjustments tend to be effective when a well-defined range of concentration is associated with efficacy . However, the bacterial target of antibiotic action-minimum inhibitory concentration (MIC) is variable, because even susceptible bacteria may differ greatly in their antibiotic susceptibility . Newly developed computerized methods for the quantitation of susceptibility allow for testing of integrated kinetic-susceptibility models in patients . Our attention has focused on fluoroquinolones, since they are relatively nontoxic and provide the necessary dosage range needed to elucidate correlations between concentration and response . Studies of patients with nosocomial gram-negative pneumonia reveal that the best correlation parameters of favorable outcome are approximately 80% of time over MIC and 24-h area under the time-concentration curve (AUC)-to-MIC values >125.

J Antimicrob Chemother, 2000 Sep, 46(3), 423 - 8
In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts; Winkler H et al.; In order to combine the effects of bone repair and eradication of infection, with both Gram-positive and Gram-negative pathogens, the behaviour of a compound of bone graft and antibiotics was investigated . Samples of human and bovine bone, cancellous and cortical, were processed and incubated with vancomycin and tobramycin, respectively . The compound was placed in 5% human albumin and the surrounding liquid was exchanged completely every 24 h . Concentrations of antibiotics in the fluid were measured over < or = 28 days using high pressure liquid chromatography and a bioassay . All tested combinations eluted mainly in the initial phase with a logarithmic decrease over the testing period . The concentration of antibiotics in the albumin was well above the MIC for common pathogens throughout the investigation in all tested specimens . The highest initial concentrations were measured in the compound of bovine bone together with vancomycin (24395.8 +/- 1138.9 mg/L), decreasing to 9.02 +/- 1.3 mg/L after 11 exchanges . Human and bovine bone did not have significantly different properties . The storage capability of cortical bone was generally lower than that of cancellous bone . Tobramycin concentrations were significantly lower in the initial phase; however, it eluted more steadily and over a longer period, so that from day 6 onwards, its concentration was greater than that of vancomycin . After 28 days, the tobramycin concentration was 18.09 +/- 2.46 mg/L (bovine cancellous bone) . In conclusion, bone, if processed adequately, is an excellent carrier for vancomycin and tobramycin . Cortical bone is as suitable as cancellous bone . The pharmacokinetics of human and bovine bone are comparable . Using an antibiotic-graft compound, eradication of pathogens and grafting of bony defects may be accomplished in a one-stage procedure.

J Clin Microbiol, 2000 Sep, 38(9), 3359 - 61
In vitro susceptibility testing of filamentous fungi: comparison of Etest and reference microdilution methods for determining itraconazole MICs; Pfaller MA et al.; The performance of the Etest for itraconazole susceptibility testing of 50 isolates of filamentous fungi was assessed in comparison with the National Committee for Clinical Laboratory Standards (NCCLS) proposed standard microdilution broth method . The NCCLS method employed RPMI 1640 broth medium, and MICs were read after incubation for 48 h at 35 degrees C . Etest MICs were determined with RPMI agar containing 2% glucose and with Casitone agar and were read after incubation for 24 h (Aspergillus spp . and Rhizopus spp.) and 48 h (all species except Rhizopus spp.) at 35 degrees C . The isolates included Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus terreus, Fusarium spp., Pseudallescheria boydii, Rhizopus spp., Paecilomyces variotii, and an Acremonium sp . Overall agreement between Etest and microdilution MICs was 96% with RPMI agar and 80% with Casitone agar . The agreement was 100% for all species except Rhizopus spp . (83%) and Paecilomyces varioti (0%) with RPMI agar . When Casitone agar was used, the agreement ranged from 50% with Rhizopus spp . to 100% with Fusarium spp., P . boydii, P . varioti, and an Acremonium sp . Notably, for Aspergillus spp., the agreement between itraconazole Etest MICs read at 24 h and reference microdilution MICs read at 48 h was 100% with both RPMI and Casitone agar . Both media supported the growth of all filamentous fungi tested . Where a discrepancy was observed between Etest and the reference method, the Etest MIC was generally higher . The Etest method using RPMI agar appears to be a useful method for determining itraconazole susceptibilities of Aspergillus spp . and other filamentous fungi.

Bioorg Med Chem Lett, 2000 Aug 21, 10(16), 1893 - 5
3-Phenyl-5-methyl-2H,5H-furan-2-ones: tuning antifungal activity by varying substituents on the phenyl ring; Pour M et al.; A series of racemic 3-phenyl-5-methyl-2H,5H-furan-2-ones related to a natural product, (-)incrustoporine, was synthesized, and their antifungal activity evaluated . The key structural feature, furanone ring, was closed via H2SO4-mediated cyclization of 2-phenylpent-4-enoic acids . The compounds displayed antifungal activity, especially against filamentous fungi . Expressed as the minimum inhibition concentration (MIC) in micromol/L, the activity of the most promising derivative against Absidia corymbifera matched that of ketoconazole (31.25 micromol/L) . In terms of microg/mL, the substance was more active (7.6 microg/mL) than this standard antifungal drug (16.6 microg/mL).

J Antimicrob Chemother, 2000 Aug, 46 Suppl B, 9 - 23
MYSTIC (Meropenem Yearly Susceptibility Test Information Collection): a global overview; Turner PJ; The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) is a global, multicentre surveillance study that compares the activity of meropenem in centres that are prescribers with that of imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin . Of the 46 centres (intensive care units, cystic fibrosis units, neutropenia units and general wards) contributing to this study, 29 were in Europe, 14 in the Americas and three in the Middle East and Asia . The results for the most common isolates obtained in the first year of the study from these three regions show that meropenem has a broad spectrum of activity and potency in these centres, with 89% of the 6890 strains tested having an MIC 4 mg/L . The overall susceptibility was lower for the comparator antibiotics . There was evidence in all regions of strains producing beta-lactamases and other resistance mechanisms against the other beta-lactams tested, fluoroquinolones and aminoglycosides . Future years' results from this surveillance study will show whether meropenem will continue to exhibit such activity.

J Med Chem, 2000 Aug 24, 43(17), 3304 - 14
A new class of antituberculosis agents; Jones PB et al.; Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause tuberculosis and leprosy . Inhibition of fatty acid synthesis or elongation is a strategy demonstrated to be clinically effective against M . tuberculosis . A new class of compounds designed to inhibit the beta-ketoacyl synthase reaction of fatty acid synthesis has been developed . Of >30 compounds described, the most active were acetamides containing alkylsulfonyl substituents . Inhibitory activities were acutely sensitive to net charge, chain length, and degree of unsaturation . The most active compound 5 (alkyl = C(10)) contained a single methylene spacer between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 microg/mL, comparable to first-line antituberculosis drugs . These compounds are species-specific, exhibiting no significant activity against bacterial species other than M . tuberculosis and closely related strains . The synthesis, biological activity, and specificity of these compounds are described.

Biol Pharm Bull, 2000 Aug, 23(8), 995 - 7
Antifungal activity of Hinokitiol-related compounds on wood-rotting fungi and their insecticidal activities; Inamori Y et al.; Hinokitiol (beta-thujaplicin), beta-dolabrin and gamma-thujaplicin isolated from Thujopsis dolabrata SIEB . et ZUCC var hondai MAKINO showed antifungal activities against all of the wood-rotting fungi examined . The antifungal activity of three compounds on Daedalea dickinsii IFO-4979 was especially strong, their minimum inhibitory concentration (MIC) values being 0.2 microg/ml . Their antifungal activities on D . dickinsii IFO-4979 were as high as that of amphotericin B used as a positive control . Three compounds had strong insecticidal activities on Tyrophagus putrescentiae {50%-lethal concentration (LC50 : g/m2) 0.25 in hinokitiol, 0.02 in beta-dolabrin and gamma-thujaplicin . Their insecticidal activities were higher than that of N,N-diethyl-m-toluamide (DEET, LC50 : 1.46 g/m2) used as a positive control . Three compounds also showed strong insecticidal activity on Coptotermes formosanus {LC50 (g/m2) 0.07 in hinokitiol, 0.05 in beta-dolabrin and gamma-thujaplicin}, although their insecticidal activities were much lower than that of commercial chloropyrifos (LC50 : 0.00016 g/m2).

J Laryngol Otol, 2000 Jun, 114(6), 432 - 6
Burow's solution in the treatment of active mucosal chronic suppurative otitis media: determining an effective dilution; Thorp MA et al.; Burow's solution (13 per cent aluminium acetate) has been found to inhibit in vitro the growth of most commonly occurring bacteria found in the discharging ear . An in vitro study has shown that the minimum inhibitory concentration of Burow's solution for these organisms lies between a 1:80 and a 1:160 dilution . This paper reports on a clinical trial that incorporated 67 discharging ears to establish the most effective strength of aluminium acetate solution . There was no statistical difference in the effectiveness of full strength Burow's solution compared to 3.25 per cent aluminium acetate solution (a quarter strength Burow's solution) . Response rates of 80.8 per cent and 75 per cent respectively following a two-week treatment period were achieved using these two solutions . A 1.3 per cent aluminium acetate solution (1/10 strength Burow's solution) was found to be markedly inferior . Bacteriological and audiological profiles were recorded for each patient.

Biochemistry, 2000 Aug 22, 39(33), 10177 - 88
RecA protein promotes strand exchange with DNA substrates containing isoguanine and 5-methyl isocytosine; Rice KP et al.; The Escherichia coli RecA protein pairs homologous DNA molecules and promotes DNA strand exchange in vitro . We have examined DNA strand exchange between a 70 nucleotide ssDNA fragment and a 40 bp duplex, in which all G and C residues (at 18 positions distributed throughout the 40 bp exchanged region) were replaced with the nonstandard nucleosides 2'-deoxyisoguanosine (iG) and 2'-deoxy-5-methylisocytidine (MiC), respectively . We demonstrate that the nonstandard oligonucleotides are substrates for the RecA protein, permitting DNA strand exchange in vitro at a rate and efficiency comparable to exchange with normal DNA substrates . This observation provides an expanded experimental basis for discussions of potential roles for iG and MiC in a genetic code . Experiments of this type also provide another avenue for exploring RecA-facilitated DNA pairing mechanisms.

J Hypertens, 2000 Aug, 18(8), 1019 - 23
Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients; Januszewicz A et al.; BACKGROUND: Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma . Germline mutations identified recently in MEN 2 can be revealed by genetic screening . OBJECTIVE: To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma . DESIGN AND METHODS: We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma . A pentagastrin test and other biochemical studies were performed in all patients . SETTING: Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany . PARTICIPANTS: Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland . The other 85 patients did not respond to the written invitation . MAIN OUTCOME MEASURES: The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma . RESULTS: Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%) . All carriers had mutation of exon 11, codon 634: TGC to CGC . In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated . Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml . Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg . Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied . CONCLUSIONS: Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene . These patients should undergo clinical screening for MEN 2 . In addition, genetic studies can be useful for the screening of the families of the carriers.

Schweiz Med Wochenschr, 2000 Jul 11, 130(27-28), 1013 - 26
Endocarditis prophylaxis revisited: experimental evidence of efficacy and new Swiss recommendations . Swiss Working Group for Endocarditis Prophylaxis; Moreillon P; Because of its severity, it is agreed that infectious endocarditis should be prevented whenever possible . Determining adequate prophylactic measures involves establishing (a) the patients at risk, (b) the procedures that might provoke bacteraemia, (c) the most effective prophylactic regimen, and (d) a balance between the risks of side effects from prophylaxis and of developing infectious endocarditis . Patients at risk and procedures inducing bacteraemia have been identified by clinical studies . On the other hand, the efficacy of prophylactic antibiotics has been based on animal studies . Randomised, placebo-controlled studies do not exist in humans because they would require large patient numbers and would raise ethical issues due to the severity of the disease . Case-control studies have indicated that infectious endocarditis prophylaxis is effective, but prevents only a limited number of cases . Animal experiments have revealed several key issues for human application . First, antibiotics do not prevent the early stages of valve colonisation, but rather kill the microorganisms after their attachment to the cardiac lesions . Second, the duration of antibiotic presence in the serum is critical . Under experimental conditions, the drugs must remain above their minimal inhibitory concentration for the organisms for > or = 10 h, to allow time for bacterial clearance from the valves . Third, antibiotic-induced killing is not the only mechanism allowing bacterial clearance . Other factors, such as platelet microbicidal proteins, may act in concert with the drugs to sterilise the lesions . Recommendations for prophylaxis have recently been revised in Europe and the USA . New information has improved the definition of groups at risk . Since most cases of infectious endocarditis are not preceded by medical procedures, primary prevention of infectious endocarditis should target infected foci responsible for spontaneous bacteraemia (e.g . poor dental hygiene) . The purpose of this article is to update the existing recommendations in Switzerland, under the perspective of changing epidemiology, the availability of new drugs, and harmonisation with recommendations in other countries.

Antimicrob Agents Chemother, 2000 Sep, 44(9), 2567 - 8
In vitro activities of six fluoroquinolones against 250 clinical isolates of Mycobacterium tuberculosis susceptible or resistant to first-line antituberculosis drugs; Ruiz-Serrano MJ et al.; Two hundred fifty isolates of Mycobacterium tuberculosis were evaluated for susceptibility to ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin, trovafloxacin, and gemifloxacin (SB-265805) . Levofloxacin, ciprofloxacin, and grepafloxacin showed the greatest activity (MIC for 90% of strains tested {MIC(90)} 1 microg/ml), although ofloxacin also showed good activity, with an MIC(90) of 2 microg/ml . Trovafloxacin and gemifloxacin showed lower in vitro activity, with MIC(90)s of 64 and 8 microg/ml, respectively.

Antimicrob Agents Chemother, 2000 Sep, 44(9), 2518 - 20
In vitro activities of a new ketolide, ABT-773, alone and in combination with amoxicillin, metronidazole, or tetracycline against Helicobacter pylori; Pendland SL et al.; The in vitro activity of ABT-773, a new ketolide, was compared with those of clarithromycin, amoxicillin, metronidazole, and tetracycline against 15 strains of Helicobacter pylori . The MIC of ABT-773 at which 90% of isolates were inhibited was 0.25 microg/ml, which was 3 dilutions higher than that of the most active agent, clarithromycin . Synergy and antagonism were not seen with any combinations . Additive activity was seen with tetracycline, metronidazole, and amoxicillin in 100, 60, and 40% of the combinations, respectively.

Antimicrob Agents Chemother, 2000 Sep, 44(9), 2498 - 502
In vitro antiproliferative effects and mechanism of action of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi; Urbina JA et al.; We describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease in Latin America . The compound was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the reference compound ketoconazole . At that MIC, growth arrest coincided with depletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24-ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry . This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14alpha demethylase, as seen with other azole derivatives . The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine . The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37 degrees C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole . The results showed that UR-9825 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.

Antimicrob Agents Chemother, 2000 Sep, 44(9), 2333 - 40
Pharmacokinetics-pharmacodynamics of a sordarin derivative (GM 237354) in a murine model of lethal candidiasis; Aviles P et al.; Sordarins are a new class of antifungal agents which selectively inhibit fungal protein synthesis (FPS) by impairing the function of elongation factor 2 . The present study investigates possible correlations between sordarin pharmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose selection in the first study of efficacy in humans . A significant correlation between PK parameters and the in vivo activity of GM 237354, taken as a representative FPS inhibitor, was demonstrated in a murine model of lethal systemic candidiasis . Area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C(max)) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in healthy animals (no significant PK changes with infection were observed for other sordarin derivatives) . These results have been used to simulate PK profiles obtained after several doses and/or schedules in animal therapy . A PK-pharmacodynamic (PD) parameter such as the time that serum drug concentrations remain above the MIC (t > MIC) was also determined . Treatment efficacies were evaluated in terms of the area under the survival time curve (AUSTC), using Kaplan-Meier survival analysis and in terms of kidney fungal burden (log CFU/gram) after s.c . doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg) . The results show all treatments to significantly prolong survival versus that of infected and nontreated controls (P < 0.05) . Relationships between simulated PK and PK-PD parameters and efficacy were explored . A good correlation independent of the dosing interval was observed with AUC (but not C(max) or t > MIC) and both AUSTC and kidney burden . Following repeated dosing every 8 h, AUC(50) (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 microg . h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid E(max) and an inhibitory sigmoid E(max) PK-PD model, respectively . For an efficacy target of 90% survival, AUC was predicted as 67 microg . h/ml . We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research . Moreover, the results obtained with this approach could be successfully applied to clinical studies.

Br J Dermatol, 2000 Aug, 143(2), 324 - 9
The A5.1 allele of the major histocompatibility complex class I chain-related gene A is associated with psoriasis vulgaris in Chinese; Cheng L et al.; BACKGROUND: Recent studies have demonstrated an association of a polymorphic (GCT)n triplet repeat in the transmembrane (TM) region of the major histocompatibility complex (MHC) class I chain-related gene A (MICA), one of the MHC class I chain-related (MIC) family members, with some autoimmune diseases, including Behcet's disease, acute anterior uveitis, Takayasu's arteritis and others . OBJECTIVES: The aim of this study was to examine whether the MICA gene is associated with psoriasis vulgaris (PS) in Chinese . PATIENTS AND METHODS: The (GCT)n polymorphism of the MICA gene was investigated in 200 healthy Chinese of Han origin and 300 patients with PS by polymerase chain reaction amplification and denaturing polyacrylamide gel electrophoresis . RESULTS: Five alleles, namely A4, A5, A6, A9 and A5.1 were found in both groups . Comparison of the data from both groups revealed that the A5.1 allele was present at a significantly higher frequency in the patient group (41.5%) than in the control group (23.0%) (Pc < 0.0001, Pc means the probability of a comparison with the control group) . The frequency of A5.1-positive cases was also significantly increased in the patient group (68.0%) as compared with the controls (38.0%) (Pc < 0.0001) . Furthermore, the carrier frequency of A5.1-positive was significantly increased in psoriatic patients with a positive family history and with early onset as compared with sporadic cases (Pc = 0.0005) and with late onset PS (Pc = 0.002) . CONCLUSIONS: These results suggest that the MICA gene may be associated with the development of PS in Chinese.

Int J Tuberc Lung Dis, 2000 Aug, 4(8), 765 - 70
rpoB mutations as an epidemiologic marker in rifampin-resistant Mycobacterium tuberculosis; Chaves F et al.; SETTING: Cases of rifampin-resistant Mycobacterium tuberculosis from the prison population in Madrid and from the general population in Spain . OBJECTIVE: To identify the rpoB mutations associated with resistance to rifampin and to investigate rpoB genotyping as an epidemiological marker in rifampin-resistant M . tuberculosis . DESIGN: Twenty-nine rifampin-resistant clinical isolates of M . tuberculosis, 15 obtained from the prison population in Madrid and 14 from the general population in Spain, were characterized by sequence analysis of the 81-bp core region of the rpoB gene and IS6110 DNA fingerprinting . RESULTS: All the isolates had mutations in rpoB, with those in codon 531 accounting for 41% of the total . Twenty-three (79%) isolates were highly resistant to rifampin (minimum inhibitory concentration > or = 64 mg/L) . Nineteen different IS6110 fingerprints were observed: one was shared by seven isolates, one by three, two by two, and 15 were unique . Two IS6110 clusters could be divided into subclusters on the basis of rpoB analysis . Epidemiologic links were identified among patients whose isolates had identical IS6110 patterns and rpoB genotypes, but not between those with identical IS6110 patterns and different rpoB genotypes . CONCLUSION: Characterization of rpoB mutations can provide information about susceptibility to rifampin and be a useful epidemiological tool for discrimination of rifampin-resistant strains of M . tuberculosis with identical IS6110 fingerprints.

Ther Drug Monit, 2000 Aug, 22(4), 386 - 91
Ciprofloxacin disposition in elderly patients with LRTI being treated with sequential therapy (200 mg intravenously twice daily followed by 500 mg per os twice daily): comparative pharmacokinetics and the role of therapeutic drug monitoring; Pea F et al.; Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI) . The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch i.v./os regimen of ciprofloxacin (200 mg i.v . bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI . The pharmacokinetic study was performed on a cohort of 17 elderly inpatients . Blood samples were collected in steady state conditions at appropriate intervals . Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package . The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower Cmax after i.v . administration and higher CL both after i.v . and oral administration) . Cmax after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 +/- 0.9 mg/L vs 2.6 +/- 1.0 mg/L; p = 0.054) . The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid i.v . administration (AUC(0-tau) 11.4 +/- 4.3 mg/L x h vs 5.5 +/- 1.8 mg/L x h) . The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microorganisms (MIC < 0.1 mg/L) . In fact, because the peak serum level to MIC ratio (Cmax/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC24h/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg i.v . bid regimen and a cost-effective treatment of LRTI . However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h i.v . and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-tau) or at least of Cmax should be performed to individualize therapy in this subpopulation.

Can J Microbiol, 2000 Aug, 46(8), 753 - 8
Streptomyces halstedii K122 produces the antifungal compounds bafilomycin B1 and C1; Frandberg E et al.; Streptomyces halstedii K122 was previously found to produce antifungal compounds on solid substrates that inhibit radial growth of fungi among Ascomycetes, Basidiomycetes, Deuteromycetes, Oomycetes, and Zygomycetes, and strongly affected hyphal branching and morphology . During growth of S . halstedii K122 in submerged culture, no antifungal activity could be detected . However, cultivation of S . halstedii in thin (1 mm) liquid substrate layers in large surface-area tissue culture flasks caused intense growth and sporulation of S . halstedii K122, and the biologically active compounds could be extracted from the mycelium with methanol . Antifungal compounds were purified using C18 solid phase extraction and silica gel column chromatography, and identified as bafilomycins B1 and C1, using 2D NMR and FAB MS . Production of bafilomycins, which are specific inhibitors of vacuolar ATPases, has not been reported from S . halstedii previously . Minimum inhibitory concentrations (MIC) of bafilomycins B1 and C1, amphotericin B, and nikkomycin Z were determined at pH 5.5 and 7.0 for the target fungi Aspergillus fumigatus, Mucor hiemalis, Penicillium roqueforti, and Paecilomyces variotii . Penicillium roqueforti was the most sensitive species to all the compounds investigated . The MIC values for amphotericin B were 0.5-4 micrograms.mL-1 for the fungi tested, and pH did not affect the toxicity . The MIC values for nikkomycin Z ranged from < 0.5 microgram.mL-1 for Mucor hiemalis to > 500 micrograms.mL-1 for Aspergillus fumigatus, and pH had no influence on toxicity . Bafilomycins B1 and C1 were equally active against the fungal species tested, with MIC values in the range of < 0.5-64 micrograms.mL-1 . All fungi were more sensitive to both bafilomycin B1 and C1 at pH 7.0 than at pH 5.5.

J Neurophysiol, 2000 Aug, 84(2), 986 - 1005
Prior information in motor and premotor cortex: activity during the delay period and effect on pre-movement activity; Crammond DJ et al.; In instructed-delay (ID) tasks, instructional cues provide prior information about the nature of a movement to execute after a delay . Neuronal responses in dorsal premotor cortex (PMd) during the instructed-delay period (IDP) between the CUE and subsequent GO signals are presumed to reflect early planning stages initiated by the prior information . In contrast, in multiple-choice reaction-time (RT) tasks, all motor planning and execution processes must occur after the GO signal . These assumptions predict that neuronal planning correlates recorded during the IDP of ID trials should share common features with early post-GO activity in RT trials, and that those response components need not be recapitulated after the GO signal of ID trials . These two predictions were tested by comparing activity recorded in RT and ID tasks from 503 neurons in PMd and caudal (MIc) and rostral (MIr) primary motor cortex . The incidence and strength of directionally tuned IDP activity declined progressively from PMd to MIc . The directional tuning of activity during the IDP of ID trials was more similar to that in the reaction-time epoch (RTE) of RT trials than after movement onset, especially in PMd . A modulation of post-GO activity was often observed between RT and ID trials and was confined mainly to the RTE . This effect was also most prominent in PMd . The most common change was a reduction in intensity of short-latency phasic responses to the GO signal between RT and ID trials, especially in PMd cells with a short-latency phasic response to CUE signals . However, the largest group of cells in each area showed no large change in peak RTE activity between RT and ID trials, whether they were active in the IDP or not . Since early phasic CUE-related responses are least likely to be recapitulated after the GO signal in ID trials, they may be a neuronal correlate of an early planning stage such as response selection . Tonic IDP responses, which are not as strongly associated with a post-GO reduction in activity, may be related to other aspects of motor planning and preparation . Finally, a major component of the movement-related activity in both MI and PMd is not susceptible to modification by prior information and is indivisibly coupled temporally to movement execution.

J Clin Pharmacol, 2000 Aug, 40(8), 869 - 74
Pharmacokinetics of ofloxacin enantiomers after intravenous administration for antibiotic prophylaxis in biliary surgery; Gascon AR et al.; The pharmacokinetics of S-(-)- and R-(+)-ofloxacin, enantiomers of the fluoroquinolone ofloxacin, were characterized after prophylactic administration in 15 patients undergoing elective biliary surgery . A single dose of ofloxacin 400 mg given intravenously as an infusion was administered 1 hour before surgery . Plasma levels of S-(-)- and R-(+)-ofloxacin showed very small differences between both enantiomers, although the ratio of S-(-)- to R-(+)-enantiomer concentration in plasma showed significant differences (p < 0.05) at 4 and 12 hours . Adequate S-(-)-ofloxacin (levofloxacin, the active enantiomer) plasma levels (> or = minimum inhibitory concentration {MIC90} for Escherichia coli) were found throughout the procedure . For pharmacokinetic parameters, the authors found small but statistically significant differences (p < 0.05) in the area under the concentration-time curve, AUC0-infinity (22.30 +/- 2.72 mg h/L for S-(-)-ofloxacin vs . 20.50 +/- 2.06 mg h/L for R-(+)-ofloxacin), and in the clearance (0.15 +/- 0.04 L/h/Kg for S-(-)-ofloxacin vs . 0.16 +/- 0.04 L/h/Kg for R-(+)-ofloxacin) . To test the penetration of ofloxacin enantiomers into tissues, the authors measured levels in subcutaneous cell tissue and gall-bladder cell tissue . They did not observe statistical differences between the two isomers, which means that distribution is not an estereoselective process . Enantiomer levels in these two tissues decreased rapidly, but the highest concentrations were reached during the 4 first hours (i.e., when the surgical procedure was being performed) . In conclusion, with the prophylactic treatment used, levofloxacin plasma and tissue levels are high enough to prevent surgical infections.

J Antimicrob Chemother, 2000 Aug, 46(2), 287 - 90
In vitro antibiotic susceptibility of Francisella tularensis isolated from humans and animals; Ikaheimo I et al.; The in vitro susceptibility of 38 strains of Francisella tularensis (biovar F . tularensis palaearctica) was determined using Etests on cysteine heart agar plates with 2% haemoglobin . All strains were susceptible to the antibiotics traditionally used to treat tularaemia, such as streptomycin (MIC(90) 4.0 mg/L), tetracycline (MIC(90) 0.38 mg/L) and chloramphenicol (MIC(90) 0.38 mg/L), and to aminoglycosides, such as tobramycin (MIC(90) 1.5 mg/L) and gentamicin (MIC(90) 1.0 mg/L) . The quinolones examined had low MIC(90)s: ciprofloxacin, 0.016 mg/L; levofloxacin, 0.016 mg/L; grepafloxacin, 0.047 mg/L; and trovafloxacin, 0.032 mg/L . In contrast, all the strains were resistant to beta-lactams and azithromycin . Quinolones thus seem to be promising drugs for the treatment of tularaemia.

J Antimicrob Chemother, 2000 Aug, 46(2), 249 - 53
Grepafloxacin against penicillin-resistant pneumococci in the rabbit meningitis model; Gerber CM et al.; Grepafloxacin, a new fluoroquinolone, produced bactericidal activity comparable to that of vancomycin and ceftriaxone in the treatment in rabbits of meningitis caused by a pneumococcal strain highly resistant to penicillin (MIC 4 mg/L) (triangle uplog(10) cfu/mL*h for grepafloxacin, -0.32 +/- 0.15; dose, 15 mg/kg iv; triangle uplog(10) cfu/mL*h for vancomycin, -0.39 +/- 0.18; dose, 2 x 20 mg/kg iv; triangle uplog(10) cfu/mL*h for ceftriaxone, -0.32 +/- 0 . 12; dose, 125 mg/kg iv) . Higher doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not improve the killing rates . The combination of grepafloxacin with vancomycin was not significantly superior to monotherapies (P > 0.05) . In vitro, grepafloxacin was bactericidal at concentrations above the MIC . Using concentrations around the MIC, addition of vancomycin to grepafloxacin showed synergic activity.

J Med Assoc Thai, 2000 Jul, 83(7), 719 - 24
Comparison between mushroom-type and balloon-type gastrostomy buttons; Ruangtrakool R et al.; The gastrostomy button has been improved rapidly over the last ten years . The gastrostomy button was divided into two groups . The first group had a mushroom tip and, in this study, the Bard button represented this group . The other had a balloon as an internal stabilizer and the Mic-key button represented this group . The authors retrospectively studied all buttons inserted at the Royal Children's Hospital, Brisbane between 1988 and 1995 . The average longevity of Bard and Mic-key buttons were 378.82 and 259.62 days respectively . Valve incompetence was the most common cause of removal of the Bard button (38%), whereas, balloon rupture was the major cause of removal of Mic-key button (44%) . Each type of gastrostomy button had its own advantages and disadvantages and these special characteristics will be discussed.

Aliment Pharmacol Ther, 2000 Aug, 14(8), 1083 - 7
Rabeprazole, amoxycillin and low- or high-dose clarithromycin for cure of Helicobacter pylori infection; Kihira K et al.; BACKGROUND: Rabeprazole sodium is a proton pump inhibitor . AIM: To evaluate the efficacy and safety of 1-week triple therapy with rabeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori . METHODS: A total of 100 subjects with H . pylori were randomly divided into two groups of 1-week triple therapy with rabeprazole 10 mg b.d., amoxycillin 750 mg b.d . and either clarithromycin 200 mg b.d . (RAC400, n=50) or clarithromycin 400 mg b . d . (RAC800, n=50) . Endoscopic examination with four biopsies (two specimens from the antrum and two from the gastric body) was performed . The status of H . pylori infection was determined using culture and histology (Giemsa stain) of the biopsy specimens . Sensitivity to clarithromycin was determined using the E-test: MIC > 8 g/mL was considered to be resistant, whereas MIC < 2 g/mL was considered to be sensitive . Cure was defined as no evidence of H . pylori infection 1 month after completion of treatment . RESULTS: There were no significant differences in the clinical characteristics of the two groups . Eradication rates (intention-to-treat and per protocol, respectively) were: RAC400: 86% (95% CI: 76-95%) and 89% (95% CI: 80-97%); RAC800: 94% (95% CI: 87-100%) and 97% (95% CI: 94-100%) . There was no significant difference between the eradication rates of either regimen . Three subjects with failed eradication in the RAC400 group were all infected with a clarithromycin-resistant strain before beginning the therapy . Haemorrhagic colitis was the only severe adverse event, which was observed in one patient in the RAC800 group . CONCLUSION: One-week triple therapy with rabeprazole, amoxycillin and low-dose clarithromycin is effective for the eradication of H . pylori infection.

Environ, Toxicol . Pharmacol. . 2000 Mar 1, 8(3), 167 - 172
Preliminary in vitro toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds: II(1); Coleman MD et al.; The in vitro toxicity of two amidrazones I {N(1)-(3-benzyloxy-4-methoxybenzylidene)-pyridine-2-carboxamidrazone} and II {N(1)-(4-benzyloxy-3-methoxybenzylidene)-pyridine-2-carboxamidrazone} and their precursors PI (3-benzyloxy-4-methoxybenzaldehyde) and PII (4-benzyloxy-3-methoxybenzaldehyde) was determined using a rat liver metabolism system with human mononuclear leucocytes (MNL) as target cells . The minimum inhibitory concentration for I and II was determined to be between 4 and 8 microg/ml against Mycobacteria fortuitum . In direct contact with human MNL at three concentrations, only II and isoniazid (INH) were significantly more toxic compared with control at 100 and 200 microM . With rat microsomes, INH and PII at 50 microM showed significant toxicity . In the two compartment system without a metabolising system, INH and II were significantly more toxic compared with control and I . In the presence of the metabolising system, INH and PI were more toxic than control and INH was more toxic compared with I . II was not significantly more toxic than control . INH caused more cell death in the presence of the metabolising system compared with its absence . Less toxic compared with INH, compound I has shown promise for future development as an antituberculosis drug.

Biosci Biotechnol Biochem, 2000 Jun, 64(6), 1203 - 9
Transcription of emrKY is regulated by the EvgA-EvgS two-component system in Escherichia coli K-12; Kato A et al.; Spontaneous mutations have been isolated in Escherichia coli that result in the constitutive expression of an emrKY promoter . These mutations were found to be single-nucleotide substitutions within the linker region of the sensor protein EvgS, which is part of a two-component regulatory system along with EvgA . In the linker mutants (evgSI and evgS4), emrKY expression became constitutive and MIC against sodium deoxycholate was 20 mg/ml, eight-fold higher than in the wild type . Furthermore, the start site of transcription from the promoter of emrKY was identified; EvgA was shown to bind at the -52 to -84 region by the footprinting experiment.

Rev Esp Quimioter, 2000 Jun, 13(2), 176 - 81
{Accumulation and efflux of quinolones by clinical isolates of Stenotrophomonas maltophilia}; Sanchez P et al.; The presence of quinolone efflux pumps was analyzed in clinical isolates of Stenotrophomonas maltophilia . The presence of the protein Omp54, which is associated with the expression of multidrug resistant systems, was also tested . Western blot analysis of outer membrane proteins demonstrated that Omp54 was expressed in strains with high-level resistance to quinolones, whereas those strains with low MIC values did not express this protein . This result shows that Omp54 has an important role in the phenotype of quinolone resistance in clinical S . maltophilia isolates . Biochemical analyses have shown that clinical S . maltophilia strains are capable of quinolone efflux (namely norfloxacin, ofloxacin and ciprofloxacin) . Quinolone efflux is dependent on the integrity of membrane potential . These data indicate the presence of active quinolone efflux pump systems in clinical S . maltophilia isolates.

J Clin Microbiol, 2000 Aug, 38(8), 2949 - 54
Comparison of NCCLS and 3-(4,5-dimethyl-2-Thiazyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) methods of in vitro susceptibility testing of filamentous fungi and development of a new simplified method; Meletiadis J et al.; The susceptibility of 30 clinical isolates belonging to six different species of filamentous fungi (Aspergillus fumigatus, Aspergillus flavus, Scedosporium prolificans, Scedosporium apiospermum, Fusarium solani, and Fusarium oxysporum) was tested against six antifungal drugs (miconazole, voriconazole, itraconazole, UR9825, terbinafine, and amphotericin B) with the microdilution method recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (M38-P) . The MICs were compared with the MICs obtained by a colorimetric method measuring the reduction of the dye 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to formazan by viable fungi . The levels of agreement between the two methods were 96 and 92% for MIC-0 (clear wells) and MIC-1 (75% growth reduction), respectively . The levels of agreement were always higher for Aspergillus spp . (97% +/- 2.5%), followed by Scedosporium spp . (87% +/- 10.3%) and Fusarium spp . (78% +/- 7.8%) . The NCCLS method was more reproducible than the MTT method: 98 versus 95% for MIC-0 and 97 versus 90% for MIC-1 . However, the percentage of hyphal growth as determined visually by the NCCLS method showed several discrepancies when they were compared with the percentages of MTT reduction . A new simplified assay that incorporates the dye MTT with the initial inoculum and in which the fungi are incubated with the dye for 48 h or more was developed, showing comparable levels of agreement and reproducibility with the other two methods . Furthermore, the new assay was easier to perform and more sensitive than the MTT method.

Vet Rec, 2000 Jun 24, 146(26), 745 - 7
Comparison of in vitro activity of danofloxacin, florfenicol, oxytetracycline, spectinomycin and tilmicosin against recent field isolates of Mycoplasma bovis; Ayling RD et al.; The minimum inhibitory concentrations (MICS) and minimum mycoplasmacidal concentrations (MMCs) of danofloxacin, florfenicol, oxytetracycline, spectinomycin and tilmicosin against 62 recent British field isolates of Mycoplasma bovis were determined in vitro by a broth microdilution method . The isolates were most susceptible todanofloxacin with MIC90 and MMC90 values of 0.5 microg/ml and 1.0 microg/ml, respectively . They were less susceptible to florfenicol with a MIC90 of 16 microg/ml and MMC90 of 32 microg/ml . Oxytetracycline and spectinomycin had only a limited effect against the majority of isolates tested with MIC50s of 32 microg/ml and 4 microg/ml, respectively and MIC90s of 64 microg/ml and more than 128 microg/ml, respectively . Nearly 20 per cent of the isolates were highly resistant to spectinomycin, and tilmicosin was ineffective, with 92 per cent of the isolates having MIC values of 128 microg/ml or greater . There was no evidence of resistance by M bovis to danofloxacin.

J Antibiot (Tokyo), 2000 May, 53(5), 516 - 24
Macrolide esterase-producing Escherichia coli clinically isolated in Japan; Nakamura A et al.; Current Japanese clinical practice involves the usage of large amounts of new macrolides such as clarithromycin and roxithromycin for the treatment of diffuse panbronchiolitis, Helicobacter pylori and Mycobacterium avium complex infections . In this study, the phenotypes, genotypes, and macrolide resistance mechanisms of macrolide-inactivating Escherichia coli recovered in Japan from 1996 to 1997, were investigated . The isolation rate of erythromycin A highly-resistant E . coli (MIC > or = 1,600 microg/ml) in Japan slightly increased from 0.5% in 1986 to 1.2% in 1997 . In six macrolide-resistant strains, recovered from the strains collected for this study during 1996 to 1997, the inactivation of macrolide could be detected with or without added ATP in the assay system . The appearance of erythromycin A-inactivating enzyme independent of ATP was novel from Japanese isolates, and the 1H NMR spectra of oleandomycin hydrolyzed by the three ATP-independent isolates were examined . It was clearly shown that the lactone ring at the position of C-13 was cleaved as 13-H signal in aglycon of oleandomycin upper shifted . These results suggested the first detection of macrolide-lactone ring-hydrolase from clinical isolates in Japan . These results suggested the first detection of an ATP-independent macrolide-hydrolyzing enzyme from Japanese clinical isolates . Substrate specificity of the macrolide-hydrolyzing enzyme was determined with twelve macrolides including the newer members of this group and it was found that not only erythromycin A but also the new macrolides, such as clarithromycin, roxithromycin, and azithromycin were inactivated . The NMR data, broad spectrum of activity, and independence of co-enzyme supported our naming of the enzyme as a macrolide esterase . PCR methodology was employed to detect an ereB-like gene from the 3 isolates producing macrolide esterase, and one of these was subsequently shown to contain both ereB-like and ermB-like genes . It was also clearly shown that the other three isolates, which inactivated macrolide in the presence of ATP, had an mphA-like gene.

Can J Microbiol, 1999 Oct, 45(10), 871 - 4
Use of spectrophotometric reading for in vitro antifungal susceptibility testing of Aspergillus spp; Dannaoui E et al.; A comparative study of visual and spectrophotometric MIC endpoint determinations for antifungal susceptibility testing of Aspergillus species was performed . A broth microdilution method adapted from the National Committee for Clinical Laboratory Standards (NCCLS) was used for susceptibility testing of 180 clinical isolates of Aspergillus species against amphotericin B and itraconazole . MICs were determined visually and spectrophotometrically at 490 nm after 24, 48, and 72 h of incubation, and MIC pairs were compared . The agreement between the two methods was 99% for amphotericin B and ranged from 95 to 98% for itraconazole . It is concluded that spectrophotometric MIC endpoint determination is a valuable alternative to the visual reference method for susceptibility testing of Aspergillus species.

Aliment Pharmacol Ther, 2000 Jul, 14(7), 893 - 900
The impact of antibiotic resistance on the efficacy of three 7-day regimens against Helicobacter pylori; Savarino V et al.; BACKGROUND: Antibiotic resistance affects the success of anti-Helicobacter pylori therapies and varies greatly from country to country . AIM: To compare the efficacy of three short-term triple regimens in relation to H . pylori primary resistance in our region . METHODS: We enrolled 210 H . pylori-positive dyspeptic patients for this randomized, open, parallel-group study . Three arms of 70 patients each received the following 1-week regimens: (1) ranitidine bismuth citrate 400 mg b.d . + clarithromycin 250 mg b.d . + metronidazole 500 mg b.d . (RCM); (2) bismuth subcitrate 240 mg b.d . + amoxycillin 1000 mg b.d . + metronidazole 500 mg b.d . (BAM); (3) omeprazole 20 mg o.d . + clarithromycin 250 mg b.d . + metronidazole 500 mg b.d . (OCM) . H . pylori was assessed by CLO-test and histology before and 4 weeks after therapy . Antibiotic resistance was assessed by E-test . RESULTS: On intention-to-treat analysis RCM was more effective than OCM (84% vs . 69%; P < 0.03) and BAM (84% vs . 63%; P < 0.004) . MIC determination was successful in 117 out of 210 patients (55%); metronidazole resistance was present in 52 out of 117 patients (44%) and clarithromycin resistance was present in 17 out of 117 patients (14%) . Excellent cure rates were achieved when strains were sensitive to both antibiotics (100% with RCM and BAM and 90% with OCM), whereas RCM was superior to OCM (P=0.009) and BAM (P=0.001) with respect to overall resistant strains (94% vs . 57% and 38%, respectively) . CONCLUSIONS: One-week RCM is the best regimen to eradicate H . pylori in our geographical area . This seems to be linked to the better ability of RCM compared to OCM and BAM in overcoming the high prevalence of H . pylori resistance to both metronidazole and clarithromycin in our region.

Antimicrob Agents Chemother, 2000 Aug, 44(8), 2225 - 9
In vitro activities of the glycylcycline GAR-936 against gram-positive bacteria; Boucher HW et al.; The in vitro activities of GAR-936, the 9-t-butylglycylamido derivative of minocycline, were compared with those of doxycycline, minocycline, and tetracycline against 527 gram-positive clinical isolates . GAR-936 inhibited all strains, including those resistant to other tetracyclines, at concentrations of </=2 microg/ml, except two strains of JK diphtheroids for which the MIC was 4 microg/ml.

Antimicrob Agents Chemother, 2000 Aug, 44(8), 2179 - 81
Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro; Cottagnoud P et al.; The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml . h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml . h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml . h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar . The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml . h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0 . 22 Delta log(10) CFU/ml . h), the regimen most commonly used in clinical practice . In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Eur J Clin Microbiol Infect Dis, 2000 May, 19(5), 344 - 9
Nosocomial cluster of Candida lipolytica fungemia in pediatric patients; Shin JH et al.; Candida lipolytica has rarely been reported as a human pathogen . An apparent outbreak of Candida lipolytica fungemia (n = 5 cases) occurred in a pediatric ward over a 9-week period . The five patients infected were hospitalized in three adjacent rooms and cared for by the same healthcare workers . The index patient had central venous catheter-related fungemia, whereas the second patient, who was in the adjacent single room, had transient fungemia . Three additional cases of fungemia occurred in patients with hematological disorders who shared the same room; all three patients had central venous catheters and had been receiving oral fluconazole prophylaxis (50 mg/day for more than 3 weeks) at the time of infection . In vitro susceptibility testing of the strains showed that the MIC of fluconazole for all the isolates was 32 microg/ml . Random amplified polymorphic DNA analysis provided evidence of the clonal origin of the isolates, but the source of the outbreak was not identified . All four patients with persistent fungemia were successfully treated via catheter removal or empiric amphotericin B treatment . This outbreak shows the potential for the nosocomial epidemic transmission of Candida lipolytica.

Bioorg Med Chem, 2000 Jun, 8(6), 1423 - 32
Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies; Ragno R et al.; A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5-33) were tested in vitro against Mycobacterium tuberculosis CIP 103471 . The majority of tested compounds were efficient antimycobacterial agents showing MIC values ranging from 0.5 to 32 microg/mL . A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M . tuberculosis . Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA) have been applied . A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5-33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents . The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure-activity relationships (r2 = 0.86) of the training set . A comparison between the QSAR, CoMFA and mixed QSAR-CoMFA models is also presented . The hybrid model is to be preferred, however, because of its lowest values of the average absolute error of prediction toward a limited external test set.

Chest, 2000 Jul, 118(1), 61 - 5
Maximum insufflation capacity; Kang SW et al.; OBJECTIVE: To investigate the effect of deep lung insufflations on maximum insufflation capacities (MICs) and peak cough flows (PCFs) for patients with neuromuscular disease . METHOD: Forty-three patients with neuromuscular disease were trained in stacking delivered volumes of air to deep lung insufflation and were prescribed a program of air stacking once their vital capacities (VCs) were noted to be < 2,000 mL . VC, MIC, and unassisted and assisted PCF were monitored . The initial data were compared with the highest MICs subsequently achieved . For those patients whose MICs only decreased, we compared the initial data with the most recent data . RESULTS: The MICs increased from (mean +/- SD) 1,402 +/- 530 mL to 1,711 +/- 599 mL (p < 0.001) for 30 patients and only decreased for 13 patients . Patients for whom the MICs increased also had a significant increase in assisted PCF from 3.7 +/- 1.4 to 4.3 +/- 1.6 L/s (p < 0.05) despite having somewhat decreasing VCs and unassisted PCFs . CONCLUSION: With training, the capacity to stack air to deep insufflations can improve despite progressive neuromuscular disease . This can result in increased cough effectiveness.

Crit Care Med, 2000 Jun, 28(6), 1754 - 9
Surgery and intensive care procedures affect the target site distribution of piperacillin; Brunner M et al.; OBJECTIVE: Therapeutic failure of antibiotic therapy has been ascribed to pharmacokinetic alterations in compromised patient populations . The present study, therefore, aimed at examining the influences of cardiac surgery and intensive care procedures on the postoperative target site distribution of piperacillin . For this purpose, the penetration of piperacillin to the interstitial space fluid, the relevant target site for most bacterial infections, was compared between patients after aortic valve replacement and healthy volunteers . DESIGN: Comparative study in two study populations . SETTING: The intensive care unit and research ward of a university hospital . PATIENTS: The study population included six otherwise healthy patients scheduled to undergo aortic valve replacement and a control group of six healthy male volunteers . INTERVENTIONS: After the administration of a single i.v . infusion of 4.0 g piperacillin, free piperacillin concentrations were measured in the interstitium of skeletal muscle and subcutaneous tissue by in vivo microdialysis and in venous serum . Piperacillin concentrations were assayed with reversed phase high-performance liquid chromatography . MEASUREMENTS AND MAIN RESULTS: Interstitial piperacillin concentrations in muscle and subcutaneous adipose tissue were significantly lower in patients compared with volunteers with the area under the curve for the interstitium/area under the curve for serum concentration ratios ranging from 0.25 to 0.27 and from 0.43 to 1.22 in patients and volunteers, respectively (p < .05 between groups) . The terminal elimination half-life was markedly prolonged in patients, leading to a concomitant increase in t > minimal inhibitory concentration (MIC) values, the relevant surrogate for therapeutic success of therapy with beta-lactam antibiotics, for strains with MIC50 <4 microg/mL . For strains with MIC50 >20 microl/mL, however, inadequate target site concentrations were attained in the patient population . CONCLUSIONS: During the postoperative and intensive care periods, target site concentrations of piperacillin are markedly altered and decreased . This may also be true for other antibiotic agents and may have clinical implications in that current dosing guidelines may result in inadequate target site concentrations for high-MIC strains . Conceivably, this could lead to therapeutic failure in some patients.

J Zoo Wildl Med, 2000 Mar, 31(1), 47 - 51
Pharmacokinetics of piperacillan after intramuscular injection in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus); Robbins PK et al.; This study characterized and compared the pharmacokinetics of piperacillin after single 100 mg/kg i.m . injections in nine red-tailed hawks (Buteo jamaicensis) and five great horned owls (Bubo virginianus) over 48 hr by a modified agar well diffusion microbial inhibition assay . The mean maximum plasma piperacillin concentrations were 204 microg/ml and 221 microg/ml for the hawks and owls, respectively, and times of maximum concentrations were 15 min and 30 min, respectively . The calculated mean terminal elimination half-lives were 77 min in the hawks and 118 min in the owls . Area-under-the-curve values were 218 +/- 52 microg x hr/ml in the hawks and 444 +/- 104 microg x hr/ml in the owls . On the basis of the most common minimal inhibitory concentration (90%) for various bacterial isolates from clinical samples of 8 microg/ml, analysis of the data suggests that the maximum dosing interval for piperacillin at 100 mg/kg in medium sized raptors should be 4-6 hr.

J Antimicrob Chemother, 2000 Jul, 46(1), 121 - 3
Resistance of helicobacter pylori to metronidazole, tetracycline and amoxycillin; Wu H et al.; Resistance to metronidazole, tetracycline and amoxycillin, and beta-lactamase production were determined for 153 clinical isolates of Helicobacter pylori . Of these isolates, 77.8% were resistant to metronidazole (MIC > 8 mg/L), 58.8% to tetracycline (MIC > 16 mg/L) and 71.9% to amoxycillin (MIC > 0.5 mg/L); 39.2% were multiresistant . Resistance to metronidazole was more common in isolates from females than in those from males (P < 0.05) . None of the isolates produced beta-lactamase, so the mechanism of amoxycillin resistance was not linked to production of beta-lactamase.

Nihon Kokyuki Gakkai Zasshi, 2000 Apr, 38(4), 253 - 8
{Community-acquired pneumococcal pneumonia: a comparative study of bacteremic and nonbacteremic patients}; Watari M et al.; We analyzed the clinical and laboratory features of 37 adult patients with community-acquired pneumococcal pneumonia requiring hospitalization . Blood culture was positive in 11, and negative in 26 . The average age of the 37 patients was 70.2 years, and 28 were male . Compared with the patients with negative blood culture, the patients with positive blood culture were more likely to have liver cirrhosis, less sputum production, lower body temperature, and higher respiratory rate on physical examination . In the laboratory data on admission, the values for serum total protein, albumin, and glucose were significantly lower in the patients with positive blood culture . Thirty-two percent of the pneumococcal isolates were resistant to penicillin G (MIC > or = 0.12 microgram/ml) . There was no difference in the frequency of drug-resistant pneumococci in the two groups . The use of mechanical ventilation was more frequent in the patients with positive blood culture than in the patients with negative blood culture (27.3% vs 3.8%) . Moreover, mortality was higher (27.3% vs 7.7%) and the duration of hospitalization was longer in the bacteremic group . However, from a univariate analytical perspective, these differences were not significant . We concluded that blood culture can be a highly valuable diagnostic aid and useful for the prognostic evaluation of patients with community-acquired pneumonia requiring hospitalization.

Rev Esp Quimioter, 1999 Sep, 12(3), 244 - 9
Oral ofloxacin versus parenteral imipenem-cilastatin in the treatment of osteomyelitis; Gomis M et al.; We conducted a prospective, randomized, open-label trial, comparing oral ofloxacin with intravenous imipenem-cilastatin for the treatment of chronic osteomyelitis in order to evaluate the efficacy and tolerance . Hospitalized patients with diagnosis of chronic osteomyelitis and isolation of susceptible organisms to ofloxacin and imipenem/cilastatin were eligible for enrollment . Ofloxacin was administered orally (400 mg every 12 hours), and imipenem-cilastatin was given intravenously (500 mg every 6 hours) . Organisms were considered susceptible to ofloxacin when the minimal inhibitory concentration (MIC) was <2 micrograms/ml, and to imipenem-cilastatin when the MIC was <4 micrograms/ml . Thirty-two patients were enrolled, 16 in each group . In the intent to treat analysis 11 (69%) patients in the ofloxacin group and eight (50%) in the imipenem-cilastatin group were cured (p = 0.473; 95% confidence interval of the difference from -14.7% to 52.2%) . In the per protocol analysis 10 (91%) patients in the ofloxacin group and seven (70%) in the imipenem/cilastatin group were cured (p = 0.311; 95% confidence interval of the difference from -12.2% to 54%) . Our trial suggests that oral ofloxacin is as effective as parenteral therapy with betalactam antibiotics in the treatment of osteomyelitis, which could allow a reduction of the period of hospitalization and economic costs.

Rev Esp Quimioter, 1999 Sep, 12(3), 234 - 6
In vitro activity of eight fluoroquinolones against multiresistant Stenotrophomonas maltophilia; Sanchez-Hernandez J et al.; We studied the activity of eight fluoroquinolones (norfloxacin, ciprofloxacin, grepafloxacin, trovafloxacin, gatifloxacin, clinafloxacin, PD-117596 and PD-138312) against 58 multiresistant Stenotrophomonas maltophilia clinical strains . Norfloxacin was the least active drug (MIC(90) = 128 mg/l) . Grepafloxacin, trovafloxacin and gatifloxacin activity was moderately higher (MIC(90) = 8 mg/l) than ciprofloxacin (MIC(90) = 16 mg/l) . The best activity was shown by clinafloxacin and PD-138312 (MIC(90) = 4 mg/l) . The most resistant strains showed similar MICs against all the fluoroquinolones tested . The highest increase of activity of newer fluoroquinolones was observed against the most sensitive strains.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2000 Mar, 17(1), 33 - 6
{Investigation of infiltration glass of the machinable infiltrated ceramic(MIC)}; Liao Y et al.; To explore the manufacture arts and determine the properties of the infiltration glass of the MIC . In order to determine the glass forming range of the MIC infiltration glass, molten glass was prepared in Al2O3 crucibles by heating the components to 1450 degrees C . Thermal analytic device was employed to study the thermal properties of the glass . Its crystal phases after micro-crystallization were analyzed with XRD . Flexural strength was measured by means of 3-point bending test . The chemical components of MIC glass were determined . Conventional fluorophlogopite glass was converted into an infiltration glass with low viscosity, good infiltration capability and low fusing temperature by introducing B2O3, La2O3 and Li2O into the glass . Fluorophlogopite crystals formed after crystallization . Conventional mica glass can be changed according to the requirements of properties . Modified mica MIC glass in this study has good infiltration ability in Al2O3 matrix while remains machinability.

Xenobiotica, 2000 May, 30(5), 441 - 56
Rapid determination of rat hepatocyte mRNA induction potential using oligonucleotide probes for CYP1A1, 1A2, 3A and 4A1; Surry DD et al.; 1 . A new assay to quantify mRNA levels in small numbers of rat hepatocytes has been developed for cytochrome P450 (CYP) isoforms 1A1, 1A2, 3A and 4A1 . The assay uses sets of oligonucleotide probes end-labelled with {35S}-dATP to hybridize to mRNA in control- or drug-treated rat hepatocytes cultured on Cytostar-T 96-well scintillating microplates . 2 . The rat hepatocyte induction potential (RHIP) assays for CYP3A, 1A1, 1A2 and 4A1 are sensitive and selective and have an excellent qualitative relationship with CYP induction data ex vivo . The robustness of the CYP3A assay was determined following a run of > 40 plates . The variation of the dexamethasone (DEX) response on each plate, calculated as %coefficient of variation, showed that there was no significant difference between the variability of the response to DEX . 3 . Assay specificity for each CYP isoform was achieved by designing probes (four per isoform) antisense to coding regions of each CYP gene sequence . In the CYP3A RHIP assay, pregnenalone 16alpha-carbonitrile (PCN), DEX, clotrimazole (CLOT) and miconazole (MIC) were all good inducers of CYP3A mRNA; beta-napthoflavone (BNF) and methylclofenapate (MCP), however, did not induce CYP3A mRNA, further defining the specificity of this methodology . Specificity was similarly confirmed for the other CYP isoforms . 4 . Ind50, the concentration of inducer required to elicit a 50% induction of CYP-specific mRNA, was derived for prototypical CYP inducers: BNF 0.54 and 0.17 microM (CYP1A1 and 1A2 respectively), 3-methylcholanthrene (3MC) 0.11 and 0.04 microM (CYP1A1 and 1A2 respectively), PCN 0.03 microM, DEX 0.17 microM, CLOT 0.48 microM, MIC 3 microM, TAO 3 microM (CYP3A), MCP 1.8 microM, clofibrate (CLOF) 65 microM and ciprofibrate (CIP) 1.9 microM (CYP4A1) . Ind50 for BNF and 3MC at CYP1A2 was 3-fold lower than that at CYP1A1 indicating a subfamily difference in inducer potency . 5 . Reducing the numbers of animals and the amount of compound required to study CYP induction is an important advantage of the RHIP assays over conventional evaluations in vivo . Typically four rats are dosed for 4 days using oral doses in the range 50-500 mg kg(-1) day(-1) . In comparison, the amount of hepatocytes required to carry out all the studies reported herein may be obtained from a single animal (< 2 x 10(8) viable cells) and CYP induction investigated using microg rather than g quantities of drug substance . 6 . With appropriately designed oligonucleotide probes, the RHIP technology can assess CYP induction in human hepatocytes, which together with preclinical data can contribute to improving the quality of compounds progressing into the expensive process of drug development.

Presse Med, 2000 May 27-Jun 3, 29(19), 1062 - 5
{Treatment of community-acquired pneumonia with levofloxacin: 500 mg once a day or 500 mg twice a day?}; Zuck P et al.; LEVOFLOXACIN: A new anti-pneumococcal fluoroquinolone, levofloxacin, has received approval in France for the treatment of community-acquired pneumonia at the dose of 500 mg once or twice a day, depending on the severity of the disease, the germ susceptibility and the patient's weight . Levofloxacin has a powerful and rapid bactericidal activity, particularly against pneumococci, whatever the level of penicillin resistance . The pharmacokinetic properties of the compound allow once daily dosage . Pharmacodynamically, it has been clinically demonstrated that the most predictive parameter of efficacy is the Cmax/MIC ratio . PNEUMOCOCCAL PNEUMONIA: Because of the potential gravity of pneumococcal pneumonia, it might be preferrable to use levofloxacin at the dose of 500 mg twice daily . The efficacy of the two levofloxacin doses for the treatment of pneumococcal pneumonia was thus analyzed . Five clinical studies including 4 comparative trials, enrolling nearly 2,000 patients with community-acquired pneumonia were reported in the international approval document . Among these patients, 310 had documented pneumococcal pneumonia including 31% with bacteriemia . TASK FORCE REPORT: On the basis of available data, the level of proof is sufficient to prescribe levofloxacin at the dose of 500 mg once daily for the treatment of mild to moderately severe community-acquired pneumonia in ambulatory patients, including those with suspected pneumococcal pneumonia, with or without bacteriemia . It would be reasonable to propose the 500 mg twice daily dosage for severe community-acquired pneumonia warranting intensive care hospitalization in accordance with the criteria of the ERS Task Force Report . The well-founded rationale of this therapeutic strategy should be validated by the results of ongoing studies and by following the evolution of germ susceptibility to these new compounds.

Clin Rheumatol, 2000, 19(3), 217 - 21
Prevalence of pulmonary disorders in patients with newly diagnosed rheumatoid arthritis; Doyle JJ et al.; Our objective was to determine the prevalence of airway hyperreactivity (AHR) in patients with newly diagnosed rheumatoid arthritis (RA) who had received no disease-modifying antirheumatic drugs (DMARDs) and to characterise the spectrum of lung diseases identifiable in these patients at the time of presentation . Eighteen consecutive patients with newly diagnosed RA referred to our medical centre's rheumatology clinic over 2 years underwent pulmonary evaluation with arterial blood gas analysis, chest radiographs, spirometry before and after bronchodilator medication, and body plethysmography . They returned on subsequent days in random order for methacholine inhalation challenge (MIC) and eucapnic voluntary hyperventilation (EVH) as bronchoprovocation techniques . One patient had severe obstructive disease at presentation and therefore did not undergo bronchoprovocation . We found a wide variety of pulmonary abnormalities, including two patients with hypoxia (12%), two with obstruction (12%), three with restriction (18%) and four with AHR (23%) . The data also suggest a strong association between pulmonary diseases in RA and cigarette smoking . Although no single characteristic lung disease such as AHR was identified in patients presenting with RA, the association between lung disease and cigarette smoking is striking and underscores the need to emphasise smoking cessation in this patient population.

Mycoses, 1999, 42 Suppl 2, 105 - 10
Antifungal susceptibilities and genetic relatedness of serial Trichophyton rubrum isolates from patients with onychomycosis of the toenail; Bradley MC et al.; Onychomycosis is a common fungal disease infecting up to 20% of the population over age 40 . The major causative agent of onychomycosis is Trichophyton rubrum . Uncontrolled infection may eventually lead to penetration of the newly forming nail plate . In spite of the encouraging cure rate with recent antifungal agents such as the allylamines (terbinafine) and azoles (itraconazole and fluconazole) some patients inevitably fail therapy . In this investigation, a group of patients from a multi-center study designed to assess the efficacy of terbinafine with known cases of onychomycosis were selected for evaluation . Nail samples from this patient group were colonized with T . rubrum throughout the terbinafine therapy . Antifungal susceptibility testing was performed on these T . rubrum isolates to detect change in MIC values . Strain relatedness was examined using random amplified polymorphic DNA (RAPD) technique . Our results revealed failure of patients to clear T . rubrum is not related to the development of resistance to the drug . While species determination was possible, we were not able to identify differences that would indicate reinfection with a new strain . Analysis of patient demographic data revealed that 70% of patients were over 45 years old, 56.6% were previously treated with antifungals, 60% came from family history with onychomycosis and 13% were diabetic . In conclusion, our data indicate that patients' failure to clear onychomycosis was not associated with resistant development . Failure of terbinafine therapy may be dependent on host-related factors.

Planta Med, 2000 May, 66(4), 337 - 42
Assessment of antimycobacterial activity of a series of mainly marine derived natural products; Konig GM et al.; A series of mainly marine derived natural products were tested for their activities against Mycobacterium tuberculosis and M . avium . Of the thirty-nine compounds tested fifteen demonstrated minimum inhibition concentrations (MICs) of 32 micrograms/ml or less, and eleven had MICs of 16 micrograms/ml or less . The most active compound found in this study was the sponge derived metabolite axisonitrile-3 (MIC 2 micrograms/ml).

J Colloid Interface Sci, 2000 Jul 1, 227(1), 78 - 83
Cationic Mixed Micelles in the Presence of beta-Cyclodextrin: A Host-Guest Study; Bakshi MS; The conductances of trimethyltetradecylammonium bromide (TTAB)+triphenyltetradecylphosphonium bromide (TTPB) and TTAB+trimethylhexadecylammonium bromide (HTAB) over the entire mole fraction range of TTAB (alpha(TTAB)) were measured in water and in beta-cyclodextrin+water (CD+W) mixtures at fixed 4 and 8 mM of CD at 30 degrees C . The conductivity plots for both binary mixtures show a single break from which the mixed critical micelle concentration (cmc) and degree of micelle ionization (chi) were computed . From the slopes of the conductivity curves, the equivalent ionic conductivities of the monomeric (Lambda(m)), associated (Lambda(ass)), and the micelle (Lambda(mic)) states were calculated and discussed with respect to the surfactant-CD complexation in the whole mole fraction range of both surfactant binary mixtures . The association constant (K) between the respective monomeric surfactant and CD cavity of fixed 4 mM CD was computed by considering 1:1 association from the surface tension measurements . A comparison among the K values for HTAB-CD, TTAB-CD, and TTPB-CD shows that the former complexation is significantly stronger in comparison to the other ones due to the longer hydrophobic tail . The nonideality in mixed micelle formation in pure water was evaluated by using the regular solution theory, and it was observed that both binary mixtures exhibit close to ideal behavior .

Arzneimittelforschung, 2000 May, 50(5), 495 - 501
{Establishment and evaluation of microdilution assays for the in vitro sensitivity testing of Aspergillus fumigatus}; Schmidt A et al.; For the in vitro sensitivity assessment of moulds different methods of micro- and macro-dilution assays as well as agar diffusion assays in different media formulations have been described so far . Until now, no standardized method has been preferred . The aim of the present study is to establish and to evaluate a microdilution assay for the in vitro chemosensitivity testing of Aspergillus fumigatus . This method should show a late onset of superficial growth and sporulation as well as a relative independency of the test inoculum . As reference substances, amphotericin B (CAS 1397-89-3) and 5-fluorocytosine (CAS 2022-85-7), which are both used for therapy of systemic mycoses, have been tested . Both substances show an excellent water solubility in liquid media . Fifty clinical isolates of A . fumigatus were used for the testings . The strains showed a better growth in Isosensitest (ISO)-medium than in Yeast-Nitrogen-Glucose (YNG)-medium . Growth was submers++ during the observation time, adherent to the bottom of the microtiter plate . Superficial growth with sporulation only occurred in a late stage of growth . Only a weak inoculum effect could be observed and the MIC (minimal inhibitory concentration) values determined macroscopically as well as using an ELISA reader showed to be almost comparable with a clearly defined breakpoint for the MIC discrimination . For amphotericin B, lower MIC values were observed in ISO-medium (0.25-2 micrograms/ml; median M = 1 microgram/ml) than in YNG-medium (0.25 microgram/ml; M = 1 microgram/ml) . For 5-fluorocytosine, in both media MIC-values of > or = 32 micrograms/ml with a median of 64 micrograms/ml in ISO-medium and 128 micrograms/ml in YNG-medium were observed, respectively . With this test procedure, a standardized chemosensitivity testing can be performed for strains of A . fumigatus by a test system which is relatively easy to handle . These in vitro sensitivity data have to be correlated with clinical data as well as data obtained from animal studies . Only after this assessment final therapeutic consequences should be drawn from these in vitro findings.

Antimicrob Agents Chemother, 2000 Jul, 44(7), 1977 - 9
In vitro activities of linezolid alone and in combination with amoxicillin, clarithromycin, and metronidazole against Helicobacter pylori; Hirschl AM et al.; Linezolid was tested against 70 strains of Helicobacter pylori by the agar dilution method . The MIC range and MICs at which 50 and 90% of strains were inhibited were 8 to 64, 16, and 32 microgram/ml, respectively . With minimum and maximum fractional inhibitory concentration summation values of 0.31 and 2.50, respectively, the combination of linezolid with amoxicillin, clarithromycin, or metronidazole showed either partial synergy or indifference for the majority of strains.

Antimicrob Agents Chemother, 2000 Jul, 44(7), 1894 - 9
Antipneumococcal activity of ABT-773 compared to those of 10 other agents; Davies TA et al.; MICs, time-kills, and postantibiotic effects (PAEs) of ABT-773 (a new ketolide) and 10 other agents were determined against 226 pneumococci . Against 78 ermB- and 44 mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC(50)s) and MIC(90)s were 0.016 to 0.03 and 0.125 microgram/ml, respectively . Clindamycin was active only against macrolide-resistant strains containing mefE (MIC(50), 0.06 microgram/ml; MIC(90), 0.125 microgram/ml) . Activities of pristinamycin (MIC(90), 0.5 microgram/ml) and vancomycin (MIC(90), 0.25 microgram/ml) were unaffected by macrolide or penicillin resistance, while beta-lactam MICs rose with those of penicillin G . Against 19 strains with L4 ribosomal protein mutations and two strains with mutations in domain V of 23S rRNA, ABT-773 MICs were 0.03 to 0.25 microgram/ml, while macrolide and azalide MICs were all >/=16.0 microgram/ml . ABT-773 was bactericidal at twice the MIC after 24 h for 8 of 12 strains (including three strains with erythromycin MICs greater than or equal to 64.0 microgram/ml) . Kill kinetics of erythromycin, azithromycin, clarithromycin, and roxithromycin against macrolide-susceptible strains were slower than those of ABT-773 . ABT-773 had longer PAEs than macrolides, azithromycin, clindamycin, or beta-lactams, including against ermB-containing strains . ABT-773, therefore, shows promising in vitro activity against macrolide-susceptible as well as -resistant pneumococci.

Antimicrob Agents Chemother, 2000 Jul, 44(7), 1846 - 9
In vitro pharmacodynamics of the new ketolides HMR 3004 and HMR 3647 (Telithromycin) against Chlamydia pneumoniae; Gustafsson I et al.; The ketolides HMR 3004 and HMR 3647 (telithromycin) are a new class of macrolides that have a potential clinical efficacy against intracellular pathogens . The objectives of this study were to investigate the MIC, minimum bactericidal concentration, and time-dependent killing of two Chlamydia pneumoniae strains of the two ketolides . The killing effect was also studied with a newly developed intracellular in vitro kinetic model . Furthermore, HMR 3647 was studied for the effect of a subinhibitory concentration of 0.5 times the MIC after a preexposure of 10 times the MIC during 12 h . The MICs for both strains were 0.0039 and 0.0156 mg/liter for HMR 3004 and HMR 3647, respectively . Killing with 10 times the MIC was time dependent, increasing from a 1-log-unit decrease in the number of inclusions per well at 48 h to a maximal effect of 2.8-log-unit decrease after 96 h . A preexposure of 10 times the MIC of HMR 3647 for 12 h followed by a subinhibitory concentration of 0.5 times the MIC increased the killing effect to a 1.2-log-unit reduction in inclusions per well . An exposure for 12 h gave poor reduction of inclusions, while a static dose of 10 times the MIC for 72 h showed a 2.2-log-unit reduction in inclusions per well . In the kinetic model, a small number of inclusions were detected after 72 h by one exposure of 10 times the MIC . Regrowth could not be detected after 120 h . The ketolides HMR 3004 and HMR 3647 have bactericidal activity and show a significant sub-MIC effect on the intracellular pathogen C . pneumoniae.

Eur J Heart Fail, 2000 Jun, 2(2), 175 - 81
MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing; Genth-Zotz S et al.; Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM) . This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II-III after 6 months of therapy with metoprolol . Methods and results: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF)<40% were enrolled in the placebo-controlled study . The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day . Three patients died due to cardiogenic shock, two received placebo and one metoprolol . Eight patients did not complete the study due to non-compliance . Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise . Vo(2)-max and Vo(2)-AT as well as the 6-min walk test improved significantly after metoprolol treatment . There was a significant increase in EF at rest (27.3-35 . 2%), submaximal (28.5-37.7%) and maximal exercise (28.7-40.9%) in the metoprolol-treated patients . No differences were found between patients with CAD and DCM . We also observed reduced left ventricular volumes . Conclusion: The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF.

Int J Antimicrob Agents, 2000 Jul, 15(2), 149 - 52
Microbiologic efficacy of moxifloxacin for the treatment of community-acquired pneumonia due to Chlamydia pneumoniae; Hammerschlag MR et al.; Nasopharyngeal specimens for culture of Chlamydia pneumoniae were obtained from patients participating in two pneumonia treatment studies: an open study of 400 mg moxifloxacin orally, qds for 10 days and a randomized, double-blind comparison of moxifloxacin, 400 mg orally, qds versus clarithromycin, 500 mg orally, bd, both for 10 days . C . pneumoniae was eradicated from the nasopharynx of seven of ten (70%) microbiologically evaluable patients who were treated with moxifloxacin and four of four who were treated with clarithromycin . Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of 21 isolates of C . pneumoniae from 18 patients obtained before and after therapy were performed against moxifloxacin and clarithromycin . The MIC(90)s and MBC(90)s for moxifloxacin and clarithromycin were 1 and 0.06 mg/l, respectively . The MICs and MBCs against moxifloxacin of six isolates from three persistently infected patients who were treated with the drug were the same at baseline and follow-up . The persistence of C . pneumoniae after treatment with moxifloxacin was probably not due to the emergence of resistance.

Eur J Clin Pharmacol, 2000 Apr, 56(1), 61 - 4
Multiple-dose pharmacokinetics of cefepime in long-term hemodialysis with high-flux membranes; Schmaldienst S et al.; OBJECTIVE: Among uremic patients on hemodialysis, infectious complications leading to a high incidence of morbidity and mortality are a well-documented problem . In this multi-dose study, the safety, tolerance, and pharmacokinetics of cefepime during high-flux hemodialysis were investigated and an improved dosing schedule is presented . METHODS: Six long-term hemodialysis patients received 2 g cefepime i.v . at the end of hemodialysis three times per week . RESULTS: Trough levels of cefepime were 23.3 +/- 7.3 mg/l and peak serum concentrations 165.6 +/- 48.7 mg/l . After 3.5 h of high-flux hemodialysis, 72.2 +/- 6.4% of cefepime was eliminated . The intradialytic half-life was 1.6 +/- 0.29 h and the interdialytic half-life 22.0 +/- 2.14 h . CONCLUSION: A dosage of 2 g cefepime after each hemodialysis session achieved drug levels well above the minimal inhibitory concentration (MIC)90 for most of the target pathogens . Thus, the described dosing schedule is an efficient and cost saving antmicrobial therapy for severe infections in long-term hemodialysis patients with no residual renal function.

Nippon Jibiinkoka Gakkai Kaiho, 2000 May, 103(5), 552 - 9
{Molecular analysis of pathogens of upper respiratory tract infections in children--a study of nasopharyngeal S . pneumoniae and PBP genes in acute otitis media}; Shimada J et al.; We have recently been confronted with refractory upper respiratory infections with an increasing prevalence of penicillin (Pc)-resistant S . pneumoniae . There has been a broad consensus that acute otitis media (AOM) is caused by migration of pathogens from nasopharynx and proliferation in the middle ear space, and thus it is, very important to study the bacterial environment in the nasopharynx as the source of middle ear infections . Eighty pneumococcal isolates from the nasopharynx of children with acute otitis media were evaluated by polymerase chain reaction (PCR) for mutation of Pc-binding protein (PBP) genes . The results showed mutation of all three PBP genes, pbp 1a, pbp 2x, and pbp 2b, in 30% of the isolates, while 74% were found to possess various PBP gene mutations, mostly in one-year-old children . Of the 46 isolates whose minimum inhibitory concentration (MIC) of Pc was < or = 0.06 microgram/mL, 43% were found to possess a pbp 2x mutaion, which affects cefem resistance . We genotyped each pneumococcal isolate from the nasopharynx of children with recurrent AOM by pulsed-field gel electrophoresis (PFGE) . In 9 of 11 pairs (82%) of consecutive AOM episodes, the nasopharyngeal isolate in the second episode was different . In addition, discrimination of each isolate based upon the mutation profile of its PBP genes in 8 pairs (72%) of consecutive AOM episodes showed that the isolates were different, and there was little difference between the results of PBP gene mutation and PFGE analysis . These findings suggest that most nasopharyngeal isolates from children with AOM possess PBP mutations and that children with increased numbers of drug-resistant bacteria in their nasopharynx during AOM has been colonized or recolonized by different strains during each episode . We therefore emphasize that clinicians should assess the antibiotic susceptibility of nasopharyngeal isolates from children during each episode . PBP gene mutation analysis of S . pneumoniae is useful not only in providing valuable information on the antibiotic susceptibility of each strain but for assessing changes in causative strains in the sequential episodes of pneumococcal infection.

Minerva Ginecol, 2000 Jan-Feb, 52(1-2), 33 - 9
{Epidemiological study of Chlamydia trachomatis infection in a sample of women requesting voluntary termination of pregnancy, treated with rokitamycin}; Carta E et al.; BACKGROUND: Infection with Chlamydia trachomatis usually involves the cervix uteri, causing no symptoms, and may easily be unrecognised and untreated until troublesome symptoms arise, such as pelvic inflammatory disease, which can affect fertility and reproductive life . Therapies include the macrolide antibiotics, and in this class rokitamycin offers marked lipophilia, excellent intracellular penetration, and bactericidal activity at concentrations close to the MIC . The present study was therefore designed to establish the frequency of intracervical infection with Chlamydia trachomatis in women applying for termination of pregnancy, and to assess the efficacy and safety of this drug in this indication . METHODS: Women aged 18-40 years were admitted for termination of pregnancy, with a positive cervical swab for Chlamydia trachomatis . The study was conducted in accordance with the Declaration of Helsinki and amendments . Patients were given one oral tablet of 400 mg rokitamycin in the morning, and one in the evening, for two weeks . Treatment started ten days before the termination, within 48 h of taking the swab . Partners were to receive the same treatment . RESULTS: 292 women requiring termination of pregnancy, on average at the 9th week of pregnancy, were assessed . Of these, 24 (8.2%), mean (+/- SD) age 27.1 +/- 6.1 years, range 18-39, with a positive cervical swab for Chlamydia trachomatis, were treated with rokitamycin; 22 of their partners were treated too . Forty days after the start of treatment 22 patients (92%) gave negative results; these were all the cases whose partners had received treatment . No adverse events were reported and the acceptability of the treatment was considered good or excellent in 91% and fair in 9% of the cases . CONCLUSIONS: The findings confirm that rokitamycin is one of the most useful and effective macrolides for the treatment of infections caused by intracellular microorganisms; it is extremely well tolerated and has marked microbiological efficacy.

Am J Vet Res, 2000 Jun, 61(6), 706 - 9
Pharmacokinetics of enrofloxacin administered intravenously and orally to foals; Bermingham EC et al.; OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals . ANIMALS: 5 clinically normal foals . PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed . Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period . Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography . RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg . For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42% . CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance . Concentration of ciprofloxacin was negligible . Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.

APMIS, 2000 Apr, 108(4), 261 - 6
Evaluation of post-antibiotic effects of antipseudomonal antibiotics using an automated system; Mayer I et al.; Different methods have been described for determination of the post-antibiotic effects (PAEs) of antibiotics, from the conventional methods to the automatic measurement of bacterial regrowth . The PAEs of ciprofloxacin, ofloxacin and perfloxacin, as compared with those of amikacin, netilmicin and ceftazidime, have now been investigated for three clinical isolates of Pseudomonas species, using automated measurement of the growth with an Anthos microplate reader . It was found that, besides the well-known PAEs of aminoglycosides, quinolone antibiotics also exhibit drug- and concentration-dependent PAEs against clinical isolates of Pseudomonas when used in concentrations of 1/2x, 1 x or 5 x MIC . Of the three quinolones tested, pefloxacin showed the greatest PAE, independently of its MICs against the different strains . Ofloxacin had no or only an insignificant PAE, while ciprofloxacin had a marked PAE for all strains, including the reference strains.

Prim, Care Update Ob Gyns . 1998 Jul 1, 5(4), 160 - 161
Positive margins after cervical conization as an indicator of residual dysplasia; Huang M et al.; Objective: To determine the significance of positive margins of resection after cervical conization as an indicator of residual dysplasia.Materials and Methods: A retrospective analysis for patients who underwent cervical conization either by loop electrosurgical excision procedure or cold knife conization between 1986 and 1997 at Montefiore Medical Center and North Central Bronx Hospital . The factors evaluated included grade of dysplasia with respect to positive or negative margins and post-procedure follow-up . Differences among groups were evaluated using the chi(2) and Fisher's Exact test.Results: Of a total of 179 patients, 99 had positive margins of resection and 80 had negative margins of resection . Twenty-six patients had CIN I, of which 10 had positive margins of resection and 16 had negative margins of resection . There were 30 patients with CIN II, of which 13 had positive margins and 17 had negative margins . One hundred fourteen patients had CIN III/carcinoma in situ (CIS), of which 68 had positive margins of resection while 46 had negative margins of resection . Nine patients had microinvasive disease (MIC), of which 8 had positive margins of resection and 1 had negative margin of resection . The correlation between higher grades of dysplasia and the likelihood of having positive margins was noted to be statistically significant (P =.02) . Patients were followed up from a period of 6 weeks to 5 years.Of the patients with CIN I and positive margins, 5 had a normal post-cone Papanicolaou smear while 2 had an abnormal post-cone Papanicolaou smear . Seven of 9 patients with CIN II and positive margins had normal initial post-procedure Papanicolaou smear while only 2 had abnormal initial post follow-up Papanicolaou smear . Twenty-five patients with CIN III/CIS and positive margins had normal Papanicolaou smears at their initial post-procedure follow-up while 36 patients had an abnormal initial follow-up . Six of 8 patients with MIC and positive margins had documented follow-up . Of these 6, 2 had normal post-procedure Papanicolaou smears while 4 had abnormal post-procedure Papanicolaou smears . This approaches statistical significance . Additionally, the incidence of residual disease was analyzed in hysterectomy specimens with respect to grade of dysplasia . No patients with CIN I and positive margins were treated with hysterectomy . Of the 3 patients with CIN II treated with hysterectomy, 2 had residual dysplasia . Of the 21 patients with CIN II/CIS who underwent hysterectomy, 10 had residual disease . Of the 5 patients with MIC who underwent hysterectomy, 3 had residual disease.Conclusion: The likelihood of positive margins of resection increases with higher dysplasia . The incidence of abnormal initial post-procedure Papanicolaou smear appears to be increased with increasing grade of dysplasia . Interestingly, there does not appear to be an increase in the incidence of residual dysplasia when hysterectomy is performed for positive margin of resection after conization for high grade dysplasia.

J Mol Evol, 2000 Jun, 50(6), 510 - 9
Using alu J elements as molecular clocks to trace the evolutionary relationships between duplicated HLA class I genomic segments; Kulski JK et al.; The class I region of the major histocompatibility complex contains two subgenomic blocks (250-350 kb each), known as the alpha and beta blocks . These blocks contain members of multicopy gene families including HLA class I, HERV-16 (previously called P5 sequences), and PERB11 (MIC) . We have previously shown that each block consists of imperfect duplicated segments (duplicons) containing linked members of different gene families, retroelements and transposons that have coevolved as part of two separate evolutionary events . Another region provisionally designated here as the kappa block is located between the alpha and the beta blocks and contains HLA-E, -30, and -92, HERV-16 (P5.3), and PERB11.3 (MICC) within about 250 kb of sequence . Using Alu elements to trace the evolutionary relationships between different class I duplicons, we have found that (a) the kappa block contains paralogous (duplicated) Alu J sequences and other retroelement patterns more in common with the beta than the alpha block; (b) the retroelement pattern associated with the HLA-E duplicon is different from all other HLA class I duplicons, indicating a more complex evolution; (c) the HLA-92 duplicon, although substantially shorter, is closely related in sequence to the HLA-B and -C duplicons; (d) two of the six paralogous Alu J elements within the HLA-B and -C duplicons are associated with the HLA-X duplicon, confirming their evolutionary relationships within the beta block; and (e) the paralogous Alu J elements within the alpha block are distinctly different from those identified within the beta and kappa blocks . The sequence conservation and location of duplicated (paralogous) Alu J elements in the MHC class I region show that the beta and kappa blocks have evolved separately from the alpha block beginning at a time before or during the evolution of Alu J elements in primates.

Compr Psychiatry, 2000 May-Jun, 41(3), 163 - 6
Convergent and discriminant validity of DSM-IV axis II personality disorder criteria in adult outpatients with binge eating disorder; Grilo CM et al.; The study objective was to evaluate the within-category cohesiveness and between-category overlap of DSM-IV axis II personality disorders (PDs) in outpatients with binge eating disorder (BED) . Seventy adult outpatients with BED were reliably administered the Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV) . Within-category interrelatedness of the criteria was evaluated by Cronbach's alpha and mean intercriterion correlations (MICs) . Between-category criterion overlap was evaluated by examining intercategory mean intercriterion correlations between all pairs of PDs (ICMICs) . Cronbach's alpha was .64 to .93 (mean, .77), the MIC was .17 to .52 (mean, .34), and the ICMIC was .11 to .39 (mean, .28) . Our findings indicate that in outpatients with BED, the DSM-IV PD criteria sets have convergent validity (acceptable alpha value and MIC) . Some degree of discriminant validity also exists: criteria for most DSM-IV PDs correlate better with each other (MIC) than with criteria for other PDs (ICMIC).

J Antimicrob Chemother, 2000 Apr, 45 Suppl 1, 41 - 6
Comparative in vitro activity and post-antibiotic effect of gemifloxacin against Legionella spp; Dubois J et al.; The comparative in vitro potency and post-antibiotic effect (PAE) of gemifloxacin (SB-265805), moxifloxacin, trovafloxacin, grepafloxacin, levofloxacin, ofloxacin, ciprofloxacin, azithromycin, clarithromycin, erythromycin and rifampicin were evaluated against Legionella pneumophila serogroups 1-9 and 12 (n = 204) and other Legionella spp . (n = 34) . MICs were determined by standard two-fold agar dilution . PAE was determined by exposing the isolates to the test agents at 4 x MIC for 1 h . Trovafloxacin was the most potent agent overall (MIC range < or =0.004-0.016 mg/L, MIC(90) < or =0.008 mg/L) . Of the other quinolones tested, gemifloxacin, moxifloxacin, grepafloxacin and levofloxacin were more potent (MIC(90) 0.016 mg/L) against L . pneumophila than ciprofloxacin and ofloxacin (MIC(90) 0 . 03 mg/L) . Against Legionella spp., the test quinolones were more potent (MIC range < or =0.004-0.06 mg/L) than either erythromycin or azithromycin (MIC(90) 0.5 and 0.25 mg/L, respectively) . Gemifloxacin had the longest PAE (4.65 h) of the agents tested against erythromycin-resistant L . pneumophila . Of the quinolones, only gemifloxacin, grepafloxacin, levofloxacin and ofloxacin had PAEs of >3 h against erythromycin-resistant Legionella spp . Azithromycin, erythromycin and clarithromycin had PAEs of <3 h against all erythromycin-resistant strains . Against erythromycin-susceptible L . pneumophila, only gemifloxacin, moxifloxacin, ofloxacin and ciprofloxacin had PAEs of >3 h, and only rifampicin, ofloxacin, gemifloxacin and erythromycin had PAEs of >2 h against erythromycin-susceptible Legionella spp . The superior potency of gemifloxacin compared with erythromycin indicates that it may be of use in the treatment of legionellosis . The significant PAE described here, combined with favourable pharmacokinetics, supports once-daily dosing for gemifloxacin in the treatment of legionella infections.

Am J Phys Med Rehabil, 2000 May-Jun, 79(3), 222 - 7
Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease; Kang SW et al.; OBJECTIVE: To investigate the relationships between vital capacity (VC), maximum insufflation capacity (MIC), and both unassisted and assisted peak cough flows (PCFs) . DESIGN: The 108 patients were divided into two groups, those whose MICs were greater than their VCs (group 1) and those whose MICs could not exceed their VCs (MIC = VC, or group 2) . RESULTS: The MIC correlated positively with the VC for group 1 patients, but the percent increase in MIC correlated negatively with VC . Both VC and MIC correlated significantly with both unassisted and assisted PCF, respectively . Assisting the cough increased the PCF of 37 patients over a previously defined critical level of 2.7 L/sec . The MIC VC difference and percent increase in MIC also correlated significantly with the difference between unassisted and assisted PCF . Although the group 2 patients did not have true cough flows because of inability to close the glottis, their peak expiratory flows were significantly less than the unassisted and assisted PCF of the group 1 patients . CONCLUSIONS: The greater the MIC VC difference, the greater the PCF, and, thereby, the ability to expel airway mucus and avert respiratory complications . The lower the VC, the greater the percent increase in MIC and the greater the percent increase in assisted PCF . Maximal insufflations are extremely important to increase PCF for patients with neuromuscular conditions who have VCs of < 1500 ml.

Pediatr Infect Dis J, 2000 May, 19(5), 449 - 53
Ciprofloxacin for treatment of tularemia in children; Johansson A et al.; BACKGROUND: Children with tularemia are, irrespective of severity of disease, usually subjected to parenteral treatment with aminoglycosides . Based on available susceptibility testing, quinolones might be effective oral alternatives of parenteral therapy . These drugs cause arthropathy in immature animals, but this risk is currently regarded to be low in humans . PATIENTS AND METHODS: In 12 patients (median age, 4 years; range, 1 to 10) with ulceroglandular tularemia, a 10- to 14-day course of oral ciprofloxacin, 15 to 20 mg/kg daily in 2 divided doses, was prescribed . Microbiologic investigations included identification of the infectious agent by PCR and culture of wound specimens, as well as determination of antibiotic susceptibility of isolates of Francisella tularensis . RESULTS: Defervescence occurred within 4 days of institution of oral ciprofloxacin in all patients . After a median period of 4.5 days (range, 2 to 24), the patients were capable of outdoor activities . In 2 cases, treatment was withdrawn after 3 and 7 days because of rash . In both cases a second episode of fever occurred . All children recovered without complications . In 7 cases F . tularensis was successfully cultured from ulcer specimens and tested for susceptibility to ciprofloxacin . MIC values for all isolates were 0.03 mg/l . CONCLUSION: In our sample of 12 patients ciprofloxacin was satisfactory for outpatient treatment of tularemia in children.

Diabetologia, 2000 Apr, 43(4), 507 - 14
Association of MHC Class I chain-related A (MIC-A) gene polymorphism with Type I diabetes; Gambelunghe G et al.; AIMS/HYPOTHESIS: A distinct family of MHC genes has been identified in the class III region and denominated MHC Class I chain-related genes (MIC) . The MIC-A gene is located between the TNFA and the HLA-B genes . The aim of our study was to test the association of the polymorphism of the MIC-A gene with Type I (insulin-dependent) diabetes mellitus and evaluate the interaction between MIC-A and TNFA, HLA-B, HLA-DR and HLA-DQ gene polymorphism . METHODS: Type I diabetic (n =95) and healthy (n = 98) Italian subjects were typed for exon 5 of MIC-A and for HLA-DRB1, HLA-DQA1, HLA-DQB1 and TNFA alleles . All subjects were also typed for the presence of HLA-B8 or HLA-B15 . RESULTS: The frequency of MIC-A5 was increased in diabetic subjects (53 % vs 15 %) (OR = 6.1) (corrected p, p(c) < 0.0005) . Among HLA class II haplotypes, both HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) ("at-risk class II haplotypes") were positively associated with diabetes (OR = 6.7 and 6.0, respectively) (p(c) < 0.003) . Also HLA-B8 was more frequent among Type I diabetic subjects than among healthy control subjects (OR = 2.8, p = 0.01) . None of the TNFA alleles were statistically significantly associated with Type I diabetes . The MIC-A5 exon was negatively associated with age at clinical onset of diabetes (p = 0.012) . Thus, 68 % diabetic subjects younger than 25 years and 29 % older than 25 years were carrying this allele . Both MIC-A5 and the at-risk class II haplotypes were independently associated with Type I diabetes and the combined association of the two markers had the highest relative risk (OR = 172) . In subjects younger than 25 years, the OR of MIC-A5 was as high as 21.7 and was more than twofold that of at-risk class II haplotypes (OR = 9.5) . The MIC-A5 exon was not in linkage disequilibrium with any of the HLA-class I, class II or TNFA alleles studied . CONCLUSIONS/INTERPRETATION: The MIC-A gene polymorphism is associated with genetic risk for Type I diabetes and the combination of MIC-A5 and at-risk class II haplotypes is now to be seen as the strongest genetic marker for this disease.

Zhongguo Yao Li Xue Bao, 1999 May, 20(5), 426 - 30
Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency in rats and prevented cardiac hypertrophy in mice; Wang Y et al.; AIM: To study the effects of quercetin (Que) on myocardial excitation-contraction coupling and cardiac remodeling . METHODS: Left ventricles and femoral arteries of rats were cannulated for hemodynamic recording . Mouse cardiac hypertrophy was induced by abdominal aortic coarctation (AAC) . Cultured myocardial cells in neonatal rats were loaded with Fura 2-AM . The intracellular calcium ({Ca2+}i) and spontaneous {Ca2+}i oscillations ({Ca2+}i-SO) were tested by AR-CM-MIC cation measurement system . RESULTS: Que 3 or 25 mg.kg-1 i.v . in rats decreased heart rate from (420 +/- 19) to (390 +/- 15) and (314 +/- 18) beat.min-1, respectively, companied with very modest changes in both left ventricular pressures (LVP) and its differential dpLV/dtmax . Que 10, 50, 250 mumol.L-1 concentration-dependently slowed the frequency of {Ca2+}i-SO in cultured myocardial cells from (26 +/- 4) to (25 +/- 3), (18 +/- 4), and (12 +/- 3) time.min-1, respectively, but did not change their resting {Ca2+}i or amplitudes of {Ca2+}i-SO . Similarly, the increases in frequency of {Ca2+}i-SO caused by either isoproterenol (Iso) or ouabain (Oua) were prevented by Que 100 mumol.L-1, while the simultaneous increases in amplitude of {Ca2+}i-SO remained . Besides, {Ca2+}i rises excited by angiotensin II (Ang II) but not high {K+}o were prevented by Que 100 mumol.L-1 . Daily administration of Que 120 mg.kg-1 i.g . for 5 d markedly prevented the cardiac hypertrophy in AAC mice, without effects on the ventricular mass to body weight ratio (VM/BW) in sham-operated mice . CONCLUSION: Que decreased myocardial {Ca2+}i-oscillation frequency and prevented cardiac remodeling, but had no direct effect on cardiac excitation-contraction coupling.

Antimicrob Agents Chemother, 2000 Jun, 44(6), 1734 - 6
In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum; Li RK et al.; The in vitro activity of voriconazole was compared to those of itraconazole and amphotericin B against the mold forms of 304 isolates of three dimorphic fungi, Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum . MICs were determined by a broth microdilution adaptation of the National Committee for Clinical Laboratory Standards M27-A procedure . RPMI 1640 medium was used for tests with voriconazole and itraconazole, whereas Antibiotic Medium 3 with 2% glucose was used for amphotericin B . Minimum fungicidal concentrations (MFCs) were also determined . Amphotericin B was active against all three dimorphic fungi, with MICs at which 90% of the isolates tested are inhibited (MIC(90)s) of 0.5 to 1 microg/ml . Itraconazole had MIC(90)s of 0.06 microg/ml for H . capsulatum, 0.125 microg/ml for B . dermatitidis, and 1 microg/ml for C . immitis . The MIC(90)s of voriconazole were 0.25 microg/ml for all three fungi . Amphotericin B was fungicidal for B . dermatitidis and H . capsulatum with MFCs at which 90% of strains tested are killed (MFC(90)s) of 0.5 and 2 microg/ml, respectively . It was less active against C . immitis, with MFCs ranging from 0.5 to >16 microg/ml . Voriconazole and itraconazole were lethal for most isolates of B . dermatitidis, with MFC(50)s and MFC(90)s of 0.125 and 4 microg/ml, respectively . Both azoles were fungicidal for some isolates of H . capsulatum, with MFC(50)s of 2 and 8 microg/ml for itraconazole and voriconazole, respectively; neither had a lethal effect upon C . immitis . Our results suggest that voriconazole possesses promising activity against these important human pathogens.

Antimicrob Agents Chemother, 2000 Jun, 44(6), 1624 - 9
Comparison of nikkomycin Z with amphotericin B and itraconazole for treatment of histoplasmosis in a murine model; Goldberg J et al.; Nikkomycin Z was tested both in vitro and in vivo for efficacy against Histoplasma capsulatum . Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole . The median MIC was 8 microg/ml with a range of 4 to 64 microg/ml for nikkomycin Z, 0.56 microg/ml with a range of 0.5 to 1.0 microg/ml for amphotericin B, and < or =0.019 microg/ml for itraconazole . Primary studies were carried out by using a clinical isolate of H . capsulatum for which the MIC of nikkomycin Z was greater than or equal to 64 microg/ml . In survival experiments, mice treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD) itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at 100 mg/kg/dose BID survived to day 14, while 70% of mice receiving nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving nikkomycin Z at 5 mg/kg/dose BID survived to day 14 . All vehicle control mice died by day 12 . Fungal burden was assessed on survivors . Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels of Histoplasma antigen in lung and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID . Studies also were carried out with a clinical isolate for which the MIC of nikkomycin Z was 4 microg/ml . All mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice survived . Fungal burden assessed on survivors showed similar levels of Histoplasma antigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID . The three surviving vehicle control mice had significantly higher antigen levels in lung and spleen than other groups (P<0.05) . The efficacy of nikkomycin Z at preventing mortality and reducing fungal burden correlates with in vitro susceptibility.

Antimicrob Agents Chemother, 2000 Jun, 44(6), 1530 - 7
Dihydropteroate synthase of Mycobacterium leprae and dapsone resistance; Williams DL et al.; Two Mycobacterium leprae genes, folP1 and folP2, encoding putative dihydropteroate synthases (DHPS), were studied for enzymatic activity and for the presence of mutations associated with dapsone resistance . Each gene was cloned and expressed in a folP knockout mutant of Escherichia coli (C600DeltafolP::Km(r)) . Expression of M . leprae folP1 in C600DeltafolP::Km(r) conferred growth on a folate-deficient medium, and bacterial lysates exhibited DHPS activity . This recombinant displayed a 256-fold-greater sensitivity to dapsone (measured by the MIC) than wild-type E . coli C600, and 50-fold less dapsone was required to block (expressed as the 50% inhibitory concentration {IC(50)}) the DHPS activity of this recombinant . When the folP1 genes of several dapsone-resistant M . leprae clinical isolates were sequenced, two missense mutations were identified . One mutation occurred at codon 53, substituting an isoleucine for a threonine residue (T53I) in the DHPS-1, and a second mutation occurred in codon 55, substituting an arginine for a proline residue (P55R) . Transformation of the C600DeltafolP::Km(r) knockout with plasmids carrying either the T53I or the P55R mutant allele did not substantially alter the DHPS activity compared to levels produced by recombinants containing wild-type M . leprae folP1 . However, both mutations increased dapsone resistance, with P55R having the greatest affect on dapsone resistance by increasing the MIC 64-fold and the IC(50) 68-fold . These results prove that the folP1 of M . leprae encodes a functional DHPS and that mutations within this gene are associated with the development of dapsone resistance in clinical isolates of M . leprae . Transformants created with M . leprae folP2 did not confer growth on the C600DeltafolP::Km(r) knockout strain, and DNA sequences of folP2 from dapsone-susceptible and -resistant M . leprae strains were identical, indicating that this gene does not encode a functional DHPS and is not involved in dapsone resistance in M . leprae.

EMBO J, 2000 May 15, 19(10), 2212 - 20
The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1; Bauskin AR et al.; Macrophage inhibitory cytokine (MIC-1), a divergent member of the transforming growth factor-beta (TGF-beta) superfamily and activation associated cytokine, is secreted as a 28 kDa dimer . To understand its secretion, we examined its processing in MIC-1-transfected Chinese hamster ovary cells . Mature MIC-1 dimer arises post-endoplasmic reticulum (ER) by proteolytic cleavage of dimeric pro-MIC-1 precursor at a furin-like site . Unlike previously characterized TGF-beta superfamily members, MIC-1 dimers are also secreted in constructs lacking the propeptide . A clue to the function of the propeptide came from the observation that a range of proteasome inhibitors, including lactacystin and MG132, cause major increases in levels of undimerized pro-MIC-1 precursor . There was no effect of proteasome inhibitors on cells expressing mature MIC-1 without the propeptide, suggesting that the propeptide can signal misfolding of MIC-1, leading to proteasomal degradation . Deletion mutagenesis showed the N-terminal 28 amino acids of the propeptide are necessary for proteasomal degradation . This is the first demonstration, to our knowledge, of a quality control function in a propeptide domain of a secretory protein and represents an additional mechanism to ensure correct folding of proteins leaving the ER.

Anticancer Res, 2000 Mar-Apr, 20(2B), 1317 - 22
Vascular endothelial growth factor expression in progression of cervical cancer: correlation with thymidine phosphorylase expression, angiogenesis, tumor cell proliferation, and apoptosis; Fujiwaki R et al.; BACKGROUND: Vascular endothelial growth factor (VEGF) has been linked not only to angiogenic activity but also to thymidine phosphorylase (TP), rapid tumor growth, and inhibition of apoptotic cell death . Our purpose was to examine how VEGF expression affect these factors in cervical cancer at varying stages of progression . METHODS: VEGF expression, TP expression, the microvessel count (reflected by factor VIII-related antigen), and proliferating cell nuclear antigen (PCNA) were assessed immunohistochemically in 19 specimens of normal cervical epithelium, 35 of carcinoma in situ (CIS), 34 of microinvasive carcinoma (MIC), and 34 of invasive cervical squamous cell carcinoma (SCC) . Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method . RESULTS: VEGF expression progressively increased along a continuum from normal epithelium to invasive SCC (P < 0.0001) . VEGF expression significantly correlated with TP expression and PCNA index (P < 0.01 and P < 0.0001, respectively) . In analyses within histological stages, VEGF expression significantly correlated with the PCNA index in CIS and MIC (P < 0.01 and P < 0.05, respectively), but not in invasive SCC . The PCNA index for combined analysis of VEGF and TP expression was similar to that for VEGF expression alone . VEGF expression tended to correlate with microvessel count, however, the difference was not significant (P = 0.09) . No significant correlation was observed between VEGF expression and the apoptotic index . CONCLUSIONS: VEGF expression may stimulate tumor cell proliferation in the early stages of cervical cancer, and may be responsible for cervical tumorigenesis.

Histol Histopathol, 2000 Apr, 15(2), 503 - 13
Characterization of ligands for galectins, natural galactoside-binding immunoglobulin G subfractions and sarcolectin and also of the expression of calcyclin in thyroid lesions; Nagy N et al.; The purpose of this study was to characterize ligands for galectins, natural galactoside-binding immunoglobulin G subfractions and sarcolectin and also the expression of calcyclin in various benign and malignant thyroid lesions . The extent of the binding of eight glycochemical probes was quantitatively assessed using computer-assisted microscopy on 76 thyroid lesions including 10 not-otherwise-specified multinodular goiters (S_MNG), 11 multinodular goiters with adenomatous hyperplasia (AH_MNG), 8 normomacrovesicular (NM_ADE) and 12 microvesicular (MIC_ADE) adenomas, and 9 papillary (P_CAR), 10 follicular variants of papillary (FvarP_CAR), 7 follicular (F_CAR) and 9 anaplastic (A_CAR) carcinomas . The 8 histochemical probes included 5 animal lectins (including galectins and sarcolectin), 1 polyclonal antibody (raised against calcyclin) and 2 immunoglobulin G subfractions from human serum with selectivity to alpha- and beta-galactosyl residues . The results show that multinodular goiters with adenomatous hyperplasia exhibited histochemical characteristics intermediate to those of normal multinodular goiters and microvesicular adenomas . Normomacrovesicular adenomas behaved very distinctly from microvesicular ones . Microvesicular adenomas were more closely related to differentiated thyroid carcinomas than any other type of benign thyroid lesions of epithelial origin . Papillary and follicular carcinomas seemed to represent the two extremes of the same biological entity with the follicular variant of the papillary carcinoma serving as a biological link between these two extremes . Anaplastic carcinomas behaved in a significantly different manner when compared to the differentiated forms of thyroid carcinomas . The results suggest that the patterns of expression of the glycoconjugates investigated in the present study may constitute useful tools for characterizing lesions in the human thyroid.

Pharmacotherapy, 2000 May, 20(5), 554 - 61
Pharmacokinetics and pharmacodynamics of ceftizoxime in patients with dosages adjusted for renal function; Neuhauser MM et al.; STUDY OBJECTIVE: Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics . Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cp(min)) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function . DESIGN: Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages . SETTING: University-affiliated hospital . PATIENTS: Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Cl(cr); ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30 . INTERVENTIONS: Ceftizoxime serum concentrations were obtained at steady state . MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were calculated . As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment . The Cp(min) and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42) . The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups . Clinical outcomes were similar among all groups . CONCLUSION: Our dosing guidelines achieved similar Cp(min) among all groups of patients . Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.

Jpn Heart J, 2000 Jan, 41(1), 15 - 26
Takayasu arteritis: insights into immunopathology; Seko Y; Takayasu arteritis is an acute and sometimes chronic form of vasculitis involving the aorta, its main branches and pulmonary arteries . Although its etiology is still unknown, immunopathologic analyses revealed that the infiltrating cells mainly consisted of gammadelta T-cells as well as alphabeta T-cells and NK cells . The infiltrating gammadelta T-cells, cytotoxic T-lymphocytes (CTLs), and natural killer (NK) cells directly injured the vascular cells by releasing a cytolytic factor, perforin . Expression of heat-shock protein (HSP)-65 as well as human leukocyte antigen (HLA) class I and II was enhanced in Takayasu arteritis lesions, supporting the pathogenic role of gammadelta T-cells and alphabeta T-cells . T-cell receptor (TCR) alphabeta gene usage by the infiltrating cells was restricted, strongly suggesting that a specific antigen was targeted . TCR gammadelta gene usage by the infiltrating cells was also restricted . Furthermore, it has been reported that a strong association with a specific haplotype of major histocompatibility complex (MHC) class I chain-related (MIC), MICA gene with Takayasu arteritis, suggesting that the HLA-linked gene susceptible to the disease is mapped near the MICA gene . This also supports a pathogenic role of gammadelta T-cells in Takayasu arteritis because gammadelta T-cells were shown to recognize MICA molecule, which can be stress-induced . These findings suggest that unknown stress, such as infection, may trigger the autoimmune process of inflammation involved in Takayasu arteritis.

Am J Surg Pathol, 2000 May, 24(5), 710 - 8
Some mullerian inclusion cysts in lymph nodes may sometimes be metastases from serous borderline tumors of the ovary; Moore WF et al.; Glandular inclusions that appear morphologically benign are occasionally found in lymph nodes as well as in peritoneal and omental biopsies . In patients with gynecologic malignancies, the nature and significance of these mullerian inclusion cysts (MIC) present a diagnostic challenge with regard to whether they are benign and incidental or are related to the coincident tumor for which surgery is being performed . Sixty-two cases of MIC were prospectively identified during a 6-year period . The frequencies were calculated and stratified by lymph node chain distribution, primary tumor site, and primary tumor type . MIC appeared as small cysts lined by a serous (mullerian)-type, cytologically bland, cuboidal to columnar epithelium with a simple architecture . Among 62 women, MIC was found in lymph nodes (27 cases), pelvic peritoneum (19 cases), omentum (16 cases), bowel serosa (9 cases), uterine serosa (8 cases), and parametrial connective tissues (4 cases) . Among a set of 417 consecutive cases in which lymphadenectomy was performed, 46 (11%) women had MIC . The MIC involved multiple sites (26 cases in the peritoneum/omentum and 27 in lymph nodes) . The primary tumor was in the ovary in 32 of the 46 women with MIC (70%) and of these, 17 were borderline serous (53%) . Sixty-two of 6,154 lymph nodes examined contained MIC (1.0%) . 3.2% of nodes contained MIC in which the primary tumor arose in the ovary, but only 0.1% with either endometrial or cervical tumors (chi2, p <0.00001) . The lymph nodes most often involved by MIC were from para-aortic sites (40%), which reflect the primary drainage route from the ovary . Not uncommonly, neighboring areas in the same lymph node group with MIC disclosed separate foci of obvious metastatic borderline tumor (4 of 10; 40%) . In summary, the increased frequency of MIC in lymph nodes sampled for primary ovarian malignancies suggests that MIC in some cases, rather than being benign, incidental inclusions, are more likely bland-appearing forms of metastatic tumor . The preponderance of inclusions occurs with serous ovarian tumors of borderline malignancy, and the inclusions are overrepresented in the lymph nodes that primarily receive drainage from the ovary.

Dakar Med, 1998, 43(2), 147 - 51
{Community nutrition strategy project: an innovation in community health}; Diallo I et al.; The strategy of the community nutrition project is based on the utilization of the community development structures to deliver the nutrition services . These structures, represented in Senegal by youth associations, women groups, GIEs and NGOs, are part of the decentralization process, and as such play an important role in health and health development activities in poor urban districts . The Community Nutrition Project (CNP), funded for five years by the World Bank, German Cooperation (KFW), World Food Program (WFP) and the Senegalese government aims to halt further deterioration in the nutrition status of the most vulnerable groups in the poorest urban districts of Senegal . All nutrition services and particularly the IEC services have been entirely contracted out the first year to 76 GIEs involving 323 unemployed persons, operating as micro-enterprises "MIC" and 17 "GIEs" of unemployed physicians, pharmacists, and social workers for a total of 34 persons, organized as "maitre d'Oeuvre communautaires "MOC", in charge of the supervision tasks . Each community nutrition center recruits and monitors every six months 460 to 600 beneficiaries composed of women at six months of pregnancy, lactating mother of children under 6 months, and a group of children aged from 6 to 35 months old . An average of 87% of registered children in the nutrition centers are weekly or monthly weighted . Thus the proportion of malnourished children in cohort of children followed from January to July 1996 has decreased from 70% to 25% within six months . The malnutrition rate has been reduced up to 65% after six months.

Mol Microbiol, 2000 Apr, 36(2), 302 - 13
Identification of an AfsA homologue (BarX) from Streptomyces virginiae as a pleiotropic regulator controlling autoregulator biosynthesis, virginiamycin biosynthesis and virginiamycin M1 resistance; Kawachi R et al.; Virginiae butanolide (VB)-BarA of Streptomyces virginiae is one of the newly discovered pairs of a gamma-butyrolactone autoregulator and the corresponding receptor protein of the Streptomyces species, and has been shown to regulate the production of antibiotic virginiamycin (VM) in S . virginiae . A divergently transcribed barX gene is situated 259 bp upstream of the barA gene, and the BarX protein has been shown to be highly homologous (39.8% identity, 74 . 6% similarity) to S . griseus AfsA . Although AfsA is thought to be a biosynthetic enzyme for A-factor, another member of the family of gamma-butyrolactone autoregulators, the in vivo function of S . virginiae BarX was investigated in this study by phenotypic and transcriptional comparison between wild-type S . virginiae and a barX deletion mutant . With the same growth rate as wild-type S . virginiae on both solid and liquid media, the barX mutant showed no apparent changes in its morphological behaviour, indicating that barX does not participate in morphological control in S . virginiae . However, the barX mutant became more sensitive to virginiamycin M1 than did the wild-type strain (minimum inhibitory concentration, 50 microgram ml-1 compared with > 200 microgram ml-1) and exhibited reduced VB and VM production . The VM production was not restored by exogenous addition of VB, suggesting that BarX per se is not a biosynthetic enzyme of VBs but a pleiotropic regulatory protein controlling VB biosynthesis . DNA sequencing of a 5.6 kbp downstream region of barX revealed the presence of five open reading frames (ORFs): barZ, encoding a BarB-like regulatory protein; orf2, encoding a Streptomyces coelicolor RedD-like pathway specific regulator; varM, encoding a homologue of ATP-dependent transporters for macrolide antibiotics; orf4, encoding a homologue of beta-ketoacyl ACP/CoA reductase; and orf5, encoding a homologue of dNDP-glucose dehydratase . Reverse transcription polymerase chain reaction (RT-PCR) analyses of the downstream five genes together with those of the three upstream genes (barA, barB, encoding a regulatory protein; and varS, encoding a virginiamycin S specific transporter) revealed that, in the barX mutant, the transcriptions of barZ, orf2, varM and orf5 were completely repressed and those of barB and varS were derepressed . Because free BarA (BarA in the absence of VB) in wild-type S . virginiae represses the transcription of bicistronic barB-varS operon through binding to a specific DNA sequence (BarA-responsive element, BARE) overlapping the barB transcriptional start site, the derepression of barB-varS transcription in the barX mutant suggested that the in vivo function of BarA was impaired by the lack of BarX protein . Gel-shift assays revealed that BarA easily lost its DNA-binding activity in the absence of BarX but that the defect was restored by the presence of recombinant BarX as a fusion with maltose-binding protein (MBP-BarX), whereas MBP-BarX itself showed no DNA-binding activity, indicating that BarX is likely to be a co-repressor of BarA, enforcing the DNA-binding activity of BarA through protein-protein interactions.

J Appl Microbiol, 2000 May, 88(5), 784 - 90
Susceptibility testing: accurate and reproducible minimum inhibitory concentration (MIC) and non-inhibitory concentration (NIC) values; Lambert RJ et al.; Measuring the minimum inhibitory concentration (MIC) of a substance by current methods is straightforward, whereas obtaining useful comparative information from the tests can be more difficult . A simple technique and a method of data analysis are reported which give the experimentalist more useful information from susceptibility testing . This method makes use of a 100-well microtitre plate and the analysis uses all the growth information, obtained by turbidometry, from each and every well of the microtitre plate . A modified Gompertz function is used to fit the data, from which a more exact value can be obtained for the MIC . The technique also showed that at certain concentrations of inhibitor, there was no effect on growth relative to a control well (zero inhibitor) . Above a threshold value, which has been termed the non-inhibitory concentration or NIC, growth becomes limiting until it reaches the MIC, where no growth relative to the control is observed.

Br J Clin Pharmacol, 2000 May, 49(5), 453 - 61
Nonspecific binding of drugs to human liver microsomes; McLure JA et al.; AIMS: To characterize the nonspecific binding to human liver microsomes of drugs with varying physicochemical characteristics, and to develop a model for the effect of nonspecific binding on the in vitro kinetics of drug metabolism enzymes . METHODS: The extent of nonspecific binding to human liver microsomes of the acidic drugs caffeine, naproxen, tolbutamide and phenytoin, and of the basic drugs amiodarone, amitriptyline and nortriptyline was investigated . These drugs were chosen for study on the basis of their lipophilicity, charge, and extent of ionization at pH 7.4 . The fraction of drug unbound in the microsomal mixture, fu(mic), was determined by equilibrium dialysis against 0.1 M phosphate buffer, pH 7.4 . The data were fitted to a standard saturable binding model defined by the binding affinity KD, and the maximum binding capacity Bmax . The derived binding parameters, KD and Bmax, were used to simulate the effects of saturable nonspecific binding on in vitro enzyme kinetics . RESULTS: The acidic drugs caffeine, tolbutamide and naproxen did not bind appreciably to the microsomal membrane . Phenytoin, a lipophilic weak acid which is mainly unionized at pH 7 . 4, was bound to a small extent (fu(mic) = 0.88) and the binding did not depend on drug concentration over the range used . The three weak bases amiodarone, amitriptyline and nortriptyline all bound extensively to the microsomal membrane . The binding was saturable for nortriptyline and amitriptyline . Bmax and KD values for nortriptyline at 1 mg ml-1 microsomal protein were 382 +/- 54 microM and 147 +/- 44 microM, respectively, and for amitriptyline were 375 +/- 23 microM and 178 +/- 33 microM, respectively . Bmax, but not KD, varied approximately proportionately with the microsome concentration . When KD is much less than the Km for a reaction, the apparent Km based on total drug can be corrected by multiplying by fu(mic) . When the substrate concentration used in a kinetic study is similar to or greater than the KD (Km >/= KD), simulations predict complex effects on the reaction kinetics . When expressed in terms of total drug concentrations, sigmoidal reaction velocity vs substrate concentration plots and curved Eadie Hofstee plots are predicted . CONCLUSIONS: Nonspecific drug binding in microsomal incubation mixtures can be qualitatively predicted from the physicochemical characteristics of the drug substrate . The binding of lipophilic weak bases is saturable and can be described by a standard binding model . If the substrate concentrations used for in vitro kinetic studies are in the saturable binding range, complex effects are predicted on the reaction kinetics when expressed in terms of total (added) drug concentration . Sigmoidal reaction curves result which are similar to the Hill plots seen with cooperative substrate binding.

J Clin Microbiol, 2000 May, 38(5), 2015 - 7
Infective endocarditis complicated with progressive heart failure due to beta-lactamase-producing Cardiobacterium hominis; Lu PL et al.; We describe a 66-year-old woman with infective endocarditis due to Cardiobacterium hominis whose condition, complicated by severe aortic regurgitation and congestive heart failure, necessitated aortic valve replacement despite treatment with ceftriaxone followed by ciprofloxacin . The blood isolate of C . hominis produced beta-lactamase and exhibited high-level resistance to penicillin (MIC, >==256 microgram/ml) and reduced susceptibility to vancomycin (MIC, 8 microgram/ml).

Zhongguo Yao Li Xue Bao, 1999 Aug, 20(8), 733 - 6
L-pyroglutamic acid protects rat cortical neurons against sodium glutamate-induced injury; Xiao XQ et al.; AIM: To evaluate the effects of L-pyroglutamic acid (L-PGA, L-5-oxo-2-pyrrolidinecaroxylic acid) on sodium glutamate-induced neurotoxicity in rat cortical neurons . METHODS: In primary cortical cultures from 16-d-old fetal rat, neuronal viability and contents of nitrite in the bathing medium after transient exposure to sodium glutamate (Glu) were measured; with Fura 2-AM as an intracellular calcium indicator, AR-CM-MIC cation measurement system was used to examine cytosolic free calcium ({Ca2+}i) . RESULTS: L-PGA 10-80 mumol.L-1, inhibited Glu (500 mumol.L-1)-induced neuronal loss in a concentration-dependent manner with IC50 value of (41 +/- 9) mumol.L-1 (95% confidence limits: 30.3-54.7 mumol.L-1) . L-PGA also attenuated Glu-induced NO release . L-PGA 1, 3, 10, 30, and 100 mumol.L-1 depressed Glu-caused {Ca2+}i elevation by 20.5%, 34.4%, 47.7%, 70.6%, and 80.4%, respectively . CONCLUSION: L-PGA protects cortical neurons against Glu-induced neurotoxity which may be related to inhibition of NO formation or suppression of the rise in {Ca2+}i.

J Assoc Physicians India, 1999 Aug, 47(8), 795 - 7
Antibiotics sensitivity pattern of N . gonorrhoeae with special emphasis on norfloxacin and ciprofloxacin; Pai A et al.; The current study is carried out to find the in-vitro susceptibility of N . gonorrhoeae to Ciprofloxacin, Norfloxacin, Gentamycin etc . in 110 isolates obtained from acute gonococcal urethritis confirmed by smear examination . The isolates obtained are from the patients attending the Skin and STD Clinic of a teaching hospital, clinically diagnosed as suffering from acute gonococcal urethritis . Antibiotic susceptibility test was done by Kirby Bauer disc diffusion technique . Four to five similar well isolated colonies of the gonococcal strains were picked up with a wire loop and transferred to 5 cc of sterile trypticase soya broth (TSB) . Tubes were incubated at 36 degrees C . GC agar base plates were inoculated with suspensions using a sterile cotton swab . Antibiotic discs were placed on these plates . The plates were incubated at 35 degrees C for 18-24 hours in a candle jar with 5-10% CO2 . The plates were then observed to note the zones of inhibition around the discs . 87.27% of isolated strains were inhibited by norfloxacin at an MIC of 0.06 mu gm/ml; 89.08% of the strains were inhibited by ciprofloxacin at an MIC of 0.025 mu gm/ml . All the strains (110) were inhibited by ciprofloxacin at a concentration of 0.2 mu gm/ml . Gentamycin sensitivity was 86.36% . Out of 110 patients, 85 were treated with norfloxacin of which 81 (95.29%) were cured . Twenty five were treated with ciprofloxacin of which 24 (96%) were cured . This study shows high sensitivity of N . gonorrhoeae to norfloxacin and ciprofloxacin.

J Agric Food Chem, 2000 Apr, 48(4), 1400 - 4
Cyclopenta{b}benzofurans from Aglaia species with pronounced antifungal activity against rice blast fungus (Pyricularia grisea); Engelmeier D et al.; Eight flavaglines, six cyclopenta{b}benzofurans, a cyclopenta{bc}benzopyran, and a benzo{b}oxepine, together with an aromatic butyrolactone were isolated from Aglaia odorata, A . elaeagnoidea, and A . edulis (Meliaceae) and tested against the three plant pathogens Pyricularia grisea, Fusarium avenaceum, and Alternaria citri for antifungal properties . Using the microdilution technique linked with digital image analysis of germ tubes, the benzofurans displayed strong activity, whereas the benzopyran, benzoxepine, and butyrolactone were inactive at the highest concentration tested . P . grisea, responsible for rice blast disease, was the most susceptible fungus against all benzofurans, with rocaglaol as the most active derivative . Based on EC(50), EC(90), and MIC values, the antifungal activity of rocaglaol was clearly higher than of the reference compounds, blasticidin S and Benlate.

Southeast Asian J Trop Med Public Health, 1999 Jun, 30(2), 220 - 4
Investigations of incidence of pretreatment, drug sensitivity in vitro, and plasma levels of pyrimethamine in patients with multidrug resistant falciparum malaria following the three combination regimens of artemether/pyrimethamine; Tippawangkosol P et al.; The study was carried out to investigate the status of in vitro susceptibility of Plasmodium falciparum to pyrimethamine (PYR) in multidrug resistant area of the Thai-Myanmar border, the incidence of unregulated use of the combination of PYR with sulfadoxine (Fansidar) in this area and the relevance of pharmacodynamic and pharmacokinetic factors in determining the treatment outcome from the three combination regimens of ART/PYR (1-, 2- and 3-day regimens), in patients with acute uncomplicated falciparum malaria . The majority of patients had baseline PYR concentrations in the range of 1-100 (50.6%) or 100-500 (34.8%) ng/ml, while concentrations of more than 500 ng/ml were found in only 1.1% . All of the isolates exhibited high grade resistance to PYR with the minimum inhibition concentration (MIC) of as high as 10(-5) M . No association was observed between treatment outcome and the presence of baseline plasma PYR concentrations . In addition, lack of association between plasma concentrations during the acute phase (day-1 and -2) and treatment outcome was found.

Nippon Geka Gakkai Zasshi, 2000 Mar, 101(3), 274 - 5
The historical impact of minimally invasive surgery; Hartel W; At first there is an idea which asks for more comfort for the patient and equal results compared to conventional procedures . This means less pain and fatigue, quicker convalescence and shorter hospital stay . The new procedures requests an entirely new operative skill and a new technique with new instruments . Those were early developed in Germany . The roads on which this was performed will be described . In another chapter the history of this development is shown, especially the German, French and US inventors with a special view on their personal experiences and disappointments like in the German surgeon M_he and the gynecologist Semm from Kiel, Germany . But they all remained enthusiastic as a common personal quality . The new technique (MIC) was translated "Mickey-Mouse-Surgery" and medicolegal consequences like in M_he were usual events . Another example of misunderstanding of the impact of the new technique: the first publication of Semm about the laoaroscopically removed appendix has been withheld so long in Germany until it was published in the USA in the Journal "Obstetrics and Gynecology" . Besides this it is reported about the life cycle of this innovation pointing out to the final promising report, the professional adoption and public acceptance and the randomized controlled trials . The last stage is characterized by "jumping on another train" . Pictures are shown of those pioneers who had the idea, who understood what they were doing and who took the responsibility . The final chapter will deal with the consequences for the future generation of surgeons and their training and the unanswered questions as to further fields . Doubtlessly, the pioneer period did not come to an end yet . A glance into the future may be allowed.

Int J Antimicrob Agents, 2000 Apr, 14(3), 231 - 4
Potentiation of the action of metronidazole on Helicobacter pylori by omeprazole and bismuth subcitrate; Andersen LP et al.; Treatment failures using triple therapy that include metronidazole, are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa . Higher eradication rates in such patients have been described when treatment regimens include bismuth salts compared to regimens that include proton pump inhibitors . In the present study, the synergistic effect of subinhibitory concentrations (0.25-0.5 MIC) of either bismuth subcitrate or omeprazole with metronidazole on the susceptibility of 42 H . pylori strains was investigated by agar dilution method and the Epsilometer test (Etest) . With 0.5 MIC of either of the two drugs, the susceptibility of all H . pylori4 mg/l) reverted to being metronidazole sensitive . These results suggested that either bismuth salts or proton pump inhibitors may be effective in the treatment of some infections with metronidazole-resistant H . pylori strains when used in sufficiently high doses.

Bull Soc Pathol Exot, 2000 Feb, 93(1), 6 - 7
{In vitro sensitivity to antibiotics in 178 strains of genital mycoplasma isolated from gynecology consultants in Dakar}; Sow AI et al.; The susceptibility to antibiotics of 144 strains of Ureaplasma urealyticum and 34 strains of Mycoplasma hominis isolated in Dakar, Senegal, was determinated by MIC determination in a medium . Doxycyclin and minocyclin are active on more than 90% of the strains of U . urealyticum, and more than 80% of M . hominis strains . Over 93% of U . urealyticum strains are susceptible to all the macrolids and apparented tested (erythromycin, pristinamycin, josamycin), but the activity of lincomycin, pristinamycin and josamycin on M . hominis was found only for 70% of the strains . Fluoroquinolones, once adequately studied, could turn out to be a useful alternative in therapeutics.

Am J Vet Res, 2000 Apr, 61(4), 407 - 12
Continuous infusion of gentamicin into the tarsocrural joint of horses; Lescun TB et al.; OBJECTIVE: To develop a method for continuous infusion of gentamicin into the tarsocrural joint of horses, to determine pharmacokinetics of gentamicin in synovial fluid of the tarsocrural joint during continuous infusion, and to evaluate effects of continuous infusion of gentamicin on characteristics of the synovial fluid . ANIMALS: 12 healthy adult horses . PROCEDURE: An infusion catheter consisting of flow control tubing connected to a balloon infuser was used . Gentamicin solution (100 mg/ml) was infused in the right tarsocrural joint and balanced electrolyte solution was infused in the left tarsocrural joint for 5 days . Synovial fluid and serum gentamicin concentrations were measured by use of a fluorescence polarization immunoassay . RESULTS: 17 of the 24 (71%) infusion catheters initially placed functioned without complications for the entire 5-day infusion period . Median gentamicin concentration in synovial fluid from treated joints during the 5-day infusion period ranged from 2875 to 982 microg/ml . Median serum gentamicin concentration during this period ranged from 2.31 to 2.59 microg/ml . Mean (+/- SD) elimination half-life and total clearance of gentamicin from the synovial fluid were 6.25+/-1.01 hours and 1.52+/-0.96 ml/min, respectively . CONCLUSIONS AND CLINICAL RELEVANCE: An infusion catheter can be used for continuous infusion of gentamicin into the tarsocrural joints of horses for up to 5 days . At a gentamicin dosage of 0.17+/-0.02 mg/kg/h, continuous intra-articular infusion results in synovial fluid gentamicin concentrations greater than 100 times the minimal inhibitory concentration reported for common equine pathogens.

Antimicrob Agents Chemother, 2000 May, 44(5), 1407 - 8
In vitro comparison of terbinafine and itraconazole against Penicillium marneffei; McGinnis MR et al.; We evaluated terbinafine and itraconazole against 30 isolates of Penicillium marneffei using a modification of the National Committee for Clinical Laboratory Standards broth macrodilution MIC testing protocol for yeasts . The minimal fungicidal concentration (MFC) was determined by plating 100 microl from each MIC drug dilution having no growth onto Sabouraud glucose agar incubated at 30 degrees C . The MFC was the dilution at which growth was absent at 72 h of incubation . The MICs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 1.0 (geometric mean titer, 0.09); itraconazole, 0.03 to 0.5 (geometric mean titer, 0.04) . The MFCs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 8 (geometric mean titer, 2.60); itraconazole, 0.03 to 8 (geometric mean titer, 2 . 45) . Primary fungicidal activity (MFC within 2 dilutions of MIC) was observed with terbinafine in eight isolates and with itraconazole in four isolates . The data indicate that terbinafine is active against P . marneffei in vitro and may have a previously unrealized role in the management of infections caused by this fungus.

Antimicrob Agents Chemother, 2000 May, 44(5), 1337 - 41
Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide concentrations; Conte JE Jr et al.; Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40 adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women) . Blood was obtained for drug assay prior to administration of the first dose, 2 h after the last dose, and at the completion of standardized bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose . Ethionamide was measured in epithelial lining fluid (ELF) and alveolar cells (AC) using a new mass spectrometric method . The presence of AIDS or gender was without significant effect on the concentrations of ethionamide in plasma, AC, or ELF . Plasma concentrations (mean +/- standard deviation {SD}) were 0.97 +/- 0.65 and 0.65 +/- 0.35 microg/ml at 2 and 4 h after the last dose, respectively, and both values were significantly greater than the concentration of ethionamide in AC (0.38 +/- 0.47 microg/ml) (P < 0 . 05) . The concentration of ethionamide was significantly greater in ELF (5.63 +/- 3.8 microg/ml) than in AC or plasma at 2 and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide-susceptible strains of Mycobacterium tuberculosis . For all 40 subjects, the ELF/plasma concentration ratios (mean +/- SD) at 2 and 4 h were 8.7 +/- 11.7 and 9.7 +/- 5.6, respectively . We conclude that the absorption of orally administered ethionamide, as measured in this study, was not affected by gender or the presence of AIDS . Ethionamide concentrations were significantly greater in ELF than in plasma or AC, suggesting that substantial antimycobacterial activity resides in this compartment.

J Bacteriol, 2000 May, 182(9), 2611 - 8
Generation of dominant selectable markers for resistance to pseudomonic acid by cloning and mutagenesis of the ileS gene from the archaeon Methanosarcina barkeri fusaro; Boccazzi P et al.; Currently, only one selectable marker is available for genetic studies in the archaeal genus Methanosarcina . Here we report the generation of selectable markers that encode resistance to pseudomonic acid (PA(r)) in Methanosarcina species by mutagenesis of the isoleucyl-tRNA synthetase gene (ileS) from Methanosarcina barkeri Fusaro . The M . barkeri ileS gene was obtained by screening of a genomic library for hybridization to a PCR fragment . The complete 3,787-bp DNA sequence surrounding and including the ileS gene was determined . As expected, M . barkeri IleS is phylogenetically related to other archaeal IleS proteins . The ileS gene was cloned into a Methanosarcina-Escherichia coli shuttle vector and mutagenized with hydroxylamine . Nine independent PA(r) clones were isolated after transformation of Methanosarcina acetivorans C2A with the mutagenized plasmids . Seven of these clones carry multiple changes from the wild-type sequence . Most mutations that confer PA(r) were shown to alter amino acid residues near the KMSKS consensus sequence of class I aminoacyl-tRNA synthetases . One particular mutation (G594E) was present in all but one of the PA(r) clones . The MIC of pseudomonic acid for M . acetivorans transformed with a plasmid carrying this single mutation is 70 microgram/ml of medium (for the wild type, the MIC is 12 microgram/ml) . The highest MICs (560 microgram/ml) were observed with two triple mutants, A440V/A482T/G594E and A440V/G593D/G594E . Plasmid shuttle vectors and insertion cassettes that encode PA(r) based on the mutant ileS alleles are described . Finally, the implications of the specific mutations we isolated with respect to binding of pseudomonic acid by IleS are discussed.

Bioorg Med Chem Lett, 2000 Apr 3, 10(7), 657 - 60
Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity . Part 9; Bottari B et al.; Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and nickel(II) 3 octahedral complexes of stoichiometry {MeL2(H2O)2} . Their antimycobacterial in vitro activity was evaluated against Mycobacterium tuberculosis H37Rv in comparison with the ligands . Complexes 2a, 2b, 2f, 3b, 3d and 3g displayed MIC values < or = 0.2 microg/mL.

Artif Organs, 2000 Mar, 24(3), 224 - 30
Nonstoichiometric hydroxyapatite-anionic collagen composite as support for the double sustained release of gentamicin and norfloxacin/ciprofloxacin; Amaro Martins VC et al.; This work studied the sustained release of ciprofloxacin or norfloxacin and gentamicin from nonstoichiometric hydroxyapatite (nHA) and anionic collagen composite . Within the first 24 and 48 h, the total antibiotic supply was significantly higher than the minimal inhibitory concentration required for the majority of the gram-negative bacteria . Although gentamicin was completely released from the matrix after 48 h by a normal diffusion mechanism, ciprofloxacin or norfloxacin release was characterized by a 2-phase release mechanism due to binding to nHA by complexation with calcium ion . Under the conditions studied, most of the norfloxacin or ciprofloxacin only will be disposable due to bioresorption or dissociation of the complexes . In conclusion, due to its biocompatibility nHA-anionic collagen composite may be a convenient support for the double sustained release of the antibiotics gentamicin and ciprofloxacin/norfloxacin for the control of bone infection while promoting bone tissue growth.

J Antimicrob Chemother, 2000 Apr, 45(4), 525 - 8
Activity of gemifloxacin, a new broad-spectrum quinolone, against 200 pneumococci by four different susceptibility testing methods; Ednie LM et al.; Agar and microdilution (in air), Etest (in air and CO(2)) and disc diffusion (in air and CO(2)) susceptibility testing methods were used to investigate the activity of gemifloxacin against 200 pneumococci . MIC(50)s were 0.016-0.03 mg/L and MIC(90)s 0.125-0.25 mg/L for all methods . With agar dilution as reference, 187/200 strains gave essential agreement with microdilution and 196 with Etest (air and CO(2)) . Disc zones were a few millimetres narrower in CO(2) than in air . With discs in CO(2), all ciprofloxacin-susceptible strains yielded zone diameters 26 mm; values in air were 28 mm . Zones for ciprofloxacin-resistant strains in CO(2) were mostly 21-26 mm; zones in air were a few millimetres wider, but mostly <31 mm.

J Clin Microbiol, 2000 Apr, 38(4), 1444 - 8
Antipneumococcal activity of telithromycin by agar dilution, microdilution, E test, and disk diffusion methodologies; Davies TA et al.; Agar dilution and microdilution (both in air) and E test and disk diffusion (both in air and CO(2)) were used to test the activity of telithromycin against 110 erythromycin-susceptible and 106 erythromycin-resistant pneumococci . The MICs at which 50 and 90% of strains are inhibited (MIC(50)s and MIC(90)s, respectively) for erythromycin-susceptible strains varied between 0.008 and 0.016 microg/ml and 0.016 and 0.03 microg/ml when the samples were incubated in air . By comparison, telithromycin MIC(50)s and MIC(90)s for erythromycin-resistant strains were in air 0.03 to 0.125 and 0 . 125 to 0.5 microg/ml, respectively . When agar dilution was used as the reference method, essential agreement was found for 112 of 216 strains (51.9%) for microdilution, 168 of 216 (77.8%) for E test in air, and 132 of 216 (61.1%) for E test in CO(2) . With the exception of four strains tested by E test in CO(2), all organisms were susceptible to a proposed telithromycin susceptibility breakpoint of < or =1 microg/ml . By disk diffusion with 15-microg telithromycin disks, all strains but one had zones of inhibition > or =19 mm in diameter when incubated in CO(2), while all strains had zone diameters of > or = 22 mm when incubated in air . Zone diameters in air were generally 4 to 5 mm larger than in CO(2) . By all methods, MICs and zones of all erythromycin-resistant strains occurred in clusters separated from those seen with erythromycin-susceptible strains . The results for macrolide-resistant strains with erm and mef resistance determinants were similar . The results show that (i) telithromycin is very active against erythromycin-susceptible and -resistant strains irrespective of macrolide resistance mechanism; (ii) susceptibility to telithromycin can be reliably tested by the agar, microdilution, E test, and disk diffusion methods; and (iii) incubation in CO(2) led to smaller zones by disk diffusion and higher MICs by E test, but at a susceptible MIC breakpoint of < or =1 microg/ml and a susceptible zone diameter cutoff of > or =19 mm in CO(2), 215 of 216 strains were found to be susceptible to telithromycin.

Tissue Antigens, 2000 Feb, 55(2), 166 - 70
Three novel MICB alleles; Fischer G et al.; The two members of the MHC class I chain-related (MIC) gene family, MICA and MICB, have been shown by several investigators to be polymorphic . Most of the research effort so far has focussed on MICA, so less is known about the extent of polymorphism in the MICB gene . Here we report three novel MICB alleles, which had been detected in the course of an SSOP typing study on a large cohort of cell lines . Two of these alleles are formed by a non-synonymous nucleotide variation . Our results confirm previous findings that most of the polymorphisms in the MICB gene, as in MICA, are coding and suggest that the extent of polymorphism in the two genes might be comparable.

Diagn Microbiol Infect Dis, 2000 Jan, 36(1), 43 - 8
Susceptibility of Legionella species to five antibiotics and development of resistance by exposure to erythromycin, ciprofloxacin, and rifampicin; Nielsen K et al.; The minimal inhibitory concentration (MIC) values of erythromycin, ciprofloxacin, ofloxacin, rifampicin, and clindamycin were determined for 56 strains of Legionella pneumophila (38 patient, 3 environmental, and 15 reference strains) and 37 strains of other Legionella species (7 patient, 2 environmental, and 28 reference strains) using the epsilon-test system on BCYEalpha agar plates . High-level resistance (MIC > or = 4 microg/mL) was found only for clindamycin (57%), with MIC values ranging from 0.25-32 microg/mL . Low-level resistance was found for erythromycin (18%) (0.5 < MIC < 8), ciprofloxacin (1%) (1 < MIC < 4), and clindamycin (40%) (0.5 < MIC < 4), but not for ofloxacin and rifampicin . MIC50 for the 45 Danish clinical Legionella strains were 0.25 microg/mL (erythromycin), 0.25 microg/mL (ciprofloxacin), 0.19 microg/mL (ofloxacin), below 0.016 microg/mL (rifampicin), and 4 microg/mL (clindamycin) . Of the clinical isolates, 64% were resistant to clindamycin . There were no significant differences between the MIC50 values obtained for clinical and nonclinical Legionella strains . Selected susceptible strains were exposed to increasing concentrations of either erythromycin, ciprofloxacin, or rifampicin to select for resistance . Isolates resistant to erythromycin (MIC 0.75-32 microg/mL) or ciprofloxacin (MIC 2-3 microg/mL) could be selected by a two-step procedure . One single strain recovered from media containing 50 microg/mL of erythromycin had an MIC value higher than 256 microg/mL to erythromycin . In contrast, high-level resistance toward rifampicin with MIC > or = 256 microg/mL developed as a one-step phenomenon in several strains.

Pediatr Dev Pathol, 2000 May-Jun, 3(3), 290 - 300
Clinicopathologic study of ectomesenchymomas from Intergroup Rhabdomyosarcoma Study Groups III and IV; Boue DR et al.; Ectomesenchymomas (EM) are rare malignant neoplasms usually consisting of rhabdomyosarcoma (RMS) with a neural component . Only 21 cases have been previously reported . Here we extend the clinicopathologic spectrum of EM by describing our findings in 15 cases . Only 5 patients were infants; 10 were < or =3 years old and 5 were > or =6 years old . No male predilection was observed; 7 were female . The originating institutional diagnoses were; RMS (12), undifferentiated sarcoma (1), or EM (2), suggesting underdiagnosis of this entity . The primary tumor sites included external genital (5), pelvis/abdomen (6), head and neck (3), and extremity (1) . The size of the primary neoplasm was usually > or =5 cm at diagnosis but dissemination only occurred in a minority . Local infiltration was not uncommon . These neoplasms were typically multilobate, thinly encapsulated, hemorrhagic, and necrotic . Light microscopic features were highly variable, but embryonal RMS with scattered or clustered ganglion cells, often in lacunae, was characteristic . In some cases, primitive neuroblastic or neuroectodermal areas were found and/or a component of alveolar RMS was seen . Focal anaplasia was occasionally observed . Mitotic activity appears higher than previously appreciated and some necrosis was invariably present . Electron microscopy was performed in 11 cases, which confirmed skeletal muscle +/- neural differentiation . Cytogenetic studies performed in five cases revealed no specific abnormality . Monoclonal neuron-specific enolase was the best marker of ganglion cells and primitive neural elements . MIC-2 (CD99) membrane expression was not definitively present in any of the six cases examined . A number of the above parameters appear to be of some prognostic significance, but overall, these neoplasms appear to have a similar outcome as would be predicted for their RMS element alone (exclusive of any neural component), with respect to the RMS subtype, age of the patient, and anatomic location of the neoplasm.

P N G Med J, 1998 Mar, 41(1), 30 - 6
In vitro susceptibility of Plasmodium falciparum isolates to halofantrine in the Central Province of Papua New Guinea; Hombhanje FW et al.; Halofantrine is a newer antimalarial drug which has not been approved for clinical use in Papua New Guinea . We assessed 21 Central Province isolates of Plasmodium falciparum for their in vitro susceptibility to halofantrine . The concentration required to inhibit 50% of parasite growth (IC50) ranged from 0.05 to 7.0 nM with a mean of 1.90 nM and a median of 1.50 nM . The minimum inhibitory concentration (MIC) values ranged from 2.5 to 50 nM with a median of 5.0 nM . All but one isolate had an MIC of 10 nM or less . These results indicate that halofantrine would be a suitable alternative for the treatment of P . falciparum malaria in the region in the future, if and when the need arises, provided that its use was carefully monitoredPIP: Halofantrine is a newer antimalarial drug which has not been approved for clinical use in Papua New Guinea . The authors assessed 21 Central Province isolates of Plasmodium falciparum for their in vitro susceptibility to halofantrine . The concentration required to inhibit 50% of parasite growth (IC50) ranged from 0.05 to 7.0 nmol with a mean of 1.90 nmol and a median of 1.50 nmol . The minimum inhibitory concentration (MIC) values ranged from 2.5 to 50 nmol with a median of 5.0 nmol . All but one isolate had an MIC of 10 nmol or less . These results indicate that halofantrine would be a suitable alternative for the treatment of P . falciparum malaria in the region in the future, if and when the need arises, provided that its use was carefully monitored .

Kansenshogaku Zasshi, 2000 Feb, 74(2), 112 - 9
{A SHV-derived extended-spectrum beta-lactamase (SHV-12) produced by an Escherichia coli recovered from wound abscess in post operative case with rectal carcinoma}; Nakamura T et al.; A 62-year-old woman admitted for rectal carcinoma suffered from a post-operative bacterial infection . Oxy-imino-beta-lactams including cefotiam (CTM) and cefozopran (CZOP) were prescribed for this case, but the patient developed a wound abscess followed by peritonitis . She recovered from the bacterial infection after drainage and recurrent washing of the abscess . An ephemeral aggravation of infectious signs was observed just after creation of an artificial anus, and CZOP was again administered, and no evident bacterial infection occurred . The patient recovered, then was followed as an outpatient to date . A CAZ-resistant (MIC, > 16 micrograms/ml) E . coli was recovered from pus of her wound abscess . Since the CAZ-resistance decreased (MIC, 64 micrograms/ml-->0.13 microgram/ml) by the presence of clavulanate (CVA) in this isolate, this strain was speculated to be an extended spectrum beta-lactamase (ESBL) producer at an early stage of infection . A similar strain was also isolated from the feces . Therefore, we immediately took measures to block the nosocomial spread of this microorganism, and we succeeded in preventing a nosocomial outbreak of this strain . It was later confirmed by PCR analysis and DNA sequencing analysis that this CAZ-resistant E . coli strain produces an ESBL (SHV-5-2a = SHV-12) . This is the first report of a case of infection with SHV-derived ESBL producing E . coli strain in Japan . We are concerned that further dissemination of this kind of microorganism might occur in the near future also in Japan, as it has been widely observed in European countries and the US . We believe that it will be very important to distinguish the type of beta-lactamases for rigorous bacterial infection control with the prudent use of antibiotics . In other words, we in Japan must recall that various gram-negative bacterial species that produce TEM-, SHV-derived ESBLs, Toho-1, AmpC, or IMP-1 are already widespread . Thus, we should take this fact into consideration when we do antibiotic susceptibility tentings and interpretation of the results for promotion of accurate chemotherapy.

Diagn Microbiol Infect Dis, 2000 Mar, 36(3), 193 - 202
Modeling approach to diameter breakpoint determination; Craig BA; In determining zone diameter breakpoints, the error-rate bounded method focuses directly on the observed discrepancy percentages (very major, major, and minor) . These percentages, however, are quite variable due to the number of isolates investigated, the drug-specific relationship between MIC and zone diameter, the location of the isolates relative to the MIC intermediate zone, and the inherent variability of each test . To overcome potential sampling problems, a hierarchical model is proposed which explicitly accounts for each of these factors and probabilities from this model are used to determine diameter breakpoints . A simulation study is performed to demonstrate the improved consistency of this model-based procedure . Application to three published scatterplots demonstrate its interpretability advantages.

FEBS Lett, 2000 Mar 17, 470(1), 77 - 82
Profile of gene expression regulated by induced p53: connection to the TGF-beta family; Kannan K et al.; The transcription regulatory function of p53 was analyzed by using two inducible p53 systems in the human lung cancer cell line H1299 . cDNA probes derived from RNA harvested 12 h after p53 induction were used to probe filters containing cDNA arrays . Over 20 genes were found to be significantly induced or suppressed by p53 . The induced genes can be classified mainly as cell cycle inhibitors like p21waf, GADD45, apoptosis-related genes like Fas/APO1 and PIG3 or DNA repair genes like DDB2, DNA ligase and G/T mismatch DNA glycosylase . The suppressed genes include mainly cell cycle regulators like cyclin B1, cyclin H and kinases like c-abl, CLK1 and others . The most notable induced gene was MIC-1, encoding a TGF-beta-related secretory protein, suggesting a potential paracrine component for p53 growth suppression.

Antimicrob Agents Chemother, 2000 Apr, 44(4), 1112 - 3
In vitro activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae; Strigl S et al.; The in vitro activities of ABT 773, telithromycin (HMR 3647), azithromycin, clarithromycin, erythromycin, and levofloxacin were tested against 20 strains of Chlamydia pneumoniae . The MIC at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed by ABT 773 were 0.015 microg/ml (range, 0.008 to 0.015 microg/ml) . ABT 773 was the most active antibiotic tested in this study.

Antimicrob Agents Chemother, 2000 Apr, 44(4), 1085 - 8
Antipneumococcal activities of GAR-936 (a new glycylcycline) compared to those of nine other agents against penicillin-susceptible and -resistant pneumococci; Hoellman DB et al.; GAR-936, a new glycylcycline, had lower MICs (< or =0.016 to 0.125 microg/ml) for 201 penicillin- and tetracycline-susceptible and -resistant pneumococcal strains than tetracycline (< or = 0.06 to 128 microg/ml), minocycline (< or =0.06 to 16.0 microg/ml), or doxycycline (< or =0.06 to 32.0 microg/ml) . GAR-936 was also bactericidal against 11 of 12 strains tested at the MIC after 24 h, with significant kill rates at earlier time points.

Audiol Neurootol, 2000 Mar-Apr, 5(2), 64 - 8
A study of tea tree oil ototoxicity; Zhang SY et al.; Tea tree oil shows promise as an effective treatment for a number of micro-organisms commonly associated with otitis externa and otitis media, but its possible ototoxicity has not been previously assessed . The ototoxicity of tea tree oil was examined in the guinea pig by measuring the thresholds of the compound auditory nerve action potential (CAP) to tone bursts before and after instillation of the oil into the middle ear . After 30 min of instillation, 100% tea tree oil caused a partial CAP threshold elevation at 20 kHz . A lower concentration of oil {2% tea tree oil dissolved in saline using 0.5% detergent (Tween-80)} did not cause any significant lasting threshold change after middle ear instillation for the same period of time . The latter concentration of oil is greater than the minimum inhibitory concentration reported for most micro-organisms in the effective spectrum of the oil and this suggests that this concentration may be safe and effective provided only short exposures (about 30 min) are used . The results suggest that high concentrations of tea tree oil applied to the round window for a relatively short time are to some extent ototoxic to the high-frequency region of the cochlea . Hence further study is needed to establish whether tea tree oil can be used with safety in the treatment of external and middle ear infections .

Arzneimittelforschung, 2000 Feb, 50(2), 167 - 72
4-(3-coumarinyl)-4-thiazolin-2-one benzylidenehydrazones with antituberculosis activity; Gursoy A et al.; In this study a new series of 4-(3-coumarinyl)-4-thiazoline-2-one benzylidenehydrazones (3a-v) were synthesized by condensation of 3-(omega-bromoacetyl)coumarins (1a and 1b) with 1-substituted benzylidene-4-substituted thiosemicarbazides (2a-1) . Structures of the title compounds were elucidated by elemental analyses and spectrometric data (UV, IR, 1H-NMR and EIMS) . These new compounds and some previously reported compounds (1a-d) were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv . The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M . tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system . 1b, 3b, 3e, 3h, 3o and 3p demonstrating activity in the primary screen were re-tested at lower concentrations against M . tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460 and Alamar Blue assay (MABA) . The most active compound was found to be 1b . The structure-activity relationships of the derivatives were investigated.

Cancer, 2000 Mar 15, 88(6), 1403 - 9
Microinvasive breast carcinoma: clinicopathologic analysis of a single institution experience; Padmore RF et al.; BACKGROUND: Microinvasive breast carcinoma (MIC) has a good prognosis but specific definitions have varied in the past, making the clinical significance of MIC a subject of debate . METHODS: Microscopic slides of 59 cases of breast carcinoma originally diagnosed as MIC were reviewed retrospectively . Histologic parameters were correlated with clinical findings and outcome to define diagnostic criteria better . RESULTS: On review, the 59 cases were recategorized as follows: pure DCIS (N = 16), DCIS with foci equivocal for microinvasion (N = 7), DCIS with > or =1 focus of microinvasion (N = 11), T1 invasive carcinomas with > or =90% DCIS (N = 18), and T1 tumors with <90% DCIS (N = 7) . The MIC cases in the current study averaged 3 separate foci of early infiltration outside the basement membrane, each one not >1.0 mm . The mean follow-up was 95 months . Six patients (10%) had only local recurrence: 1 case each in patients with equivocal microinvasion, microinvasion, and T1 tumors with <90% DCIS and 3 cases among the patients with T1 tumors with > or = 90% DCIS . Four patients, all with T1 tumors with > or =90% DCIS, had distant failure (7%) . In the MIC group, only one patient developed a local recurrence after breast conservation . No patient had axillary lymph node metastasis . For the entire series, factors associated with local recurrence were younger age, breast conservation versus mastectomy, and close surgical margins . The only factor associated with distant failure was the size of the DCIS component . Seven patients with T1 tumors with > or =90% DCIS experienced local or distant failure and 5 of these (71%) developed progressive disease or died of disease . All other patients who developed a recurrence were disease free at last follow-up . In a retrospective series, poorer outcome in carcinomas with > or =90% DCIS may be related to the greater likelihood of missed larger areas of invasive carcinoma . Therefore, meticulous and extensive sampling of these carcinomas is required . CONCLUSIONS: MIC as defined has a good prognosis . It has a different biology than T1 invasive carcinoma with > or =90% DCIS, which may progress and cause death . Large tumors with multiple foci of microinvasion may have metastatic potential .

Scand J Infect Dis, 2000, 32(1), 59 - 62
Metronidazole and clarithromycin susceptibility and the subtypes of vacA of Helicobacter pylori isolates in Estonia; Loivukene K et al.; The prevalence of metronidazole and clarithromycin resistance of Helicobacter pylori strains under different growth conditions (microaerophilic or anaerobic preincubation) was tested in 56 patients suffering from gastritis and peptic ulcer . vacA subtypes were detected in 46 H . pylori strains and were subsequently compared with the antibiotic resistance pattern . From 56 isolates, 26 proved resistant and 30 sensitive to metronidazole . The patients with peptic ulcer and gastritis were infected with both metronidazole-sensitive and metronidazole-resistant strains . In anaerobic preincubation all the strains were sensitive to metronidazole (MIC < 8 mg/l) . All the strains were clarithromycin-sensitive (MIC < 2 mg/l) . In the patients with gastritis and peptic ulcer s1 was the predominant vacA subtype . Comparison of vacA subtypes with the diagnoses revealed no correlation; different virulence factors such as vacA subtypes and antibiotic resistance to metronidazole in a microaerophilic milieu proved unrelated.

FEMS Microbiol Lett, 2000 Mar 15, 184(2), 297 - 302
Plasmid curing effect of trovafloxacin; Brandi L et al.; The effect of sub-inhibitory concentrations of trovafloxacin, a recently developed fluoroquinolone molecule, on the capability of Escherichia coli cells to maintain three different types of plasmids has been investigated by a number of approaches, including the quantification of the loss of plasmid-borne functions and of plasmid DNA by quantitative PCR . The results obtained demonstrate that at concentrations ranging from the MIC to 1/8 of the MIC, trovafloxacin induces a clear, albeit incomplete, 'episome-curing' effect which was observed with plasmids differing in copy number, size and nature of the replication origin of the episome . This effect was most likely not due to an alteration of DNA supercoiling.

J Med Assoc Thai, 2000 Feb, 83(2), 151 - 9
Primary gastrostomy button: a means of long-term enteral feeding in children; Ruangtrakool R et al.; Between June 1992 and December 1997, forty-two patients (M 19, F 23) received 94 primary gastrostomy buttons due to 22 intellectual handicap, 7 cystic fibrosis, 4 severe gastrooesophageal reflux, 2 bronchopulmonary dysplasia, 2 tumours in the neck region and 5 miscellaneous causes . Open fundoplication concomitant with primary button, primary open button and laparoscopic fundoplication concomitant with primary button were performed in 20, 15 and 7 patients respectively . The average longevity +/- standard deviation of all buttons was 388.36 +/- 360.35 days . The average longevity of the buttons of the laparoscopic fundoplication group was significantly lower than the others . The major causes of removal of Bard buttons were valve incompetence and flap damage, whereas, balloon leakage was the major cause of removal of the Mic-key button . There were merely minor stomal complications and no gastric separation and peritonitis . Because of the acceptable longevity of the buttons and minimal complications, we concluded that the primary gastrostomy button was the preferable method of long term enteral feeding in children.

What Is MIC?, What Is Biofilm?, What Is Nitrification?, What Is Molecular Microbiology?, What Is Biotechnology?, e, Bacterium, e, Microbes, i, Microbiology, c, Bacteria, a, Microorganism, c, Proteus, r, Yeasts, a, Escherichia coli, n, Bacillus subtilis, o, Staphylococcus aureus, a, Microorganism, i, Campylobacter, s, Kluyveromyces, o, Escherichia coli, r, Salmonella, i, Haemophilus, a, Haemophilus, r, Gram negative, e, Microbiological, a, Escherichia coli, s, Antimicrobials, r, Bacteriological, a, S. cerevisiae, s, Pseudomonas aeruginosa, i, Yeasts, e, Bacteriophages

Scientific Publications - Work Done by Microbiology Reader Bioscreen C
Agricultural Microbiology Anaerobic Microbiology Antimicrobial Susceptibility Artificial Atmosphere Bioassay of Antibiotics Biofilm Microbiology Bioreactor Technology Biotechnology Cell Biology Clinical Microbiology Environmental Microbiology Experiments with Yeast	Fermentation Food Microbiology Functional Genomics Gene Technology Growth Media Development Growth Rate and Lag Time Industrial Microbiology Medical/Pharmaceutical Field Microbiological Assay Microbiological Research Microbiology of Cosmetics go to a specific theme...	Military Microbiology Molecular Microbiology Mutagenicity and Genotoxicity Oral Microbiology Patents Postantibiotic Studies Soil Microbiology Spore Microbiology Veterinary Microbiology Waste/Wastewater Treatment Water Microbiology Wine Microbiology

� 2005 Transgalactic Ltd (manufacturer of Bioscreen C software) | Privacy Statement | P.O. Box 1393, 00101 Helsinki, Finland, phone: +358 9 85172920, fax: +358 9 8749481, e-mail: microbiology@bionewsonline.com

Last modified: May 25, 2005