Minimum inhibiting concentration

J Chemother, 1997 May, 9 Suppl 1, 84 - 92
Therapeutic monitoring, the concentration-effect relationship and impact on the clinical efficacy of antibiotic agents; Dawson SJ et al.; Therapeutic monitoring is now technically feasible for a wide variety of antibiotic agents and data are accumulating on the relationship of blood levels and clinical efficacy . For each antibiotic a therapeutic range and dosage regimen can be based theoretically on its known pharmacokinetics, pharmacodynamics in vitro, and also use in animal and human treatment studies . Antibiotics can be characterised into types by their mechanism of kill, as either concentration-dependent (for which achieving a large post-dose concentration to MIC ratio appears important) or concentration-independent/time-dependent (where efficacy is related to maintain the overall concentration above the MIC) . Hopefully, concentration-controlled trials will be performed when new antibiotics are introduced, to determine a therapeutic range which correlates with clinical efficacy, and so enable monitoring to lead to a more rational approach to antibiotic administration.

Trop Med Int Health, 1997 May, 2(5), 461 - 7
Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum . In vitro simulation of in vivo pharmacokinetics; Bwijo B et al.; The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine-sensitive (F32) strain of Plasmodium falciparum . A method of repetitive dosing and extending the culture observation period to 28-30 days was used to mimic the in vivo pharmacokinetic situation . Plasmodium falciparum was exposed to artemisinin from 10(-8) to 10(-5) M, mefloquine from 3 x 10(-9) to 10(-5) M and their combinations . The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours . The drug-dosing duration was 3 days . Neither artemisinin nor mefloquine alone provided radical clearance of P . falciparum, even when maximum concentrations (10(-5) M) were applied . The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone . Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination . At concentrations normally reached in vivo, this effect was clearly synergistic (P = 0.016) Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds . Lower combination concentrations around the MIC-values for the individual compounds showed synergistic effect, and high concentrations showed additive effect . This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single-drug treatment.

Kansenshogaku Zasshi, 1997 May, 71(5), 437 - 42
{Suppressive effect of clarithromycin on the production of verotoxin by E . coli O157}; Nakata K et al.; Effects of low concentration of clarithromycin (CAM) on the production of Verotoxin (VT) by Escherichia coli O157 was investigated in vitro . The production of VT1 was suppressed up to 10 hours when bacteria was incubated with 0.64 micrograms/ml (equivalent to the 1/100th of MIC) or higher concentrations . However, the production of VT1 reached to the control level after 22 hours even with 6.4 micrograms/ml of CAM . On the other hand, production of VT2 by 22 hours was partially suppressed with 0.64 micrograms/ml of CAM and completely with 6.4 micrograms/ml of CAM . When the eight clinical isolates were incubated with 0.64 or 6.4 micrograms/ml of CAM, VT1 and VT2 were suppressed in two and eight strains, respectively . In these strains, similar but less efficient suppression of the toxin production was also observed with erythromycin . In contrast to the macrorides, ampicillin did not inhibit or rather stimulated the production of VT1 and VT2 in some strains.

Bioorg Med Chem, 1997 May, 5(5), 955 - 70
Antiviral and tumor cell antiproliferative SAR studies on tetracyclic eudistomins . II; van Maarseveen JH et al.; In a search for the minimum pharmacophore of the naturally occurring tetracyclic eudistomins, five structural analogues (4-8) were evaluated for their in vitro antiviral and tumor cell antiproliferative activities . For the synthesis of these derivatives both intra- and intermolecular Pictet-Spengler reactions have been used . Opening of the beta-carboline annulated 7-membered D-ring in 6 and 7 resulted in a complete loss of activity . On the other hand, replacement of either the oxygen atom or the sulfur atom in the 7-membered ring by a methylene group in 5 and 8, respectively, is allowed . These results combined with previous SAR data underline the crucial importance of the D-ring in eudistomins as a scaffold for the correct positioning of both basic nitrogen atoms . Also bioisosteric replacement of the bicyclic indole system with a dimethoxyphenyl group, to give the isoquinoline skeleton, is allowed . The tricyclic isoquinoline derivative 4 is, so far, the most promising antiviral analogue; it combines a high potency (MIC at 100 ng/ mL (340 nM)) with high MCC/MIC ratios (ranging from 1000 to 5000 against HSV-1, HSV-2, vaccinia virus, and vesicular stomatitis virus.

J Cell Sci, 1997 May, 110 ( Pt 10), 1227 - 38
Mesenchyme-mediated effects of retinoic acid during rat intestinal development; Plateroti M et al.; In previous experiments we showed that intestinal development was dependent upon epithelial-mesenchymal cell interactions . The aim of this study was to investigate the possible role of retinoic acid (RA), a morphogenetic and differentiating agent, on the gut epithelial-mesenchymal unit . For this purpose we first analyzed the effects of a physiological dose of RA on 14-day fetal rat intestine using short-term organ culture experiments, or long-term grafts under the skin of nude mice . In these conditions, RA accelerated villus outgrowth and epithelial cell differentiation as assessed by the onset of lactase expression, and it also stimulated muscle and crypt formation . In order to analyze potential effects of RA mediated by mesenchymal cells, we isolated and characterized gut mucosa mesenchyme-derived cell cultures (mesenchyme-derived intestinal cell lines, MIC) . These cells were shown to express mRNAs for retinoid binding proteins similar to those expressed in situ in the intestinal mesenchyme . MIC cells co-cultured with 14-day intestinal endoderms promoted endodermal cell adhesion and growth, and the addition of exogeneous RA enhanced epithelial cell polarization and differentiation assessed by cytokeratin and lactase immunostaining . Such a differentiating effect of RA was not observed on endodermal cells when cultured without a mesenchymal feeder layer or maintained in conditioned medium from RA-treated MIC cells . In the co-cultures, immunostaining of laminin and collagen IV with polyclonal antibodies, as well as alpha1 and beta1 laminin chains mRNAs (analyzed by RT-PCR) increased concurrently with the RA-enhanced differentiation of epithelial cells . It is worth noting that this stimulation by RA was also obvious on the mesenchymal cells cultured alone . These results show that RA plays a role in intestinal morphogenesis and differentiation . In addition, they indicate that RA acts on the mesenchymal cell phenotype and suggest that RA may modify the mesenchymal-epithelial cell interactions during intestinal development.

J Antimicrob Chemother, 1997 May, 39(5), 597 - 601
Stereoselective interaction of SCH 39304, a triazole, with sterol 14alpha-demethylase of Aspergillus fumigatus; Venkateswarlu K et al.; The inhibitory activity of SCH 39304 and its enantiomers on radial growth and on the target enzyme, sterol 14alpha-demethylase, in Aspergillus fumigatus was studied to assess the role of stereochemistry in the efficacy of the drug . SCH 39304 and the RR(+) enantiomer were active in inhibiting the growth while no inhibition in the growth was observed with the SS(-) enantiomer . The MIC of SCH 39304 for the growth was about twice that of the RR(+) enantiomer . The differences in IC50s of SCH 39304 and its enantiomers for cell-free ergosterol biosynthesis correlated with their variations in MICs and type II binding spectra indicated the SS(-) enantiomer failed to bind to microsomal P450 . These results show that the difference between SS(-) and RR(+) enantiomers in interacting with the target enzyme is the cause for significant difference in the potency between these two forms.

Infection, 1997 May-Jun, 25(3), 178 - 84
Tissue penetration of sparfloxacin in a rat model of experimental Escherichia coli epididymitis; Ludwig M et al.; The epididymal, testicular, and prostatic tissue penetration of sparfloxacin, a new quinolone, was assessed in a rat model of acute epididymitis . Seventy-two hours after injection of 0.1 ml (10(6) cfu/ml) of an Escherichia coli suspension into the right epididymis via the right ductus deferens, a single oral dose of sparfloxacin 50 mg/kg body weight was administered . One, 2, 4, 8, 12, and 24 h after administration the animals were sacrificed and the sparfloxacin concentrations and "areas under the curve" (AUC0-24) in both epididymides, both testes, the prostate gland and in the serum were measured by bioassay . The highest mean AUC0-24 was found in the prostate gland, followed by left epididymis, right epididymis, serum, right testis, and left testis (190, 79, 60, 28, 12, and 9 mg/kg x h, respectively) . Though there was no statistically significant difference in the sparfloxacin concentration of both epididymides (p = 0.09), the mean AUC0-24 was significantly higher in the non-infected left epididymis (p < 0.0001) . The AUC0-24 and sparfloxacin concentrations of the right infected epididymis were significantly higher than those observed in the serum (p < 0.0001) . In both testes, the AUC0-24 and sparfloxacin concentrations were lower than in the serum (p < 0.0001), however, the concentration exceeded the MIC tenfold for approximately 20 h . It is concluded that the pharmacokinetic properties of sparfloxacin (good in vitro activity, high penetration into the prostate gland, testes, infected and non-infected epididymides) make this drug a recommendable choice for the initial treatment of acute epididymitis caused by E . coli.

Mod Pathol, 1997 May, 10(5), 510 - 4
Spindle epithelial tumor with thymus-like differentiation: a case report with cytologic, histologic, immunohistologic, and ultrastructural findings; Su L et al.; Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare and distinctive low-grade neoplasm of thymic or related branchial pouch differentiation . The tumor usually presents in the thyroid or lateral neck of children and adolescents and could mimic spindle-cell carcinoma, synovial sarcoma, or malignant teratoma . We report the clinical, cytologic, histologic, immunohistochemical, and ultrastructural features of a SETTLE present for 10 years in a 15-year-old boy . The fine-needle aspirate, initially interpreted as synovial sarcoma, contained numerous clusters of bland spindle cells, with a few detached sheets of columnar mucous cells in a homogeneous background of dissociated spindle cells . Mitoses, necrosis, and atypia were not present . The excised tumor was a well-circumscribed, white-tan mass, with occasional microcysts . Microscopically, the mass consisted of a lobulated, highly cellular, spindle-cell neoplasm arranged in intersecting, whorled, and storiform fascicles separated by fibrous bands . Entrapped within the fibrous bands were squamous-lined cysts and benign-appearing glands lined by columnar epithelium with goblet cells or ciliated pseudostratified epithelium . Immunohistochemically, the spindle cells showed diffuse reactivity for cytokeratins, smooth muscle actin, muscle-specific actin, and MIC-2, and they were negative for epithelial membrane antigen, calcitonin, and thyroglobulin . Ultrastructurally, numerous perinuclear tonofilaments, some aligned with mature desmosomes, were identified in the spindle cells . Occasional cells showed thin filaments with fusiform dense bodies occupying the peripheral cytoplasm . These findings distinguish SETTLE from ectopic thymoma, synovial sarcoma, medullary carcinoma, and teratoma, and they support a thymic epithelial origin for SETTLE, possibly with myoepithelial differentiation.

Chemosphere, 1997 May, 34(9-10), 2237 - 50
The lessons of Bhopal {toxic} MIC gas disaster scope for expanding global biomonitoring and environmental specimen banking; Sriramachari S et al.; Bhopal Toxic gas tragedy represents one of the worst chemical accidents of the world . Autopsy and toxicological studies, apart from presenting evidence of acute and even chronic cyanide toxicity, provided a unique example of the incriminated chemical being traced to the bodies of the victims . The entry of methyl isocyanate (MIC) into the blood stream was established by the presence of carbamoylated end-terminal amino acids of haemoglobin and other tissue proteins . The presence of MIC trimer and a few other identified as well as unidentified tank residue constituents in the blood and viscera further established a close nexus of the products of pyrolysis of MIC in the aerosol inhaled by the victims . The Bhopal studies exemplify the scope for biological monitoring (BM) and environmental specimen banking (ESB) in chemical accidents as part of the global efforts.

Antimicrob Agents Chemother, 1997 May, 41(5), 1124 - 6
In vitro activity of SCH-56592 and comparison with activities of amphotericin B and itraconazole against Aspergillus spp; Oakley KL et al.; In this study, we investigated the in vitro activity of SCH-56592 (SCH), a new triazole antifungal agent . We compared the activity of SCH with those of itraconazole (ITZ) and amphotericin B (AB) against 60 clinical isolates of Aspergillus spp . by using a microtiter format . Incubation was done at 37 degrees C for 48 h, and MIC endpoints (no growth) were read visually . The medium used for all of the drugs was RPMI 1640 buffered with morpholinepropanesulfonic acid (MOPS) and supplemented with 2% glucose . MICs and minimum fungicidal concentrations (MFCs; killing of > or = 99.99%) were measured for all isolates . The geometric mean (GM) MICs and ranges (in micrograms per milliliter) were as follows: SCH, 0.09 and < or = 0.01 to 1; ITZ, 0.25 and 0.06 to 32; AB, 1.46 and 0.25 to 32 . Aspergillus terreus (n = 7) was markedly more susceptible to SCH (GM, 0.05 microg/ml) and ITZ (GM, 0.07 microg/ml) than to AB (GM, 8.8 microg/ml) . For all isolates, the GM MFCs and ranges (in micrograms per milliliter) were as follows: SCH, 3.64 and 0.125 to 16; ITZ, 15.09 and 0.125 to 32; AB, 10.3 and 1 to 32 . In the drug concentration range tested, 71, 32, and 64% of the isolates against which SCH, ITZ, and AB, respectively, were tested were killed . A reproducibility study was performed with 20% of the isolates; for 11 of the 12 isolates retested, the MIC was the same or within 1 well of the original MIC of each drug . Therefore, in vitro mould testing of SCH is feasible and reproducible . SCH was found to be very active against all species of Aspergillus and at lower concentrations than either ITZ or AB.

Antimicrob Agents Chemother, 1997 May, 41(5), 1115 - 9
Pharmacokinetics of gentamicin at traditional versus high doses: implications for once-daily aminoglycoside dosing; Demczar DJ et al.; Two doses of gentamicin (2 and 7 mg/kg of body weight) were administered to 11 healthy volunteers in a randomized, crossover single-dose study to compare their pharmacokinetics . Doses were infused over 1 h with a syringe infusion pump, and 14 concentrations in sera were obtained over an 8-h period . Concentration in serum versus time data were fitted to a two-compartment pharmacokinetic model . In addition, to mimic the clinical setting, subjects' data were fitted by the Sawchuk-Zaske method . Distributional and postdistributional peak concentrations, along with the last obtained concentration in serum, were utilized to compare the following pharmacokinetic variables: volume of distribution at steady state (Vss), half-life, clearance (CL), and maximum concentration in serum (Cmax) . With two-compartment pharmacokinetic fitting, significant differences in distribution half-life (average, 21.8 and 41.6 min {P < or = 0.05}) and gentamicin CL (76.6 +/- 6.6 and 67.2 +/- 4.2 ml/min/1.73 m2 {P < or = 0.001}) were found between traditional-dose and high-dose groups, respectively . When the data for concentrations in sera were fitted to a one-compartment pharmacokinetic model by using either the distributional or the postdistributional Cmax, statistically significant differences (P < or = 0.001) were found between Vss, half-life, CL, and Cmax values for both dosage groups . The results show that the pharmacokinetics of gentamicin at a large dose differ significantly from those at the traditional dose . This information has direct implications for once-daily aminoglycoside (ODA) literature when the Cmax values reported are distributional and therefore show falsely high Cmax/MIC ratio estimates . In addition, ODA nomogram dosing tools developed with distributional Cmax values are probably inaccurate.

Antimicrob Agents Chemother, 1997 May, 41(5), 1033 - 6
Susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, compared with susceptibilities to 16 other agents; Ednie LM et al.; The susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, were tested by agar dilution, and the results were compared with those for penicillin G, erythromycin, azithromycin, clarithromycin, rokitamycin, clindamycin, pristinamycin, ciprofloxacin, sparfloxacin, trimethoprim-sulfamethoxazole, doxycycline, chloramphenicol, cefuroxime, ceftriaxone, imipenem, and vancomycin . RU 64004 was very active against all strains tested, with MICs at which 90% of the isolates are inhibited (MIC90s) of 0.016 microg/ml for erythromycin-susceptible strains (MIC, < or = 0.25 microg/ml) and 0.25 microg/ml for erythromycin-resistant strains (MIC, > or = 0.5 microg/ml) . All other macrolides had MIC90s of 0.03 to 0.25 and > or = 128 microg/ml for erythromycin-susceptible and -resistant strains, respectively . Among erythromycin-resistant strains, clindamycin MICs for 28 of 91 (30.7%) were < or = 0.125 microg/ml . Pristinamycin MICs for all strains were < or = 1.0 microg/ml . MIC90s of ciprofloxacin and sparfloxacin were 4.0 and 0.25 microg/ml, respectively, and were unaffected by susceptibility to penicillin or erythromycin . Vancomycin and imipenem inhibited all strains at < or = 0.5 and < or = 0.25 microg/ml, respectively . MICs of cefuroxime and cefotaxime rose with those of penicillin G . MICs of trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol were variable but were generally higher for penicillin- and erythromycin-resistant strains . RU 64004 is the first member of the macrolide group which has low MICs for erythromycin-resistant pneumococci.

J Med Chem, 1997 Apr 25, 40(9), 1401 - 6
Carbocyclic oxetanocins lacking the C-3' methylene; Wu J et al.; Using the observation that the side effects of aristeromycin (carbocyclic adenosine) were reduced by removing the methylene at the center in aristeromycin where phosphorylation occurs, derivatives of carbocyclic oxetanocin A (4a), oxetanocin G (4b), and 2-aminooxetanocin A (16) lacking the 3'-methylene have been prepared in racemic form . The only viruses for which an appreciable inhibitory effect of the compounds (minimum inhibitory concentration ranging from 1 to 40 microg/mL) was noted were herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) . However, when directly compared for their antiviral potency against HSV-1 with their parents oxetanocin A and oxetanocin G, compounds 4a and 4b proved clearly less active.

FEBS Lett, 1997 Apr 14, 406(3), 275 - 8
Contribution of beta-lactamase production to the resistance of mycobacteria to beta-lactam antibiotics; Quinting B et al.; Mycobacterium fallax (M . fallax) is naturally sensitive to many beta-lactam antibiotics (MIC < 2 microg/ml) and devoid of beta-lactamase activity . In this paper, we show that the production of the beta-lactamase of Mycobacterium fortuitum by M . fallax significantly increased the MIC values for good substrates of the enzyme, whereas the potency of poor substrates or transient inactivators was not modified . The rates of diffusion of beta-lactams through the mycolic acid layer were low, but for all studied compounds the half-equilibration times were such that they would only marginally affect the MIC values in the absence of beta-lactamase production . These results emphasize the importance of enzymatic degradation as a major factor in the resistance of mycobacteria to penicillins.

Diagn Microbiol Infect Dis, 1997 Apr, 27(4), 117 - 22
Evaluation of the Etest for detection of tetracycline resistance in Mycoplasma hominis; Waites KB et al.; The Etest was compared with microbroth dilution for performing in vitro susceptibility tests in 38 isolates of Mycoplasma hominis chosen to represent a wide range of MIC values . MIC50s were 4 micrograms/ml for both methods; whereas, MIC90s were 64 and > 256 micrograms/ml for broth and Etest, respectively . Etest MICs determined on SP 4 agar were usually two or more dilutions greater than microbroth MICs in SP 4 broth, and values were prone to change by one to two dilutions when different inoculum densities were used . Inocula of 10(5) to 10(6) color-changing units/ml gave the most consistently readable MICs, with discrete colony formation surrounding the ellipse . Etest MICs for 5 isolates tested a second time at the same inoculum on SP 4 agar agreed with the original value within 1 dilution . For 12 isolates tested on A 8 agar simultaneously with SP 4 agar, MICs for 10/12 agreed within one dilution; whereas, in the other 2 isolates, MICs varied by two dilutions . These findings suggest that the Etest, when properly controlled, can be used to determine tetracycline MICs for M . hominis.

Biosci Biotechnol Biochem, 1997 Apr, 61(4), 664 - 9
Quantitative study of yeast growth in the presence of added ethanol and methanol using a calorimetric approach; Antoce OA et al.; Using a calorimeter with 24 sample units the heat evolved during incubation of yeast cultures at 30 degrees C was detected in the form of growth thermograms . Ethanol and methanol added to the culture medium produced changes in the growth thermograms that could be analyzed to calculate the 50% inhibitory concentration (Ki) and minimum inhibitory concentration (MIC) . Correlation of the heat evolution curves with the number of cells and the turbidity of the culture was found to be very good . It was found that addition of ethanol and methanol up to 7.65% had clear effects of inhibition on growth of all yeast strains studied, reducing the growth rate constant and delaying growth . However, the amounts of ethanol produced from the nutrients available in the culture vial was only little affected by the initial addition of up to 7.65% (v/v) of ethanol or methanol in the medium.

J Clin Periodontol, 1997 Apr, 24(4), 254 - 9
Development of resistance to metronidazole and minocycline in vitro; Larsen T et al.; By local delivery of antibiotics to periodontal pockets, very high initial concentrations are often quickly succeeded by subinhibitory concentrations, which may facilitate development of bacterial resistance . The purpose of the present study was to investigate possible development of resistance in suspected periodontal pathogens after exposure to subinhibitory concentrations of metronidazole and minocycline . The minimal inhibitory concentration (MIC) of 18 reference strains and 12 clinical isolates was determined by a broth dilution method . Subsequently, all strains with MIC < 8 micrograms/ml were exposed to serial passage on plates containing subinhibitory and gradually increasing concentrations of antibiotics, until growth was inhibited . Initially, most strains were inhibited at < or = 0.250 microgram/ml of minocycline and < or = 0.5 microgram/ml of metronidazole, though A . actinomycetemcomitans was resistant to metronidazole . After growth at subinhibitory concentrations, 8 strains survived 1-2 x and 11 stains survived 8-32 x their initial MIC of metronidazole, growing at up to 8 micrograms/ml . All A . actinomycetemcomitans survived 8-64 x their initial MIC of minocycline, growing at > or = 2 micrograms/ml, while all other strains were inhibited at < or = 0.250 microgram/ml, corresponding to a 1-8 x increase in their initial MIC . Thus, development of resistance was observed for periodontal bacteria growing at up to 64 x their initial MIC, but the final level of resistance was moderate.

J Vet Pharmacol Ther, 1997 Apr, 20(2), 124 - 8
Pharmacokinetics of enrofloxacin in the red pacu (Colossoma brachypomum) after intramuscular, oral and bath administration; Lewbart G et al.; The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu . The half-life for enrofloxacin following i.m . administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises . The 4 h maximum concentration (Cmax) of 1.64 micrograms/ml, following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish . At 48 h post i.m . administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens . The gavage method of oral enrofloxacin administration produced a Cmax of 0.94 microgram/mL at 6-8 h . This Cmax was well above the reported in vitro MIC . A bath immersion concentration of 2.5 mg/L for 5 h was used in this study . The Cmax of 0.17 microgram/mL was noted on the 2 hour post-treatment plasma sample . Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded . Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration . It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration . The i.m . route is the most predictable and results in the highest plasma concentrations of the drug.

Am J Gastroenterol, 1997 Apr, 92(4), 659 - 62
Minimum inhibitory concentration of various single agents and the effect of their combinations against Helicobacter pylori, as estimated by a fast and simple in vitro assay method; Bamba H et al.; OBJECTIVES: Fast and simple in vitro methods of accurately assaying anti-Helicobacter pylori (H . pylori) activity are needed to facilitate the selection of optimal drugs for the eradication of H . pylori . With that purpose in mind, we developed a broth microdilution technique that uses a 96-well flat-bottom microplate . METHODS: Clinical isolates of H . pylori were placed in 25-cm2 tissue culture flasks and were grown in an atmosphere of 5% CO2 in air at 37 degrees C and 100% humidity . Then they were inoculated in 96-well flat-bottom microplates . After 24 h, the bacterial growth was assessed by automatic measurement at A450 with a microplate reader . Minimum inhibitory concentrations (MICs) of 11 drugs against H . pylori and the effect of two-drug combinations were respectively evaluated by the broth microdilution technique and by calculating the fractional inhibitory concentration index according to the checkerboard titration method . RESULTS: The MICs of all drugs tested with this system roughly agreed with those of previous reports in which the agar dilution method was used . The MIC of lansoprazole, a proton pump inhibitor, was low (0.88 microg/ml) and surpassed that of metronidazole (3.15 microg/ml) . The effect of the combination of macrolide antibiotics with tetracycline was favorable . The proton pump inhibitor demonstrated a strong additive effect with macrolide antibiotics and fostered the activity of ecabet sodium (mucosal protective agent) . CONCLUSION: This system could estimate the MIC of individual drugs quickly and simply, and could accurately measure the efficacy of two-drug combinations in vitro.

Infect Immun, 1997 Apr, 65(4), 1395 - 401
Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isoniazid resistance of Mycobacterium tuberculosis; Heym B et al.; Mutations to the regulatory region of the ahpC gene, resulting in overproduction of alkyl hydroperoxide reductase, were encountered frequently in a large collection of isoniazid (INH)-resistant clinical isolates of Mycobacterium tuberculosis but not in INH-susceptible strains . Overexpression of ahpC did not seem to be important for INH resistance, however, as most of these strains were already defective for catalase-peroxidase, KatG, the enzyme required for activation of INH . Transformation of the INH-susceptible reference strain, M . tuberculosis H37Rv, with plasmids bearing the ahpC genes of M . tuberculosis or M . leprae did not result in a significant increase in the MIC . Two highly INH-resistant mutants of H37Rv, BH3 and BH8, were isolated in vitro and shown to produce no or little KatG activity and, in the case of BH3, to overproduce alkyl hydroperoxide reductase as the result of an ahpC regulatory mutation that was also found in some clinical isolates . The virulence of H37Rv, BH3, and BH8 was studied intensively in three mouse models: fully immunocompetent BALB/c and Black 6 mice, BALB/c major histocompatibility complex class II-knockout mice with abnormally low levels of CD4 T cells and athymic mice producing no cellular immune response . The results indicated that M . tuberculosis strains producing catalase-peroxidase were considerably more virulent in immunocompetent mice than the isogenic KatG-deficient mutants but that loss of catalase-peroxidase was less important when immunodeficient mice, unable to produce activated macrophages, were infected . Restoration of virulence was not seen in an INH-resistant M . tuberculosis strain that overexpressed ahpC, and this finding was confirmed by experiments performed with appropriate M . bovis strains in guinea pigs . Thus, in contrast to catalase-peroxidase, alkyl hydroperoxide reductase does not appear to act as a virulence factor in rodent infections or to play a direct role in INH resistance, although it may be important in maintaining peroxide homeostasis of the organism when KatG activity is low or absent.

Antimicrob Agents Chemother, 1997 Apr, 41(4), 763 - 6
In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents; Pfaller MA et al.; LY303366 is a new semisynthetic echinocandin derivative with potent, broad-spectrum fungicidal activity . We investigated the in vitro activity of LY303366, amphotericin B, flucytosine (5FC), fluconazole, and itraconazole against 435 clinical yeast isolates (413 Candida and 22 Saccharomyces cerevisiae isolates) obtained from over 30 different medical centers . MICs for all five antifungal agents were determined by the National Committee for Clinical Laboratory Standards method with RPMI 1640 test medium . LY303366 was also tested in antibiotic medium 3 as specified by the manufacturer . Overall, LY303366 was quite active against all of the yeast isolates when tested in RPMI 1640 (MIC at which 90% of the isolates are inhibited {MIC90}, 1.0 microg/ml) but appeared to be considerably more potent when tested in antibiotic medium 3 (MIC90, 0.03 microg/ml) . When tested in antibiotic medium 3, LY303366 was 16- to >2,000-fold more active than itraconazole, fluconazole, amphotericin B, or 5FC against all species except Candida parapsilosis . When tested in RPMI 1640, LY303366 was comparable to amphotericin B and itraconazole and more active than fluconazole and 5FC . All of the isolates for which fluconazole and itraconazole had elevated MICs (> or = 128 and > or = 2.0 microg/ml, respectively) were inhibited by < or = 0.007 microg of LY303366/ml when tested in antibiotic medium 3 and < or = 0.5 microg/ml when tested in RPMI 1640 . Based on these studies, LY303366 has promising antifungal activity and warrants further in vitro and in vivo investigation.

J Zoo Wildl Med, 1997 Mar, 28(1), 36 - 42
Pharmacokinetics of a single intravenous enrofloxacin dose in scimitar-horned oryx (Oryx dammah); Gamble KC et al.; Based on a 1.3 mg/kg mean dosage determined by metabolic energy scaling, enrofloxacin pharmacokinetics of a single i.v . dose of enrofloxacin in five adult scimitar-horned oryx (Oryx dammah) were determined . Drug concentration versus time curves were best fit by residual analysis to a one-compartment open model with a maximum (mean +/- SD) serum concentration after distribution of 1.887 +/- 0.632 micrograms/ml and an elimination half-life of 41.2 +/- 27.5 min . Model-independent parameters were area under the curve (173.63 +/- 147.5 micrograms.min/ml), mean volume of distribution (steady state) (0.80 +/- 0.30 L/kg), clearance (12.07 +/- 7.12 ml/min/kg), and residence time (77.22 +/- 72.8 min) . Mean serum enrofloxacin concentrations reached the recommended minimum inhibitory concentration (1.0 micrograms/ml) . Drug concentrations remained above the minimum inhibitory concentration of most sensitive bacteria (0.5 micrograms/ml) consistently for 90 min . Based on this study, enrofloxacin would have to be administered parenterally to scimitar-horned oryx at 1.6 mg/kg every 6-8 hr (minimally) to maintain appropriate serum concentrations against susceptible bacteria . The metabolic energy scaled dosed regiment from this study appeared to be too low for the oryx.

Ann Pathol, 1997 Mar, 17(1), 41 - 3
{Undifferentiated soft tissue tumor with rhabdoid phenotype (extra-renal rhabdoid tumor) . Report of a congenital case associated with medulloblastoma in a brother}; Costes V et al.; We report a case of congenital cervical rhabdoid tumor with association of a medulloblastoma in a brother . The immunohistochemical features of this tumor are compatible with a neuroectodermal differentiation (MIC 2+, Leu 7+) . Extrarenal rhabdoid tumors share a common morphology but do not represent a single entity with only one histogenesis . Most of them are now considered to be of neuroectodermal origin . In our case, the association with a medulloblastoma in a brother seems to confirm this concept.

Crit Care Med, 1997 Mar, 25(3), 538 - 44
Colonization with antibiotic-resistant gram-negative organisms in a pediatric intensive care unit; Toltzis P et al.; OBJECTIVE: To measure the prevalence of colonization with antibiotic-resistant Gram-negative organisms and its association with potential risk factors, including antibiotic exposure, in a pediatric intensive care unit (ICU) . DESIGN: Prospective, observational study . SETTING: A 16-bed tertiary care pediatric ICU . PATIENTS: All children admitted to the pediatric ICU for > 24 hrs over a 5-month period . MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-six patients, approximately half of all patients admitted to the ICU, were enrolled in the study; 236 patients had sufficient data collected for analysis and were prospectively examined for nasopharyngeal and gastrointestinal colonization by antibiotic-resistant Gram-negative organisms (ceftazidime minimal inhibitory concentration of > 16 micrograms/mL, or tobramycin minimal inhibitory concentration > 8 micrograms/mL) . Association between colonization and potential predisposing factors including demographics, diagnosis, Pediatric Risk of Mortality (PRISM) score, invasive instrumentation, and prior ICU antibiotic exposure was assessed . More than 20% of patients were found to be colonized with an antibiotic-resistant Gram-negative organism . Examination of the timing of colonization indicated that more than half were identified within 72 hrs of admision . Colonization was associated by unadjusted analysis to prior ICU antibiotic exposure, as well as by factors associated with the severity of illness (PRISM score and invasive instrumentation) and young age . However, when the independence of these factors was tested by logistic regression, prior antibiotic exposure was no longer associated with resistant organism colonization . CONCLUSIONS: These data suggest that antibiotic-resistant Gram-negative organisms are a significant risk to intensively III children and that in many instances, they are imported into the unit or rapidly acquired from environmental reservoirs . Since risk factors for colonization are multiple, policies confined to antibiotic utilization within the ICU may have fixed, and possibly limited, benefit in their control.

Crit Care Med, 1997 Mar, 25(3), 460 - 8
Liposome-encapsulated hemoglobin modulates lipopolysaccharide-induced tumor necrosis factor-alpha production in mice; Rudolph AS et al.; OBJECTIVE: To investigate the effect of liposome-encapsulated hemoglobin, an experimental blood substitute, on the function of the mononuclear phagocytic system in normovolemic mic, in ex vivo murine splenocytes and in a transformed murine monocytic cell line, RAW 264.7 . DESIGN: Prospective, randomized trial . SETTING: Center for Biomolecular Science and Engineering, Naval Research Laboratory, and the Thomas Jefferson University . SUBJECTS: Female Balb/c mice (n = 27) . INTERVENTIONS: Mice were injected into the tail vein with liposome-encapsulated hemoglobin or liposome vehicle and were killed at varying time points for blood sampling and splenocyte isolation and culture . MEASUREMENTS AND MAIN RESULTS: Injection of liposome-encapsulated hemoglobin in mice (2.2 of lipid/kg and 0.56 g of hemoglobin/kg, n = 9) did not increase serum tumor necrosis factor (TNF)-alpha concentrations at 2, 8, 15, and 24 hrs after administration . In the ex vivo procedure, lipopolysaccharide (1 microgram/mL)-induced TNF-alpha production by splenocytes from mice injected with liposome-encapsulated hemoglobin was attenuated at 2 and 4 hrs (73%, p = .002 at 2 hrs), compared with TNF-alpha production by splenocytes from sham animals challenged with the same concentration of lipopolysaccharide . In the in vitro procedure, simultaneous exposure of liposome-encapsulated hemoglobin (0.88 to 8.8 mg/mL) and lipopolysaccharide (0.125 to 1 microgram/mL) to the murine-derived, peritoneal monocytic RAW 264.7 cell line showed significantly reduced TNF-alpha peptide, but not messenger RNA, 1 to 4 hrs after exposure as compared with cells challenged with lipopolysaccharide alone . This effect correlated with the rapid phagocytosis (1 hr to 4 hrs) of liposome-encapsulated hemoglobin by RAW 264.7 cells . Phagocytic activity in RAW 264.7 cells exposed to both liposome-encapsulated hemoglobin and lipopolysaccharide showed reduced uptake compared with uptake of liposome-encapsulated hemoglobin . The liposome-induced reduction in TNF-alpha peptide production elicited by lipopolysaccharide was countered by extending the time period to an overnight delay between liposome-encapsulated hemoglobin exposure and lipopolysaccharide challenge . Liposome-encapsulated hemoglobin incubated with lipopolysaccharide in vitro, and subsequently washed to remove free lipopolysaccharide, stimulated TNF-alpha expressed by RAW 264.7 cells . Incubation with liposome-encapsulated hemoglobin alone did not evoke TNF-alpha production in these cells . CONCLUSIONS: These data suggest that liposome-encapsulated hemoglobin modulates the response of the mononuclear phagocyte system to endotoxin, possibly through binding of lipopolysaccharide, presentation to macrophages with subsequent phagocytosis, and modulation of cytokine response by a posttranscriptional mechanism . This effect is attenuated by extending the period between exposure to liposome-encapsulated hemoglobin and endotoxin . The clinical relevance of these findings awaits further investigation.

Pharm Res, 1997 Mar, 14(3), 358 - 61
Antifungal activity of a new triterpenoid glycoside from Pithecellobium racemosum (M.); Khan IA et al.; PURPOSE: In a continuation of our search for novel antifungal compounds from higher plants, the standard extract of the bark of Pithecellobium racemosum was found to have good activity against important AIDS-related opportunistic yeasts . METHODS: The extract was subjected to bioguided fractionation using silica gel column chromatography which led to purification of triterpene glycosides . The structures of these compounds were determined by a combination of spectroscopic (IR, NMR, HRMS) and chemical methods . RESULTS: Compound 1 is a new glycoside, 3-O{alpha-L-arabinopyranosyl (1-2)}{alpha-L arabinopyranosyl (1-6)}2-acetoamido-2-deoxy-beta-D-glucopyranosyl oleanolic acid and Compound 2 was identified as the known compound 3-O-{alpha-L-arabinopyranosyl (1-2)}alpha-L-arabinopyranosyl (1-6)} 2-acetamido-2-deoxy-beta-D-glucopyranosyl echinocystic acid . CONCLUSIONS: Compound 1 is a new glycoside, 3-O-{alpha-L-arabinopyranosyl (1-2)}alpha-L-arabinopyranosyl (1-6)}-2-acetoamido-2-deoxy-beta-D-glucopyranosyl oleanolic acid and exhibits moderate antifungal activity against T . mentogrophytes, C . albicans and S . cerevisiae with MIC values of 6.25, 12.5 and 12.5 micrograms/ml respectively.

Clin Chest Med, 1997 Mar, 18(1), 79 - 87
Using therapeutic drug monitoring to dose the antimycobacterial drugs; Peloquin CA; The available data suggest that selected patients with tuberculosis and MAC fail to respond to therapy because they malabsorb their medications . In particular, patients with AIDS and known gastrointestinal diseases have problems absorbing these drugs . In addition, because MDR-TB and MAC are so difficult to treat, TDM with the antimycobacterial drugs offers the clinician a chance to ensure that the patient achieves serum concentrations above the MIC of the pathogen . TDM has become the standard of practice at the National Jewish Center for Immunology and Respiratory Medicine . By combining specific and sensitive assays, carefully collected samples, and clinical expertise, we are able to control and optimize antimycobacterial drug therapy . We continue to refine our approach with ongoing pharmacokinetic and pharmacodynamic research, including the development of population pharmacokinetic models . We hope that these efforts will provide insight into the nature of current therapeutic problems . We also hope they will help us improve the clinical outcomes of our patients.

J Burn Care Rehabil, 1997 Mar-Apr, 18(2), 116 - 24
Wide variation in single, daily-dose aminoglycoside pharmacokinetics in patients with burn injuries; Hoey LL et al.; Five to seven mg/kg single, daily-dose aminoglycoside regimens have been recently advocated as effective alternatives to traditional aminoglycoside regimens . The rationale for single, daily-dose aminoglycoside therapy is to produce an optimal ratio between aminoglycoside peak concentrations (Cmax) and pathogen minimal inhibitory concentration to maximize bacterial killing and to produce an aminoglycoside-free period during the 24-hour dosing interval . Single, daily-dose aminoglycoside therapy has not been recommended to date for use in the population of patients with burn injuries . The purpose of this study was to determine the magnitude and variability of aminoglycoside Cmax and the duration of the aminoglycoside-free period after simulated single, daily-dose regimens in patients with burn injuries . Fifty-two patients receiving gentamicin or tobramycin in the burn unit were studied retrospectively to determine the individualized pharmacokinetic parameters and the simulated Cmax and 24-hour after the dose trough minimum concentrations for 5 and 7 mg/kg single, daily-dose aminoglycoside regimens . Patients were only included in the final analysis if they had been treated for burn wound infections and exhibited a calculated creatinine clearance exceeding 60 ml/min (N = 40) . Mean {percentage coefficient of variation} Cmax/minimum concentrations were 15.4{30.5}/0.03{200.0} and 21.6{30.6}/0.04{200.0} mg/L for 5 and 7 mg/kg daily doses, respectively . The mean coefficient of variation time to reach an extrapolated concentration of 0.1 mg/L was 15.9{30.8} hours and 17.0{30.6} hours for the 5 and 7 mg/kg daily doses, respectively . Substantial variability in aminoglycoside Cmax and duration of the aminoglycoside-free period was observed . These data suggest that many patients with burn injuries are not candidates for single, daily-dose aminoglycoside therapy because of restrictive creatinine clearance criteria and pronounced variability in length of the aminoglycoside-free interval . If single, daily-dose aminoglycoside therapy is to be used in this patient population, therapeutic drug monitoring is recommended to screen for appropriate candidates and to optimize Cmax and minimal inhibitory concentration ratios and duration of the aminoglycoside-free interval.

FEMS Microbiol Lett, 1997 Mar 1, 148(1), 59 - 62
Tazobactam is a potent inactivator of selected inhibitor-resistant class A beta-lactamases; Bonomo RA et al.; The beta-lactam beta-lactamase inhibitor combinations (ampicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate and piperacillin/tazobactam) were tested against selected inhibitor-resistant class A beta-lactamases of the TEM and OHIO-1 varieties . Minimum inhibitor concentrations (MIC) revealed that the Escherichia coli DH5 alpha transconjugate strains that possessed the OHIO-1 beta-lactamase, Met69Ile mutant of the OHIO-1 beta-lactamase, TEM-30 (Arg244Ser) and TEM-31 (Arg244Cys) beta-lactamase were most susceptible to piperacillin and piperacillin/tazobactam . Kinetic experiments with each beta-lactamase demonstrated that tazobactam was 10-25-fold more potent than clavulanate or sulbactam against TEM-30 and TEM-31 beta-lactamase . Tazobactam was also as effective as clavulanate against the Met69Ile mutant of the OHIO-1 beta-lactamase . Among the clinically available beta-lactams and beta-lactamase inhibitors, piperacillin/tazobactam appears to be the most potent combination against selected inhibitor-resistant strains of TEM and OHIO-1 beta-lactamase.

Antimicrob Agents Chemother, 1997 Mar, 41(3), 712 - 4
A PCR-oligonucleotide ligation assay to determine the prevalence of 23S rRNA gene mutations in clarithromycin-resistant Helicobacter pylori; Stone GG et al.; We have developed a rapid PCR-oligonucleotide ligation assay that can discriminate single base substitutions that are associated with clarithromycin resistance in Helicobacter pylori . Susceptible isolates were wild type at positions 2143 and 2144 (cognate to 2058 and 2059 in Escherichia coli), while 93% of the resistant isolates contained A-to-G mutations at either position and 7% of the isolates contained A-to-C mutations at position 2143 . In addition, the MIC for 86% of the resistant isolates with an A2143 mutation was > or = 64 micrograms per ml, and that for 89% of the resistant isolates with an A2144 mutation was < or = 32 micrograms per ml.

Antimicrob Agents Chemother, 1997 Mar, 41(3), 696 - 8
Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis; Murphy M et al.; Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp . in vitro . For A . fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml . In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality.

Antimicrob Agents Chemother, 1997 Mar, 41(3), 617 - 23
Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro; Moran GP et al.; Candida dubliniensis is a recently described species of Candida associated with oral candidiasis in human immunodeficiency virus (HIV)-infected individuals . Nineteen oral isolates of C . dubliniensis recovered from 10 HIV-positive and 4 HIV-negative individuals and one vaginal isolate from an additional HIV-negative subject were assessed for fluconazole susceptibility by broth microdilution (BMD), hyphal elongation assessment, and Etest . The susceptibilities of these 20 isolates to itraconazole and amphotericin B and of 10 isolates to ketoconazole were also determined by BMD only . Sixteen of the C . dubliniensis isolates were susceptible to fluconazole (MIC range, 0.125 to 1.0 microgram ml-1), and four (recovered from two AIDS patients) were fluconazole resistant (MIC range, 8 to 32 micrograms ml-1) . Fluconazole susceptibility data obtained by hyphal elongation assessment correlated well with results obtained by BMD, but the corresponding Etest MIC results were one to four times higher . All of the isolates tested were found to be sensitive to itraconazole, ketoconazole, and amphotericin B . Sequential exposure of two fluconazole-sensitive (MIC, 0.5 microgram ml-1) C . dubliniensis isolates to increasing concentrations of fluconazole in agar medium resulted in the recovery of derivatives which expressed a stable fluconazole-resistant phenotype (BMD-determined MIC range, 16 to 64 micrograms ml-1), even after a minimum of 10 consecutive subcultures on drug-free medium and following prolonged storage at -70 degrees C . The clonal relationship between the parental isolates and their respective fluconazole-resistant derivatives was confirmed by genomic DNA fingerprinting and karyotype analysis . The results of this study demonstrate that C . dubliniensis is inherently susceptible to commonly used antifungal drugs, that fluconazole resistance does occur in clinical isolates, and that stable fluconazole resistance can be readily induced in vitro following exposure to the drug.

Proc Natl Acad Sci U S A, 1997 Feb 18, 94(4), 1298 - 303
Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease; Mizuki N et al.; A member of a novel family of the human major histocompatibility complex (MHC) class I genes termed MIC (MHC class I chain-related genes), MICA, has been recently identified near the HLA-B gene on the short arm of human chromosome 6 . The predicted amino acid sequence of the MICA chain suggests that it folds similarly to typical class I chains and may have the capacity to bind peptides or other short ligands . Therefore, MICA is predicted to have a specialized function in antigen presentation or T cell recognition . During nucleotide sequence analyses of the MICA genomic clone, we found a triplet repeat microsatellite polymorphism of (GCT/AGC)n in the transmembrane (TM) region of the MICA gene . In 68 HLA homozygous B cell lines, 5 distinct alleles of this microsatellite sequence were detected . One of them contained an additional one base insertion that created a frameshift mutation resulting in a premature termination codon in the TM region . This particular allele may encode a soluble, secreted form of the MICA molecule . In addition, we have investigated this microsatellite polymorphism in 77 Japanese patients with Behcet disease, which is known to be associated with HLA-B51 . The microsatellite allele consisting of 6 repetitions of GCT/AGC was present at significantly higher frequency in the patient group (Pc = 0.00055) than in a control population . Furthermore, the (GCT/AGC)6 allele was present in all B51 positive patients and in an additional 13 B51 negative patients . These results suggest the possibility of a primary association of Behcet disease with MICA rather than HLA-B.

Rinsho Byori, 1997 Feb, 45(2), 190 - 9
{Multisite evaluation of a colorimetric broth microdilution antifungal susceptibility testing}; Yamane N et al.; A new colorimetric microdilution antifungal susceptibility testing using an air-dried microplate containing serially diluted antifungal agents and an oxidation-reduction dye, sodium resazurin, as a color indicator to detect the growth of yeasts was evaluated at multiple sites . Six ATCC reference strains described in the National Committee for Clinical Laboratory Standards (NCCLS) M27-T, two quality control and four reference strains, were repeatedly tested against five antifungal agents, amphotericin B(AMPH), flucytosine (5-FC), fluconazole (FCZ), miconazole (MCZ) and itraconazole (ITZ) at 17 different laboratories . Of 1,521 MIC determinations, 1,393 (91.6%) were within the acceptable limits described in the M27-T, ranging from 23.8% to 100% . However, significant discrepancies from the M27-T limits were noted in some combinations, such as FCZ against C . albicans ATCC 90028 . In addition, the MIC limits for MCZ and ITZ against the six reference strains were determined . A total of 1,645 clinical isolates of yeasts were tested against five antifungal agents . Most isolates of C . albicans were highly susceptible to the five agents with MIC90 ranging from 0.03 microgram/ml (MCZ) to 1.0 microgram/ml (AMPH) . The MICs against AMPH and 5-FC were tightly clustered, except with C . krusei and Trichosporon spp . Whereas, the distribution of MICs for FCZ, MCZ and ITZ had a wide range from < or = 0.03 microgram/ml to > 64 micrograms/ml . From these results, it can be concluded that our colorimetric broth microdilution antifungal susceptibility test is reliable, easy-to-perform and a suitable alternative for the determination of the MICs in clinical microbiology laboratories.

Eur J Clin Microbiol Infect Dis, 1997 Feb, 16(2), 162 - 4
Evaluation of rapid molecular methods for detection of clarithromycin resistance in Helicobacter pylori; Szczebara F et al.; Resistance of Helicobacter pylori to clarithromycin is due to point mutations at position A2143 or A2144 of the rrnH 23S rRNA gene, each mutation creating an additional restriction site for BsaI or MboII . A procedure combining PCR and RFLP analysis was evaluated for detection of these mutations using primers specific for the 23S rRNA gene, and BsaI and MboII enzymes . All clarithromycin-resistant isolates (8/8), as defined by the MIC, were found to be resistant by PCR-RFLP . No clarithromycin-sensitive isolates (14/14) gave a positive reaction.

Jpn J Antibiot, 1997 Feb, 50(2), 195 - 9
{In vitro antifungal activity of rilopirox, a new hydroxypyridone antimycotic agent}; Harada I et al.; In vitro antifungal activities of rilopirox (RIL), a new topical hydroxypyridone antifungal agent, were studied against 7 species (31 strains) of yeast-like fungi and 15 species (17 strains) of mycerial fungi from stock cultures of a wide range of medically important fungi . Tests were carried out by the liquid dilution method using Neopeptone dextrose broth with ciclopirox olamine (CPO) and oxiconazole nitrate (OCZ) as reference drugs . RIL exhibited a broad spectrum of antifungal activities; the MIC of RIL against yeasts were about 1 microgram/ml, those against other fungi were 0.5-4 micrograms/ml . Antifungal activities were similar to CPO, and compare to OCZ, RIL showed characteristically little differences in its activities against different species or strains of target organisms.

Hinyokika Kiyo, 1997 Feb, 43(2), 97 - 101
{Comparative histological analysis of needle biopsy specimens, prostatectomized specimens and metastatic lymph nodes in prostatic adenocarcinoma--on the basis of the WHO histological classification}; Kondo I et al.; The histological characteristics were comparatively analyzed among biopsy specimens, surgically removed prostates and metastatic lymph nodes obtained from 60 patients with prostatic adenocarcinoma treated by radical prostatectomy . According to the WHO-Mostifi's classification, the proportion of the 6 histologic components, large and/or small simple glands (LSG), micro-glands (MIC), cribriorm (CRB), fused glands (FUS), medullary/solid (MED) and columns-cords/trabecular (C-C), was determined semiquantitatively . LSG, MIC, and CRB are androgen-sensitive components, while FUS, MED and C-C are androgen-refractory components . The proportions of 5 histologic components excluding MIC were similar in the biopsy and prostate specimens . In 78.3% of the patients, the presence (or absence) of androgen-refactory components in the biopsy specimens coincided with that in the prostate specimens . However, the histologic except for the C-C component . Metastatic lymph nodes contained androgen-refactory components in all cases and tended to have more CRB and FUS and fewer LSG . The histology of the needle biopsy specimens may reflect that of the prostate glands, and may serve as a valuable parameter for determining therapeutic modalities . In addition, androgen-refactory components are frequently present in lymph node metastasis.

Zentralbl Bakteriol, 1997 Feb, 285(3), 431 - 9
Excellent activity of newer quinolones on Legionella pneumophila in J774 macrophages; Walz A et al.; The activity of six antibiotics directed against intracellularly multiplying Legionella pneumophilia was examined in tissue cultures with J774 macrophages . The drugs tested were the new quinolones, BAY Y 3118 and clinafloxacin, and ciprofloxacin, erythromycin, gentamicin and ampicillin served as reference drugs . Additionally, the MICs of these drugs against L . pneumophila were determined in vitro by broth microdilution . Despite their low MIC values, ampicillin and gentamicin did not inhibit intracellular multiplication of L . pneumophila in J774 macrophages . In contrast, an inhibition of intracellular growth could be demonstrated for the four other antibiotics . The new quinolones BAY Y 3118 and clinafloxacin showed the highest activity against intracellular L . pneumophila . At a concentration of 0.00078 mg/L already, a marked reduction in bacterial counts was seen for both drugs in comparison to the growth control without antibiotics . The corresponding effective concentrations were 0.0125 mg/L for ciprofloxacin and 0.2 mg/L for erythromycin . It may be concluded that new quinolone derivatives might become an alternative to erythromycin and rifampicin which at present are the drugs of primary choice for the treatment of legionnaires' disease.

J Antimicrob Chemother, 1997 Feb, 39(2), 141 - 8
Time-kill studies on susceptibility of nine penicillin-susceptible and -resistant pneumococci to cefditoren compared with nine other beta-lactams; Spangler SK et al.; Broth MIC and time-kill methodology was used to determine the activity of cefditoren relative to those of penicillin G, ampicillin, amoxycillin, WY-49605, cefuroxime, cefpodoxime, cefdinir, cefixime and cefaclor against three penicillin-susceptible, three intermediate and three penicillin-resistant pneumococci . MICs of all agents rose with those of penicillin G . Cefditoren was the most active agent (MICs 0.002-0.5 mg/L), followed by WY-49605 (0.008-1.0 mg/L), amoxycillin (0.015-2.0 mg/L), cefuroxime (0.015-4.0 mg/L), cefpodoxime (0.03-4.0 mg/L), ampicillin (0.015-8.0 mg/L), cefdinir (0.03-16.0 mg/L), cefixime (0.125-64.0 mg/L) and cefaclor (0.5-128.0 mg/L) . All beta-lactams were bactericidal at the MIC after 24 h, and produced 90% killing after 12 h at concentrations above the MIC . Bactericidal concentrations of cefditoren, even for penicillin-resistant strains, were < or = 0.5 mg/L at 24 h . Additionally, cefditoren and WY-49605 were the only compounds that killed 99% of all strains after 6 h at > or = 4 x MIC . Cefditoren and amoxycillin killed 90% of all strains at 8 x MIC, and WY-49605 at 4 x MIC, after 4 h . Ampicillin had time-kill kinetics similar to those of amoxycillin, but MICs were 1-2 dilutions higher than the latter drug . Cefuroxime and cefpodoxime were the most active of other oral cephalosporins tested . Cefditoren and WY-49605 had the lowest MICs and most favourable time-kill kinetics of all beta-lactams tested.

J Med Microbiol, 1997 Feb, 46(2), 122 - 8
Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli; Lun MT et al.; The binding capacity and the protective activity of three monoclonal antibodies (MAbs)-ARM 1-4, ARM 1-7 and ARM 2-2-obtained from spleen cells of mice immunised with Escherichia coli O6:K-pre-treated with sub-MIC of aztreonam were studied . The MAbs belonged to IgG1 isotype and showed different reactivity toward protein epitopes of E . coli in an immunoblotting assay . ARM 1-4 recognised epitopes on molecules of 30 kDa and 40 kDa . ARM 1-7 identified an epitope of a molecule of 41 kDa, and ARM 2-2 recognised epitopes of molecules of 15 kDa and 41 kDa . In ELISA the MAbs cross-reacted with E . coli O7:K-, E . coli O111:B4 and E . coli O128:K- with different binding affinity . Furthermore, the MAbs showed complement-dependent bactericidal activity . The MAbs displayed different protective capacities when given to mice 90 min before lethal challenges with 2 x LD50, 4 x LD50 and 8 x LD50 of E . coli strains . In all but one instance (ARM 1-4 versus E . coli O7:K-) it was not possible to correlate protective capacity with binding affinity of a MAb to a given bacterial cell . Therefore, the epitopes recognised by the MAb may be more closely associated with bacterial virulence than in binding to the bacterial cell.

Indian J Med Res, 1997 Feb, 105, 58 - 60
In vitro susceptibility of clinical isolates of Mycobacterium tuberculosis to cefadroxil--a cephalosporin antibiotic; Selvakumar N et al.; The bactericidal activity (BA) of cefadroxil, a semisynthetic cephalosporin antibiotic, against M . tuberculosis H37Rv was studied in Middlebrook 7H9 medium . Cefadroxil showed good BA (average fall of viable counts = log10 0.32 colony forming units/ml/day) against the log phase culture of M . tuberculosis H37Rv . Its minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were found to be 15 micrograms/ml or less . The MIC of cefadroxil for 29 clinical isolates of M . tuberculosis and a laboratory strain, M . tuberculosis H37Rv was also determined by agar dilution method using Middlebrook 7H11 agar as a screening procedure . The MIC of cefadroxil was found to be 10 micrograms/ml or less for M . tuberculosis H37Rv and 16 (55.1%) of 29 clinical isolates tested . The MIC for 3 of 10 drug sensitive and 9 of 19 drug resistant isolates was 40 or more, a concentration much higher than the peak plasma concentration (28 micrograms/ml) attained in human beings . The higher MIC observed in 12 of 29 clinical isolates irrespective of their susceptibility pattern requires further studies to assess the usefulness of cefadroxil in the treatment of tuberculosis.

Arch Ophthalmol, 1997 Feb, 115(2), 173 - 6
Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin; Donnenfeld ED et al.; OBJECTIVES: To investigate the intracorneal, aqueous, and vitreous penetration of ofloxacin, and to assess the concentration of the drug after topical administration alone and after combined topical and oral administration . METHODS: Twenty consecutive patients undergoing penetrating keratoplasty with vitrectomy for bullous keratopathy received 2 drops of 0.3% ofloxacin every 30 minutes starting 4 hours before surgery . Group A (10 patients) received topical therapy alone . Group B (10 patients) received an additional 3 doses of oral ofloxacin, 400 mg, every 12 hours starting 26 hours before surgery . Aqueous humor, vitreous humor, and corneal specimens were analyzed for ofloxacin levels . RESULTS: For group A, the mean intracorneal ofloxacin level was 4.51 micrograms/mL (range, 0.58-8.77 micrograms/mL; 10 specimens), the mean aqueous humor level was 1.34 micrograms/mL (range, 0.07-4.98 micrograms/mL; 8 specimens), and the mean vitreous humor level was 0.37 micrograms/mL (range, 0.05-0.90 micrograms/mL; 8 specimens) . For group B, the mean intracorneal ofloxacin level was 8.59 micrograms/mL (range, 1.18-23.24 micrograms/mL; 10 specimens), the mean aqueous humor level was 2.77 micrograms/mL (range, 0.25-5.80 micrograms/mL; 10 specimens), and the mean vitreous humor level was 2.55 micrograms/mL (range, 0.28-4.97 micrograms/mL; 9 specimens) . CONCLUSIONS: Topically applied ofloxacin achieves therapeutic levels in the cornea and aqueous . Mean levels achievable are well above the 90% minimal inhibitory concentration (MIC90) for the majority of bacteria responsible for endophthalmitis and corneal ulceration . The addition of oral ofloxacin to topical therapy increased vitreous penetration 7-fold in this assay trial.

Antimicrob Agents Chemother, 1997 Feb, 41(2), 481 - 3
Fungicidal activity of cecropin A; DeLucca AJ et al.; Cecropin A (CA) fungicidal properties were explored . Nongerminated and germinated Aspergillus spp . and Fusarium spp . conidia were treated with CA . CA achieved complete lethality at < or = 25 microM (99 micrograms/ml) for germinating, but not nongerminating, conidia of Aspergillus spp . CA achieved total lethality for nongerminated and germinating conidia of Fusarium spp at 1.5 microM (6 micrograms/ml) . MIC and minimal lethal concentration assays in buffered RPMI medium gave similar results.

Antimicrob Agents Chemother, 1997 Feb, 41(2), 410 - 4
Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum; Wheat J et al.; An AIDS patient with disseminated histoplasmosis who improved during treatment with fluconazole but remained fungemic and subsequently relapsed is described . Isolates obtained from blood during therapy showed a progressive increase in fluconazole MIC from 0.625 to 20 micrograms/ml . The pretreatment, or parent, isolate and the posttreatment, or relapse, isolate demonstrated identical genetic patterns by PCR fingerprinting with three different primers . Fluconazole was less potent inhibitor of the growth of the relapse isolate than of the pretreatment isolate (50% inhibitory concentration {IC50} = 11.7 microM), while itraconazole was more potent (relapse isolate IC50 = 0.0011 microM versus pretreatment isolate IC50 = 0.0064 microM) . Neither the increased sensitivity to itraconazole nor the decreased activity of fluconazole on the growth of the relapse isolate results from changes in the intracellular content of these agents . To reach 50% inhibition of ergosterol synthesis in both the parent and relapse isolates, about 2 nM itraconazole was needed; with fluconazole, 50% inhibition was achieved at 20.9 microM and 55.5 microM, respectively . Resistance to fluconazole may develop during treatment and results from decreased sensitivity of ergosterol synthesis.

Phytochemistry, 1997 Feb, 44(3), 415 - 8
Chemical basis of the resistance of barley seeds to pathogenic fungi; Garcia S et al.; The 5-(n)-alkylresorcinol fraction of the epicuticular waxes of Hordeum vulgare seeds appeared to be responsible for their in-born resistance to pathogenic fungi such as Aspergillus niger and Penicillium crysogenum . The antifungal properties of this fraction were evaluated qualitatively and quantitatively with a novel bioassay where the extreme lipophilicity of these compounds was taken into account . The minimum inhibitory concentration in the fungi tested ranged from 5.6 to 10 micrograms cm-2 for the alkyresorcinols . The behaviour of the different cultivars against these fungi could be predicted by measuring the natural amount of resorcinols of each variety by TLC-scanning densitometry . The ranking of cultivars thus established correlated well with the field behaviour of each cultivar, providing a useful and rapid method for predicting the behaviour against fungi of new varieties being developed.

Cytometry, 1997 Feb 1, 27(2), 169 - 78
Rapid assessment of ceftazidime, ciprofloxacin, and gentamicin susceptibility in exponentially-growing E . coli cells by means of flow cytometry; Walberg M et al.; Exponentially growing E . coli cells were cultivated in the presence of ceftazidime, ciprofloxacin, and gentamicin in concentrations ranging from 0.5-8 minimal inhibitory concentration (MIC), permeabilized by means of cold shock in EDTA/azide, and stained with the DNA-specific dye combination of ethidium bromide and mithramycin before the fluorescence, light scattering, and cell number were measured flow-cytometrically . In order to evaluate the applicability of the cold-shock procedure, cells were also permeabillized by 70% ethanol . Permeabilization by cold shock, which eliminates washing of the cells, reduced the preparation time to <5 min . A statistically significant increase in light scattering and fluorescence, i.e., cell size and DNA content, could be detected already after 30 min of ceftazidime and ciprofloxacin exposure, even at sub-MIC concentrations . The results obtained with these drugs with cold-shock permeabilization were similar to those seen with ethanol fixation . For gentamicin-treated cells, however, a majority of the cells lost their fluorescence after cold shock . In gentamicin-treated cells fixed in ethanol, there was no consistent effect on either light scattering or fluorescence; however, we observed a substantial fragmentation and leakage of DNA in such cells . The cell proliferation was completely inhibited within 30 min of gentamicin incubation . For all three drugs, loss of light scattering and DNA were associated with cellular disintegration, i.e., reduced viability . The present results demonstrate that effects of ceftazidime, ciprofloxacin, and gentamicin on E . coli can be detected by flow cytometry within 1 h from the beginning of drug exposure to the completed measurement.

Ann Ital Med Int, 1997 Jan-Mar, 12(1), 20 - 5
Pathogenesis and therapy of Behçet's disease; Emmi L et al.; Behcet's disease is a relapsing-remitting systemic vasculitis characterized by oral and genital ulcers, uveitis and thrombophlebitis which can involve many organs . Although its pathogenesis is not fully understood, a possible pathogenetic model can be proposed on the basis of recent studies . Genetic factors, in particular, have been investigated and the role of the genes encoding tumor necrosis factor, transporter in antigen processing proteins and MIC (MHC class I chain related) has been emphasized . In addition, a possible polarization of T lymphocytes towards the Th1 phenotype in Behcet's disease has been suggested by recent observations in experimental uveoretinitis and by preliminary data in humans . Neutrophils may also play a role in the pathogenesis of this disease, as they are attracted by macrophage-released cytokines at the site of the lesions, and thus contribute to tissue damage and self-maintenance of inflammation . New strategies for the treatment of Behcet's disease are being devised . In particular, immunosuppressive drugs used in association or in sequence may be administered to patients with particular clinical features or very severe disease.

Microbios, 1997, 89(360-361), 135 - 41
Minimal inhibitory concentrations of sulbactam/ampicillin against drug sensitive and drug resistant isolates of Mycobacterium tuberculosis; Paramasivan CN et al.; A total of 92 isolates of Mycobacterium tuberculosis consisting of equal numbers of sensitive and resistant strains was tested for their susceptibility to sulbactam and ampicillin (in the ratio of 1:2) on Lowenstein-Jensen (LJ) and 7H11 agar media . The geometric mean MIC was 63.97 micrograms/ml for the drug sensitive strains and 65.92 micrograms/ml for the resistant strains, and the overall mean was 65.01 micrograms/ml . The high MIC on LJ medium could be attributed to the higher protein content which resulted in greater binding of sulbactam/ampicillin . On the other hand, the geometric mean MIC on 7H11 medium was 26.73 micrograms/ml for sensitive strains and 23.82 micrograms/ml for resistant strains; the overall mean being 25.23 micrograms/ml . Although these MICs of sulbactam-ampicillin are higher than those reported earlier, they can be easily achieved in serum . Further studies on experimental tuberculosis and in humans will be needed to prove the efficacy of sulbactam/ampicillin in the treatment of patients with multidrug resistant tuberculosis.

Mycoses, 1997 Jan-Feb, 40(1-2), 25 - 32
Plasma and tissue concentrations of fluconazole and their correlation to breakpoints; Pittrow L et al.; The prediction of clinical outcome during antifungal therapy is an issue of paramount importance in clinical research, because no consistently reliable parameters are available . Minimum inhibitory concentration (MIC) values and breakpoint interpretation may serve as surrogate criteria until standardized in vitro antifungal susceptibility testing is developed, especially for fluconazole . With reproducible susceptibility testing methods for Candida species now available, tentative fluconazole interpretive breakpoints derived from MIC values determined by the National Committee on Clinical Laboratory Standards (NCCLS) M27-T broth macrodilution method are open for public comment . Besides the in vitro susceptibility of the fungus, clinical response to antifungal therapy with fluconazole depends to a great extent on the daily dose and corresponding plasma and tissue concentrations . Promising results from a few dose-finding studies in non-neutropenic patients show that fluconazole doses of up to 1000 mg day-1 result in higher clinical response rates than lower dosages . Therapeutic success depends substantially on achieving fluconazole plasma and tissue levels that are sufficiently higher than MIC values indicated by in vitro testing . However, this simplified concept must be related to the clinical situation and it is essential to consider the immunological status and underlying disease of the patient . Misinterpretation of MIC values may result in selection of an antifungal agent for life-threatening infections that does not provide optimal efficacy or toleration.

Scand J Infect Dis Suppl, 1997, 104, 13 - 4
Assay of antibiotic susceptibility of Chlamydia pneumoniae; Hjelm E et al.; It is well known that treatment of Chlamydia pneumoniae infections is difficult . High doses and prolonged treatment is often needed to achieve clinical cure despite good in vitro effect of the drugs used . We here discuss different methodological problems in the determination of MIC and MBC values of C . pneumoniae . The length of the preincubation time and the lack of fluctuation of the antibiotic concentrations may affect the outcome of the currently used assay.

Ophthalmologica, 1997, 211(4), 229 - 31
Penetration of oral cefuroxime axetil into the human aqueous humor; Ghia M et al.; The purpose of this study was to investigate the penetration into the aqueous humor of cefuroxime after a single oral dose as cefuroxime axetil . Fourteen patients scheduled for cataract extraction received a single oral dose of cefuroxime axetil corresponding to 500 mg of cefuroxime 2-8 h preoperatively . Aqueous humor samples were obtained at the beginning of the cataract surgery and blood samples were drawn at the time of anesthesia . Cefuroxime levels were determined by high-performance liquid chromatography . The aqueous levels were (mean +/- SEM) 0.48 +/- 0.13 microgram/ml from 3 to 8 h after administration . Serum levels averaged 3.80 +/- 0.58 micrograms/ml . These data indicate that detectable levels of cefuroxime, exceeding the MIC of some bacterial species that frequently cause intraocular infections, may be achieved in uninflamed eyes after a low dose of cefuroxime axetil.

Int Rev Immunol, 1997, 14(1), 33 - 48
Pathogenic gene responsible for the predisposition of Behçet's disease; Mizuki N et al.; HLA-B51 is well known to be associated with Behcet's disease (BD) in many different ethnic groups . The hypothesis may be presented that B51 molecules are primarily involved in BD development through specific antigen presentation . Furthermore, HLA-C genotyping by the polymerase chain reaction-sequence specific primers method suggests that the BD pathogenic gene is not the HLA-C gene itself but some other gene located near the HLA-B gene . Polymorphic analysis of the Tau-a microsatellite between the HLA-B and TNF genes indicates that the pathogenic gene of BD is not the HLA-B51 gene itself but other gene located around the HLA-B gene . Recent studies suggest that many novel genes exist in the region between the TNF and HLA-B or HLA-C genes such as MIC and PERB, etc . and furthermore, many unidentified new genes have been suggested to exist in this region . In this paper, the present situation of the investigations on the genetic predisposition responsible for BD was reviewed.

Parasitol Res, 1997, 83(5), 489 - 91
Potentiation of the antimalarial activity of atovaquone by doxycycline against Plasmodium falciparum in vitro; Yeo AE et al.; The effect of doxycycline, obtained from human volunteers administered doxycycline, on the minimum inhibitory concentration (MIC) of atovaquone was determined against the K1 and FC27 isolates of Plasmodium falciparum in vitro . Doxycycline concentrations ranging from 0.10-1.18 microg/ml added to atovaquone produced MIC ratios {atovaquone + doxycycline/atovaquone alone} ranging from 0.38 to 0.70 . These results suggest that the antimalarial activity of atovaquone is potentiated by doxycycline . Additionally, these drugs may be rational partners for the treatment and prophylaxis of falciparum malaria.

Ann Chir Gynaecol, 1997, 86(1), 19 - 22
Laparoscopy aided gastrostomy in children; Andersson L et al.; BACKGROUND AND AIMS: The aim of this report is to describe a method for laparoscopy aided button gastrostomy in children . MATERIAL AND METHODS: The method includes the use of two ports, one umbilical and one subcostal on the left side . The stomach is exteriorized using a grasping forceps in the subcostal port . Under direct vision the gastrostomy button, MIC-KEY, is inserted into the stomach at the lesser curvature and secured by purse string sutures . The stomach is attached to the anterior abdominal wall . RESULTS: The results show that this method has been successfully used in 33 children without operative complications . CONCLUSIONS: We conclude that by inserting the gastrostomy button under direct vision, damage to other abdominal organs is avoided and a correct placement at the lesser curvature obtained . The combination of laparoscopic and open procedures makes the method easy and safe.

Dermatology, 1997, 194 Suppl 1, 37 - 9
Oral terbinafine (Lamisil) in the treatment of fungal infections of the skin and nails; Roberts DT; The efficacy and safety of antifungal drugs depend upon their mode of action, the minimal inhibitory concentration (MIC) and its relationship to the minimal fungicidal concentration (MFC), the spectrum of activity and drug kinetics at the involved site . Terbinafine acts at the fungal cell wall . Its MIC against dermatophytes is the lowest of all currently available systemic antifungal agents . It is the only one with an MIC:MFC ratio of 1:1 so that terbinafine should be effective over very short treatment durations in dermatophyte infections of the scalp, palms and soles, and nail, providing that drug penetration is adequate, as it appears to be . Therapeutic levels persist for a considerable period after the cessation of treatment, also favouring short-duration therapy . Terbinafine is effective against all varieties of dermatophyte . Terbinafine given over 4 weeks or less is effective against Trichophyton of the scalp in children and adults . Its efficacy in zoophilic ectrothrix infection is anecdotal, but it is likely on theoretical grounds . Terbinafine is also effective against pityriasis versicolor and vaginal candidosis, but only topically . As of March 1996, around 3,000,000 patients have been treated worldwide with terbinafine, mostly for 12 weeks for toe-nail onychomycosis . Gastro-intestinal disturbance and minor skin rashes are seen in 5 and 2% of patients, respectively.

Diagn Microbiol Infect Dis, 1997 Jan-Feb, 27(1-2), 29 - 33
Efficacy of beta-lactam antibiotics: integration of pharmacokinetics and pharmacodynamics; Cars O; The study of pharmacokinetics teaches us how drugs are distributed and eliminated, whereas, pharmacodynamics looks at the relationship between drug concentration and drug activity . The free, nonprotein-bound fraction of the serum concentration can be used as a surrogate marker for the levels at the site of infection . It is tempting to use tissue levels for this purpose, but their use is fraught with difficulties . The single pharmacodynamic parameter that correlates best with therapeutic efficacy for beta-lactam antibiotics is time that free serum levels stay above the minimum inhibitory concentration (MIC) . Recent clinical studies seem to confirm the value of time above MIC in predicting clinical and bacteriological outcome.

J Cataract Refract Surg, 1997 Jan-Feb, 23(1), 111 - 4
Anterior chamber concentrations of vancomycin in the irrigating solution at the end of cataract surgery; Adenis JP et al.; PURPOSE: To verify that therapeutic levels of vancomycin were present in the irrigating solution at the end of cataract surgery . SETTING: Service d'ophtalmologie, Universite de Limoges, France . METHODS: An irrigating solution that contained 20 mg/L of vancomycin was used in 15 patients having phacoemulsification . Antibiotic concentrations in the phacoemulsification handpiece and in the aqueous humor were measured at the end of surgery . RESULTS: Passage through the phacoemulsifier did not affect antibiotic concentration . In the aqueous humor, after wound closure, the concentration constantly exceeded the minimal inhibitory concentration of the principal gram-positive bacteria responsible for human endophthalmitis . CONCLUSION: Vancomycin added to the irrigating solution used during cataract surgery was found in effective concentrations in the anterior chamber at the end of surgery.

Z Naturforsch {C}, 1997 Jan-Feb, 52(1-2), 45 - 8
Effect of platinum (II) complexes of 4-methoxy- and 4-chlorobenzoic acid hydrazides on Saccharomyces cerevisiae; Tabakova S et al.; This study reports the anti-yeast effect of the 4-methoxybenzoic acid hydrazide (pmbah), 4-chlorobenzoic acid hydrazide (pcbah) and their Pt(II) complexes: cis- {PtL2X2} and cis- {PtL(NH3)Cl2} where L is either pcbah or pmbah and X is Cl, Br or I . MICs of the 4- substituted analogues (20,000-625 microM) are much lower than those of the previously reported benzoic acid hydrazide and 3-methoxybenzoic acid hydrazide . Complex formation results in significant increase of potency which may be due to a change in the mechanism of action, but the MIC (> 400-50 microM) and the IC50 (> 400-1 microM) values show that higher activity of the ligands in the free state does not result in enhanced complex activity . Differences in the potency of iodo-, chloro- and bromo complexes suggest MIC and IC50 values may be in correlation with the stability of the complex, rather than with the activity of the free ligands . Osmotically unstable mutants were more susceptible to the compounds than their parent strains, but differences among the parent strains, but differences among the parent strains were greater.

J Pathol, 1997 Jan, 181(1), 62 - 6
Chromosomal rearrangement t(11;22) in extraskeletal Ewing's sarcoma and primitive neuroectodermal tumour analysed by fluorescence in situ hybridization using paraffin-embedded tissue; Nagao K et al.; The clonal chromosomal rearrangement t(11;22) has been reported by karyotypic analysis to be specific for Ewing's sarcoma of bone and soft tissue origin as well as primitive neuroectodermal tumour . In this report, immunohistological analysis of MIC 2 expression and fluorescence in situ hybridization (FISH) were performed using paraffin-embedded tissues . We examined t(11;22) in the nuclei isolated from two Ewing's sarcomas, four primitive neuroectodermal tumours, and three neuroblastomas, which served as negative controls by FISH with an alpha-satellite DNA probe for chromosome 11, a chromosome 22 marker probe, and whole chromosome painting probes for both chromosomes 11 and 22 . Both cases of Ewing's sarcoma and the four primitive neuroectodermal tumour specimens were immunoreactive for MIC 2 . Both Ewing's sarcomas and three of the four primitive neuroectodermal tumours contained the tumour-specific t(11;22), but the three neuroblastomas did not show this translocation . Based on the cytogenetic results and on the immunohistological investigation of MIC 2 expression, Ewing's sarcoma is suggested to be related closely to primitive neuroectodermal tumour . FISH is a useful aid in determining the tumour type of Ewing's sarcoma and putative related tumours.

Eur J Clin Microbiol Infect Dis, 1997 Jan, 16(1), 42 - 50
Key issues concerning fungistatic versus fungicidal drugs; Graybill JR et al.; Are there any fungicidal drugs available today? A critical issue in answering this question is that of definition . The simplest, most stringent definitions identify fungistatic drugs as those that inhibit growth, whereas fungicidal drugs kill fungal pathogens . The immunocompetent host is usually far better equipped to eliminate fungal pathogens than the immunosuppressed host . Therefore, it would be especially desirable to have a truly fungicidal drug, one that absolutely kills and fungi, as a treatment option for the immunosuppressed patient . The critical question would be whether a fungicidal drug can be delivered to the target site in a concentration high enough for a sufficient time to reduce the intralesional fungal counts to zero . By this simple definition, there are no fungicidal drugs available today . However, an accepted alternative definition is that often used by the bacteriologist: Fungicidal drugs are those that lead to a reduction of 99.9% of the initial inocula . Although this less restrictive in vitro standard is more easily met, it has serious limitations . Whether the 99.9% kill should be an acceptable standard remains uncertain . As an alternative, the minimum inhibitory concentration, though indicating static activity, has served well; perhaps it should be the only information reported for fungal susceptibility testing.

Zentralbl Bakteriol, 1997 Jan, 285(2), 291 - 8
Pyrolysis mass spectrometry: a predictor of clinical response to treatment in pulmonary opportunist mycobacterial infection: preliminary work with M . malmoense; Heginbothom ML et al.; Pyrolysis mass spectrometry (Py-MS) yields data reflecting overall cell composition . The changes in composition induced by treatment with rifampicin and ethambutol, alone and in combination, were investigated for a collection of seven strains of Mycobacterium malmoense from pulmonary infections . Two strains, both from patients that had responded to therapy with this combination, showed large changes in composition from control, untreated cultures . The difference was particularly marked for the ethambutol treated cultures . Four strains, all from patients who had failed to respond to therapy with this combination, showed minimal changes in composition for all treatments . The remaining strain also showed minimal treatment-induced change, but, for this patient, therapy with the combination had proved successful . Minimum inhibitory concentrations (MICs) were determined radiometrically . All strains showed MICs < 0.5 microgram/mL for rifampicin (sensitive) and of 8 micrograms/mL for ethambutol (resistant) . MIC results did not correlate with clinical response, whereas the Py-MS results correlated with clinical response for six of the seven isolates . Py-MS may have a role in predicting effective therapy for this problem group.

J Antimicrob Chemother, 1997 Jan, 39(1), 19 - 24
Effect of temperature on aminoglycoside binding sites in Stenotrophomonas maltophilia; Rahmati-Bahram A et al.; In this study we used strains of Stenotrophomonas maltophilia grown at 30 degrees C and 37 degrees C to investigate the role of lipopolysaccharide (LPS) in temperature-dependent variations in sensitivity (TDVS) to gentamicin . TDVS was scored as 'good' if a four-fold or greater difference in minimum inhibitory concentration (MIC) was found between the two incubation temperatures (good TDVS strains; n = 23), and otherwise as 'poor' (poor TDVS strains; n = 15) . Phosphate content of isolated LPS in the strains exhibiting good TDVS grown at 37 degrees C was significantly (P < 0.001) higher than those grown at 30 degrees C . However, the phosphate content from LPS of strains exhibiting poor TDVS did not alter significantly with growth temperature . There was no significant difference in 3-deoxy-D-manno-octulosonic acid (KDO) content between the strains grown at the different incubation temperatures . Fluorescence-activated cell sorting analysis showed significant differences in binding of fluorescein Isothiocyanate conjugated gentamicin to cells grown at 30 degrees C or 37 degrees C . We conclude that the temperature-dependent variation in the aminoglycoside susceptibility of this species was not correlated with any detectable change in KDO content, but correlated well with phosphate content of LPS and that LPS phosphate is the major site of ionic interaction for aminoglycosides in S . maltophilia.

Cytometry, 1997 Jan 1, 27(1), 84 - 91
Flow cytometric assessment of hydroxypyridinone iron chelators on in vitro growth of drug-resistant malaria; Pattanapanyasat K et al.; The resurgence of drug-resistant malaria makes urgent the evaluation of new antimalarial agents . This study describes a flow cytometric method (FCM) for testing in vitro drug susceptibility of Plasmodium falciparum malaria to several orally active hydroxypyridinone (CP) iron chelators and to the parenteral iron chelator desferrioxamine (DF) . After exposure of parasites to various concentrations of iron chelating agents, aliquots of cultures were fixed with glutaraldehyde . The fixed samples were washed and stained for parasite DNA with propidium iodide and analyzed by flow cytometry . The remaining cells were pulsed with 3H-hypoxanthine, using the microdilution radioisotope method . Both CP and DF showed dose-dependent inhibition of parasite growth . Of the compounds studied, DF exerted a stronger inhibitory effect . Fifty percent of inhibitory concentrations (IC50) of CP and DF determined by DNA fluorescence profiles in the flow cytometer were consistent with those obtained from the radioisotope method and by microscopic examination . Moreover, the minimum inhibitory concentrations (MIC) of drug required to inhibit parasite growth, as detected by the decreasing DNA fluorescence intensity of the schizont, correlated with observed abnormal microscopic morphology . The validity of the MIC, as indicated by decreased fluorescence intensity, was confirmed by subsequent parasite culture . Our FCM study demonstrated the sensitivity of both chloroquine- and pyrimethamine-resistant malaria parasites to iron chelators . Addition of equimolar concentrations of ferric ion completely abolished the inhibitory effect of iron chelators, indicating the importance of iron for parasite growth and the primary effect of the compounds as iron (III) chelating agents . These data demonstrate that FCM provides a simple and reliable means for antimalarial drug susceptibility testing, and suggest that iron chelators have potential for the treatment of drug-resistant malaria.

Cornea, 1997 Jan, 16(1), 64 - 71
Ocular penetration and pharmacokinetics of topical fluconazole; Yee RW et al.; The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent . The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC) . Peak corneal levels occurred essentially immediately at 5 min in the corneas {debrided, 8.2 +/- 1.2 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)} and at 15 min after application in the aqueous {debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)} . Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min . A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor . A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous . The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous . Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml . Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 215 - 7
In vitro susceptibility of Helicobacter pylori to protolichesterinic acid from the lichen Cetraria islandica; Ingolfsdottir K et al.; With reference to the traditional use of Cetraria islandica (Iceland moss) for relief of gastric and duodenal ulcer, plant extracts were screened for in vitro activity against Helicobacter pylori . (+)-Protolichesterinic acid, an aliphatic alpha-methylene-gamma-lactone, was identified as an active component . The MIC range of protolichesterinic acid, in free as well as salt form, was 16 to 64 micrograms/ml.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 200 - 3
Efficacies of two novel azole derivatives each containing a morpholine ring, UR-9746 and UR-9751, against systemic murine coccidioidomycosis; Clemons KV et al.; UR-9746 and UR-9751 are novel azole derivatives each containing a morpholine ring . They were examined for both in vitro and in vivo activities against Coccidioides immitis . In vitro, UR-9746 and UR-9751 were active, with MICs of 25 and 3.1 micrograms/ml, respectively, against C . immitis Silveira; minimum fungicidal concentrations were > 100 micrograms/ml, the highest concentration tested, for both compounds . Antifungal activity in serum showed the desirable characteristic of remaining severalfold above the MIC at all times . Against systemic murine coccidioidomycosis, UR-9746 and UR-9751 prolonged survival at dosages of > or = 10 mg/kg/day and showed increased reduction of infectious burden in the spleens, livers, and lungs of treated mice with escalating dosage . Both compounds lacked observable toxicity and on a milligram-per-kilogram of body weight basis were > or = 10-fold superior to fluconazole in prolonging survival and clearing infection with C . immitis.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 175 - 9
Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of the parE gene encoding a subunit of topoisomerase IV; Breines DM et al.; The locus nfxD, which contributes to high-level quinolone resistance in Escherichia coli KF111b (gyrAr nfxB nfxD), is only expressed in the presence of a gyrA mutation, and maps to the region of the parC and parE genes, was outcrossed into strain KF130, creating strain DH161 (gyrAr nfxD) . DNA sequence analysis of DH161 revealed no changes in the topoisomerase IV parC quinolone resistance-determining region but did identify a single T-to-A mutation in parE at codon 445, leading to a change from Leu to His . Full-length cloned parE+ partially complemented the resistance phenotype in KF111b and DH161, but did not complement the resistance phenotype in strain KF130 (gyrAr) . No complementation was seen with cloned, truncated parE+ . To confirm these findings, gyrAr was first outcrossed from KF130 into E . coli W3110parE10 {parE temperature sensitive(Ts)} and KL16 . The transduced strains KL16 and W3110parE10 were subsequently transformed with plasmids containing cloned parE from DH161 or KL16 . Cloned parE from DH161 increased norfloxacin resistance in the parE(Ts) background twofold at 30 degrees C and fourfold at 42 degrees C compared to those for cloned parE from KL16 . The same experiment with a non-Ts background revealed a twofold increase in the norfloxacin MIC at both 30 and 42 degrees C . These data identify the nfxD conditional resistance locus as a mutant allele of parE . This report is the first of a quinolone-resistant parE mutant and confirms the role of topoisomerase IV as a secondary target of norfloxacin in E . coli.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 148 - 55
MIC and time-kill studies of antipneumococcal activity of GV 118819X (sanfetrinem) compared with those of other agents; Spangler SK et al.; Agar dilution MIC methodology was used to test the activities of GV 118819X (sanfetrinem), ampicillin, amoxicillin, amoxicillin-clavulanate, cefpodoxime, loracarbef, levofloxacin, clarithromycin, ceftriaxone, imipenem, and vancomycin against 53 penicillin-susceptible, 84 penicillin-intermediate and 74 penicillin-resistant pneumococci isolated in the United States . GV 118819X was the most active oral beta-lactam, with MIC at which 50% of the isolates were inhibited (MIC50)/MIC90 values of 0.008/0.03, 0.06/0.5, and 0.5/1.0 micrograms/ml against penicillin-susceptible, -intermediate, and -resistant stains, respectively . Amoxicillin and amoxicillin in the presence of clavulanate (2:1) were the second most-active oral beta-lactams, followed by ampicillin and cefpodoxime; loracarbef was not active against penicillin-intermediate and -resistant strains . Clarithromycin was most active against penicillin-susceptible strains but was less active against intermediate and resistant stains . All pneumococcal stains were inhibited by ceftriaxone and imipenem at MICs of < or = 4.0 and < or = 1.0 micrograms/ml, respectively . The activities of levofloxacin and vancomycin were unaffected by penicillin susceptibility . Time-kill studies of three penicillin-susceptible, three penicillin-intermediate, and three penicillin-resistant pneumococci showed that all compounds, at the broth microdilution MIC, yielded 99.9% killing of all strains after 24 h . Kinetic patterns of all oral beta-lactams, ceftriaxone, and vancomycin were similar relative to the MIC, with 90% killing of all strains first observed after 12 h . However, killing by amoxicillin-clavulanate, imipenem, and levofloxacin was slightly faster and that by clarithromycin was slower than that by the above-described drugs . At 2 x the MIC, more strains were killed earlier than was the case at the MIC, but the pattern seen at the MIC prevailed . When MICs and kill kinetics were combined, sanfetrinem was the most active oral antipneumococcal agent in this study.

Antimicrob Agents Chemother, 1997 Jan, 41(1), 76 - 9
Antibiotic susceptibility of the newly cultivated agent of human granulocytic ehrlichiosis: promising activity of quinolones and rifamycins; Klein MB et al.; Human granulocytic ehrlichiosis (HGE) is a rapidly emerging tick-borne infection which presents as an acute febrile illness and is associated with hematologic abnormalities, elevated hepatic transaminase levels, and characteristic intracellular organisms in peripheral blood granulocytes . Although HGE has been successfully treated with tetracyclines, its susceptibility to other antibiotics remains unknown . No clear treatment alternative exist for young children, pregnant women, or allergic individuals, in whom tetracyclines are contra-indicated . We performed in vitro antibiotic susceptibility tests with this recently isolated agent grown in the human promyelocytic leukemia cell line HL-60 . Doxycycline (MIC, 0.25 micrograms/ml), rifampin (MIC, 0.5 micrograms/ml), rifabutin (MIC, < or = 0.125 micrograms/ml), ciprofloxacin and ofloxacin (both with MICs of 2 micrograms/ml), and trovafloxacin (MIC, < or = 0.125 micrograms/ml) ciprofloxacin and ofloxacin (both with MICs of 2 micrograms/ml), and trovafloxacin (MIC, < or = 0.125 micrograms/ml) demonstrated significant activity against the HGE agent . These agents were also bactericidal . The HGE agent was resistant to clindamycin, trimethoprim-sulfamethoxazole, and imipenem-cilastatin, as well as to ampicillin, ceftriaxone, erythromycin, and azithromycin, antibiotics commonly used to treat Lyme disease . Both chloramphenicol and gentamicin had weak inhibitory activities but were not bactericidal . Our findings confirm the observed clinical efficacy of doxycycline and further suggest that the rifamycins and quinolones, particularly trovafloxacin, hold promise as alternative agents for treating this new infection.

J Clin Microbiol, 1997 Jan, 35(1), 139 - 43
Multicenter evaluation of proposed standardized procedure for antifungal susceptibility testing of filamentous fungi; Espinel-Ingroff A et al.; A multicenter study was conducted to expand the generation and analysis of data that supports the proposal of a reference method for the antifungal susceptibility testing of filamentous fungi . Broth microdilution MICs of amphotericin B and itraconazole were determined in 11 centers against 30 coded duplicate pairs of Aspergillus spp., Fusarium spp., Pseudallescheria boydii, and Rhizopus arrhizus . The effect of inoculum density (approximately 10(3) and 10(4) CFU/ml), incubation time (24, 48, and 72 h), and procedure of MIC determination (conventional and colorimetric {Alamar Blue} evaluation of growth inhibition) on intra- and interlaboratory agreement was analyzed . Based on intra- (97 to 100%) and interlaboratory (94 to 95%) agreement for both drugs, the overall optimal testing conditions identified were determination of colorimetric MICs after 48 to 72 h of incubation with an inoculum density of approximately 10(4) CFU/ml . These testing conditions are proposed as guidelines for a reference broth microdilution method.

Antimicrob Agents Chemother, 1996 Dec, 40(12), 2882 - 3
Dialysis culture enables more accurate determination of MIC of benzylpenicillin for Borrelia burgdorferi than does conventional procedure; Stiernstedt SH et al.; A constant benzylpenicillin (penicillin G) concentration for determination of the MIC for strains of Borrelia burgdorferi was achieved by dialysis culture . The strains were grown in dialysis membrane bags with daily transfer to tubes with freshly added benzylpenicillin . The MICs decreased by one or several dilution steps compared with the conventional procedure.

Antimicrob Agents Chemother, 1996 Dec, 40(12), 2785 - 91
Naturally azole-resistant Leishmania braziliensis promastigotes are rendered susceptible in the presence of terbinafine: comparative study with azole-susceptible Leishmania mexicana promastigotes; Rangel H et al.; Leishmania braziliensis (isolate 2903) was naturally resistant to ketoconazole or the bis-triazole D0870, inhibitors of sterol C-14 demethylase, which produced only moderate effects on the proliferation of promastigotes at 10 microM . In contrast, Leishmania mexicana (isolate NR) was extremely susceptible to the azoles, as complete growth arrest and cell lysis were induced by incubation of the parasites with 0.05 microM concentrations of the drugs for 72 h . The opposite response was observed with terbinafine, an inhibitor of squalene epoxidase: L . braziliensis 2903 was three times more susceptible to the drug than L . mexicana NR (MICs of 5 and 15 microM, respectively) . However, when the L . braziliensis stock was grown in the presence of 1 microM terbinafine, which by itself produced only marginal (< 10%) effects on growth, it became highly susceptible to the azoles, with an MIC of 0.03 microM . Analysis of cellular free sterols by high-resolution capillary gas chromatography coupled to mass spectrometry showed that 14-methyl sterols can support normal growth of L . braziliensis 2903 but not of L . mexicana NR . On the other hand, the higher susceptibility of the L . braziliensis isolate to terbinafine was correlated with a massive accumulation of squalene in the presence of the allylamine while no significant effects on L . mexicana sterol composition were observed at drug concentrations up to 1 microM . Thus, the > 300-fold increase in the susceptibility of L . braziliensis promastigotes to azoles in the presence of terbinafine was attributed to the combined effect of squalene and the methylated sterol precursors on the physical properties of the cell's membranes, leading to the loss of cell viability . Combination therapy with azoles and terbinafine in the treatment of human L . braziliensis infections deserves further study.

Antimicrob Agents Chemother, 1996 Dec, 40(12), 2703 - 9
Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans; Muller M et al.; The calculation of pharmacokinetic/pharmacodynamic surrogates from concentrations in serum has been shown to yield important information for the evaluation of antibiotic regimens . Calculations based on concentrations in serum, however, may not necessarily be appropriate for peripheral-compartment infections . The aim of the present study was to apply the microdialysis technique for the study of the peripheral-compartment pharmacokinetics of select antibiotics in humans . Microdialysis probes were inserted into the skeletal muscle and adipose tissue of healthy volunteers and into inflamed and noninflamed dermis of patients with cellulitis . Thereafter, volunteers received either cefodizime (2,000 mg as an intravenous bolus; n = 6), cefpirome (2,000 mg as an intravenous bolus; n = 6), fleroxacin (400 mg orally n = 6), or dirithromycin (250 mg orally; n = 4); the patients received phenoxymethylpenicillin (4.5 x 10(6) U orally; n = 3) . Complete concentration-versus-time profiles for serum and tissues could be obtained for all compounds . Major pharmacokinetic parameters (elimination half-life, peak concentration in serum, time to peak concentration, area under the concentration-time curve {AUC}, and AUC/MIC ratio) were calculated for tissues . For cefodizime and cefpirome, the AUCtissue/AUCserum ratios were 0.12 to 0.35 and 1.20 to 1.79, respectively . The AUCtissue/AUCserum ratios were 0.34 to 0.38 for fleroxacin and 0.42 to 0.49 for dirithromycin . There was no visible difference in the time course of phenoxymethylpenicillin in inflamed and noninflamed dermis . We demonstrated, by means of microdialysis, that the concept of pharmacokinetic/pharmacodynamic surrogate markers for evaluation of antibiotic regimens originally developed for serum pharmacokinetics can be extended to peripheral-tissue pharmacokinetics . This novel information may be useful for the rational development of dosage schedules and may improve predictions regarding therapeutic outcome.

Antimicrob Agents Chemother, 1996 Dec, 40(12), 2686 - 90
Correlation of pharmacodynamic parameters of five beta-lactam antibiotics with therapeutic efficacies in an animal model; Soriano F et al.; The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics . However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics . In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed . The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime . The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca . 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml) . The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice . The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h . A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h . The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

Ann Pathol, 1996 Dec, 16(6), 445 - 8
{Primary pericardial thymoma: an unusual etiology of neoplastic pericarditis}; Ben Hami B et al.; We present a case of a primary pericardic thymoma, revealed by a pericardic effusion . This ectopic localisation is very unusual; neoplastic pericarditis are usually due to metastasis of carcinomas or lymphomas . Sometimes, they are secondary to pericardic invasion by mediastinal malignant thymomas or a metastasis of thymomas . Our patient presented a single pericardic localisation of thymoma without any other site . We discuss ectopic localisations of thymic tissue and thymomas and the diagnostic usefulness of the MIC 2 antibody.

Jpn J Antibiot, 1996 Dec, 49(12), 1095 - 108
{Fundamental and clinical studies on the efficacy of bifonazole in patients with tinea pedis at 10 years after approval . Part 2 . Clinical evaluation}; Watanabe S et al.; The usefulness of bifonazole (Mycospor), a topical imidazole antifungal agent approved 10 years ago, was evaluated for the treatment of tinea pedis . Mycospor cream was applied by 141 patients with tinea pedis once daily for 4 233ks, and the clinical efficacy and adverse reactions (as well as any correlations with susceptibility of isolates and the mycological activity of the agent against these isolates) were studied . The results were then compared to those of a previous study . The following results were obtained . 1 . Mycological activity Mycological examination results became negative in 63.2% (36/57) of the patients with plantar tinea pedis, in 94.1% (32/34) of those with interdigital tinea pedis, and in 74.7% (68/91) of all tinea pedis patients . 2 . Mycological activity and MIC No correlation was found between the MICs of bifonazole against the pathogenic fungi and the rate of eradication on mycological examination . 3 . Improvement of symptoms The improvement rates for local symptoms were 82.5% for plantar tinea pedis, 85.7% for interdigital tinea pedis, and 83.7% for all tinea pedis . 4 . Clinical efficacy Good clinical efficacies were found in 61.4% of the patients with plantar tinea pedis, in 88.6% of those with interdigital tinea pedis, and in 71.7% of all patients . 5 . Safety Regarding adverse reactions, what seemed to be contact dermatitis was reported in 5 out of 127 cases (3.9%) . The reaction decreased or disappeared in all cases . 6 . Usefulness Mycospor was found to be useful in 64.9% of patients with plantar tinea pedis, in 88.6% of those with interdigital tinea pedis, and in 73.9% of all tinea pedis patients . 7 . Comparison with former results The results obtained in the present clinical study were comparable to those obtained in patients with tinea pedis treated in a double-blind comparative study conducted during the development of as a new topical antifungal agent . From the above results, Mycospor cream was confirmed to be still useful, although it has been used widely for the topical treatment of cutaneous mycoses in the past 10 years since its approval.

J Antimicrob Chemother, 1996 Dec, 38(6), 1085 - 9
Killing kinetics of meropenem against penicillin-resistant pneumococci; Barakett V et al.; The killing kinetics of meropenem against sixteen clinical isolates of pneumococci (12 penicillin-resistant, three penicillin-intermediate and one penicillin-sensitive) were studied . Meropenem was tested at 1x, 2x and 4x the MIC for each individual isolate . The results showed a good bactericidal activity with rapid killing of pneumococci (killing > 3 log10 cfu/mL was obtained for nine strains) . This strategy needs clinical assessment and might prove to be a suitable alternative to penicillin and cephalosporins for the treatment of mixed infections involving multiresistant pneumococci.

J Chemother, 1996 Dec, 8(6), 445 - 8
In vitro susceptibility of Trichosporon beigelii to antifungal agents; Perparim K et al.; The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of amphotericin B, flucytosine, miconazole, fluconazole and itraconazole against 21 isolates of Trichosporon beigelii in RPMI-1640 medium were determined using National Committee for Clinical Laboratory Standards (NCCLS) methodology in microdilution method . Most isolates were sensitive to miconazole (MIC90 0.78 microgram/ml), fluconazole (MIC90 6.25 micrograms/ml), and itraconazole (MIC90 0.19 microgram/ml), with the former being the most active agent tested (MFC90 3.12 mu/ml) . Although amphotericin B inhibited most strains (MIC range, 0.78-3.12 micrograms/ml), poor fungicidal activity was observed (MFC range, 1.56-12.5 micrograms/ml) showing a pattern of relative resistance in vitro . Flucytosine showed generally poor activity against most isolates tested . These in vitro findings confirm the resistance of T.beigelii to amphotericin B and suggest that azoles may be an alternative to the former for the treatment of disseminated trichosporonosis . However, in vivo studies would better validate these in vitro findings.

J Chemother, 1996 Dec, 8(6), 425 - 31
Inhibitory and bactericidal activity of rokitamycin against Helicobacter pylori and morphological alterations; Brenciaglia MI et al.; Rokitamycin is a macrolide antibiotic, recently entered into clinical use . Its in vitro activity and kill kinetics against Helicobater pylori have been evaluated at 1 x the minimum inhibitory concentration (MIC), 2 x MIC and 4 x MIC at 2, 4, 8, 24 hours and compared with those of clarithromycin, erythromycin and amoxicillin . Morphological changes in H . pylori induced by rokitamycin incubation at these MICs and times were also investigated by scanning electron microscopy . All the antibiotics tested had good inhibitory activity against H . pylori, a slow growing microorganism . The order of MIC activity was clarithromycin > amoxicillin > rokitamycin > erythromycin . Rokitamycin killed more rapidly than the other antibiotics, in fact H . pylori strains were totally killed at 8 h (2 x MIC) and 4 h (4 x MIC) and after only 2 h incubation all concentrations greatly decreased the CFU/ml . These effects were also confirmed by the rapid appearance of surface and morphological alterations (focal blebs, constrictions, rounded forms) in the normal structure of H . pylori observed by scanning electron microscopy . Clinical studies should be conducted to investigate the in vivo activity of rokitamycin, as an agent to be used in the combination therapies against H . pylori.

Clin Exp Immunol, 1996 Dec, 106(3), 568 - 76
Antibody reactivity profiles following immunization with diverse peptides of the PERB11 (MIC) family; Leelayuwat C et al.; PERB11 (MIC) is a gene family possessing multiple copies located within the MHC . Structurally, PERB11 is related to the MHC class I, neonatal IgG Fc receptor (FcRn) and Zn-alpha 2-glycoprotein molecules . The MHC class I family is complex in terms of its genomic arrangement, expression and function, and available evidence suggests that the PERB11 family may be similarly complex . We have adopted an approach to study the expression of such complex gene families by immunizing with multiple peptides and by screening the resulting antibodies against a large range of tissues . The amino acid sequences of PERB11.1 and PERB11.2 as well as those of other related molecules were analysed and compared . Peptides were chosen for immunization based upon (i) loop formation within the equivalent known structure of the MHC class I molecules; (ii) immunogenicity by computer analysis; and (iii) evolutionary relationships . Antibodies in serum from immunized rabbits bound to three out of six peptides used for immunization . ELISA and immunoprecipitation demonstrated binding both to the peptides and to the PERB11.2 recombinant protein . By immunofluorescent staining of various tissues of several species, the three antisera generated overlapping profiles of activity . These included reactions with kidney, small and large intestine, oesophagus, testis, ovary and human neutrophils . This is the first description of antibodies induced by the PERB11 peptides . The extreme complexity of these profiles requires further investigation, but may be explained in terms of antibodies against diverse products of the PERB11 gene family and/or related molecules.

Mem Inst Oswaldo Cruz, 1996 Nov-Dec, 91(6), 779 - 84
Chromoblastomycosis murine model and in vitro test to evaluate the sensitivity of Fonsecaea pedrosoi to ketoconazole, itraconazole and saperconazole; Cardona-Castro N et al.; An experimental model of murine chromoblastomycosis and in vitro tests with Fonsecaea pedrosoi were used to test the sensitivity of this fungus to three different antimycotics . The experimental model was standardized in BALB/c mice inoculated intraperitoneally with a 10(6) CFU/ml suspension of a F . pedrosoi isolate . Clinical infection was evident after 5 days of inoculation . Three groups of 27 mice each were used in the experiment . One group was treated with ketoconazole (KTZ), another with itraconazole (ITZ) and the other with saperconazole (SPZ) . Antimycotic therapy was continued for 21 days . The control group consisted of 40 mice which were inoculated, but not treated . Infection was documented by macroscopic and microscopic examination of affected tissue in addition to culture of tissue macerates . Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) for the F . pedrosoi strain used were done . The in vitro results showed that SPZ was the most active with MIC 0.01 microgram/ml and MFC 0.1 microgram/ml, followed by ITZ . SPZ was also the most effective in vivo since 63% of the treated animals (p = 0.01) showed a curative effect after the observation period . We concluded that SPZ had the best in vitro and in vivo activity against F . pedrosoi.

Mycoses, 1996 Nov-Dec, 39(11-12), 453 - 6
In vitro antifungal activity of the new triazole D0870 against Penicillium marneffei compared with that of amphotericin B, fluconazole, itraconazole, miconazole and flucytosine; Boon-Long J et al.; The in vitro activity of D0870, a new triazole, was compared with that of fluconazole, itraconazole, miconazole, amphotericin B and flucytosine against recent clinical isolates of Penicillium marneffei in Thailand . The minimum inhibitory concentrations (MIC) values were determined by a microbroth dilution method using morpholinopropanesulphonic acid (MOPS)-buffered RPMI-1640 and brain heart infusion (BHI) medium . Yeast nitrogen base (YNB) medium with glucose was also used for the assay of flucytosine . D0870 was less active against P . marneffei than itraconazole, but its activity was similar to that of miconazole, superior to that of amphotericin B and markedly superior to that of fluconazole and flucytosine . Much lower MIC values of D0870 were observed with BHI medium.

Eur J Clin Microbiol Infect Dis, 1996 Nov, 15(11), 879 - 82
Activity of trimethoprim/sulfamethoxazole plus polymyxin B against multiresistant Stenotrophomonas maltophilia; Munoz JL et al.; The inhibitory activity of eight antibiotics and the inhibitory and bactericidal activities of combinations of trimethoprim/sulfamethoxazole (TMP/SMX) plus three fixed concentrations of polymyxin B (0.01 microgram/ml, 0.1 microgram/ml and 0.5 microgram/ml) against 30 multi-resistant strains of Stenotrophomonas maltophilia were tested . Polymyxin B at 0.01 microgram/ml modified the inhibitory activity of TMP/SMX against only 40% of strains . At 0.1 microgram/ml and 0.5 microgram/ml, polymyxin B enhanced the inhibitory activity of TMP/SMX activity against all strains . Polymyxin B enhanced the bactericidal activity of TMP/SMX only at concentrations near the minimum inhibitory concentration of polymyxin B alone.

J Antimicrob Chemother, 1996 Nov, 38(5), 871 - 6
Enteric absorption of ciprofloxacin during tube feeding in the critically ill; Cohn SM et al.; To determine the pharmacokinetic properties of ciprofloxacin in the critically ill, we studied seven mechanically ventilated patients with pneumonia during enteral feedings . Subjects received ciprofloxacin 750 mg every 12 h via nasogastric tube and serial serum drug concentrations were measured after the first and fourth dose . After the initial dose, the maximum serum concentration ranged from 1.24-3.06 mg/L, and the area under the time curve from 0-12 h ranged from 3.2-19.65 mg.h/L . Similar levels were noted after dose four . Gastrointestinal absorption of ciprofloxacin in tube fed critically ill patients was decreased, but well above MIC values for many pathogenic bacteria.

J Appl Toxicol, 1996 Nov-Dec, 16(6), 469 - 73
Changes in brain and plasma amino acids of mice intoxicated with methyl isocyanate; Gupta M et al.; Precolumn derivatization with OPA was used for the analysis of brain and plasma free amino acids of mice after the administration of different doses (0.25 LD50, 0.5 LD50 and LD50) of methyl isocyanate (MIC) for different durations (45 min, 4 h, 4 days and 7 days) . In general, there were a dose-dependent decrease in brain free amino acid content with the exception of glycine and arginine (increased above the control level with 0.25 LD50 and 0.5 LD50 doses), and taurine which increased with 0.5 LD50 and LD50 doses in 45 min . All the amino acids from plasma were increased with all the three doses, with the exception of arginine which decreased at the 0.25 LD50 dose in 45 min . With increase in duration of observation to 4 h, 4 days and 7 days, the brain amino acid content was still below the control levels and plasma levels were higher as compared to the respective controls . The only exceptions were serine, histidine, alanine and arginine, which decreased on the 7th day . This study suggests that MIC produced an imbalance of both the brain and plasma amino acids, suggesting neurotoxic and systemic effects.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2661 - 3
Comparative activities of LY 333328, a new glycopeptide, against penicillin-susceptible and -resistant pneumococci; Fasola E et al.; Microdilution MIC testing was used to test the susceptibility of 202 pneumococci to LY 333328 and six other agents . LY 333328 was the most active glycopeptide (MIC at which 90% of the pneumococci were inhibited {MIC90}, 0.008 microgram/ml), followed by teicoplanin (MIC90, 0.06 microgram/ml) and vancomycin (MIC90, 0.5 microgram/ml) . Rifampin resistance was seen in some penicillin-resistant strains . The MICs of imipenem and ceftriaxone rose with those of penicillin . Time-kill testing confirmed the excellent antipneumococcal activity of LY 333328.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2644 - 5
Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex; Shah LM et al.; WR99210, a dihydrofolate reductase inhibitor, has promising in vitro activity against Mycobacterium avium complex (MAC) . The in vitro activities of WR99210 alone and in combination with a fixed concentration of dapsone (0.5 microgram/ml) were evaluated against 35 clinical MAC isolates by a broth dilution method . The MIC at which 50% of isolates were inhibited (MIC50) and MIC90 of WR99210 alone were 2 and 8 micrograms/ml, respectively . The MIC50 and MIC90 of WR99210 in combination with dapsone were 0.25 and 4 micrograms/ml, respectively . Overall, 75% of the MAC isolates displayed enhanced susceptibility to the combination.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2632 - 6
In vivo activities of ceftriaxone and vancomycin against Borrelia spp . in the mouse brain and other sites; Kazragis RJ et al.; Borrelia burgdorferi, the agent of Lyme disease, and B . turicatae, a neurotropic agent of relapsing fever, are susceptible to vancomycin in vitro, with an MIC of 0.5 microgram/ml . To determine the activity of vancomycin in vivo, particularly in the brain, we infected adult immunocompetent BALB/c and immunodeficient CB-17 scid mice with B . burgdorferi or B . turicatae . The mice were then treated with vancomycin, ceftriaxone as a positive control, or normal saline as a negative control . The effectiveness of treatment was assessed by cultures of blood and brain and other tissues . Ceftriaxone at a dose of 25 mg/kg of body weight administered every 12 h for 7 to 10 days eliminated cultivable B . burgdorferi or B . turicatae from all BALB/c or scid mice in the study . Vancomycin at 30 mg/kg administered every 12 h was effective in eliminating infection from immunodeficient mice if treatment was started within 3 days of the onset of infection . If treatment with vancomycin was delayed for 7 days or more, vancomycin failed to eradicate infection with B . burgdorferi or B . turicatae from immunodeficient mice . The failure of vancomycin in eradicating established infections in immunodeficient mice was associated with the persistence of viable spirochetes in the brain during antibiotic treatment.

Antimicrob Agents Chemother, 1996 Nov, 40(11), 2483 - 7
Spectrum of activity of levofloxacin against nontuberculous mycobacteria and its activity against the Mycobacterium avium complex in combination with ethambutol, rifampin, roxithromycin, amikacin, and clofazimine; Rastogi N et al.; The spectrum of activity of levofloxacin was initially determined against 29 strains belonging to 16 species of atypical mycobacteria by measuring radiometric MICs . Levofloxacin MICs were 1 to 2 dilutions lower compared with those obtained for ofloxacin and 8 to 64 dilutions lower compared with those obtained for its D-isomer . Levofloxacin MICs were below its peak level in serum (5.5 micrograms/ml following administration of a single oral dose of 350 mg) for 25 of 29 isolates tested . It possessed MICs below its peak level in serum for M . scrofulaceum, M . szulgai, M . malmoense, M . xenopi, M . marinum, M . kansasii, M . chelonei, M . abcessus, M . fortuitum, and M . peregrinum . Regarding the M . avium complex, the MICs of levofloxacin for 11 clinical isolates (7 from human immunodeficiency virus-positive patients and 4 from human immunodeficiency virus-negative patients) were 1 to 2 dilutions lower than those of ofloxacin . Among 20 isolates belonging to 12 pathogenic mycobacterial species, the MBC/MIC ratios varied from 1 to 4 for levofloxacin and 2 to 4 for ofloxacin . When drug combinations were screened by using the radiometric x/y quotient methodology against five M . avium complex isolates, levofloxacin activity against all five isolates was enhanced by ethambutol and activity against three isolates was enhanced by clofazimine . Screening of three-drug combinations showed that the combination levofloxacin-ethambutol with a third potential anti-M . avium drug (rifampin, roxithromycin, amikacin, or clofazimine) resulted in enhanced activity for all 20 drug combinations screened.

Circulation, 1996 Nov 1, 94(9), 2254 - 9
Antiviral treatment with WIN 54 954 reduces mortality in murine coxsackievirus B3 myocarditis; Fohlman J et al.; BACKGROUND: Coxsackieviruses B (CBVs) are dominant causative agents in myocarditis and are associated with pathogenesis is some cases of dilated cardiomyopathy, a clinical entity with a poor survival without heart transplantation . METHODS AND RESULTS: In vitro, the antiviral agent WIN 54 954 was shown to inhibit replication of CBV3 at a minimal inhibitory concentration value of 0.02 mg/L . Administration of WIN 54 954, 100 mg/kg BID PO, beginning on the day of infection resulted in complete protection from enteroviral mortality (P < .01) . WIN 54 954 treatment did not abrogate the inflammatory reaction in the myocardium . No difference was found in the expression of surface lymphocyte subset markers . At 3 weeks, macrophages seemed to dominate the inflammatory reaction, regardless of treatment . There was no difference in CBV3 antibody titers, indicating that WIN 54 954 does not interfere with the development of protective immunity . Complement factors C3 and B were synthesized at a higher level during infection and correlated well with the degree of inflammatory reaction . CONCLUSIONS: The results show that WIN 54 954 is a potent antiviral agent with a highly significant effect on survival in CBV-induced myocarditis in the A/J mouse if treatment is started early . It is suggested that the reduction in mortality seen with WIN 54 954 administration is due to an inhibitory effect on virus replication in affected organs that does not interfere with cellular or humoral immunity.

Am J Surg Pathol, 1996 Nov, 20(11), 1394 - 400
Primary hepatic malignant tumor with rhabdoid features . A histological, immunocytochemical, and electron microscopic study of four cases and a review of the literature; Scheimberg I et al.; Malignant tumors of the liver with rhabdoid features (MTR) are uncommon: Only 14 previous cases are reported in the literature . These tumors are characterised morphologically by sheets of large polygonal cells with abundant eosinophilic cytoplasm containing a periodic acid Schiff's-positive hyaline globular inclusion and vesicular nuclei with a central prominent nucleolus . Immunohistochemically, the inclusions at least show positivity for vimentin and epithelial markers and sometimes for other antigens . Ultrastructurally, the inclusions are composed of whorled intermediate filaments . Despite the superficial resemblance to cells of muscle origin implied in the term rhabdoid, there is no immunohistochemical or ultrastructural evidence to support such a derivation . We describe four additional children with tumors of this type, in three of whom tumor cells showed focal membrane positivity for MIC-2 on immunostaining . Its expression in an hepatic MTR may indicate neuroepithelial differentiation . Hepatic MTR should be considered in the differential diagnosis of an undifferentiated primary liver tumor in an infant in whom the alpha-fetoprotein concentration is normal or only slightly elevated for age.

Curr Microbiol, 1996 Nov, 33(5), 317 - 22
Inhibition of spiralin processing by the lipopeptide antibiotic globomycin; Beven L et al.; The cyclic lipopeptide globomycin, a specific inhibitor of signal-peptidase II (Lsp A), proved toxic for the mollicute Spiroplasma melliferum with a minimal inhibitory concentration (MIC) in the range 6.25-12.5 microM, about one order of magnitude higher (that is, less efficient) than bee-venom mellitin . SDS-PAGE analysis of cell proteins followed by immunolabeling ("Western blotting") and by crossed immunoelectrophoresis demonstrated that the cleavage of the prespiralin leader peptide was prevented by globomycin . Cell fractionation experiments showed that prespiralin was membrane bound and did not accumulate in the cytoplasm or in the culture medium . Furthermore, the use of the potential-sensitive fluorescent dye 3,3'-dipropyl-2,2'-thiadicarbocyanine iodide (diS-C3-{5}) revealed that, in contrast to valinomycin and mellitin, globomycin up to 30 microM has no effect on the electrical transmembrane potential of S . melliferum . This indicates that the toxicity of globomycin for spiroplasma cells is mainly if not exclusively owing to the inhibition of spiralin processing . Added to previously published data, these results suggest that spiralin and probably other lipoproteins of mollicutes are acylated and membrane targeted by a mechanism involving notably the processing of the prelipoprotein precursor by a type II, globomycin-sensitive signal peptidase.

J Biol Chem, 1996 Oct 18, 271(42), 26209 - 13
Molecular engineering study on electron transfer from NADPH-P450 reductase to rat mitochondrial P450c27 in yeast microsomes; Sakaki T et al.; We have reported the localization on yeast microsomes for a modified P450c27 (mic-P450c27) that contains the microsomal targeting signal of bovine P450c17 in front of the mature form of rat mitochondrial P450c27 (Sakaki, T., Akiyoshi-Shibata, M., Yabusaki, Y., and Ohkawa, H . (1992) J . Biol . Chem . 267, 16497-16502) . In this study, we found that mic-P450c27 could be reduced by NADPH in the yeast microsomes without supplement of its physiological redox partners, adrenodoxin and NADPH-adrenodoxin reductase . In order to elucidate the direct electron transfer from NADPH-P450 reductase to mic-P450c27, we carried out simultaneous expression of mic-P450c27 and yeast P450 reductase . The reduction rate of mic-P450c27 was increased by overproduction of yeast P450 reductase, roughly in proportion to the reductase content in the microsomes . In addition, we constructed a fused enzyme between mic-P450c27 and yeast P450 reductase . The reduction rate of heme iron in the fused enzyme was too rapid to be measured . These recombinant yeast microsomes showed a notable 27-hydroxylation activity toward 5beta-cholestane-3alpha,7alpha, 12alpha-triol in the absence of adrenodoxin and adrenodoxin reductase . Finally, we purified mic-P450c27 from the recombinant yeast microsomes and reconstituted the hydroxylation system in liposomal membranes using the purified mic-P450c27 and yeast NADPH-P450 reductase . Mic-P450c27 was reduced by NADPH and showed its monooxygenase activity on the reconstituted system . Therefore, yeast NADPH-P450 reductase alone was found to transfer two electrons from NADPH to mic-P450c27 . These results clearly show that mic-P450c27 not only localizes on the microsomes but also functions as a microsomal cytochrome P450 that accepts electrons from NADPH-P450 reductase.

Spine, 1996 Oct 15, 21(20), 2363 - 7
The effect of intraoperative blood loss on serum cefazolin level in patients undergoing instrumented spinal fusion . A prospective, controlled study; Polly DW Jr et al.; STUDY DESIGN: This study is a prospective, controlled study of the effect of intraoperative and postoperative blood loss during spinal surgery on serum cefazolin level . OBJECTIVES: To determine what effect, if any, intraoperative blood loss has on serum antibiotic levels, and to determine if adjustment of the dose or dose interval is appropriate in operative cases of significant blood loss . SUMMARY OF BACKGROUND DATA: The problem of infection at the operative site after posterior spinal fusion with internal fixation is significant . It commonly has been accepted that blood loss results in a more rapid clearance of antibiotic . METHODS: Nineteen patients scheduled for elective spinal fusion with internal fixation were enrolled in this study . Each patient served as his or her own control . Baseline cefazolin clearance was determined the week before surgery . Cefazolin clearance again was determined intraoperatively . Blood loss was recorded throughout the procedure . RESULTS: The mean blood loss was 650 mL . There was no significant difference between preoperative and intraoperative cefazolin clearance, and there was no correlation between blood loss and cefazolin level . CONCLUSIONS: It is not necessary to give cefazolin at a dosing interval of less than 4 hours with blood losses of up to 1200 mL . This will maintain the antibiotic concentrations well above the minimum inhibitory concentration.

FEMS Microbiol Lett, 1996 Oct 15, 144(1), 103 - 8
Rifampicin resistance and mutation of the rpoB gene in Mycobacterium tuberculosis; Taniguchi H et al.; Using 39 clinical isolates of Mycobacterium strains with a broad range of susceptibility to rifampicin, we examined the relationship between the degree of resistance to rifampicin and mutational sites of the rpoB gene . All rifampicin-resistant strains had missense mutations . Twenty strains (95%) had a mutation in the cluster I region, which has also been reported in Escherichia coli {Jin and Gross (1988) J . Mol . Biol . 202, 45-58}, and the remaining one strain had a mutation at codon 381 {Ala-->Val} in the N-terminal region, which has not been reported in E . coli . Among 18 rifampicin-susceptible strains, two had a mutation in the cluster I region and the other three strains had a mutation in the cluster III region . The mutations at codons 513 (5%), 526 (33%) or 531 (43%) in the cluster I region led to high level resistance to rifampicin (50 micrograms ml-1 < or = MIC) . The mutations at the other sites, in the cluster III region (codons 679 or 687) and even in the cluster I region (codon 514, 521, or 533), showed low level (MIC = 12.5 micrograms ml-1) or no (MIC < 0.39 microgram ml-1) resistance to rifampicin . These results suggest that mutations in the rpoB gene are, mostly, but not necessarily, associated with rifampicin resistance of M . tuberculosis, and the sites of mutations on the rpoB gene will affect the level of resistance to rifampicin.

Diagn Microbiol Infect Dis, 1996 Oct, 26(2), 53 - 61
Beta-lactam stability in frozen microdilution PASCO MIC panels using strains with known resistance mechanisms as biosensors; Valdezate S et al.; The stability of amoxicillin/clavulanate, piperacillin/tazobactam, cefepime, imipenem, and meropenem in PASCO (PASCO System, DIFCO Laboratories, Detroit, MI, USA) frozen microdilution susceptibility panels stored for 16 weeks at -20 degrees C and -70 degrees C was evaluated . The increase in MIC values for the five American-Type Culture Collection (ATCC) quality control strains for susceptibility testing recommended by the National Committee for Clinical Laboratory Standards (NCCLS) and for 13 strains with different well-characterized resistance mechanisms was indicative of bioactivity deterioration . The overall agreement (+/- 1 twofold dilution) at purchase between the MIC values of PASCO frozen microdilution susceptibility panels and the standard agar dilution method was 97.7% . Minimum inhibitory concentration values for the associations of amoxicillin/clavulanate and piperacillin/tazobactam remained unchanged for the study period at -70 degrees C . In contrast, a carbapenem bioactivity decrease was detected only with strains having well-characterized resistance mechanisms from the 12th week onwards . At -20 degrees C, antibiotic deterioration with these latter strains was observed earlier than with ATCC strains: the activity of meropenem and imipenem remained unchanged only for the first 2 weeks, while a loss of activity was detected for amoxicillin/clavulanate and piperacillin/tazobactam at the 7th and 10th week, respectively . Cefepime was highly stable both at -20 degrees C and -70 degrees C . Strains with well-characterized resistance mechanisms should be used in routine quality control studies of antibiotic stability for susceptibility testing panels during the storage period.

Pathol Biol (Paris), 1996 Oct, 44(8), 724 - 8
{Methods for the determination of the sensitivity of Candida strains to fluconazole: focus of a micromethod and correlation with 2 other techniques}; Goutaland C et al.; 107 Strains of different species of Candida have been tested by three methods of susceptibility to fluconazole . In addition, one reference strain has been used to verify three methods' reliability: one diffusion method on Shadomy's medium and two MIC liquid methods, on tube and on microtiter plate . Method on Shadomy's medium seems less sensitive for yeast susceptibility . Comparison of two liquid method of MIC show discordances on resistant strains (14% for method on tube and 26% for micromethod) By simplicity of execution and reliability in detection of natural resistances, micromethod of MIC seems the most convenient for yeasts determination in vitro to fluconazole.

Eur J Clin Microbiol Infect Dis, 1996 Oct, 15(10), 817 - 20
Antibiotic susceptibility of pneumococci isolated in Austria over a four-year period; Mittermayer H et al.; The antibiotic susceptibility of pneumococci isolated from clinical specimens from 1991 through 1994 was investigated . Of 305 strains tested by the agar dilution method, 16 (5.2%) were resistant to penicillin (MICs > or = 0.12 mg/l) . Of the resistant strains, 0.3% showed high-level resistance (MIC > or = 2 mg/l) . The rate of resistance to erythromycin (MIC > or = 4 mg/l) was 2.3%, to tetracycline (MIC > or = 8 mg/l) 8.5%, to chloramphenicol (MIC > or = 8 mg/l) 1.0%, and to trimethoprim sulfamethoxazole (MIC > or = 3.2/64 mg/l) 3.3% . Penicillin-resistant strains showed significantly higher resistance to the other antibiotics tested . Resistance to penicillin was higher in isolates from the respiratory tract than in those from blood and cerebrospinal fluid (6.2% vs . 2.4%, respectively) . There was no increase in penicillin resistance from 1991 through 1994 (5.3% vs . 4.9%, respectively).

Nippon Ika Daigaku Zasshi, 1996 Oct, 63(5), 349 - 55
{Effect of treatment with lansoprazole and amoxicillin in combination on healing process of duodenal ulcer}; Maruyama M; The important role of Helicobacter pylori (H . pylori) in idiopathic duodenal ulcer disease is widely acknowledged . Treatment with amoxicillin and omeprazole has been highly successful in eradicating H . pylori in some pilot studies . We conducted a study in patients with active duodenal ulcer disease and H . pylori colonization of gastric mucosa using a combination of amoxicillin and lansoprazole . Lansoprazole has been shown to exhibit lower MIC than omeprazole . Sixty three patients who qualified for admission to the study were randomly assigned to receive either oral lansoprazole (30 mg, p.o., qam, daily for 6 weeks) (n = 30) or lansoprazole (6 weeks) plus amoxicillin (1500 mg, p.o, t.i.d., daily for 2 weeks) (n = 33) . Six weeks after the initiation of treatment with lansoprazole, healing of the ulcers was assessed using electronic endoscope according to the classification of Sakita & Miwa . When lansoprazole alone was administered to the patients, H . pylori dormancy was attained in none of the patients, whereas dormancy was ascertained in 17 out of 33 patients when lansoprazole and amoxicillin were administered in combination . H . pylori dormancy was assessed by 13C urea breath test, histological examination of gastric mucosa and rapid urease test . Endoscopic evaluations revealed that S2/S1 ratio was significantly higher in patients with H . pylori dormancy than in those without . The results of our study confirmed that treatment to eradicate H . pylori with drugs such as lansoprazole and amoxicillin is effective in the healing of idiopathic duodenal ulcer disease.

J Vet Pharmacol Ther, 1996 Oct, 19(5), 352 - 8
Disposition of metronidazole in hens (Gallus gallus) and quails (Coturnix coturnix japonica): pharmacokinetics and whole-body autoradiography; Cybulski W et al.; Hens were given single intravenous or oral doses (30 mg/kg body weight) of metronidazole and the plasma concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at intervals from 10 min to 24 h after drug administration . Pharmacokinetic variables were calculated by the Lagrange algorithm technique . The elimination half-life (t1/2 beta) after the intravenous injection was 4.2 +/- 0.5 h, the volume of distribution (Vd(ss) 1.1 +/- 0.2 L/kg and the total body clearance (ClB) 131.2 +/- 20 mL/h.kg . Oral bioavailability of the metronidazole was 78 +/- 16% . The plasma maximum concentration (Cmax) 31.9 +/- 2.3 micrograms/mL was reached 2 h after the oral administration and the oral elimination half-life (t1/2 beta) was 4.7 +/- 0.2 h . The binding of metronidazole to proteins in hen plasma was very low (less than 3%) . Whole body autoradiography of {3H} metronidazole in hens and quails showed an even distribution of labelled material in various tissues at short survival intervals (1-4 h) after oral or intravenous administration . A high labelling was seen in the contents of the small and large intestines . In the laying quails a labelling was also seen in the albumen and in a ring in the periphery of the yolk at long survival intervals . Our results show that a concentration twofold above the MIC is maintained in the plasma of hens for at least 12 h at an oral dose of 30 mg/kg metronidazole.

Antimicrob Agents Chemother, 1996 Oct, 40(10), 2426 - 7
Enhanced in vitro activity of pyrimethamine in combination with dapsone against Mycobacterium avium complex; Shah LM et al.; The in vitro activities of pyrimethamine and dapsone alone and in combination were evaluated against 23 clinical isolates of Mycobacterium avium complex . The broth dilution MICs of dapsone and pyrimethamine alone ranged from 16 to > 64 micrograms/ml . Pyrimethamine in combination with a fixed concentration of dapsone at 0.5 microgram/ml showed enhanced activity, with an MIC range of 0.5 to 16 micrograms/ml.

Ann Otol Rhinol Laryngol, 1996 Oct, 105(10), 838 - 43
Ewing's sarcoma and peripheral primitive neuroectodermal tumor: an interim report; Batsakis JG et al.; The primitive neuroectoderm and its progeny seemingly give rise to an ever-increasing number of clinicopathologic entities . Ewing's sarcoma and peripheral primitive neuroectodermal tumor have recently been united by relatively unique antigens expressed by the MIC-2 gene, commonly coexpressed neural markers, and cytogenetic and molecular genetic abnormalities . Because of these factors, the current thinking is that Ewing's sarcoma and the peripheral primitive neuroectodermal tumor are parts of a phenotypic spectrum . We present an "interim report" on this group of neoplasms, emphasizing their presentation in the head and neck.

Gastroenterology, 1996 Oct, 111(4), 1011 - 7
Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis; Navasa M et al.; BACKGROUND & AIMS: Treatment of spontaneous bacterial peritonitis currently involves intravenous antibiotic administration . To test the possibility of treating spontaneous bacterial peritonitis with oral antibiotics, oral ofloxacin was compared with intravenous cefotaxime in this infection . METHODS: One hundred twenty-three cirrhotics with uncomplicated spontaneous bacterial peritonitis (no septic shock, grade II-IV hepatic encephalopathy, serum creatinine level of > 3 mg/dL, and gastrointestinal hemorrhage or ileus) were randomly given oral ofloxacin (64 patients) or intravenous cefotaxime (59 patients) . RESULTS: Infection resolution rate was 84% in the ofloxacin group and 85% in the cefotaxime group . Peak serum levels and trough serum and ascitic fluid levels of ofloxacin and cefotaxime measured on days 3 (23 patients) and 6 (11 patients) of therapy were greater than the minimal inhibitory concentration of isolated organisms . Hospital survival rate was 81% in each group of patients . Blood urea nitrogen and hepatic encephalopathy at diagnosis were associated with prognosis . None of the 36 nonazotemic patients with community-acquired spontaneous bacterial peritonitis and without hepatic encephalopathy developed complications during hospitalization, and all were alive at time of discharge . CONCLUSIONS: Oral ofloxacin is as effective as intravenous cefotaxime in uncomplicated spontaneous bacterial peritonitis . Nonazotemic cirrhotic patients with uncomplicated community-acquired spontaneous bacterial peritonitis and without hepatic encephalopathy have an excellent prognosis and may be treated with oral ofloxacin without requiring hospitalization.

Biochem Biophys Res Commun, 1996 Sep 13, 226(2), 362 - 8
Involvement of an efflux system in mediating high level of fluoroquinolone resistance in Mycobacterium smegmatis; Banerjee SK et al.; A wild type strain of Mycobacterium smegmatis mc2 155 was serially adapted to 64 fold of minimal inhibitory concentration of an antimycobacterial agent, ciprofloxacin . This clone (CIPr) exhibited cross resistance to ofloxacin and ethidium bromide . The rate of drug efflux was accelerated in CIPr compared to the wild type strain . Verapamil, a calcium channel blocker, enhanced the drug accumulation in CIPr by diminishing the efflux and thus reversed the resistant phenotype . Additionally, a missense mutation was detected in the quinolone resistance determining region of the DNA-gyrase A subunit of CIPr . Taken together, these results suggest that drug efflux plays a major role in conferring such a high level of resistance in CIPr, in addition to the mutation in the DNA-gyrase locus.

Srp Arh Celok Lek, 1996 Sep-Oct, 124(9-10), 276 - 82
{Non-Hodgkin's lymphoma: morphologic, immunologic and cytogenetic classification}; Ristic S et al.; Malignant lymphomas (ML) encompass about 1/6 of all malignant neoplasms . They have been divided into two major categories: Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) . While the classification of Hodgkin's disease is clearly established, classification of non-Hodgkin's lymphomas is still a histopathological problem, and requires a great pathological experience . Many morphological classifications of NHL are used in different countries . In the last few years the "Working formulation for clinical usage" is widely used . Advances in immunology allowed immunological determination of different histopathological lymphoma cell types . Progress in the field of cytogenetics discovered particular cytogenetics abnormalities in patients with different types of NHL . Modern diagnostic procedures in each patient with NHL, besides clinical staging, require a detailed morphological-immunological-cytogenetical (MIC) classification . MIC classification provides the basis for the modern therapeutical management and better estimation of prognosis and evolution of the disease.

J Orthop Res, 1996 Sep, 14(5), 749 - 54
Gentamicin distribution from a collagen carrier; Mehta S et al.; Local delivery of antibiotics by a degradable carrier has the potential for high local antibiotic levels and avoids systemic toxicity . Intravenous access, renal function monitoring, and subsequent surgical removal may not be required when degradable local delivery modalities are used . This study examined the in vivo elution of gentamicin from processed bovine collagen (type I) in 66 adult White rabbits . Collagen impregnated with gentamicin (3 mg/kg) was implanted into the vastus lateralis, and data were collected from 15 minutes to 28 days after implantation . Local tissue biopsies were taken a minimum of 2 mm from the implantation site . The gentamicin was released into the local tissue and averaged more than 3,800 micrograms/ml during the initial 4 hours after implantation . Local levels fell to 6.90 +/- 5.22 micrograms/ml at 24 hours and subsequently were 2.70 +/- 1.75 micrograms/ml or more through day 28 . Serum levels reached an average peak of 4.04 +/- 1.75 micrograms/ml at 5 hours after implantation, decreased after the initial 24 hours, and subsequently were less than 0.41 +/- 0.20 microgram/ml through day 28 . Collagen impregnated with gentamicin proved to be an effective degradable carrier of gentamicin in the healthy rabbit; it provided local tissue concentrations above the minimum inhibitory concentration and serum concentrations below levels associated with systemic toxicity for 28 days after implantation.

J Antimicrob Chemother, 1996 Sep, 38(3), 539 - 42
Comparative activity of azithromycin against clinical isolates of mycobacteria; Watt B et al.; Azithromycin exhibited in-vitro activity against 20 clinical isolates of Mycobacterium avium complex for which the MIC90 was 32 mg/L and 22 clinical isolates of other mycobacteria but showed no activity against 20 isolates of Mycobacterium tuberculosis (MIC90 > 128 mg/L) nor against the single isolate of Mycobacterium marinum tested (MIC 128 mg/L) . These results suggest that the drug may prove useful for the prophylaxis and treatment of infections due to non-tuberculous mycobacteria, including M . avium complex in patients with AIDS.

Antimicrob Agents Chemother, 1996 Sep, 40(9), 2071 - 4
MIC and time-kill study of antipneumococcal activities of RPR 106972 (a new oral streptogramin), RP 59500 (quinupristin-dalfopristin), pyostacine (RP 7293), penicillin G, cefotaxime, erythromycin, and clarithromycin against 10 penicillin-susceptible and -resistant pneumococci; Pankuch GA et al.; Broth MICs and time-kill studies were used to test the activity of RP 59500 (quinupristin-dalfopristin), RPR 106972, pyostacine (RP 7293), erythromycin, clarithromycin, and cefotaxime for four penicillin-susceptible (MICs of 0.008 to 0.03 microgram/ml), two penicillin-intermediate (MIC of 0.25 microgram/ml), and four penicillin-resistant (MIC of 2.0 to 4.0 micrograms/ml) strains of pneumococci: 6 of 10 strains were resistant to macrolides (MICs of > or = 0.5 microgram/ml) . MICs of RP 59500 (0.5 to 1.0 microgram/ml), RPR 106972 (0.125 to 0.25 microgram/ml), and pyostacine (0.125 to 0.25 microgram/ml) did not alter with the strain's penicillin or macrolide susceptibility status . Three penicillin-susceptible strains and one penicillin-intermediate strain were susceptible to macrolides (MICs of < or = 0.25 microgram/ml); the macrolide MICs for the remaining strains were > or = 4.0 micrograms/ml . Cefotaxime MICs rose with those of penicillin G, but all strains were inhibited at MICs of < or = 2.0 micrograms/ml . RP 59500 was bactericidal for all strains after 24 h at 2 x MIC and yielded 90% killing of all strains at 6 h at 2 x MIC; at 8 x MIC, RP 59500 showed 90% killing of six strains within 10 min (approximately 0.2 h) . In comparison, RPR 106972 was bactericidal for 9 of 10 strains at 2 x MIC after 24 h and yielded 90% killing of all strains at 2 x MIC after 6 h; 90% killing of six strains was found at 8 x MIC at 0.2 h . Results for pyostacine were similar to those of RPR 106972 . Erythromycin and clarithromycin were bactericidal for three of four macrolide-susceptible strains after 24 h at 4 x MIC . Clarithromycin yielded 90% killing of three strains at 8 x MIC after 12 h . Cefotaxime was bactericidal for all strains after 24 h at 4 x MIC, yielding 90% killing of all strains after 6 h at 4 x MIC . All three streptogramins yielded rapid killing of penicillin- and erythromycin-susceptible and -resistant pneumococci and were the only compounds which killed significant numbers of strains at 0.2 h.

Antimicrob Agents Chemother, 1996 Sep, 40(9), 2054 - 61
Sequence analysis, purification, and study of inhibition by 4-quinolones of the DNA gyrase from Mycobacterium smegmatis; Revel-Viravau V et al.; We determined the nucleotide sequence of a 6-kb DNA region harboring the recF, orf192, gyrB, and gyrA genes from Mycobacterium smegmatis mc(2)155 . The amino acid sequences deduced from gyrA and gyrB displayed 89 and 86% identity, respectively, with the DNA gyrase from Mycobacterium tuberculosis, and 67 and 65% identity, respectively, with that from Streptomyces coelicolor . An open reading frame encoding the C-terminal region of the M . smegmatis RecF polypeptide was found upstream from gyrB and was 57% identical to the open reading frame encoding the C-terminal region of the S . coelicolor RecF protein . The gene orf192 was identified between recF and gyrB and was 39% identical to orf191 found in S . coelicolor in the recF-gyrB region . The M . smegmatis DNA gyrase, which was purified by affinity chromatography on novobiocin-Sepharose, consisted of two polypeptides with apparent molecular masses of 98 and 80 kDa . Determination of the N-terminal amino acid sequence of the B subunit confirmed GTG as the start codon in gyrB . Analysis of the supercoiling activity of the enzyme indicated that the M . smegmatis DNA gyrase was characterized by a specific activity equivalent to that of the Escherichia coli DNA gyrase . Inhibition of this activity by 4-quinolones was investigated by determining the 50% inhibitory concentrations (IC50S) of nalidixic acid, ofloxacin, and ciprofloxacin . The results indicated that the inhibitory activities of these drugs against the M . smegmatis DNA gyrase were markedly lower than those previously reported for the E . coli DNA gyrase . The results also suggested that the higher levels of activity of ofloxacin and ciprofloxacin against M . smegmatis (MICs, 0.5 to 1 microgram/ml), in contrast to that of nalidixic acid (MIC, 256 micrograms/ml), could be related to the higher inhibitory activities of fluoroquinolones against the DNA gyrase from this species (IC50S, 7 to 14 micrograms/ml) compared with that of nalidixic acid (IC50, 1,400 micrograms/ml).

Ann Pharmacother, 1996 Sep, 30(9), 1024 - 8
AUIC--a general target for the optimization of dosing regimens of antibiotics?
Dalla Costa T, Derendorf H.
OBJECTIVE: To present a systematic evaluation of the are under the inhibitory curve (AUIC) approach for the optimization of antibiotic dosing schedules for three major antibiotic classes (beta-lactams, quinolones, aminoglycosides) . It has been proposed that an AUIC over 24 hours of at least 125 may be an applicable target parameter for the optimization of antibiotic dosing schedules across these antibiotic classes . Some limitations of this approach are presented and discussed . METHODS: A precise equation for the calculation of AUIC is derived . Moreover, a specific equation is derived for the situation that results in a trough concentration at the end of the dosing interval equal to the minimum inhibitory concentration (MIC) . With the same three drugs used for deriving the target AUIC value (tobramycin, cefmenoxime, ciprofloxacin), different dosing regimens are simulated to obtain the target AUIC of 125 . RESULTS: Very different serum concentration profiles can result in the same AUIC . In an example for cefmenoxime, dosing regimens of 1 g q6h and 4.2 g q24h resulted in equal AUIC values of 125, whereas the respective time above MIC differed dramatically (99% of the dosing interval for q6h vs . 36% for q24h) . CONCLUSIONS: It does not seem valid to accept the proposed breakpoint AUIC target of at least 125 as an applicable value for determining the appropriate dosing schedule of these classes of antibiotics . Based on the limitations discussed about the AUIC approach, the same conclusion also holds for any other fixed AUIC breakpoint target value.

J Nat Prod, 1996 Sep, 59(9), 850 - 3
New macrocyclic spermine (budmunchiamine) alkaloids from Albizia gummifera: with some observations on the structure--activity relationships of the budmunchiamines; Rukunga GM et al.; The CH2Cl2 extract of the stem bark of Albizia gummifera yielded four macrocyclic spermine alkaloids (budmunchiamines), three of them being new analogues . On the basis of spectral analysis and comparison with related compounds they were identified as budmunchiamine G (1) and the new analogues budmunchiamine K (2), 6'xi-hydroxybudmunchiamine K (3), and 9-normethylbudmunchiamine K (4) . The four isolated alkaloids and other related budmunchiamines isolated from Albizia schimperana were all active against two Gram-positive and two Gram-negative bacteria at MIC levels below 80 micrograms mL(-1), and showed toxicity to brine shrimp larvae (with LC50 values below 100 micrograms mL(-1)) . The negative impact of side chain hydroxylation and N-demethylation on both measures of biological activity was shown to be considerable.

Can J Microbiol, 1996 Sep, 42(9), 960 - 4
A comparative study of the broth micro- and macro-dilution techniques for the determination of the in vitro susceptibility of Aspergillus fumigatus; Manavathu EK et al.; The effects of inoculum size, medium, temperature, and duration of growth on the in vitro susceptibility testing of Aspergillus fumigatus were investigated using broth micro- and macro-dilution techniques . The minimum inhibitory concentrations (MICs) of ketoconazole, miconazole, itraconazole, fluconazole, and amphotericin B were significantly influenced by the inoculum size, regardless of the techniques used . Two- to four-fold higher MIC values were obtained when the inoculum size was increased 100-fold . The use of peptone yeast extract glucose and RPMI 1640 media provided essentially identical MIC values at 30 and 35 degrees C after incubation for 48 h or longer . A comparison of broth micro- and macro-dilution techniques revealed that, under equivalent conditions, the latter with an inoculum size between 1 x 10(3) and 1 x 10(4) conidia (strain W73355)/mL consistently provided the lowest MICs of fluconazole (256 micrograms/mL), ketoconazole (8 micrograms/mL), miconazole (2 micrograms/mL), itraconazole (0.25 micrograms/mL), and amphotericin B (0.25 micrograms/mL) . Using the broth macrodilution technique we screened 24 clinical isolates of A . fumigatus obtained from the Detroit Medical Center in 1994 . The MIC values of fluconazole, ketoconazole, miconazole, itraconazole and amphotericin B for all the isolates were 128-256, 8-16, 1-2, 0.25-0.5, and 0.25-1.0 micrograms/mL, respectively, indicating that none of the clinical isolates that we tested shows acquired resistance to the antifungals used.

J Clin Microbiol, 1996 Sep, 34(9), 2158 - 62
Heterogeneity in susceptibility to metronidazole among Helicobacter pylori isolates from patients with gastritis or peptic ulcer disease; Weel JF et al.; Combination therapies that include metronidazole (MTZ) are the most successful therapies used in eradicating Helicobacter pylori . In this study, the prevalence and the relevance of heterogeneity in susceptibility to MTZ among H . pylori populations of 156 patients were evaluated . The results of this study show that 37 patients (24%) were infected with MTZ-resistant H . pylori (MIC > or = 8 micrograms/ml) . Furthermore, 33% (52 of 156) of the patients were found to be infected with H . pylori populations heterogeneous for their susceptibility to MTZ . The reassessment of the MICs of MTZ for these 52 H . pylori populations revealed MTZ resistance in 28 of them, increasing the number of MTZ-resistant H . pylori populations among the 156 patients to 65 (42%) . Out of 20 isolates, 2 (10%) heterogeneous in their susceptibility to MTZ also appeared to be heterogeneous at the genome level as determined by randomly amplified polymorphic DNA fingerprinting . In conclusion, the results show the limitations and risk of possible misinterpretations when only a single colony, picked from the primary H . pylori populations isolated from patients, is analyzed for its susceptibility to MTZ.

J Clin Microbiol, 1996 Sep, 34(9), 2154 - 7
Fluconazole disk diffusion procedure for determining susceptibility of Candida species; Barry AL et al.; A simple disk diffusion test was defined for quick determination of the susceptibility of Candida species to fluconazole . The standard macrotube dilution reference method, the fluconazole E test, and a 25-microgram fluconazole disk test were all performed with each of 250 Candida species selected to provide a broad range of fluconazole MICs . All three methods were in excellent agreement . On RPMI 1640-glucose agar, isolates with inhibition zone diameters of > or = 19 mm were all susceptible (MIC, < or = 8.0 micrograms/ml) by the E test and 94% were susceptible by the macrotube method . Strains with smaller zones were either resistant, intermediate (dose-dependent susceptibility), or susceptible by the reference methods . The disk test did not adequately separate fully resistant strains from those with dose-dependent susceptibility: additional quantitative tests are needed for the few strains that are not unequivocally susceptible by the disk method.

Biochem J, 1996 Sep 1, 318 ( Pt 2), 451 - 7
Determination of the primary target for isoniazid in mycobacterial mycolic acid biosynthesis with Mycobacterium aurum A+; Wheeler PR et al.; The target of the potent antituberculosis drug isoniazid was investigated in Mycobacterium aurum A+, against which isoniazid has an MIC (the minimum concentration required to give growth inhibition) of 0.3 microgram/ml . Mycolic acid biosynthesis, measured by the incorporation of label from {1-14C}acetate into mycolic acids, was inhibited differentially by isoniazid in cell-wall preparations of M . aurum A+ . Thus at an isoniazid concentration of 1 microgram/ml, mycolic acid biosynthesis was inhibited by 80% but concomitant biosynthesis of non-hydroxylated fatty acids was inhibited by only 15% . Three lines of evidence identified 24:1 cis-5 elongase as the primary isoniazid target . First, 24:1 cis-5 did not restore isoniazid-inhibited mycolic acid biosynthetic activity in a crude cell-wall preparation, suggesting that the drug acts after the formation of the delta-5 double bond . Secondly, a 24:1 cis-5 elongase assay in which the product is mycolic acid is completely inhibited by isoniazid . Finally, the only intermediates that accumulate as a result of the addition of isoniazid are acids of 24 carbons . Both 24:0 and 24:1 are observed in a similar ratio whether or not isoniazid is present, even though concomitant mycolic acid biosynthesis is inhibited by isoniazid . These results are consistent with studies of the M . tuberculosis InhA protein by Dessen, Quemard, Blanchard, Jacobs and Sacchettini {(1995) Science 267, 1638-1641}.

Dig Dis Sci, 1996 Sep, 41(9), 1845 - 52
Effect of omeprazole on movement of intravenously administered metronidazole into gastric juice and its significance in treatment of Helicobacter pylori; Veldhuyzen van Zanten SJ et al.; Four healthy, Helicobacter-negative volunteers were studied to determine the effect of omeprazole on the movement of metronidazole across the gastric mucosa into the gastric lumen . Each received a 500-mg intravenous infusion of metronidazole and repeated serum, and gastric juice samples were obtained concomitantly over an 8-hr study via indwelling intravenous catheter and nasogastric tube . The same protocol was repeated following one week of oral omeprazole 20 mg twice daily . Metronidazole concentrations were measured by high-performance liquid chromatography . The results demonstrated that: metronidazole moves rapidly from serum into gastric juice; omeprazole causes a marked reduction in total metronidazole concentrations in gastric juice, completely accounted for by pH-related shifts in the proportion of ionized metronidazole, but does not alter concentrations of nonionized metronidazole, which remain above the MIC level against H . pylori; and even under conditions where no pH-related drug trapping occurs (pH > 4), concentrations of metronidazole were higher in gastric juice than in serum during most of the study, indicating that a special transport mechanism may be operational . The practical implication of this effect of omeprazole in combination therapy with metronidazole remains to be established.

N Z Med J, 1996 Aug 9, 109(1027), 288 - 90
Pneumococci causing invasive disease in New Zealand, 1987-94: serogroup and serotype coverage and antibiotic resistances; Martin DR et al.; AIMS: Development of polysaccharide-conjugated pneumococcal vaccines, prompted by the ineffectiveness of the current 23-valent vaccine for young children, requires an understanding of the pneumococci causing invasive disease worldwide . We have reviewed the capsular serogroups and serotypes, and the antibiotic resistances of pneumococci identified from invasive disease in New Zealand, for the period 1987-94 . METHODS: Pneumococci referred from invasive disease were serogrouped and serotyped using the Neufeld test and allocated a capsular type according to the Danish system of nomenclature . Antibiotic susceptibility testing was performed by an agar dilution method following National Committee for Clinical Laboratory Standards (NCCLS) guidelines . RESULTS: A total of 1506 pneumococci were examined of which, 584 (39.8%) were sourced from children less than 15 years and 573 (39%) were from adults 60 years or greater . The majority (88.3%) were from blood cultures . In descending order of frequency serogroups or serotypes 14, 19, 6, 9, 23, 7, 4 and 1 were common to all age-groups but serogroups 6 and 18 were significantly (p < 0.001) associated with children under 15 years and serotype 3 with adult patients . Penicillin resistance was demonstrated by 22 (1.4%) isolates, five of which showed high level resistance (MIC > or = 2 mg/L) and multidrug resistance . Fourteen percent of all isolates were resistant to at least one antibiotic and serogroups 23, 6, 18, 19 and serotype 14 accounted for 82.6% of these resistant isolates . CONCLUSIONS: The serogroups and serotypes found most frequently associated with pneumococcal disease, and antibiotic resistance, were consistent with those described overseas . Continuing surveillance of antibiotic resistances and serotypes of pneumococci causing invasive disease is recommended.

Arch Pharm (Weinheim), 1996 Aug-Sep, 329(8-9), 421 - 5
In vitro anti-Mycobacterium avium activity of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one and -thione carbamic esters; Pagani G et al.; A series of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one and -thione carbamic esters have been synthesised and tested against Mycobacterium avium strains . The MIC values determined by the radiometric broth dilution method were between 2 and 8 micrograms/mliters for the benzisothiazolthione derivatives and between 16 and 32 micrograms/mliters or higher for the corresponding benzisothiazolone derivatives.

J Antimicrob Chemother, 1996 Aug, 38(2), 237 - 43
Pefloxacin penetration into human necrotic pancreatic tissue; Bertazzoni Minelli E et al.; Antibiotic prophylaxis may be useful in acute necrotising pancreatis, a disease associated with a considerable incidence of infectious complications . The aim of this study was to assess pefloxacin penetration into necrotic pancreatic tissue during human necrotic pancreatitis . Ten patients (mean age 53.2 +/- 17.4 years) with severe acute pancreatitis (mean Ranson score 4.3) were studied . Pefloxacin was administered at a dose of 400 mg bd every 12 h by i.v . infusion (bolus, 15 min) . Intraoperative samples of necrotic pancreatic tissue and blood were collected simultaneously 1, 2, 4.5, 6, 8.5 or 10 h after the last pefloxacin administration in patients treated for 1, 3, 4, 7, 8, 17 or 20 days . Drug concentrations were determined by the microbiological agar-well diffusion method (Escherichia coli Kp 05124 as test micro-organism in Isosensitest Agar) . Levels in serum ranged from 2.0 to 9.0 mg/L (at 2 and 6 h, respectively), in necrotic pancreatic tissue from 2.0 to 29.0 micrograms/g depending on different sampling time . Maximum tissue peak concentrations appeared between 4 and 6 h . The necrotic pancreatic tissue/serum concentration ratio ranged from 0.9 to 5.1, values depending on tissue sample collection . Therapeutic concentrations (20.6 micrograms/g) above the MIC of potentially pathogenic enteric microorganisms were still present in necrotic pancreatic tissue 10 h after the last drug administration . Pefloxacin appeared to concentrate in necrotic pancreatic tissue, without appreciable accumulation after multiple-dose administration . The pefloxacin concentrations in necrotic pancreatic tissue showed high variability, depending on the degree of necrosis, inflammation and sample vascularization . Our results provided evidence of good, prompt penetration of pefloxacin into necrotic pancreatic tissue . Pefloxacin seems to exhibit favourable pharmacokinetic and pharmacodynamic properties for pancreatic infections.

J Antimicrob Chemother, 1996 Aug, 38(2), 227 - 36
Correlation of in-vitro activity and pharmacokinetic parameters with in-vivo effect of amoxycillin, co-amoxiclav and cefotaxime in a murine model of pneumococcal pneumonia; Soriano F et al.; In an attempt to determine the susceptibility breakpoints for amoxycillin, co-amoxiclav and cefotaxime in pneumococcal pneumonia, a neutropenic mouse model was established and tested with two strains having different susceptibility to penicillins and cefotaxime . With a penicillin-sensitive strain (MIC/MBC = 0.01/0.01 mg/L) the minimum dosage tested achieving significant cure was 2 mg/kg for amoxycillin, co-amoxiclav and cefotaxime . For the penicillin-insensitive strain (MIC/MBC = 1/2 mg/L), the minimum dosage tested giving significant cure was 50 mg/kg for amoxycillin and co-amoxiclav but 100 mg/kg for cefotaxime . Our results support the belief that MICs of amoxycillin, co-amoxiclav and cefotaxime for pneumococcal strains of < or = 0.5 or < or = 1 mg/L can be considered as clinically relevant susceptibility breakpoints.

J Chemother, 1996 Aug, 8(4), 254 - 60
Influence of subinhibitory concentrations of ceftazidime, ciprofloxacin and azithromycin on the morphology and adherence of P-fimbriated escherichia coli; Vranes J et al.; The influence of subinhibitory concentrations (1/2, 1/4, 1/8, 1/16 and 1/32 x MIC) of ceftazidime, ciprofloxacin and azithromycin on the morphology and adherence of 29 wild-type P-fimbriated strains of Escherichia coli was studied . Bacterial adherence to the Buffalo green monkey (BGM) cell line was tested before and after treatment with antibiotics and detected by means of an immunofluorescence staining . Significant dose dependent reduction of bacterial adherence was observed, which correlated with the alterations in bacterial cell morphology . After exposure of strains to sub-MICs of antibiotics, normal shapes, spherical forms and filaments were noted . The greatest filamentation and the greatest loss of adherence ability occurred at 1/2 x MIC of ceftazidime . Treatment with sub-MICs of ciprofloxacin resulted in shorter filaments, while filamentation did not occur after bacterial exposure to sub-MICs of azithromycin . Azithromycin was least damaging to the adherence ability of E . coli and at a concentration of 1/2 x MIC caused globoid cell formation.

J Otolaryngol, 1996 Aug, 25(4), 223 - 6
Glottic microinvasive carcinoma: is it different from carcinoma in situ?
Nguyen C, Naghibzadeh B, Black MJ, Rochon L, Shenouda G.
OBJECTIVE: To determine the impact of different treatment modalities on the outcome of microinvasive carcinoma . DESIGN: Retrospective review of patients presenting between 1976 and 1990 . SETTING: Fifteen patients with microinvasive carcinoma (MIC) of the glottic larynx treated at McGill University teaching hospitals . METHODS: All patients had MIC involving the glottis confirmed pathologically . Nine patients (60%) had right vocal cord involvement, four (27%) had left vocal cord involvement, and two (13%) had involvement of both cords . Five patients (33%) were treated by stripping(S), three patients (20%) by stripping and radiotherapy (S + RT), and six patients (40%) by radiotherapy (RT) alone as the primary treatment . Only one patient underwent hemilaryngectomy . RESULTS: With a median follow-up time of 63 months (range 20-208 months), the 15-year actuarial survival rate is 100% for all patients . CONCLUSIONS: Surgery alone, RT alone, or S + RT is equally effective in treating MIC of the glottic larynx; however, single-modality therapy is preferred . The choice of treatment modality should be individualized for each patient.

Mol Biochem Parasitol, 1996 Aug, 79(2), 195 - 206
Molecular cloning and characterization of a novel acidic microneme protein (Etmic-2) from the apicomplexan protozoan parasite, Eimeria tenella; Tomley FM et al.; A 50 kDa acidic protein, which is found within the microneme organelles of Eimeria tenella sporozoites and merozoites and called E . tenella mic-2, was cloned by immunoscreening of a cDNA expression library . The expression of the protein and its mRNA during the development cycle of the parasite was consistent with de novo formation of microneme organelles during both sporulation and schizogony . Although micronemal origin, indirect immunofluorescent antibody labelling on gluraraldehyde fixed parasites, indicated that the protein was translocated to the sporozoite surface, and, during host cell invasion the protein was focussed at the point of parasite entry and secreted from the host-parasite interface . Either during or just after invasion, Etmic-2 protein became transiently dispersed over the entire surface of the infected cell . One hour after adding sporozoites to host cells, no detectable Etmic-2 protein remained on the host cell surface . A full length cDNA corresponding to Etmic-2 predicted a protein with a classical signal peptide that preceded the mature N-terminus of the protein as determined by direct microsequencing . Regions of the Etmic-2 protein have highly significant similarities to regions within Drosophila melanogaster tropomyosin II and within two known substrates of the cellular regulatory enzyme protein kinase C.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1961 - 3
Response to fluconazole by 23 patients with human immunodeficiency virus infection and oral candidiasis: pharmacological and mycological factors; Lacassin F et al.; The MICs of fluconazole for strains of Candida species and the levels of fluconazole in serum were determined at day 0 and day 14 for 23 human immunodeficiency virus-infected patients with oral candidiasis who were treated orally with 100 mg of fluconazole per day for 14 days . Among the 23 patients, 11 (48%) were not clinically cured and had persistent isolation of Candidiasis albicans (n = 10) and/or presence of non-C . albicans (n = 6) . Clinical response could be predicted by the susceptibility of the strain to fluconazole determined at day 0 . All 12 patients who were cured were infected with a strain for which the MIC was < 0.78 mg/liter . All four patients who were infected with a strain for which the MIC was > 3.12 mg/liter experienced clinical failure . These data suggest that a C . albicans strain could be defined as being susceptible when the MIC of fluconazole is < 0.78 mg/liter and as being resistant when the MIC is > 3.12 mg/liter.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1950 - 2
Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci; Ednie LM et al.; Activities of clarithromycin, erythromycin, and azithromycin against 120 pneumococci from the United States were tested by agar dilution MIC . All three compounds yielded MICs at which 90% of the isolates were inhibited (MIC90S) of < or = 0.125 micrograms/ml against penicillin-susceptible and -intermediate strains, but MIC90S against resistant strains were > 128.0 micrograms/ml . All erythromycin-resistant strains were also resistant to clarithromycin and azithromycin . Clarithromycin yielded MICs which were generally one or two dilutions lower than those of the other two compounds for all strains . The respective bacteriostatic and bactericidal values (micrograms per milliliter) for two susceptible, two intermediate, and two resistant strains were 0.004 to 0.03 and 0.016 to 0.03 (0.004 to 0.03/0.016 to 0.03) (clarithromycin), 0.008 to 0.06/0.016/0.016 to 0.125 (erythromycin), and 0.016 to 0.06/0.03 to 0.125 (azithromycin); clarithromycin yielded the lowest values . All compounds were uniformly bactericidal after 24 h only; erythromycin was bactericidal at eight times the MIC, and azithromycin and clarithromycin were both bactericidal at two time the MIC . The relevance of these in vitro differences requires clarification by clinical trials.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1843 - 5
In vitro activities of azithromycin and doxycycline against 15 isolates of Chlamydia pneumoniae; Gnarpe J et al.; Fourteen isolates of Chlamydia pneumoniae, 12 from clinically ill patients and 2 from subjectively healthy individuals from an area within a 400-km proximity of Gavle, Sweden, and strain IOL-207, originally from the eye of an Iranian child, were tested for susceptibilities to the antibiotics doxycycline and azithromycin . MICs and minimum chlamydiacidal concentrations were found to correlate well with values reported earlier by other investigators . In addition to MIC and minimum chlamydiacidal concentration testing, testing for the viability of C . pneumoniae after exposure to antibiotic concentrations as high as 50 mg/liter was carried out by passaging antibiotic-treated, infected cell cultures four times in the absence of antibiotics . It was found that all Chlamydia strains were viable after four passages, regardless of antibiotic concentration in the cell culture.

Antimicrob Agents Chemother, 1996 Aug, 40(8), 1768 - 74
Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra; Kocagoz T et al.; To characterize mechanisms of resistance to fluoroquinolones by Mycobacterium tuberculosis, mutants of strain H37Ra were selected in vitro with ofloxacin . Their quinolone resistance-determining regions for gyrA and gyrB were amplified and sequenced to identify mutations in gyrase A or B . Three types of mutants were obtained: (i) one mutant (TKp1) had no mutations in gyrA or gyrB; (ii) mutants that had single missense mutations in gyrA, and (iii) mutants that had two missense mutations resulting in either two altered gyrase A residues or an altered residue in both gyrases A and B . The TKp1 mutant had slightly reduced levels of uptake of {14C}norfloxacin, which was associated with two- to fourfold increases in the MICs of ofloxacin, ciprofloxacin, and sparfloxacin . Gyrase mutations caused a much greater increase in the MICs of fluoroquinolones . For mutants with single gyrA mutations, the increases in the MICs were 4- to 16-fold, and for mutants with double gyrase mutations, the MICs were increased 32-fold or more compared with those for the parent . A gyrA mutation in TKp1 secondary mutants was associated with 32- to 128-fold increases in the MICs of ofloxacin and ciprofloxacin compared with the MICs for H37Ra and an eight-fold increase in the MIC of sparfloxacin . Sparfloxacin was the most active fluoroquinolone tested . No sparfloxacin-resistant single-step mutants were selected at concentrations of > 2.5 micrograms/ml, and high-level resistance (i.e., MIC, > and = 5 micrograms/ml) was associated with two gyrase mutations . Mutations in gyrB and possibly altered levels of intracellular accumulation of drug are two additional mechanisms that may be used by M . tuberculosis in the development of fluoroquinolone resistance . Because sparfloxacin is more active in vitro and selection of resistance appears to be less likely to occur, it may have important advantage over ofloxacin or ciprofloxacin for the treatment of tuberculosis.

J Clin Microbiol, 1996 Aug, 34(8), 1992 - 4
Vancomycin-resistant Aureobacterium species cellulitis and bacteremia in a patient with acute myelogenous leukemia; Nolte FS et al.; A 39-year-old male with acute myelogenous leukemia and concomitant porphyria cutanea tarda was admitted to the hospital for consolidation chemotherapy of his leukemia . During his hospitalization, he developed cellulitis of the left hand and persistent bacteremia with a yellow-pigmented, nonfermenting coryneform bacterium that was identified as Aureobacterium sp . The portal of entry for the Aureobacterium infection was probably through the skin lesions due to porphyria cutanea tarda . The infection developed while the patient was receiving vancomycin prophylaxis, and the vancomycin MIC for the isolate was 32 micrograms/ml.

Mol Gen Genet, 1996 Jul 26, 251(6), 692 - 8
An ABC transporter is essential for resistance to the antitumor agent mithramycin in the producer Streptomyces argillaceus; Fernandez E et al.; Mithramycin is an antitumor antibiotic synthesized by Streptomyces argillaceus . This producer strain is highly resistant in vivo to mithramycin (MIC 100 micrograms/ml) but sensitive to the related drugs chromomycin and olivomycin (MIC 10 micrograms/ml) . From a genomic library of S . argillaceus DNA two cosmid clones were isolated which confer a high level of resistance to mithramycin on S . albus . The resistance genes were mapped by subcloning to a 3.9-kb PstI-PvuII fragment . DNA sequence analysis of this fragment revealed one incomplete and three complete open reading frames . Subcloning experiments demonstrated that resistance to mithramycin is mediated by the genes mtrA and mtrB . The mtrA gene can potentially encode an ATP-binding protein of the ABC transporter superfamily, containing one nucleotide-binding domain and showing similarity with other ABC transporters involved in resistance to daunorubicin, oleandomycin and tetronasin in their respective producer strains . The mtrB gene codes for an integral membrane protein with six putative transmembrane helices . A mithramycin-sensitive mutant was generated in a gene replacement experiment by disrupting the mtrA gene, thus demonstrating that the system encoded by the mtrAB genes is essential for conferring resistance to mithramycin in S . argillaceus.

Rev Rhum Engl Ed, 1996 Jul-Sep, 63(7-8), 520 - 7
Immunogenetic studies of Behçet's disease; Mizuki N et al.; Behcet's disease has been shown to be strongly associated with the human leukocyte antigen (HLA) B51, not only in the Japanese but also in many other ethnic groups living in the area that extends from the Middle East to Japan . Specific antigen presentation by B51 molecules may be involved in the development of Behcet's disease . Furthermore, studies of the HLA-C genotype conducted using a polymerase chain reaction-sequence specific primers method have suggested that the gene involved in the pathogenesis of Behcet's disease is not the HLA-C gene but some other gene located near the HLA-B gene . Polymorphic analysis of the Tau-a microsatellite located between the HLA-B and TNF genes have also indicated that the Behcet's disease gene is located near the HLA-B gene but is not the HLA-B51 gene itself . We and others believe that many important genes exist in the region located between the TNF and HLA-B or HLA-C genes, including the MIC, PERB, and NOB genes . In this paper, we review current data on genetic factors involved in the development of Behcet's disease.

J Antimicrob Chemother, 1996 Jul, 38(1), 5 - 15
Is continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations; Mouton JW et al.; The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion . Studies in vitro and in laboratory animals comparing efficacy of continuous and intermittent infusion of beta-lactam antibiotics generally show continuous infusion to be more efficacious . While comparative trials in humans are scarce and a significant difference was only found in subgroup analysis in one study, several case-reports support the use of continuous infusion . Arguments in favour and against continuous infusion are discussed . Although dose-ranging studies have not yet been performed in humans, the results from in-vitro and in-vivo experiments indicate that 4 x MIC for the infecting bacterium would be the target concentration . Pharmacokinetic studies which have been performed in humans during continuous infusion show that serum concentrations can be predicted from total clearance or, using population pharmacokinetic modelling, the elimination rate constant as obtained during intermittent infusion . A nomogram is presented which allows calculation of the daily dose to obtain the target steady state blood concentrations suggested by the susceptibility of the infecting bacterium, usually 4 x MIC . For bacteria with a low MIC, the daily dose may be substantially lower than that used in conventional dosing regimens, while in infections which are difficult to treat as a result of more resistant bacteria, continuous infusion may be more effective than an equivalent bolus dose.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1653 - 6
Antipneumococcal activities of RP 59500 (quinupristin-dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid time-kill methodologies; Pankuch GA et al.; Previous time-kill studies have shown that RP 59500 is rapidly bactericidal against pneumococci . To extend these findings, the activities of RP 59500, its two components RP 57669 RP 54476, penicillin G, erythromycin and sparfloxacin against 26 penicillin-susceptible, 25 penicillin-intermediate, and 25 penicillin-intermediate, and 25 penicillin-resistant pneumococci were determined by the agar dilution MIC and the time-kill testing methodologies within 10 min (ca . 0.2 h) and at 1 and 2 h . Respective agar dilution MICs at which 90% of isolates are inhibited for penicillin-susceptible, -intermediate, and -resistant strains were as follows: penicillin G, 0.03, 1, and 4 micrograms/ml;RP 59500, 1, 1, and 1 microgram/ml; RP 57669, 8, 32, and 16 micrograms/ml; RP 54476, > 128, > 128, and > 128 micrograms/ml; erythromycin, 0.06, 2, and > 128 micrograms/ml; and sparfloxacin, 1, 0.5, and 0.5 microgram/ml . RP 59500 was equally active (MIC at which 90% of isolates are inhibited, 1.0 microgram/ml) against erythromycin-susceptible and -resistant strains . Time-kill testing results showed that only RP 59500 at one to four times the MIC killed pneumococci at 0.2 h; RP 59500 was also the most active compound at 1 and 2 h . By comparison, penicillin and sparfloxacin at one, two, and four times the MICs reduced the original inoculum by > or = 1 log at 2 h for 46, 80, and 95% and for 50, 72, and 86% of strains, respectively . The killing activity of RP 59500 was the same against erythromycin-susceptible and -resistant strains . RP 57669, RP 54479, and erythromycin were either inactive or bacteriostatic at 2 h . Of all drugs tested, RP 59500 yielded the most rapid killing.

Antimicrob Agents Chemother, 1996 Jul, 40(7), 1610 - 6
In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis; Rastogi N et al.; By using the radiometric BACTEC 460-TB methodology, the inhibitory and bactericidal activity of the optically active L-isomer of ofloxacin (levofloxacin) was compared with those of the D-isomer and the commercially available mixture containing equal amounts of DL-isomers (ofloxacin) against the Mycobacterium tuberculosis complex (type strain H37Rv, a panel of drug-susceptible and -resistant clinical isolates including multidrug-resistant isolates of M . tuberculosis, as well as M . africanum, M . bovis, and M . bovis BCG) . Levofloxacin MICs (range 0.50 to 0.75 microgram/ml) were about 1 dilution lower than those of ofloxacin (MIC range, 0.75 to 1.00 microgram/ml) and 5 to 6 dilutions lower than those of the D-isomer (MIC range, 32 to 60 micrograms/ml) . The MICs of levofloxacin, ofloxacin, and D-ofloxacin at which 90% of the strains are inhibited were 0.50, 1.00, and 64 micrograms/ml, respectively . The multidrug-resistant M . tuberculosis strains resistant to first-line drugs were as susceptible to quinolones as the wild-type drug-susceptible isolates . Levofloxacin at 0.5 microgram/ml showed bactericidal activity comparable to the activities of 1.0 microgram of ofloxacin per ml and 64 micrograms of D-ofloxacin per ml, with MBCs within the range of 0.5 to 2.0 micrograms/ml, compared with MBCs of 0.75 to 4.0 micrograms of ofloxacin per ml for M . tuberculosis, M . africanum, M . bovis BCG . Combination testing of sub-MICs of levolofoxacin with other first-line (isoniazid, rifampin, and ethambutol) and second-line (amikacin and clofazimine) antituberculous drugs was evaluated with various two-, three-, and four-drug combinations; enhanced drug activity was observed in 8 of 25, 12 of 20, and 8 of 15 tests, respectively, indicating that levofloxacin acts in synergy with other antituberculous drugs.

J Clin Microbiol, 1996 Jul, 34(7), 1794 - 7
Simple method for detecting fluconazole-resistant yeasts with chromogenic agar; Patterson TF et al.; A method for detecting fluconazole-resistant yeasts was developed that uses chromogenic agar containing fluconazole . Yeasts were plated on media with fluconazole at 0, 8, and 16 micrograms/ml . On media without fluconazole, normal growth of susceptible yeasts (defined as those having a fluconazole MIC of < 8 micrograms/ml) was detected, while fluconazole-containing media suppressed susceptible strains and normal colonies of resistant yeasts (fluconazole MICs of > or = 8 micrograms/ml) were detected . This method was used to screen for resistance in oropharyngeal candidiasis . Isolates having fluconazole MICs of > or = 8 micrograms/ml and < 8 micrograms/ml were correctly predicted in 43 of 45 cultures and 115 of 116 cultures, respectively . This screening method appears to be rapid and sensitive for detection of fluconazole-resistant yeasts.

J Clin Microbiol, 1996 Jul, 34(7), 1691 - 3
Multisite reproducibility of the Etest MIC method for antifungal susceptibility testing of yeast isolates; Pfaller MA et al.; A multicenter study was performed to establish the interlaboratory reproducibility of Etest, to provide an additional comparison of Etest MICs with reference broth macrodilution MICs, and to develop some tentative quality control (QC) guidelines for using Etest for antifungal susceptibility testing of Candida spp . Two QC strains, Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258, were tested by Etest against amphotericin B, fluconazole, flucytosine, itraconazole, and ketoconazole in each of four laboratories . The QC strains were tested 20 times each against the five antifungal agents by using a common lot of RPMI agar . A total of 80 MICs per drug per strain were generated during the study . Overall, 98 to 100% of the MICs fell within a 3 log2 dilution range for the respective yeast-antifungal agent combinations . The level of agreement of Etest MICs with broth macrodilution MICs was 86 to 100% with amphotericin B (C . krusei and C . parapsilosis), itraconazole (C . krusei and C . parapsilosis), flucytosine (C . parapsilosis), and fluconazole (C . parapsilosis) . A lower level of agreement was observed with ketoconazole (C . krusei and C . parapsilosis) . Although all participants reported identical Etest MICs, the MICs of flucytosine and fluconazole when tested against C . krusei fell well above the upper limits of the reference range for this strain . The tentative QC limits for the two QC strains and five antifungal agents when tested by the Etest methodology are the same as the QC limits when tested by the reference broth macrodilution method for amphotericin B and C . krusei, itraconazole and C . krusei, flucytosine and C . parapsilosis, fluconazole and C . parapsilosis, and itraconazole and C . parapsilosis . The Etest QC ranges are 1 dilution broader (4-dilution range) than the reference macrodilution method QC ranges for ketoconazole and C . krusei, amphotericin B and C . parapsilosis, and ketoconazole and C . parapsilosis.

J Clin Microbiol, 1996 Jul, 34(7), 1672 - 6
Testing of Mycobacterium tuberculosis susceptibility to ethambutol, isoniazid, rifampin, and streptomycin by using Etest; Wanger A et al.; Etest (AB BIODISK, Solna, Sweden) is a precise MIC method and the practical method of choice for the susceptibility testing of many fastidious organisms, including rapidly growing mycobacteria . Methods recommended by the National Committee for Clinical Laboratory Standards for the susceptibility testing of Mycobacterium tuberculosis include the Bactec (Becton Dickinson, Sparks, Md.) broth and agar proportion methods . A comparison of Etest with the Bactec broth method for testing the susceptibility of M . tuberculosis to four first-line antituberculous agents demonstrated equivalent interpretive results for 100% of the isolates tested . Agreements with agar proportion MICs, within +/-2 log2 dilutions, were 90, 93, 100, and 94% for ethambutol, isoniazid, rifampin, and streptomycin, respectively . Etest MICs were easily read within 5 to 10 days of inoculation . Preparation of the inoculum with a turbidity equivalent to a McFarland 3.0 standard prepared from growth on an agar surface and with a broth with a Bactec growth index of > 999 yielded equivalent results . Clinical isolates for which the MICs were reproducible were also identified as possible quality control strains . The Etest method appears to be an alternative method for testing the susceptibility of M . tuberculosis isolates to the four most commonly used therapeutic agents.

Rinsho Byori, 1996 Jul, 44(7), 665 - 8
{Evaluation of differential media in Helicobacter pylori culture}; Uehara N et al.; Culture is one of the important methods for detecting Helicobacter pylori(Hp) . Culture method is generally lower sensitive in comparison with other Hp detection methods . However, culture is necessary for determination of MIC and analysis of bacteriological characteristics . Several culture media are now commercially available for Hp . In this study, we compared commercial media with our original medium . Original medium for Hp culture was most sensitive and showed no false-positive results compared with other commercial media.

Virology, 1996 Jul 1, 221(1), 218 - 25
Mapping nucleotides in the 126-kDa protein gene that control the differential symptoms induced by two strains of tobacco mosaic virus; Shintaku MH et al.; The differential symptom determinants of the Holmes' masked (M) and U1 strains of tobacco mosaic virus previously were mapped to the 5'-coterminal open reading frame (ORF) encoding the 126-kDa protein and the N-terminal two-thirds of the 183-kDa protein . Both proteins influence viral RNA accumulation, but the function of, and impact on, symptom formation by large domains within the 126-kDa gene, which are not conserved with sequences in analogous ORFs from other related viruses, are unknown . In the current study, cDNA clones representing each strain (i.e., MIC-TMV and U1-TMV) were mutated in these nonconserved domains to further define the nucleotides responsible for mosaic symptom induction on Nicotiana tabacum . Progeny virus of a mutant containing only eight nucleotide substitutions from the MIC-TMV sequence to the U1-TMV sequence within the 126-kDa protein ORF of MIC-TMV induced U1-TMV-like symptoms . Single or multiple substitutions among these eight nucleotides further defined residues critical for symptom modulation . Complementary substitutions in the MIC-TMV and U1-TMV sequences did not always yield progeny virus that induced complementary visual symptoms . Progeny of some mutants contained second-site spontaneous mutations at specific positions shown to influence symptom phenotype . For a subset of the stable site-directed mutants, there was no correlation between severity of systemic symptoms and chlorotic lesion size or virus accumulation in these chlorotic lesions on inoculated leaves.

Diagn Microbiol Infect Dis, 1996 Jun, 25(2), 77 - 81
Clinical evaluation of a dried commercially-prepared microdilution panel for antifungal susceptibility testing; Messer SA et al.; A commercially-prepared dried broth microdilution panel (Sensititre) was compared with a reference microdilution method for antifungal susceptibility testing of two reference yeast strains and 98 clinical isolates of Candida spp . The antifungal agents tested include 5-fluorocytosine (5FC), fluconazole, itraconazole, and D0870 . Microdilution testing was performed according to National Committee for Clinical Laboratory Standards (NCCLS) recommendations . Minimum inhibitory concentration (MIC) endpoints were read visually after 48 hours of incubation and were assessed independently for each microdilution panel . The MICs for the reference strains were within published control limits for both reference and Sensititre microdilution panels . Discrepancies among MIC endpoints of no more than two dilutions (two wells) were used to calculate the percent agreement . An acceptable level of agreement between Sensititre and reference panels was observed for all antifungal agents when tested against the 98 clinical isolates . Agreement ranged from 83% for itraconazole to 93% for 5FC . The Sensititre dried microdilution panel appears to be a viable alternative to inhouse prepared microdilution panels and to the NCCLS microdilution reference method.

Eur J Clin Microbiol Infect Dis, 1996 Jun, 15(6), 484 - 8
Risks related to lack of standardization of tests to detect in vitro metronidazole resistance in Helicobacter pylori; Henriksen TH et al.; The correlation between metronidazole MIC readings obtained in vitro on two different media for two different inoculum dilutions was studied after two, three, and five days of incubation using 20 clinical isolates of Helicobacter pylori . The PDM epsilometer (E test) was used . After two days of incubation, log MIC values on chocolate PDM and Vestfold charcoal medium, a new charcoal medium, showed good correlation . Charcoal media can thus be used for metronidazole sensitivity tests . In terms of double-dilution gradients, prolongation of incubation time from two to three days and change of inoculum dilution from 0.5 to 4 McFarland had little impact when studied separately . However, the combined effect of the two variables was marked . The matching of a sparse inoculum incubated for two days against a heavy inoculum incubated for three days resulted in readings which, for 30% of the pairs, differed by two double-dilution gradients or more . On the other hand, the separate influence of both variables was found to affect the correlation coefficients significantly . Five days of incubation was associated with a poor correlation when the variables on MIC readings was not exposed in a scale of double-dilution gradients because the intervals were too large . For this reason, scales without thresholds are recommended.

J Vet Pharmacol Ther, 1996 Jun, 19(3), 171 - 5
Concentrations of tinidazole in gingival crevicular fluid and plasma in dogs after multiple dose administration; Sarkiala-Kessel EM et al.; Tinidazole 15 mg/kg was administered to eight Beagle dogs with gingivitis or periodontitis twice daily for 3 days . Tinidazole concentrations in blood and gingival crevicular fluid (GCF) were measured 1, 3, 6 and 9 h after the morning dose each day . The concentration of tinidazole was determined by high performance liquid chromatography (HPLC) . The mean concentration of tinidazole in GCF for each dog ranged from 6.05 to 9.32 micrograms/mL at different time points after the first dose, and on the first day the highest concentration was observed 6 h after the drug administration . Tinidazole concentrations were 34 +/- 4%-72 +/- 9% (mean +/- SEM) of simultaneous plasma concentration . At steady-state, on the third treatment day, the mean tinidazole concentrations in GCF ranged from 6.68 to 13.1 micrograms/mL, i.e . 44 +/- 6%-75 +/- 25% of the corresponding concentrations in plasma . Tinidazole concentration in GCF exceeded the MIC values for putative path-ogenic periodontal bacteria and it is concluded that, when indicated, tinidazole could be used for chemotherapy of periodontitis in dogs.

J Occup Environ Med, 1996 Jun, 38(6), 625 - 30
Effects of prolonged low exposure to methyl isocyanate; Avashia B et al.; An assessment of human pulmonary effects from long-term, low-level exposure to methyl isocyanate (MIC) has been undertaken . Serial pulmonary function data, cigarette smoking histories, and other information were available for over 400 workers from a large chemical facility . In addition, industrial-hygiene measurements had been made and were used to classify jobs according to level of MIC exposure . In some instances, work records were incomplete and workers' predominant job and extent of inferred exposures were therefore based on the ratings of their supervisors and coworkers . The availability of these data allowed us to evaluate the frequency of pulmonary impairment in workers according to the assumed four levels of MIC exposure . No specific or consistent pulmonary impairment was evident . Long-term, low-level exposure to MIC at the levels existing at this particular facility could not be shown to be producing detectable effects on lung function.

Phytochemistry, 1996 Jun, 42(3), 713 - 7
Antiviral activity of lignans and their glycosides from Justicia procumbens; Asano J et al.; Ten antiviral lignans, seven known (justicidins A, B, C and D, diphyllin, diphyllin apioside and diphyllin apioside-5-acetate) and three new compounds, justicidinosides A (justicidin C 6'-O-glucoside), B (justicidin A 6'-O-glucoside) and C (justicidin B 6'-O-glucoside), were isolated from a methanolic extract of the aerial parts of Justicia procumbens var . leucantha . Justicidins A and B, diphyllin, diphyllin apioside and diphyllin apioside-5-acetate showed strong antiviral activity (the MIC were less than 0.25 microgram ml-1, respectively) against vesicular stomatitis virus and low cytotoxicity (the MTC were larger than 31 micrograms ml-1, respectively) against cultured rabbit lung cells (RL-33).

Antimicrob Agents Chemother, 1996 Jun, 40(6), 1531 - 3
Oxygen concentration influences proton pump inhibitor activity against Helicobacter pylori in vitro; Midolo PD et al.; Omeprazole and lansoprazole are proton pump inhibitors that have shown activity against Helicobacter pylori and other Helicobacter species when tested by agar dilution . Lansoprazole was more active against H . pylori than was omeprazole, and the activity was independent of urease production . Disk susceptibility tests and agar dilution MIC determinations were performed to investigate the effects of incubation under different sets of atmospheric conditions on H . pylori inhibition . Oxygen concentration was found to influence proton pump inhibitor activity in vitro, with higher concentrations leading to greater susceptibility . The method of testing is important in determining the anti-Helicobacter activity of proton pump inhibitors.

Antimicrob Agents Chemother, 1996 Jun, 40(6), 1504 - 7
Resistance to fluoroquinolones in Escherichia coli isolated from poultry; Bazile-Pham-Khac S et al.; Quinolone-resistant Escherichia coli strains were isolated from poultry clinical samples in Saudi Arabia . The poultry flocks had been treated with oxolinic acid or flumequine prophylaxis . The measure of the uptake of fluoroquinolones showed that none of the strains had a reduced accumulation of quinolones . The result of complementation with the wild-type E . coli gyrA gene, which restored fluoroquinolone susceptibility, and the isolation of DNA gyrase from six isolates indicated that the resistant strains had an altered DNA gyrase . The minimum effective dose of ciprofloxacin for inhibition of supercoiling catalyzed by the isolated gyrases varied from 0.085 microgram/ml for a susceptible isolate (MIC < 4 micrograms/ml) up to 96 micrograms/ml for the more resistant one (strain 215, MIC > 64 micrograms/ml) . For the same two isolates, the minimum effective doses of sparfloxacin varied from 0.17 up to 380 micrograms/ml . The in vitro selection of spontaneous single-step fluoroquinolone-resistant mutants using ciprofloxacin suggested that the more resistant mutants are likely the result of several mutations . These results also show that, as in human medicine, cross-resistance between older quinolones and fluoroquinolones can exist in veterinary isolates and reiterate the need for the prudent use of these drugs.

Antimicrob Agents Chemother, 1996 Jun, 40(6), 1394 - 6
Penetration of ceftibuten into middle ear fluid; Lin C et al.; The penetration of ceftibuten, an extended-spectrum oral cephalosporin, into middle ear fluid (MEF) was evaluated in pediatric patients during a course of daily oral doses of 9 mg/kg of body weight for 10 days . Plasma and MEF collected at 2, 4, 6, or 12 h after at least 3 days of dosing were analyzed for ceftibuten by a high-pressure liquid chromatography method, and the data were used to calculate pharmacokinetic parameters . Plasma and MEF had almost identical maximum concentrations (Cmax) of ceftibuten (14 micrograms/ml) . These Cmax values in MEF during acute otitis media were well in excess of the MIC for 90% of the isolates of each of four major pathogens in this disease . The time to Cmax was longer in MEF (4 h) than in plasma (2 h) . Excellent penetration (71%) of ceftibuten into MEF was observed on the basis of the area under the curve ratio (MEF/plasma) . These data clearly indicate that ceftibuten penetrated well into the MEF to yield clinically effective concentrations.

Am J Vet Res, 1996 Jun, 57(6), 807 - 11
Prevalence of Serpulina species in relation to diarrhea and feed medication in pig-rearing herds in Sweden; Fellstrom C et al.; OBJECTIVE: To determine prevalence of various pheno- and genotypes of Serpulina sp in young pigs in relation to diarrhea and feed medication in Swedish pig-rearing herds . DESIGN: Isolation of spirochetes . Phenotypical and genotypical classification . SAMPLE POPULATION: Young pigs (n = 358) in 19 pigrearing herds . PROCEDURE: Serpulina isolates were classified according to a biochemical scheme based on hemolysis, indole production, hippurate hydrolysis, and alpha-galactosidase, alpha-glucosidase, and beta-glucosidase activities . The 16S rRNA sequences for 10 of the field strains and 2 type strains of Serpulina spp were aligned and compared . Minimum inhibitory concentrations of olaquindox for 9 of the strains were determined . RESULTS: Weakly beta-hemolytic intestinal spirochetes (WBHIS) were isolated from 17 of the herds and 65% of the samples . More than 1 phenotype of WBHIS was found in 12 of the 19 herds . S hyodysenteriae was not isolated in any of the herds . Hippurate-positive WBHIS were isolated in 6 of 7 herds affected by diarrhea, but in only 1 of 8 herds without diarrhea . Hippurate-positive strains were closely related to the pathogenic strain P43 if judged from sequence comparisons . Strains with the same biochemical profile isolated within a herd had identical sequences, but when isolated from different herds, sequence differences were observed . The prevalence of WBHIS was reduced in herds medicated with olaquindox . Investigated field strains had minimum inhibitory concentration values < or = 1 microgram/ml for olaquindox . CONCLUSION: The presence of WBHIS, with the ability to hydrolyze hippurate, was related to diarrhea in pig herds . CLINICAL RELEVANCE: Potentially pathogenic WBHIS can be distinguished from nonpathogenic strains by the hippurate hydrolysis test.

Am J Med, 1996 Jun, 100(6), 617 - 23
The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance; Nguyen MH et al.; OBJECTIVES: To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration . DESIGN: Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata . SETTING: Four tertiary care medical centers . RESULTS: Four hundred twenty-seven consecutive patients were enrolled . The frequency of candidemia due to non-C . albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01) . Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents . Candidemias developing while receiving antifungal therapy were more likely caused by non-C . albicans species than by C . albicans species (P = 0.0005) . C . parapsilosis and C . krusei were more commonly seen with prior fluconazole therapy, whereas T . glabrata was more commonly seen with prior amphotericin B therapy . Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001) . CONCLUSION: In this large scale study, the non-C . albicans species, especially T . glabrata, emerged as important and frequent pathogens causing fungemia . This finding has major clinical implications given the higher complication and mortality rate associated with the non-C . albicans species . The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy . This is an ominous sign given the in vitro resistance of the non-C . albicans species to currently available antifungal agents.

Rev Inst Med Trop Sao Paulo, 1996 May-Jun, 38(3), 217 - 9
Norfloxacin monodose use in patients with cholera in Salta Argentina; Seijo AC et al.; The use of monodose (800 mg) per os of Norfloxacin was evaluated in 32 patients with cholera at Salvador Mazza's Hospital, Salta, Argentina . It was considered the celerity in negativization of stool culture (100% of cases: 12 hours post administration), it efficiency along time (24/24 controlled patients were negative at 10th day) and MIC of isolated strains (100% of strains were sensitive: range 0.008 to 0.016 micrograms/ml) . It was included oral administration of sorbitol 70% in peanut oil in order to study patients at 10th day's control . This method could be an alternative one in the study of asymptomatic carrier . Norfloxacin monodose shows good performance in early negativization of stool culture and it was also effective along the whole observation period, suggesting it could prevent carriage.

Chemotherapy, 1996 May-Jun, 42(3), 177 - 85
Effect of subinhibitory concentrations of ceftazidime, ciprofloxacin, and azithromycin on the hemagglutination and adherence of uropathogenic Escherichia coli strains; Vranes J; The effect of subinhibitory concentrations (sub-MICs) of ceftazidime, ciprofloxacin, and azithromycin on the hemagglutination (HA) and adherence ability of 29 P-fimbriated Escherichia coli strains to the buffalo green monkey kidney (BGMK) cell line was investigated . Comparisons were made between the values of HA titer before and those after exposure of strains to 1/2, 1/4, 1/8, 1/16 and 1/32 MIC of antibiotics, as well as between the number of bacteria attached to the BGMK cells before and the number after their exposure to the same concentrations of antibiotics . Azithromycin at concentrations of 1/2 and 1/4 MIC damaged the HA capacity of the studied strains, while ceftazidime at concentrations of 1/2, 1/4, 1/8 and 1/16 MIC and ciprofloxacin at concentrations of 1/2 and 1/4 MIC increased the HA capacity of P-fimbriated E . coli . All three antibiotics decreased the adhesive capacity of E . coli to the BGMK cells . Comparing the number of adhered bacteria before and after exposure to sub-MICs of antibiotics, statistically significant differences were determined (p < 0.01) after exposure of the strains to all the concentrations of ceftazidime used after exposure to 1/2, 1/4, 1/8 and 1/16 MIC of ciprofloxacin, and after exposure to 1/2, 1/4 and 1/8 MIC of azithromycin . Filaments formed by sub-MICs of ceftazidime and ciprofloxacin in a static experimental system caused HA, but in an experimental system imitating in vivo conditions, the strains adhered poorly to the cells.

Mycoses, 1996 May-Jun, 39(5-6), 237 - 40
Oral terbinafine in tinea capitis in children; Gruseck E et al.; Tinea capitis is a disease that frequently affects children . In most cases systemic antimycotic treatment is necessary Griseofulvin is still the drug of choice, but requires prolonged periods of treatment (several months) . To estimate the efficiency and tolerability of terbinafine for treatment of tinea capitis in children, four patients (aged 3-9 years) with tinea capitis proven by culture were treated with terbinafine at a dose of 125 mg a day for different periods (4-10 weeks) . Isolates were subjected to minimal inhibitory concentration testing against terbinafine and griseofulvin . In all four cases terbinafine treatment resulted in complete remission . The clinical response was accompanied by negative culture results on follow-up . Terbinafine was well tolerated in each case . Determination of the minimal inhibitory concentration confirmed the excellent in vitro activity of terbinafine against dermatophytes . Controlled studies involving a larger number of children are necessary to answer questions concerning dose and duration of terbinafine treatment as well as the frequency and severity of drug-related side-effects.

J Antimicrob Chemother, 1996 May, 37(5), 999 - 1003
Evaluation of the Etest for rapid susceptibility testing of Mycobacterium avium to clarithromycin; Lebrun L et al.; MICs of clarithromycin were determined by the Etest method for thirty clinical strains of Mycobacterium avium complex (MAC) and compared with MICs results as determined by the reference agar dilution method . Agreement (within +/- 1 log2 dilution) between the Etest and the reference method was 70% for susceptible strains and 100% for resistant strains . No major errors resulting in misclassification in susceptibility or resistance categories were detected for the Etest MIC method . It is suggested that the Etest is easy to perform and is an accurate method for determining susceptibility of MAC strains to clarithromycin.

Free Radic Res, 1996 May, 24(5), 361 - 7
Effect of MCI-186 on postischemic reperfusion injury in isolated rat heart; Minhaz U et al.; MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) is a newly developed antioxidant which has been shown to reduce brain edema in cerebral ischemia through inhibition of the lipoxygenase pathway of arachidonic acid . However, its effect on myocardial reperfusion injury after prolonged ischemia has not yet been demonstrated . We compared the mode of the effect of MIC-186 and recombinant human CuZn superoxide dismutase (rh-SOD) in isolated perfused rat hearts subjected to 60-min ischemia followed by 60-min reperfusion . Left ventricular developed pressure (LVDP), necrotic area and the release of creatine phosphokinase (CPK) and endogenous CuZn superoxide dismutase (endoge-SOD) were measured to evaluate myocardial damage . The decrease in left coronary flow (CBF) was measured as an index of the damage of left coronary circulation . MCI-186 (14.5 mg/L) was perfused for 10 min in the MCI group and rh-SOD (70 mg/L) was perfused during the reperfusion period in the SOD group starting 5 min prior to reperfusion . The release patterns of CPK and endoge-SOD were analyzed to elucidate the difference in the mode of protection of MCI-186 and rh-SOD . The LVDP remained higher in both MCI and SOD groups than that of control (76 +/- 1, 77 +/- 2 and 69 +/- 1% of preischemic value, respectively) . The necrotic area was significantly attenuated in both MCI and SOD groups compared with that in the control group (16 +/- 1, 14 +/- 1 and 32 +/- 1%, respectively, p < 0.05) . Total CPK release was lower in both MCI and SOD groups than in the control (78 +/- 7, 100 +/- 2 and 116 +/- 4 x 10(3) units/g myocardium respectively) . The decrease in CPK release was more marked in the MCI group than that in the SOD group (p < 0.05) . The reduction in CBF was significantly attenuated by the treatment with rh-SOD or MCI-186, but the effect was much higher in the SOD group than in the MCI group (69 +/- 5, 58 +/- 2, and 48 +/- 2% in SOD, MCI and control groups, respectively) . The release pattern of endoge-SOD was identical to that of CPK and thus this did not distinguish the mode of effect of MCI-186 from that of rh-SOD . These results indicate that MCI-186 reduces reperfusion injury in isolated perfused hearts with prolonged ischemia and the effect is more closely related to the reduction of myocyte damage than the preservation of the coronary circulation.

J Clin Microbiol, 1996 May, 34(5), 1321 - 2
Stability of amoxicillin-clavulanate in BACTEC medium determined by high-performance liquid chromatography and bioassay; Moore TD et al.; The stabilities of amoxicillin (16 micrograms/ml) and clavulanate (8 micrograms/ml), alone and in combination in BACTEC medium (Middlebrook 7H12B medium), were determined by high-performance liquid chromatography (HPLC) and bioassay . By HPLC, the half-life of amoxicillin (trihydrate and sodium) in combination with clavulanate in nonradiolabelled 7H12B medium was 6.7 days, whereas the half-life of clavulanate in combination with amoxicillin was 2.0 days . By bioassay, the half-lives of amoxicillin trihydrate and clavulanate in radiolabelled 7H12B medium were comparable (7 and 2 days, respectively) to those determined by HPLC . When clavulanate was tested alone, the half-life was determined to be 1.88 days by HPLC and 1.87 days by bioassay . The relatively short half-life of clavulanate can be adjusted by a procedure of "topping up," or adding one-half the concentration of clavulanate every second day, in order to allow accurate amoxicillin-clavulanate MIC testing with the BACTEC mycobacterial susceptibility system.

Am J Vet Res, 1996 May, 57(5), 720 - 3
Pharmacokinetic model for cefazolin distribution during total hip arthroplasty in dogs; Marcellin-Little DJ et al.; OBJECTIVES--To compare cefazolin pharmacokinetics in serum and concentrations in tissues during total hip arthroplasty in dogs with and without hip dysplasia, and to calculate the optimal dosage of cefazolin for prophylactic use during total hip arthroplasty . ANIMALS--10 dogs with hip dysplasia and 3 clinically normal dogs . PROCEDURE--Blood samples and tissue specimens from the coxofemoral joint capsule, acetabulum, and femur were obtained during unilateral total hip arthroplasty . Cefazolin concentrations in serum and tissue specimen supernatant were determined, using high-performance liquid chromatography, for use in pharmacokinetic analysis . Mathematical simulation of serum cefazolin concentration was used to to predict the optimal dose . RESULTS--Mean pharmacokinetic constants (SEM) were 0.146 (0.013) min-1 for alpha, 4.47 min for t1/2 alpha 0.015 (0.004) min-1 for beta, 46.83 min for t1/2 beta . Significant different was not detected for cefazolin distribution and elimination between dogs with and without hip dysplasia . Additional, significant difference was not observed in pharmacokinetic parameters describing distribution and elimination between the first and second doses of cefazolin . The predicted optimal dosage regimen was 8 mg/kg of body weight, i.v . every hour or mg/kg, i.v . every 2 hours . CLINICAL RELEVANCE--For prophylactic i.v . treatment during total hip arthroplasty, use of cefazolin at a dosage of 8 mg/kg every hour or 22 mg/kg every 2 hours should maintain serum cefazolin concentrations at least 10x the minimum inhibitory concentration for 3 to 4 hours.

Antimicrob Agents Chemother, 1996 May, 40(5), 1314 - 6
In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis; Sugar AM et al.; The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole . SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml . The results of the treatment of mice infected with B . dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592 . Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole . SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.

Antimicrob Agents Chemother, 1996 May, 40(5), 1139 - 42
Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation; Amaker RD et al.; Extracorporeal membrane oxygenation (ECMO) is a widely used therapy for neonates with respiratory failure . Because of sepsis, many of these infants require antibiotics like vancomycin during ECMO treatment . ECMO transiently alters renal function and increases the circulating blood volume by 75% . Initial vancomycin pharmacokinetics were determined in 12 infants undergoing ECMO to determine an adequate drug administration regimen . Vancomycin dosage was based on current recommendations for weight and gestational age . Pharmacokinetic parameters were determined by fitting the data to a two compartment model . This study yielded a mean steady-state volume of distribution of 1.1 +/- 0.5 (range, 0.6 to 2.1) liters/kg and a mean vancomycin clearance of 0.78 +/- 0.19 (range, 0.49 to 1.07) ml/min/kg . The mean vancomycin half-life was 16.9 +/- 9.5 (range, 8.8 to 42.9) h . Nomogram-calculated creatinine clearance was a significant predictor of vancomycin terminal rate constant and clearance . These data suggest alterations in the pharmacokinetics of vancomycin in infants on ECMO . With the goal of achieving vancomycin concentrations in serum above the MIC for the offending pathogen while using the least amount of the drug necessary, new administration guidelines for term infants without renal impairment undergoing ECMO should be 20 mg of vancomycin per kg at an interval of 24 h . With significant renal impairment, the interval should be extended on the basis of concentrations in serum . In comparison with previously published data, the neonates undergoing ECMO in our study demonstrated a much larger volume of distribution, a lower clearance, and consequently a longer vancomycin half-life.

Antimicrob Agents Chemother, 1996 May, 40(5), 1104 - 7
Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis; Karlsson M et al.; Concentrations of doxycycline and penicillin G in serum and cerebrospinal fluid (CSF) were analyzed in 46 patients during treatment for neuroborreliosis . Twenty patients were treated intravenously with penicillin G at 3 g every 6 h (q6h), and 26 patients were treated orally with doxycycline at 200 mg q24h . All samples were collected on day 13 of treatment . The median concentrations of penicillin G in serum were 0.5, 37, and 5.6 micrograms/ml before and 1 and 3 h after drug administration, and that in CSF was 0.5 (range, 0.3 to 1.6) microgram/ml after 2 to 3 h . The median concentrations of doxycycline in serum were 2.1, 6.1, and 4.7 micrograms/ml before and 2 and 6 h after drug administration, and that in CSF was 0.6 (range, 0.4 to 2.5) microgram/ml after 4 h . All patients had concentrations of penicillin G or doxycycline in CSF above the lowest reported MICs of penicillin G (0.003 microgram/ml) and doxycycline (0.12 microgram/ml) for Borrelia burgdorferi . However, no patients had a drug concentration in CSF above the highest reported MIC of penicillin G (8 micrograms/ml), and only one had a drug concentration in CSF above the highest reported MIC of doxycycline (2 micrograms/ml), despite good clinical response to treatment . No treatment failure or relapse was observed during a 1-year follow-up, although one patient treated with penicillin G and one treated with doxycycline were retreated because of residual pain . The chosen dosages of penicillin G and doxycycline seem to give sufficient concentrations in serum and CSF for the treatment of neuroborreliosis.

J Cell Biol, 1996 May, 133(4), 895 - 910
Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions; Lowell CA et al.; Cross-linking of the neutrophil-beta 2- or beta 3-related leukocyte response integrins by extracellular matrix (ECM) proteins or monoclonal antibodies (mAb) stimulates cytoskeletal rearrangement leading to cell spreading and respiratory burst . Tyrosin phosphorylation of a variety of proteins and activation of the Src family kinases within polymorphonuclear leukocytes (PMN) have recently been implicated in the intracellular signaling pathways generated by leukocyte integrins (Yan, S.R., L . Fumagalli, and G Berton . 1995 . J . Inflammation . 45:217-311.) To directly test whether these functional responses are dependent on the Src family kinases p59/61hck and p58c-fgr, we examined adhesion-dependent respiratory burst in PMNs isolated from hck -/-, fgr -/-, and hck -/- fgr -/- knockout mice . Purified bone marrow PMNS from wild-type mice released significant amounts of O2- when adherent to fibrinogen-, fibronectin-, or collagen-coated surfaces, in the presence of activating agents such as tumor necrosis factor (TNF) or formyl-methionyl-leucyl-phenylalanine, as described for human PMNs . PMNs from hck-/-fgr-/- double-mutant mic, however, failed to respond . This defect was specific for integrin signaling, since respiratory burst was normal in hck-/-fgr-/-PMNs stimulated by immune complexes or PMA . Stimulation of respiratory burst was observed in TNF-primed wild-type PMN plated on surfaces coated with murine intracellular adhesion molecule-1 (ICAM-1), while hck-/-fgr-/- PMNs, failed to respond . Direct cross-linking of the subunits of beta 2 and beta 2 integrins by surface-bound mAbs was elicited O2- production by wild-type PMNs, while the double-mutant hck-/-fgr-/- cells failed to respond . Photomicroscopy and cell adhesion assays revealed that the impaired functional responses of hck-/-fgr-/- PMNs were caused by defective spreading and tight adhesion on either ECM protein- or mAb-coated surfaces . In contrast, hck-/-or fgr-/-single mutant cells produced O2- at levels equivalent to wild-type cells on ECM protein, murine ICAM-1, and antiintegrin mAb-coated surfaces . Hence, either p59/61 hck and p 58c-fgr is required for signaling through leukocyte beta 2 and beta 3 integrins leading to PMN spreading and respiratory burst . This is the first direct genetic evidence of the importance of Src family kinases in integrin signaling within leukocytes, and it is also the best example of overlapping function between members of this gene family within a defined signal transduction pathway.

Toxicology, 1996 Apr 30, 108(3), 185 - 90
Mechanism of prolongation of pentobarbital-induced sleeping time by empenthrin in mice; Tsuji R et al.; The effect of empenthrin, a synthetic pyrethroid, on pentobarbital (PTB)-induced sleeping time was examined in mice and rats . In mice, pretreatment with empenthrin prolonged PTB-induced sleeping time in a dose-dependent manner . The maximum effect on PTB-sleeping time was noted when mice were pretreated orally with empenthrin 2-4 h before PTB injection . However, empenthrin did not change the sleeping time induced by diethyl ether which is hardly metabolized in liver . Empenthrin inhibited the clearance of serum PTB in mic, but did not change the PTB concentration in serum at which animals recovered from sleeping . To examine the effect of PTB on metabolic enzymes in mouse liver, PTB was incubated aerobically with a hepatic microsomal fraction in the presence of NADPH at 37 degrees C . Empenthrin inhibited the vitro metabolism of PTB dose-dependently . In rats, empenthrin neither changed the PTB sleeping time, nor inhibited the clearance of serum PTB . No inhibitory effect of empenthrin was observed on the in vitro metabolism of PTB using rat hepatic microsomal fraction . These findings indicate that empenthrin prolongs PTB-sleeping time in mice through an inhibition of the PTB-metabolizing enzyme(s) in the liver , an effect that does not occur in rats . Also, there is a clear species-specificity in the inhibitory effect of empenthrin on the PTB-metabolizing enzyme(s).

Cancer, 1996 Apr 15, 77(8), 1489 - 93
Efficacy of radical hysterectomy as treatment for patients with small cell carcinoma of the cervix; Sevin BU et al.; BACKGROUND . This study was performed to identify pathologic and clinical features that best predict disease free survival of patients with early stage small cell carcinoma of the cervix treated by radical hysterectomy . METHODS . Three hundreds and seventy patients with cervical carcinoma were analyzed retrospectively to define those variable that best predict disease free survival (DFS) . Variables included age, weight, race, marital status, economic status, tumor size, depth of invasion (DI), lymph-vascular space involvement (LVSI), cell type, tumor grade, lymph node metastasis (LNM), and total number of lymph nodes removed . Patients with lymph node metastasis, parametrial involvement, and positive or close surgical margins were offered postoperative radiation . RESULTS . Twelve patients were found to have small cell carcinoma (3.2%) . One patient had microinvasive carcinoma of the cervix (MIC) as defined by the Society of Gynecologic Oncologists with a depth of invasion of 3 mm or less and no lymph-vascular space invasion, and has been reported previously . A detailed analysis of the other patients with nonsmall cell carcinoma is presented separately . Five patients achieved a DFS of at least 5 years, whereas 7 patients died with disease . Excluding the patient with MIC, the 5-year DFS rate was 36.4% . CONCLUSIONS . Relative to other cell types, small cell carcinomas of the cervix is an aggressive neoplasm with a higher rate of LVSI and LNM despite smaller DI and tumor size . These data suggest that multimodality therapy, combining radical surgery and radiation with cytotoxic chemotherapy, may provide these patients with the best chance for cure.

Am J Physiol, 1996 Apr, 270(4 Pt 1), G554 - 64
Transport of an influenza virus vaccine formulation (iscom) in Caco-2 cells; Lazorova L et al.; The influenza virus envelope glycoproteins hemagglutinin and neuraminidase were administered to the apical or basolateral sides of Caco-2 monolayers either as native protein micelles (mic-ag) or after incorporation into the orally active adjuvant formulation, immune stimulating complexes (iscoms) (isc-ag) . Biotin-conjugated isc-ag were localized in intracellular vesicles as early as 2 min after administration to the apical side at 37 degrees C . Ten minutes after administration, both intracellular vesicles and intercellular spaces were labeled, and extracellular labeling was observed on the basolateral side of the cells, indicating that isc-ag were transported across the epithelium within 10 min of exposure . Transport of 125I-labeled isc-ag and mic-ag in the apical-to-basolateral and basolateral-to-apical directions across Caco-2 monolayers was comparable at 37 degrees C . Gel chromatography analysis revealed that only 0.55-3.1% of transported isc-ag and mic-ag had a molecular weight of > 5,000, while 21.0-42.3% was eluted at a position corresponding to peptides of approximately 10 amino acids . Although isc-ag and mic-ag were transported and degraded by Caco-2 monolayers in comparable amounts, only transported isc-ag induced a dose-dependent proliferative response in vitro of T cells primed with influenza virus antigen . High-performance gel chromatography and reverse-phase high-performance liquid chromatography indicated that transported antigenic isc-ag consisted of hydrophobic peptides with a molecular weight of < or = 3,000 . These results indicate that antigens incorporated into the orally active adjuvant formulation iscom are degraded to antigenic peptides during transport across the intestinal epithelium.

J Biomater Appl, 1996 Apr, 10(4), 338 - 47
In vitro release of new quinolones from biodegradable systems: a comparative study; Andreopoulos AG et al.; A new biodegradable delivery system based on low molecular weight poly(lactic acid) has been formulated, with potential application in the sustained antibiotic release against bone infection . The in vitro release of two new quinolones (ofloxacin and ciprofloxacin) from the biodegradable matrix showed that the delivery of ofloxacin from the matrix lasted fifty-six days, whereas that of ciprofloxacin lasted fifty-one days . In both cases, release is controlled by the drug diffusion and the matrix degradation, the latter being the most critical factor . The obtained concentration levels are well above the Minimum Inhibitory Concentration (MIC) against the major causative bacteria of osteomyelitis . This fact in combination with the good reproducibility of measurements indicated that the system studied could be of value for the preparation of implantable controlled release systems for treatment of diseases in the bone system.

Antimicrob Agents Chemother, 1996 Apr, 40(4), 879 - 85
Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli; Heisig P; Fifteen strains of Escherichia coli with MICs of ciprofloxacin (CIP) between 0.015 and 256 micrograms/ml were examined for the presence of mutations in the quinolone resistance-determining region of the gyrA gene and in an analogous region of the parC gene . No mutation was found in a susceptible isolate (MIC of CIP, 0.015 microgram/ml) . Four moderately resistant strains (MIC of CIP 0.06 to 4 micrograms/ml) carried one gyrA mutation affecting serine 83, but in only one strain was an additional parC mutation (Gly-78 to Asp) detected . All ten highly resistant strains examined (MIC of CIP, > 4 micrograms/ml) carried two gyrA mutations affecting residues serine 83 and aspartate 87, and at least one parC mutation . These parC mutations included alterations of serine 80 to arginine or isoleucine and glutamate 84 to glycine or lysine . The parC+ and two mutant alleles (parCI-80 and parCI-80,G-84) were inserted into the mobilizable vector pBP507 . Transfer of a plasmid-coded parC+ allele into parC+ strains did not alter the susceptibilities towards ciprofloxacin or nalidixic acid, while a significant increase in susceptibility was detectable for parC mutants . This increase, however, did not restore wild-type susceptibility, whereas transfer of a plasmid-coded gyrA+ allele alone or in combination with parC+ did . These data are in agreement with the view that topoisomerase IV is a secondary, less sensitive target for quinolone action in Escherichia coli and that the development of high-level fluoroquinolone resistance in E . coli requires at least one parC mutation in addition to the gyrA mutation(s).

Antimicrob Agents Chemother, 1996 Apr, 40(4), 874 - 8
Activities of the glycylcyclines N,N-dimethylglycylamido-minocycline and N,N-dimethylglycylamido-6-demethyl-6-deoxytetracycline against Nocardia spp . and tetracycline-resistant isolates of rapidly growing mycobacteria; Brown BA et al.; Susceptibilities to the new semisynthetic tetracycline (Tet) compounds N,N-dimethylglycylamido-minocycline (DMG-MINO) and N,N-dimethylglycylamido-6-demethyl-6-deoxytetracycline (DMG-DMDOT) were compared with those to doxycycline, minocycline, and Tet for 198 Tet-resistant (Tetr) and 33 Tet-susceptible (Tets) clinical isolates of rapidly growing mycobacteria (RGM) including the Mycobacterium fortuitum group, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium mucogenicum and 68 isolates belonging to six taxa of Nocardia spp . All Tetr RGM were highly susceptible to the glycylcyclines . The MICs at which 50 and 90% of isolates are inhibited were < or = 0.125 and < or = 0.25 microgram/ml, respectively, for DMG-DMDOT and < or = 0.25 and 1 microgram/ml, respectively, for DMG-MINO . The MIC of DMG-DMDOT at which 50% of Tetr strains are inhibited was the same as that for Tets strains for each of the four taxa of RGM . The new agents were less active against Nocardia spp . MICs of DMG-DMDOT were comparable to those of minocycline except for the MICs for Nocardia brasiliensis sensu stricto, the new taxon Nocardia pseudobrasiliensis, and some isolates of Nocardia nova, against which they were four- to eightfold more active . The MICs of DMG-DMDOT were consistently lower than those of DMG-MINO for RGM . This class of drugs offers exciting therapeutic potential for RGM and for selected species of Nocardia.

Antimicrob Agents Chemother, 1996 Apr, 40(4), 1048 - 9
Susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to a new quinolone, trovafloxacin (CP-99,219); Kenny GE et al.; The susceptibilities of mycoplasmas to a new quinolone, trovafloxacin (CP-99,219), were compared with those to sparfloxacin and ofloxacin . Mycoplasma pneumoniae was as susceptible to trovafloxacin (MIC = 0.25 microgram/ml) as to sparfloxacin and fourfold less susceptible to ofloxacin . Mycoplasma hominis was highly susceptible to trovafloxacin (MIC = 0.06 microgram/ml) and sparfloxacin (MIC = 0.03 microgram/ml) and less susceptible to ofloxacin (MIC = 0.5 microgram/ml) . Ureaplasma urealyticum was most susceptible to trovafloxacin, with susceptibilities ranging from 0.06 to 0.5 microgram/ml compared with 0.25 to 1.0 microgram of sparfloxacin per ml and 1 to 4 micrograms of ofloxacin per ml.

Antimicrob Agents Chemother, 1996 Apr, 40(4), 1036 - 8
Reaction of roxithromycin and clarithromycin with macrolide-inactivating enzymes from highly erythromycin-resistant Escherichia coli; O'Hara K et al.; The activities of two new 14-membered-ring macrolide antibiotics, roxithromycin (RXM) and clarithromycin (CAM), against highly erythromycin (EM)-resistant Escherichia coli strains were evaluated . Pretreatment of macrolide phosphotransferase (MPH) (2') I-producing strains with EM increased the MICs of EM and CAM without any noticeable change in the MIC of RXM . The MPH (2') II-producing strain was more susceptible to CAM, while the EM esterase-producing strains were more susceptible to RXM than EM . Pretreatment of these latter two strains with EM did not alter their susceptibility to either RXM or CAM . In addition, the compounds were assessed as substrates for inactivation by crude enzyme preparations . Of the 14-membered-ring macrolides, RXM was the least favored substrate for MPH (2') I or II . CAM and RXM were substrates for the EM esterase but were the least preferred of the 14-membered-ring macrolides.

Eur J Ophthalmol, 1996 Apr-Jun, 6(2), 137 - 42
Ocular penetration kinetics of fosfomycin administered as a one-hour infusion; Forestier F et al.; The penetration of fosfomycin in aqueous humour was studied in 21 patients who were to undergo cataract surgery . All patients received 4 grams of fosfomycin as an infusion lasting one hour . Concentrations of the drug in aqueous humour were measured 1, 2, 4, 6 and 12 hours after the start of infusion . Drug concentrations in aqueous humour and serum were measured by HPCE (High Performance Capillary Electrophoresis) . The aqueous humour concentration at one hour was 11.46 mg/l +/- 2.12 . Peak concentration was 14.63 mg/l +/- 5.54, reached two hours after the infusion . Concentrations were high until 6 hours and remained significant at 12 hours . These results confirm the excellent diffusion of fosfomycin in aqueous humour, with high levels at 12 hours . They justify its use in intraocular infections, by infusions repeated every eight hours, to maintain concentrations above the MIC 90 for organisms usually susceptible to the drug.

J Clin Microbiol, 1996 Apr, 34(4), 842 - 7
Fluconazole and amphotericin B antifungal susceptibility testing by National Committee for Clinical Laboratory Standards broth macrodilution method compared with E-test and semiautomated broth microdilution test; van Eldere J et al.; A comparative study of fluconazole and amphotericin B susceptibility testing was performed with 68 clinical Candida species isolates and three test methods . The methods used were an agar diffusion method (E-test) and two broth dilution methods, the National Committee for Clinical Laboratory Standards (NCCLS) reference broth macrodilution method and an in-house-prepared semiautomated broth microdilution method based on the Bioscreen turbidometer . In the microdilution method, growth of the yeasts was measured continuously by the automatic turbidometer (Bioscreen), which permitted precise and objective determination of endpoints . MIC endpoints were read after 24 h for the microdilution method and the E-test . Amphotericin B susceptibility testing with the NCCLS method and the E-test yielded comparable results in 89% of the tests, meaning that the endpoints obtained were identical or differed by no more than 2 twofold dilutions . The NCCLS and broth microdilution tests scored 97% comparable results, and the E-test and the broth microdilution test yielded 90% comparable results . Fluconazole susceptibility testing produced 96% comparable results with the NCCLS test and the E-test, 100% comparable results with the NCCLS and the microdilution methods, and 98.5% comparable results with the microdilution method and the E-test . We conclude that the E-test and the Bioscreen microdilution method are valuable alternatives to the NCCLS reference method for routine susceptibility testing of Candida species with fluconazole and amphotericin B.

Indian Pediatr, 1996 Apr, 33(4), 287 - 91
Pharmacokinetics of isoniazid in pulmonary tuberculosis--a comparative study at two dose levels; Roy V et al.; OBJECTIVES: To compare the pharmacokinetic parameters and the clinical efficacy of isoniazid, administered in 10 mg/kg or 5 mg/kg to children suffering from pulmonary tuberculosis . DESIGN: A randomized, open, controlled clinical trial . SETTING: Teaching hospital in New Delhi . SUBJECTS: Twenty children suffering from pulmonary tuberculosis in the age group 6-12 years . INTERVENTIONS: A three drug antitubercular regimen comprising of rifampicin (10 mg/kg), pyrazinamide (30 mg/kg) and isoniazid in a dose of either 10 mg/kg (Group I) or 5 mg/kg (Group II) was administered for fourteen days . On day fifteen serial blood samples were collected at 0,1,2,3,6 and 24 h of isoniazid administration and analyzed spectrofluorometrically . MAIN OUTCOME MEASURES: Serum isoniazid concentrations and clinical response in both the groups . RESULTS: In both the groups, serum concentration of isoniazid were above the therapeutic range (0.5-2 micrograms/ml) at 6 h following drug administration . The minimum serum concentration of isoniazid was within or above minimum inhibitory concentration of the drug at 24 h in both the groups . The time to achieve maximum serum concentration, elimination half life, elimination rate constant, mean residence time, volume of distribution at steady state and plasma drug clearance were also comparable . At the end of 6 months follow up, all children showed comparable clinical and radiological improvement . CONCLUSION: Isoniazid in a dose of 5 mg/kg administered with other antitubercular drugs appears adequate for treatment of pulmonary tuberculosis in children.

Presse Med, 1996 Mar 2-9, 25(8), 408 - 10, 412-4, 416-8
{Therapeutic applications of tissue pharmacokinetics of antibiotics}; Bergogne-Berezin E; Antibiotic therapy is constantly changing . Among the criteria used to choose the right antibiotic, tissue pharmacokinetics provides useful, though controversial, information on drug distribution in organs and body fluids at potential sites of infection . Various study models have established i) the high rate of penetration of third-generation cephalosporins, aminoglycosides and fluoroquinolones into cerebrospinal fluid when meninges are inflamed; and ii) high levels of macrolides and fluoroquinolones in lung parenchyma and other respiratory sites of infection . These data should be analyzed in terms of pharmacodynamic activities in sites in the cerebrospinal fluid where the minimum inhibitory concentration and the minimum bactericidal concentration have been determined for the pathogen . In other situations, the criteria with the most clinical significance is the correlation between tissue concentrations and clinical outcome . There has been much progress in targeted (liposomes) antibiotic therapy with promising advances toward better tissue distribution of drugs.

Zhonghua Zhong Liu Za Zhi, 1996 Mar, 18(2), 150 - 3
{Classification of ninety-eight adult cases of acute leukemia according to morphology, immunology and cytogenetics}; Li J et al.; Ninety-eight cases of adult acute leukemia (AL) were diagnosed and classified based on morphologic, immunologic and cytogenetic (MIC) features . The results showed that: the conformity rate of cytomorphologic/cytochemical classification with MIC classification was 90.8% . For ALL, the conformity rate of immunologic classification with MIC classification was 95.6%, but it was only 70.8% for AML . Of the 48 AML, 10 expressed lymphoid lineage, associated antigens and 8 of 43 ALL expressed myeloid lineage-associated antigens . Seven cases were diagnosed as hybrid acute leukemia according to Catovsky criterion . The chromosome aberrations were found in 70 cases, of them 46 cases showed characteristic abnormalities including t(9;22), t(4;11), t(11;14), t(8;12), t(8;14), 6q-, 9p-, and t(15;17), t(8;21), inv(16), etc.

J Antimicrob Chemother, 1996 Mar, 37(3), 483 - 9
In-vitro activity of azithromycin in against intracellular Helicobacter pylori; Hulten K et al.; We studied the effect in vitro of azithromycin on the clinical strain Helicobacter pylori H:72 growing intracellularly in monolayers of HEp-2 epithelial cells . After using gentamicin to eradicate extracellular bacteria, different concentrations of azithromycin were added to the infected cells and samples were taken after 0, 4, 8 and 24 h . Infected cells not exposed to antibiotic were included as controls . The MIC of azithromycin to the H . pylori was 0.25 mg/L and the MBC 0.5 mg/L in a broth dilution plate count method . A bactericidal effect was observed on intracellular H . pylori, with inhibition increasing with increasing azithromycin concentrations . However, extracellular concentrations of 200 x MBC were necessary to achieve intracellular killing . Our results show that azithromycin is active against intracellular H . pylori suggesting that it might be possible to exploit this activity when treating infections due to the organism.

Indian J Med Res, 1996 Mar, 103, 138 - 41
In vitro activities of tetracycline & ciprofloxacin against Chlamydia trachomatis isolates from conjunctivitis patients; Madhavan HN et al.; Twenty seven Chlamydia trachomatis isolates from patients of conjunctivitis were tested for their in vitro sensitivities to ciprofloxacin and tetracycline in cyclohexamide treated McCoy cells on cover slip (shell vial) cultures . After a 48 h exposure of chlamydia infected monolayers to varying concentrations of each of the drugs, the cover slips were processed and stained for detection of major out membrane protein of C . trachomatis by fluorescent antibody test (FAT) using fluorescein conjugated monoclonal . Minimum inhibitory concentration (MIC90) and minimum lethal concentration (MLC90) of ciprofloxacin were 2.9 micrograms/ml and 5.7 micrograms/ml and for tetracycline 9.1 micrograms/ml and 18.0 micrograms/ml respectively . Ciprofloxacin may have a more promising role in treating chlamydial conjunctivitis than the commonly used tetracycline.

Southeast Asian J Trop Med Public Health, 1996 Mar, 27(1), 19 - 23
Artemether-pyrimethamine in the treatment of pyrimethamine-resistant falciparum malaria; Na-Bangchang K et al.; In vitro susceptibility and clinical response of multidrug resistant Plasmodium falciparum to the combination artemether-pyrimethamine were evaluated in patients with acute uncomplicated falciparum malaria . Sixty patients were randomized to receive 3 oral regimens of the combination artemether-pyrimethamine as follows: Regimen-I: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then placebo on the two consecutive days; Regimen-II: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second day, and placebo on the third day; Regimen-III: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second and third days . All patients had a rapid initial response to treatments with 95% of parasitemia being cleared within the first 24 hours . PCT24hours and PCT48hours were similar among the three drug regimens (11 vs 4, 6 vs 12, and 9 vs 11 patients for a 1-day, 2-day, and 3-day combination regimen, respectively) . Fever was cleared within 48 hours in all patients in either group . Transient mild nausea, vomiting and loss of appetite were found in a few patients during the first 2 days of treatment . Seven patients did not complete the 28 day follow-up period (5 vs 2 in a 1-day vs 2-day regimen), the reason for withdrawal was not associated with drug-related adverse effects . Only 53 patients were therefore qualified for the efficacy assessment . There was 15, 13 and 5 patients in a 1-day, 2-day and 3-day combination regimens, respectively, who had reappearance of the parasitemia between days 11 and 21 . The cure rates of the 3 treatment groups were statistically significantly different (0, 27.8, and 75% for a 1-day, 2-day and 3-day combination regimen, respectively) . Two patients developed P . vivax malaria on days 20 and 24 . All of the isolates were highly resistant to pyrimethamine, with MIC of 10(-5) M . There is potential advantage of this combination therapy in reducing the dosage and treatment period of artemisinin derivative, which is therefore likely to improve complaince in clinical practice . The use of a 3-day combination regimen (300 mg artemether plus 100 mg pyrimethamine on the first day, then 150 mg artemether plus 50 mg pyrimethamine on the second and third days) seems to be a good alternative regimen to sulfadoxine/ pyrimethamine in areas where P . falciparum is sensitive to pyrimethamine eg in Africa.

J Clin Microbiol, 1996 Mar, 34(3), 489 - 95
Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome; Ghannoum MA et al.; In summary, it is clear that in vitro susceptibility testing can predict outcome in selected clinical situations . The clearest data are from the fluconazole-treated AIDS patients with oropharyngeal candidiasis . In this setting, the homogeneity of the underlying immune defect, combined with the ease of identification and monitoring of the infection, creates a near-perfect test situation . In more complex scenarios, such as the heterogeneous population of patients enrolled in a recent study of candidemia, no such clear-cut correlation was present . The importance of host factors in the correlation of the MIC with outcome cannot be overemphasized . Examples of these parameters include patient status (underlying disease, the presence of intravascular catheters, and CD4+ T-cell number), drug pharmacokinetics (absorption and distribution), patient compliance, and drug-drug interactions . Identification of relevant factors can substantially improve the degree of the MIC-outcome correlation and thus improve the clinical utility of in vitro testing . An important feature in this entire process is the role of standardized susceptibility testing procedures . While not without flaws, the proposed NCCLS reference method has been invaluable in allowing multiple investigators to contribute data that can be used to clarify the correlation between the fluconazole MIC and outcome . While the development of simplified second-generation methods is eagerly anticipated, the role of the reference method as a common touchstone is critical . Only by use of either the reference method itself or methods with a known relationship to the reference method can this broad collaborative process really proceed . Current work is focusing on defining interpretive breakpoints for fluconazole and Candida species, refinement of the in vitro procedures used to measure susceptibility to amphotericin B, ketoconazole, and itraconazole, and the acquisition of a broad base of data on the relationship between the MIC and outcome for these three drugs . Although considerable work remains to be done, the available data suggest that solutions to each of these problems are possible and that routine susceptibility testing of fungi will become meaningful for clinical decision making in the foreseeable future.

Kekkaku, 1996 Mar, 71(3), 245 - 52
{Drug susceptibility test for Mycobacterium tuberculosis using non-radioactive substance, alpha-antigen}; Shigeto E et al.; BACTEC system is a reliable and rapid drug susceptibility test for mycobacteria and is widely accepted in Europe and in the United States of America . In Japan, it is impossible to introduce the BACTEC system in clinical laboratories because of strict regulations for the use of radioactive substances in Japan . To resolve this dilemma, we adopted alpha-antigen (alpha-antigen), a widely distributed secretory protein of mycobacteria, as the index substance replacing the radioactive substance 14C in BACTEC system . Alpha-antigen was detected by reverse passive latex agglutination (LA), using latex sensitized with rabbit anti-alpha-IgG . Susceptibility of 17 M . tuberculosis strains isolated from patients, grown on Ogawa egg medium and then cultured in 7H9 medium, and of 46 M . tuberculosis strains freshly isolated from patients by 7H9 medium of MB check system, was tested for four antituberculosis drugs, isoniazid (INH), rifampicin (RFP), streptomycin (SM) and ethambutol (EB) . Ninety four percent of the control cultures were positive for alpha-antigen within 7 days after the inoculation . The MIC values of H37Rv strain in 7H9 medium determined by the method of Heifets were 0.05 micrograms/ml for INH, 0.03 micrograms/ml for RFP, 0.025 micrograms/ml for SM and 1.9 micrograms/ml for EB . In 17 strains from Ogawa egg medium, the results obtained from all but 4 strains for SM, 1 for INH, 1 for RFP and 7 for EB were concurrent with that obtained by the method using 1% Ogawa egg medium . No strains were determined to be resistant to any drug by the alpha-antigen method and be sensitive by the Ogawa medium method . In 46 strains cultured by the MB check system, the results of 42 strains for SM, 35 for INH, 39 for RFP and 36 for EB coincided with those determined by the Microtiter method . Among the strains determined to be resistant by Microtiter method, 1/2 for SM, 10/14 for INH, 4/17 for RFP and 8/10 for EB were determined to be sensitive by alpha-antigen LA method . The disagreement was seen mostly in strains which were determined to be resistant by the method using egg medium, while sensitive by the alpha-antigen LA method . The discrepancy might originate from the difference of critical concentration due to heat inactivation of the drugs and absorption in the egg medium . However, some instability was observed in latex agglutination and its cause should be examined further . This method of utilizing 7H9 medium for culture and alpha-antigen as the index of mycobacterial growth can be an expedient and economical drug susceptibility test because it does not use radioactive substance as in the case of BACTEC system.

AIDS, 1996 Mar, 10(3), 263 - 8
Oropharyngeal yeast flora and fluconazole resistance in HIV-infected patients receiving long-term continuous versus intermittent fluconazole therapy; Heald AE et al.; OBJECTIVE: To examine the impact of continuous versus intermittent fluconazole therapy on fungal colonization and fluconazole resistance in the oropharynx of HIV-infected patients . DESIGN: Case-control study . SETTING: Duke University Adult Infectious Diseases Clinic, a tertiary referral center in North Carolina which provides care for 700 HIV-infected persons . PATIENTS: Nineteen HIV-infected patients on daily continuous fluconazole for a minimum of 6 months and eleven HIV-infected patients on intermittent fluconazole for a minimum of 6 months were matched by sex and CD4 cell count to HIV-infected patients who had not received fluconazole in the preceding 6 months . MAIN OUTCOME MEASURES: Fungal isolation and fluconazole susceptibility testing were performed on oral saline rinses from each patient . RESULTS: The patients taking continuous fluconazole were more likely than matched controls to have had sterile mouth rinses (14 out of 19 versus five out of 19; P < 0.001), and the yeasts that were isolated were more likely than matched controls to be non-Candida albicans species and to have minimum inhibitory concentrations (MIC) to fluconazole > or = 16 micrograms/ml . None of these isolates were associated with symptoms . In contrast, none of the patients in the intermittent fluconazole group had sterile cultures . When this group was compared to controls, they were more likely to have had non-C . albicans species, and the C . albicans isolates obtained had higher MIC to fluconazole . CONCLUSIONS: Long-term continuous therapy with fluconazole may prevent the appearance of Candida in the oral cavity . This finding may reduce recurrence rates and might favorably impact on the clinical appearance of mucosal candidiasis with resistant C . albicans.

Zentralbl Bakteriol, 1996 Mar, 283(3), 375 - 90
Factors affecting the results of a broth microdilution antifungal susceptibility testing in vitro; Buchta V et al.; In experiments involving 10 antifungal drugs and 46 strains of potentially pathogenic fungi, the factors affecting the results of in vitro susceptibility testing were studied . The composition of the test medium, inoculum size, temperature and length of incubation were the most pronounced effects influencing the results of testing in vitro . Minimal inhibitory concentrations (MIC) of the antimycotics tested were lowest in complex media (Brain Heart Infusion, Antibiotic Medium 3, Sabouraud broth) except for 5-fluorocytosine which was most effective in Yeast Nitrogen Base medium . Inoculum sizes of 10(3) to 10(4) cfu* mL(-1) had no marked effect on MIC but starting from a final concentration of 10(5) cfu*mL(-1), an abrupt increase in MIC in azole derivatives and 5-fluorocytosine was observed . There was a direct relationship between the duration of incubation and MIC of fungistatic antimycotics . The influence of the incubation temperature became generally manifest primarily in fungi with retarded growth at elevated temperature (>35 degrees C) . In these fungal species, a tendency towards a decrease in MIC with increasing temperature was apparent . The other factors studied (medium pH, buffer, solvent) had no substantial influence on the antifungal activity of the drugs tested.

Antimicrob Agents Chemother, 1996 Mar, 40(3), 807 - 8
In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to four fluoroquinolones (levofloxacin, d-ofloxacin, ofloxacin, and ciprofloxacin), cefpirome, and meropenem; Hoppe JE et al.; The in vitro activities of levofloxacin, ofloxacin, d-ofloxacin, ciprofloxacin, cefpirome, and meropenem against 34 clinical isolates each of Bordetella pertussis and Bordetella parapertussis were determined by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood . Levofloxacin was as active as ciprofloxacin against both species (MIC, 0.06 microgram/ml) and more active than ofloxacin and d-ofloxacin . Cefpirome was more active against B . pertussis (MIC, 1.0 microgram/ml) than against B . parapertussis (MIC, > 2 micrograms/ml), while the reverse was true for meropenem (MIC, 2.0 micrograms/ml against B . pertussis and 1.0 microgram/ml against B . parapertussis).

Pharmacotherapy, 1996 Mar-Apr, 16(2), 286 - 94
Exploration of once-daily dosing of aminoglycosides through Bayesian simulation; Garrelts JC; STUDY OBJECTIVES: To simulate peak and trough concentrations, using Bayesian forecasting, achieved with a variety of once-daily dosing (ODD) regimens; to evaluate dosing regimens required to produce target peak and trough concentrations; to compare the peak-to-MIC (minimum inhibitory concentration) ratios and time above MIC for various dosing regimens and MICs; to stratify the information based on renal function estimates; and to use the results from these simulations to make recommendations regarding optimum ODD of aminoglycosides . DESIGN: Simulation of ODD using a Bayesian technique and existing patient data . SETTING: A tertiary referral, community teaching hospital . PATIENTS: One hundred consecutive adults from the author's data base, with a wide variety of infections and underlying illnesses, who met strict inclusion criteria . INTERVENTIONS: Two methods of dosing, weight-based (4-7 mg/kg) and target concentration-based (peak 10, 15, or 20 mu g/ml, trough < or = 0.3 mu g/ml), were evaluated . Each patient had a known dosing-sampling history, stable renal function, and at least two measured serum concentrations, and were being treated with either gentamicin or tobramycin . MEASUREMENTS AND MAIN RESULTS: A wide range of peak and trough serum concentrations are achieved when dosages are chosen based on patient weight . Even with large dosages, some patients had very low peak-to-MIC ratios and time above the MIC, and vice versa . Variations in MIC had a much greater effect on dosing target values than did variations in dosage . A large degree of variability was also noted in doses and dosing intervals when using a target serum concentration approach . For both methods, an inverse relationship existed between calculated creatinine clearance and time above MIC, although there was little change over the range of 60-119 ml/minute . CONCLUSIONS: Bayesian simulation showed that weight-based ODD of aminoglycosides did not produce clinically acceptable serum concentrations or target values in many patients . Young and elderly patients, and any patient with a creatinine clearance below 60 or above 119 ml/minute, are especially likely not to achieve an optimum serum concentration profile . Aminoglycoside ODD should be individualized by evaluating the peak-to-MIC ratio, time above MIC, and patient response.

Infection, 1996 Mar-Apr, 24(2), 174 - 7
beta-lactam antibiotics in the treatment of neuroborreliosis in children: preliminary results; Millner MM et al.; In vitro beta-lactam antibiotics like ceftriaxone and penicillin G sodium have been shown to be active against Borrelia burgdorferi . Results of quantitative determinations of both antibiotic substances in the CSF for children are limited . Seventy-five children (median age 96 months, range 10 to 176 months) with probable or definite neuroborreliosis were treated with ceftriaxone (1 x 50-90 mg/kg/day) or penicillin G sodium (4 x 80,000-120,000 IU/kg/day) intravenously . On day 10 of therapy levels of penicillin G sodium (1,1.5,2,3,4, 5, or 6 h after i.v . administration), and ceftriaxone (1,2,4,6,12 or 24 h after i.v . administration) in serum and CSF were measured with a micro agar diffusion bioassay . Results demonstrate that after 5 h penicillin G sodium in CSF was above the minimal inhibitory concentration (MIC) but after 6 h penicillin G sodium levels were below the determination limit in 60% of the cases . All ceftriaxone results in CSF-even after 24 h-were above MIC . Penicillin G sodium serum values ranged from 46.6 to 0.1 mg/L (1 to 6 h post dose) and ceftriaxone serum values from 261 to 5 mg/l (1 to 24 h post dose) . The role of penicillin G sodium and ceftriaxone and administration intervals of both antibiotics in the therapy of neuroborreliosis in children are discussed.

Chemotherapy, 1996 Mar-Apr, 42(2), 112 - 7
Antifungal activity of sertaconazole in vitro against clinical isolates of Candida spp.; Martin-Mazuelos E et al.; Sertaconazole is a new azolic derivative containing a benzo(b)-thiophene group, for topical use . It showed in vitro fungistatic and fungicidal activity against yeasts, dermatophytes, opportunistic filamentous fungi and Gram-positive bacteria . In this study, we have evaluated the activity of sertaconazole in vitro against 215 strains of Candida spp . Fluconazole and ketoconazole were used throughout as reference compounds . The minimum inhibitory concentration (MIC) was determined in Casitone medium and the breakpoint was obtained spectrophotometrically and visually . Visual reading of MICs correlated with the spectrophotometric determination, the values of MIC50 and MIC90 showed no difference (+/- 1 dilution) in any of the species tested (range 0.1-16 mg/l) . These results show that sertaconazole is an excellent antifungal agent and fungicide in vitro against various species of Candida.

J Med Microbiol, 1996 Mar, 44(3), 227 - 30
Comparison of the E test and a proportion dilution method for susceptibility testing of Mycobacterium avium complex; Fabry W et al.; The newly developed E test was compared with an extended 1% proportion dilution method for determining the susceptibility of Mycobacterium avium complex (MAC) strains to amikacin, streptomycin, fusidic acid, rifampicin, clarithromycin, ciprofloxacin, ofloxacin and fleroxacin . For all antibiotics tested except clarithromycin and ciprofloxacin, no more than one strain gave a different susceptibility result with the two methods . The discrepant results occurred near the chosen breakpoint concentration of clarithromycin and outside the concentration range of the E test for ciprofloxacin . For the minimum inhibitory concentration (MIC) values obtained within the range of antibiotic concentrations tested, there was good correlation between the two methods; the MICs differed by more than one two-fold dilution in no more than two strains per antibiotic . It is concluded that the E test is suitable for susceptibility testing of MAC.

Vet Rec, 1996 Feb 17, 138(7), 158 - 60
Sensitivity of strains of Serpulina hyodysenteriae isolated in Hungary to chemotherapeutic drugs; Molnar L; The sensitivity of 332 strains of Serpulina hyodysenteriae isolated in Hungary between 1978 and 1992 was tested against seven chemotherapeutic drugs frequently used for the treatment of swine dysentery, and the changes in the patterns of resistance were also monitored . All the strains remained sensitive to carbadox, with minimum inhibitory concentrations (MIC) of only 0.05 to 0.40 microgram/ml at present . The susceptibility of the strains to dimetridazole has gradually decreased, but about half of the strains are still sensitive, with large numbers of "moderately sensitive' strains; the MIC values varied within wide limits (0.1 to 50 micrograms/ml) . Most of the strains were resistant to tylosin, with MIC values from 0.1 to 100 micrograms/ml . The number of strains resistant to lincomycin has gradually increased, but about half of the strains remain sensitive; the MIC values ranged from 0.2 to 100 micrograms/ml . Recently, tiamulin has proved the most effective antibiotic, but some resistant strains have already emerged (MIC values 0.05 to 50 micrograms/ml) . Monensin was good for the prevention of swine dysentery, but resistance may evolve quickly; the MIC values ranged from 0.4 to 25 micrograms/ml . For sedecamycin, the MIC values (6.25 to 100 micrograms/ml) were much higher than expected.

Schweiz Med Wochenschr, 1996 Feb 3, 126(5), 153 - 8
{Effectiveness of triple therapy to eradicate H . pylori in patients after failed therapy with omeprazole/amoxicillin}; Zala G et al.; Helicobacter pylori (H . pylori) eradication rates with omeperazole/amoxicillin range from 0-90% . The best regimen for retreatment after failure of omeprazole/amoxicillin has not been established so far . The aim of this prospective study was to evaluate the efficacy of triple therapy with bismuth, tetracycline and ornidazole in eradicating H . pylori after failure of omeprazole/amoxicillin . 79 duodenal ulcer patients with H . pylori infection were treated with oral omeprazole (40 mg bid) and amoxicillin solute (750 mg tid) for 10 days . Eradication rate was 28/79 (35%) and was distinctly lower in smokers (> 10 cigarettes/day) vs nonsmokers (10/49 {20%} vs 18/30 {60%}, p < 0.001) . 37 patients with persistent H . pylori infection in whom omeprazole/amoxicillin had failed agreed to retreatment with triple therapy . Persistence of H . pylori was confirmed by histology (3 antral and 2 gastric body biopsies; H&E, Giemsa), urease test (CLO) and/or H . pylori culture . Patients smoking > 10 cigarettes/day were classified as smokers . Retreatment consisted of oral bismuth-subcitrate 4 x 120 mg/d for 28 days (day 1-28), tetracycline 4 x 500 mg/d and ornidazole 3 x 500 mg/d for 10 days (day 1-10) . Control endoscopy was done 30 days after the end of treatment . Criteria for H . pylori eradication was negative urease test, culture and histology . 34/37 patients (6 females/28 males; 39 {23-64} years) completed the study (24/34 smokers, 10/34 nonsmokers) . 3/37 patients dropped out because of side effects (n = 1) or incompliance (n = 2) . H . pylori subcultures for resistance testing were possible in 32/34 patients: H . pylori was metronidazole-sensitive in 11/32 (1 female, 10 males; 38 {24-55} years; 9 smokers, 2 nonsmokers) and metronidazole-resistant (minimal inhibitory concentration for metronidazole > 8 mg/ml) in 21/32 (5 females, 16 males; 40 {23-64} years; 13 smokers, 8 nonsmokers) . The overall H . pylori eradication rate of the triple therapy was 27/34 (79%) . H . pylori was eradicated in 19/24 (79%) smokers and in 8/10 (80%) nonsmokers . Eradication rate for metronidazole-sensitive H . pylori was 11/11 (100%) vs 14/21 (67%) for metronidazole-resistant H . pylori (p = 0.012) . Triple therapy is effective and safe in eradicating H . pylori in patients after failure of omeprazole/amoxicillin . Smoking had no negative effect on the eradication rate of the triple therapy after failure of omeprazole/amoxicillin . Eradication failures were due to metronidazole-resistance.

J Vet Pharmacol Ther, 1996 Feb, 19(1), 32 - 8
Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle; Brown SA et al.; The effects of maturation on the intravenous (IV) and intramuscular (IM) pharmacokinetics of ceftiofur sodium following a dose of 2.2 mg ceftiofur equivalents/kg body weight were evaluated in 16 one-day-old Holstein bull calves (33-53 kg body weight initially; Group 1) and 14 six-month-old Holstein steers (217-276 kg body weight initially; Group 2) . Group 1 calves were fed unmedicated milk replacer until 30 days of age and were then converted to the same roughag/concentrate diet as Group 2 . Groups 1-IV and 2-IV received ceftiofur sodium IV, and Groups 1-IM and 2-IM received ceftiofur sodium IM . Group 1 calves were dosed at 7 days of age and at 1 and 3 months of age; group 2 calves were dosed at 6 and 9 months of age . Blood samples were obtained serially from each calf, and plasma samples were analysed using an HPLC assay that converts ceftiofur and all desfuroylceftiofur metabolites to desfuroylceftiofur acetamide . Cmax values were similar in all calves, and were no higher in younger calves than in older calves . Plasma concentrations remained above 0.150 microgram ceftiofur free acid equivalents/mliter for 72 h in 7-day-old calves, but were less than 0.150 microgram/mliter within 48 h following IV or IM injection for 6- and 9-month-old calves . Intramuscular bioavailability, assessed by comparing the model-derived area under the curve (AUCmod) from IM and IV injection at each age, appeared to be complete . After IV administration, the AUCmod in 7-day-old and 1-month-old calves (126.92 +/- 21.1 micrograms.h/mliter and 135.0 +/- 21.6 micrograms.h/mliter, respectively) was significantly larger than in 3-, 6- and 9-month-old calves (74.0 +/- 10.7 micrograms.h/mliter, 61.0 +/- 17.7 micrograms.h/mliter and 68.5 +/- 12.8 micrograms.h/mliter, respectively; P < 0.0001) . The Vd(ss) decreased linearly within the first 3 months of life in cattle (0.345 +/- 0.0616 L/kg, 0.335 +/- 0.919 L/kg and 0.284 +/- 0.0490 L/kg, respectively; P = 0.031), indicative of the decreasing extracellular fluid volume in maturing cattle . The ClB was significantly smaller in 7-day-old and 1-month-old calves (0.0178 +/- 0.00325 L/h.kg and 0.0167 +/- 0.00310 L/h.kg, respectively) than in 3-, 6- and 9-month-old calves (0.0303 +/- 0.0046 L/h.kg, 0.0398 +/- 0.0149 L/h.kg and 0.0330 +/- 0.00552 L/h.kg, respectively; P < or = 0.001) . This observation may be indicative of maturation of the metabolism and/or excretion processes for ceftiofur and desfuroylceftiofur metabolites . The approved dosage regimens for ceftiofur sodium of 1.1-2.2 mg/kg administered once daily for up to 5 consecutive days will provide plasma concentrations above the MIC for bovine respiratory disease pathogens for a longer period of time in neonatal calves than in older calves . Peak plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were no higher in neonatal calves than in more mature cattle, highly suggestive that peak tissue concentrations would be no higher in neonatal calves than in more mature cattle.

J Chemother, 1996 Feb, 8(1), 47 - 51
Antibiotic susceptibility of clinical isolates of Prevotella bivia in Lagos, Nigeria; Egwari LO et al.; The susceptibility of 40 clinical isolates of Prevotella bivia to 11 anti-anaerobic agents was determined by disk diffusion and agar dilution methods in accordance with the NCCLS (1990) recommended guidelines . With the disk diffusion method all the P . bivia tested were susceptible to rifampicin, cefoxitin, chloramphenicol, clindamycin and metronidazole . Twelve (30%) isolates were resistant to cefotaxime and ceftriaxone while 2 (5%) each were resistant to tetracycline and erythromycin . Worthy of note, 39 (97.5%) and all 40 (100%) isolates were resistant to ampicillin and penicillin respectively . Determination of minimum inhibitory concentrations (MIC) showed that the first set of 5 antibiotics, except rifampicin, were shown to be as active against all the strains tested as with the disk diffusion sensitivity method: cefoxitin, chloramphenicol, clindamycin and metronidazole had MIC90 values ranging from 0.5-1 microgram/ml . The MIC90s of erythromycin and tetracycline were 4 micrograms/ml each while the range of MIC of cefotaxime and ceftriaxone was 0.5-32 micrograms/ml with a MIC90 of 8 micrograms/ml, well below their breakpoints, which is somewhat at variance with disk diffusion results . The clinical significance of this, however, is not clear, especially in the absence of controlled clinical trials . Ampicillin and penicillin MIC90 values were 64 micrograms/ml and 80 U/ml respectively which essentially confirmed the resistance observed by the disk method . All the P . bivia isolates were beta-lactamase producers, hence the resistance of these isolates to penicillin and ampicillin . It is conceivable that in infections with monoculture of P . bivia, agents like tetracycline, or erythromycin may still be a useful alternative for treatment.

Antimicrob Agents Chemother, 1996 Feb, 40(2), 362 - 6
MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci; Visalli MA et al.; MIC and time-kill methods were used to test the activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible, -intermediate, and -resistant pneumococci . The MIC of penicillin for penicillin-susceptible strains was 0.016 micrograms/ml, those for intermediate strains were 0.25 to 1.0 microgram/ml, and those for resistant strains were 2.0 to 4.0 micrograms/ml . Of the four quinolones tested, DU-6859a had the lowest MIC (0.064 micrograms/ml), followed by sparfloxacin (0.25 to 0.5 micrograms/ml) and levofloxacin and ciprofloxacin (both 1.0 to 4.0 micrograms/ml) . Vancomycin inhibited all strains at MICs of 0.25 to 0.5 micrograms/ml . The MICs of imipenem and cefotaxime for penicillin-susceptible, -intermediate, and -resistant strains were 0.004 to 0.008, 0.008 to 0.032, and 0.25 micrograms/ml and 0.016, 0.125 to 0.5, and 2.0 micrograms/ml, respectively . DU-6859a was bactericidal at eight times the MICs (0.5 micrograms/ml) for seven of the nine strains after 4 h and bactericidal for all nine strains after 6 h at eight times the MICs and after 12 h at two times the MICs . By comparison, sparfloxacin, the next most active quinolone, was uniformly bactericidal at two times the MICs only after 24 h, with little activity after 2 h . Levofloxacin and ciprofloxacin were bactericidal against all strains after 12 h at eight times the MICs and against all strains at 24 h at four times the MICs . Imipenem was bactericidal against all strains, at concentrations exceeding the MICs, after 24 h . Cefotaxime was also uniformly bactericidal only after 24 h of incubation at two times the MICs . Vancomycin, despite having uniformly low MICs for all strains irrespective of their penicillin susceptibility, was uniformly bactericidal only at two times the MICs after 24 h.

J Clin Microbiol, 1996 Feb, 34(2), 426 - 8
Effect of antibiotics contained in two Brucella selective media on growth of Brucella abortus, B . melitensis, and B . ovis; Marin CM et al.; The MIC and the highest concentration enabling bacterial growth (CEG) of the antibiotics contained in two selective media were determined for Brucella abortus, B . melitensis, and B . ovis . The nalidixic acid and bacitracin contained in Farrell's selective medium were responsible for the inhibitory effects observed.

Sheng Li Xue Bao, 1996 Feb, 48(1), 43 - 7
{Correlation between ability of learning-memory and synaptosomal free {Ca2+}i in mice of different age}; Du HY et al.; In the present investigation, the behavior of learning and memory of 1-month and 6-month-old mice was studied by using Y-maze and one-trial passive avoidance response device . The synaptosomal free {Ca2+}i of four main brain regions (Hippocampus, Cerebral cortex, Cerebellum, Tectum of midbrain) of these mice were measured by fluorescent probe Ca2+ indicator Fura-2 and an AR-CM-MIC cation measurement system . The results showed that, in comparison with 1-month-old mice, the ability of discrimination learning and memory of 6-month-old ones were attenuated, and the synaptosomal free {Ca2+}i of hippocampus was increased.

Pharmazie, 1996 Feb, 51(2), 119 - 22
{Nisin, a potential preservative for topical preparations}; Valenta C et al.; The lantibiotic compound nisin has a bacterial effect on gram positive bacteria and was investigated for the possible use as a preservative in topical formulations . For this reason, its minimal inhibitory concentration (MIC) was determined in different types of ointments . Beside its effect on gram positive bacteria it had also a bactericidal activity on gram negative bacteria in concentrations of 0.06% (W/W) . Within the first month there was no detectable reduction of nisin activity in different dermatological preparations . We conclude from these results that the combination of nisin with fungicidal substances represents a possible alternative to well known preservatives.

J Antimicrob Chemother, 1996 Feb, 37(2), 357 - 9
In-vitro activity of 3-azinomethyl-rifamycin (SPA-S-565) against Chlamydia trachomatis; Zanetti S et al.; The in-vitro activity of a 3-azinomethyl-rifamycin (SPA-S-565) against Chlamydia trachomatis was compared to that of rifampicin and of erythromycin . The compound showed excellent activity for standard strains as well as isolates from patients with sexually transmitted diseases, being more active than the other drugs tested . SPA-S-565 also showed a low frequency of emergence of resistance . Passage of standard strains at sub-inhibitory concentrations caused an increase in MIC values of rifampicin while those for SPA-S-565 remained unchanged.

Lung Cancer, 1996 Feb, 14(1), 109 - 17
Efficacy and toxicity of mitomycin, ifosfamide, and cisplatin (MIP) in patients with inoperable non-small cell lung cancer; Urban T et al.; Seventy-two patients with advanced stage IIIB (42%) or stage IV (58%) non-small cell lung cancer (median age 57 years, Karnofsky PS 60-100) were treated with mitomycin C (6 mg/m2, day 1), ifosfamide (1500 mg/m2, days 1-3), and cisplatin (30 mg/m2, days 1-3) every 4 weeks . The objective response rate was 37% in the overall population; 50% in stage IIIB patients and 29% in stage IV patients . Twenty four patients achieved partial response (33%) and three patients achieved complete response . Despite this relatively high objective response rate, the overall median survival time was 32 weeks . The median survival was significantly better in stage IIIB patients (55 weeks) than in stage IV patients (25 weeks) (P = 0.003) . MIP regimen was permanently suspended in 14 patients because of toxic events . Seventeen patients developed grade III or IV febrile neutropenia and two patients died from sepsis . Two patients experienced acute mitomycin peumonitis . Despite increased doses of cisplatin and ifosfamide, compared with the original description for MIC chemotherapy, with probably higher toxicity, no apparent increased response rate or median survival was observed in this study . The MIP regimen could be tested in a randomized trial in comparison with other administration plans in a comparable population.

J Clin Pathol, 1996 Feb, 49(2), 134 - 8
Correlation of apoptosis with tumour cell differentiation, progression, and HPV infection in cervical carcinoma; Shoji Y et al.; AIMS: To clarify the significance of apoptosis in the progression of uterine cervical neoplasias, including cervical intraepithelial neoplasia (CIN), microinvasive carcinoma (MIC), and invasive squamous cell carcinoma (ISCC) categories, in relation to cell proliferation and human papilloma virus (HPV) infection . METHODS: Forty six cases of CIN I/II, 75 of CIN III, 16 of MIC, and 44 of ISCC were examined using formalin fixed and paraffin wax embedded samples . The TdT mediated dUTP-biotin nick end labelling (TUNEL) method for detection of apoptotic cells was performed along with Ki-67 immunohistochemistry . Presence of HPV-DNA was confirmed by PCR-RFLP assay . RESULTS: Apoptotic labelling indices, calculated after counting positive nuclei among at least 2000 nuclei, showed significant positive correlation with histological malignant grading in CIN and tumour cell invasion into stroma . In contrast, similar Ki-67 labelling index values were found in CIN, MIC, and ISCC . Although HPV-DNA was detected in 35/46 CIN I/II (76.1%), 53/74CIN III (71.6%), 9/16 MIC (56.3%), and 36/44 ISCC (81.8%), there was no apparent relation with the apoptotic labelling indices . CONCLUSIONS: Apoptosis in cervical neoplasias may be closely related to tumour cell differentiation and progression . It also seems unlikely that HPV itself is directly related to pathways regulating apoptosis.

Am J Gastroenterol, 1996 Feb, 91(2), 264 - 7
Azithromycin for the cure of Helicobacter pylori infection; Di Mario F et al.; OBJECTIVES: Azithromycin, a new antibiotic chemically related to erythromycin, has been proposed for the cure of Helicobacter pylori, achieving high gastric tissue levels (above the MIC for H . pylori) after oral administration . The aim of the study was to establish whether azithromycin plus metronidazole in association with either omeprazole or bismuth subcitrate is useful in curing H . pylori infection of the stomach . PATIENTS AND METHODS: The study involved 132 dispeptic patients who proved to be H . pylori infected by antral and corpus histology (Giemsa, modified) and rapid urease test (CLOtest); the Sydney system was used to classify the gastritis . Sixty-three patients received bismuth subcitrate 120 mg q.i.d . for 14 days plus azithromycin 500 mg o.d . for the first 3 days plus metronidazole 250 mg q.i.d . for the first 7 days; 69 patients received omeprazole 40 mg for 14 days plus azithromycin 500 mg o.d . for the first 3 days plus metronidazole 250 mg q.i.d . for the first 7 days . Patients were well matched for common clinical variables . Cure of H . pylori infection was assessed by the same methods 2 months after completion of treatment . RESULTS: Eleven patients dropped out of the study, only one reporting side effects (nausea, vomiting, and epigastric pain) . Cumulative "per protocol" cure rate was 66.1% (CI 95%, 58.5-75.3%) . There was no statistically significant difference between the two treatment groups: 58.9% (CI 95% 48.4-74.6%) versus 72.3% (CI 95%, 60.7-82.5%) . Intention to treat does not substantially modify results . Few side effects were recorded . Cured patients showed a significant reduction in the activity of gastritis . CONCLUSION: Azithromycin, combined with omeprazole and metronidazole, the cure rate of H . pylori was about 70% . The cure of H . pylori infection improves the activity of gastritis.

Am J Respir Crit Care Med, 1996 Feb, 153(2), 597 - 603
Airway reactivity changes in asthmatic patients undergoing blinded food challenges; James JM et al.; To investigate the possible pathogenic role of food allergy in asthma, airway hyperresponsiveness was measured by methacholine inhalation challenges (MIC) performed before and after double-blind, placebo-controlled food challenges (DBPCFC) in 26 food-allergic, asthmatic patients . Airway hyperresponsiveness was classified as severe in two cases (PD20FEV1 < 2 breath units, BU), moderate in 18 (PD20FEV1: 2-20 BU), and mild in six (PD20FEV1 > 20 BU) . Medications included albuterol (81%), inhaled steroids (38%), cromolyn (35%), and theophylline (23%) . MICs were performed in the afternoon after DBPCFC . Of the 22 positive DBPCFC, 12 involved chest symptoms (cough, wheezing, or both) . Another 10 positive DBPCFCs included laryngeal, gastrointestinal, and/or skin symptoms without any chest symptoms . Significant increases in airway hyperresponsiveness were evident in seven of 12 patients experiencing chest symptoms during DBPCFC . Significant increases in airway hyperresponsiveness were observed in one patient without chest symptoms during a positive DBPCFC and one patient after a negative DBPCFC . However, this last patient had a negative MIC with the same antigen 1 yr later . These studies indicate that food-induced allergic reactions can increase airway reactivity, and may do so without inducing acute asthma.

Mycopathologia, 1996-97, 136(3), 125 - 31
Effect of amphotericin B on the lipids of yeast cells of Sporothrix schenckii; Hamdan JS et al.; Yeast cells of five strains of Sporothrix schenckii were obtained for partial analysis of lipid composition . Quantitative analysis of lipids and sterols were completed, as well as qualitative analysis of sterols by thin layer chromatography and by ultraviolet spectra . These determinations were made on cells cultured in the absence and presence of amphotericin B at sub-MIC (minimum inhibitory concentration) levels . Marked alterations in lipid content were observed in the amphotericin B-treated cells . The major alterations were the reduction of total lipid (18.7-57.6%) and sterols (48.5-96.7%) after exposure to the polyenic antibiotic . It is concluded that amphotericin B altered the lipid profiles, especially sterols of S . schenckii.

Mycoses, 1996, 39 Suppl 2, 58 - 65
{Plasma and tissue concentrations of fluconazole: discussion of the breakpoint problem}; Pittrow L et al.; The reliable prediction of the clinical outcome during antifungal therapy is an issue of paramount priority in clinical research, since there are no appropriate parameters available . MIC values and in the future breakpoints may serve as surrogate criteria if further standardization of in vitro antifungal susceptibility testing especially for fluconazole leading to improved interlaboratory reproducibility of the test results can be provided . With reproducible susceptibility testing methods for Candida species now being available, tentative fluconazole interpretative breakpoints derived from MICs determined by the NCCLS M27-T broth macrodilution methodology are now open for public commentary . Besides the proven susceptibility of the fungus, clinical response to antifungal therapy with fluconazole also depends to a great extent on the daily dosage and the corresponding plasma and tissue concentrations as well as the immunological status and the underlying disease of the patient . The promising results of a relatively small number of dose finding studies with fluconazole in non-neutropenic patients indicate that with daily doses up to 1000 mg/die higher clinical response rates compared to those under lower dosages can be achieved . In view of future valid breakpoints, higher corresponding plasma and tissue levels of fluconazole should be achieved on which the therapeutic success depends substantially . However, this simplified concept needs several adjustments . Misinterpretation of MIC values and breakpoints may have as a consequence that patients with often life-threatening fungal infections may not be treated with an efficacious and better tolerated agent.

Mycoses, 1996, 39 Suppl 2, 47 - 50
{Comparison of three antifungal susceptibility testing methods for the in vitro testing of Candida isolates from patients with HIV infection}; Ruhnke M et al.; The MIC values of fluconazole were determined for 96 Candida isolates (56 C . albicans, 15 C . glabrata, 9 C . krusei and 10 C . tropicalis) . The methods employed for antifungal susceptibility testing were: microdilution according to the protocol M27-P of the NCCLS (M 27-Pmicro) using RPMI 1640 medium or HR medium following Troke & Pye (HRmicro) as well as the agar diffusion method by means of the Etest (YNB agar) . The in vitro results were compared with the clinical outcome of patients . All C . albicans isolates received from AIDS patients with fluconazole-refractory candidosis showed MICs of > or = 6.25 mg/ml (M27-Pmicro) or > or = 25 mg/ml (MRmicro) and Etest) . On the other hand some MICs of C . albicans isolates from AIDS patients with fluconazole-sensitive candidosis were also beyond these breakpoints . Therefore, a possible success of a fluconazole therapy cannot unequivocally be predicted from the MIC value determined in vitro.

Mycoses, 1996, 39 Suppl 2, 31 - 8
{Susceptibility testing of yeasts against fluconazole: comparison of the Etest method with microdilution and agar dilution}; Schmalreck AF et al.; In bacteriology, the Etest has a broad field of application in bacteriology and is recently available for the antimycotics fluconazole and itraconazole . By means of the presence of gradient concentrations of the active substance on the carrier material, it is possible to obtain reproducible MICs of the antimycotic substances . The results of susceptibility testing of 326 clinical yeast isolates with the Etest were compared to those MICs obtained by microdilution and agar dilution . A 100% concordance of the MIC markers (mode-, MIC50- and MIC90-value, standard deviation of the mean log2-MIC-dilution steps) was given when compared by a +/- 1 MIC-dilution step range with microdilution and by +/- 2 MIC-dilution steps with agar dilution; species dependent all strains were within 2 x standard deviation of the individual MIC-mean of the species . By comparison of the individual MIC-values maximum differences of +/- 6 MIC-dilution steps were obtained, where 70% of all results were within +/- 2 MIC-dilution steps, and more than 92% of all strains were within +/- 3 MIC-dilution steps . The Pearson's correlation coefficients show a good agreement of the Etest with microdilution (r = 0.92) resp., agar dilution (r = 0.88) demonstrate, however, clearly insufficient correlations (r < 0.65) to the reference methods, for species with difficult to read Etest inhibition zones (e.g., Candida glabrata, Candida krusei, Candida parapsilosis) . The differences between the proposed test methods recommended by the NCCLS and the working group "Clinical Mycology" of the German Speaking Mycological Society (AG-KMYK) are tabled.

Mycoses, 1996, 39 Suppl 2, 17 - 21
{In vitro susceptibility testing of Candida species against fluconazole using the microdilution test with Alamar Blue}; Schroder G et al.; The investigation of susceptibility of Candida species to fluconazole was performed in microdilution to a supplemented HR-medium . The sufficient reproducibility of the test was verified using special control isolates and isolates of patients . The excellent applicability of the method in routine diagnostics was evaluated by in vitro testing of susceptibility of 279 Candida isolates from patients being colonised or suffering from endomycoses . The Candida species showed different susceptibility against fluconazole: 96% of the C . albicans isolates were sensitive, 55% of the C . glabrata isolates had a reduced sensitivity, and 26% were resistant against fluconazole (MIC > 25 micrograms/ml) . C . krusei isolates were highly resistant (9 of 11 strains).

Mycopathologia, 1996, 135(3), 141 - 3
In vitro susceptibility of Trichophyton rubrum isolates to griseofulvin and tioconazole . Induction and isolation of a resistant mutant to both antimycotic drugs . Mutant of Trichophyton rubrum resistant to griseofulvin and tioconazole; Fachin AL et al.; The in vitro susceptibility of three clinical Trichophyton rubrum isolates to griseofulvin and tioconazole, determined by the minimal inhibitory concentration (MIC), was 2 and 0.5 to 1.0 micrograms/ml, respectively . One mutant (gril) obtained after mutagenic treatment of one of these isolates was selected and showed simultaneous resistance to griseofulvin (MIC > 2000 micrograms/ml) and tioconazole (MIC = 1.0 microgram/ml) . The clinical importance and the possibility of a multidrug resistance (MDR)-type mechanism being involved in this event is discussed.

Med Tekh, 1996 Jan-Feb, (1), 4 - 9
{The status of and problems in the development of Russian medical instrument making}; Viktorov VA et al.; Recently, there have been great changes in the nomenclature of manufactured medical equipment (ME) items and hence there is a considerable renewal of products due to the fact that a lot of conversed enterprises of the military-industrial complex (MIC) have settled down in producing ME . By and large, the output of new ME items is 37% of their total medical instrument making nomenclature . Thus, in 1988 the proportion of the items was 35% of the total output of medical devices and apparatuses while in 1995 it is 65% . The output and technical level of some extremely complex ME items, Russian devices for hemodialysis and extracorporeal circulation have been increased . The Russian enterprises have designed and are manufacturing diagnostic nuclear magnetic systems, pulse oximeters, Billitest bilirubin meters, complex laboratory sets for radioimmunochemical assay, a G202-5 lit-par-lit scanning complex, Mammodiagnost apparatus, new Roentgen-48 and Roentgen-60 X-ray complexes, etc . The paper gives specific examples how a number of medical devices and apparatuses are designed and launched into production at the electronic and radio industrial and MIC enterprises.

Scand J Infect Dis, 1996, 28(3), 313 - 6
Fatal outcome of disseminated candidosis after allogeneic bone marrow transplantation under treatment with liposomal and conventional amphotericin-B . A report of 4 cases with determination of the Mic values; Kruger W et al.; Four patients undergoing allogeneic bone marrow transplantation were treated with liposomal (3 patients) and conventional (one patient) amphotericin-B for disseminated candidosis . Candida krusei was isolated from 3, and C . glabrata from 1 patient . The patients were treated with liposomal amphotericin-B in doses from 3 to 5 mg/kg . The fourth patient received conventional amphotericin-B in a reduced dose due to renal impairment . The patients died from multiorgan failure due to disseminated fungal infection . In 1 case, the switch to the conventional drug resulted in clearance before death . The 3 fungus isolates, together with the fourth strain obtained from patient no . 4 without any exposition to liposomal amphotericin-B were tested for their susceptibility to conventional, liposomal and discoidal amphotericin-B . All strains showed good sensitivity to the conventional and discoidal drug . The minimal inhibitory concentrations (MIC) of liposomal amphotericin-B were 1 to 3 titre steps higher indicating a reduced sensitivity of the tested strains to this preparation . We conclude that the use of liposomal amphotericin-B is recommended mainly on the base of the low incidence of side-effects . Intensive microbial resistance tests, pharmacokinetic investigations and randomized studies are necessary before the conventional drug is replaced as the gold standard for systemic antimycotic therapy.

Polim Med, 1996, 26(1-2), 3 - 57
{Use of mini-septopal in trauma surgery of the hand . Experimental and clinical studies}; Zimmer K; The antibiotics application in treatment of infections makes necessary that they are present in the focus of infection in concentration which is enough to fight back bacteria responsible for the symptoms of disease . Concentration higher then MIC is especially difficult to obtain in tissue with poor blood supply.c . in the cortical bone . Many attempts has been made to find proper method to obtain high antibiotic concentration in the infection focus without overloading the rest of the organism . In the years 1972-1973 Klemm in Frankfurt/Main had first very promising results treating bone infections by filling bone cavities after proper surgical debridement with hand-made beads made of bone cement with gentamicin . This method has been developed by the E . MERCK company which started to produce drug as Septopal . Very good results of treatment using this form of antibiotic created natural demand for this method also in hand surgery, where big sized Septopal beads couldn't be used . E . MERCK company has provided us with Septopal Mini Chains where small ellipsoids are gathered in 10- or 20 elements chains . Starting investigations on SMC application the following aims of experimental and clinical studies has been pointed out: observation of tissue reaction for the implanted ellipsoids, studies on gentamicin releasing velocity and its concentration in the implantation site as well as in the tissues of peripheral organs, observation of the potential toxicity and observation of the ellipsoids structure in the scanning electron microscopy, evaluation of usefulness of the SMC in the treatment of bone and soft tissue infections and in prophylactics in high risk wounds treatment, evaluation of its efficiency in comparison with gentamicin-resisted bacterial strains . Statistical analysis of results has proved very high efficiency of this form of drug by obtaining very high local antibiotic concentration even 100 times higher then after parenteral application . No toxic reactions has been noticed . In the Department of Traumatology Medical Academy in Wroclaw in the years 1983-1991 Septopal Mini Chains has been applied in 76 cases and very good results-complete healing has been obtained in 83% of patients . These data allow us to evaluate very high the usefulness of the Septopal Mini Chains as very good, new method of bone and soft tissue infection treatment in the area of hand.

Mol Microbiol, 1996 Jan, 19(1), 113 - 23
The katE gene, which encodes the catalase HPII of Mycobacterium avium; Milano A et al.; Disseminated Mycobacterium avium-Mycobacterium intracellulare disease is a prevalent opportunistic infection in patients with acquired immune deficiency syndrome (AIDS) . These pathogens are generally resistant to isoniazid (INH), a powerful antituberculosis drug . It is now generally accepted that the INH susceptibility of Mycobacterium tuberculosis results from the transformation of the drug into a toxic derivative, as a result of the action of the enzyme catalase-peroxidase (HPI), encoded by the katG gene . It has been speculated that the presence of a second catalase (HPII) in some mycobacterial species, but lacking in M . tuberculosis, may impair the action of INH . In this report, the nucleotide sequence of the M . avium katE gene, encoding catalase HPII, is described . This enzyme shows strong similarity to Escherichia coli catalase HPII and eukaryotic catalases . All amino acids previously postulated as participating directly in catalysis by liver catalase and most of the amino acids binding the prosthetic group are conserved in M . avium catalase HPII . The enzyme is expressed in E . coli and is inhibited by 3-amino-1,2,4-triazole (AT) . Furthermore, Southern blot hybridizations and polymerase chain reaction experiments demonstrate the distribution of katE gene in several mycobacterial species . To evaluate the potentially antagonistic effect of HPII catalase on INH susceptibility, the katE gene was transformed into M . tuberculosis H37Rv and the minimum inhibitory concentration (MIC) for INH was determined . Despite strong expression of the katE gene, no change in MIC was observed, thus ruling out a possible contribution of this enzyme to the natural resistance of M . avium to the drug . The availability of the gene probe, encoding the second mycobacterial catalase HPII, should open the way for the development of new drugs and diagnostic tests to combat drug-resistant pathogen strains.

Antimicrob Agents Chemother, 1996 Jan, 40(1), 212 - 4
In vitro activities of azithromycin, clarithromycin, erythromycin, and tetracycline against 13 strains of Chlamydia pneumoniae; Welsh L et al.; Thirteen strains of Chlamydia pneumoniae were evaluated for their in vitro susceptibilities to azithromycin, clarithromycin, erythromycin, and tetracycline . The MIC ranges were 0.125 to 0.5 micrograms/ml for azithromycin, 0.031 to 1.0 micrograms/ml for clarithromycin, 0.125 to 1.0 micrograms/ml for erythromycin, and 0.25 to 1.0 micrograms/ml for tetracycline . The ranges for the minimal lethal concentrations were 0.125 to 0.5 micrograms/ml for azithromycin, 0.031 to 1.0 micrograms/ml for clarithromycin, 0.125 to 1.0 micrograms/ml for erythromycin, and 0.25 to 1.0 micrograms/ml for tetracycline . Clarithromycin and azithromycin were the most active antibiotics against C . pneumoniae in vitro.

Antimicrob Agents Chemother, 1996 Jan, 40(1), 14 - 6
Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility; Klemens SP et al.; The activity of pyrazinamide (PZA) against eight isolates of Mycobacterium tuberculosis in a murine infection model was evaluated . M . tuberculosis isolates with various degrees of in vitro susceptibility to PZA (MIC range, 32 to > 2,048 micrograms/ml) were used . Four-week-old female mice were infected intravenously with approximately 10(7) viable M . tuberculosis organisms . PZA at 150 mg/kg of body weight was started 1 day postinfection and given 5 days/week for 4 weeks . Infected but untreated mice were compared with PZA-treated mice . Mice were sacrificed at the completion of the treatment period, and viable cell counts were determined from homogenates of spleens and right lungs . PZA had activity in the murine test system against M . tuberculosis isolates for which the MICs were < or = 256 micrograms/ml . However, there was an inconsistent correlation between the absolute MICs and the reductions in organ viable cell counts . Studies with drug-resistant M . tuberculosis isolates with an isogenic background would improve evaluation of drug efficacy in the murine test system . Further evaluation of antimycobacterial agents against monodrug-resistant isolates will provide data that will be useful for development of algorithms for treatment of infection with drug-resistant organisms.

Mycoses, 1996 Jan-Feb, 39(1-2), 67 - 70
Fungistatic and fungicidal activity of east African medicinal plants; Fabry W et al.; Extracts of the traditionally used medicinal plants Entada abyssinica (stem bark), Terminalia spinosa (young branches), Harrisonia abyssinica (roots), Ximenia caffra (roots), Azadirachta indica (stem bark), Zanha africana (stem bark) and Spilanthes mauritiana (roots and flowers) were investigated for fungistatic and fungicidal activity against Candida spp . and Aspergillus spp . by a microtitre serial dilution technique . Entada abyssinica, T . spinosa, X . caffra, A . indica, and Z . africana showed activity against various Candida species . The minimum inhibitory concentrations (MICs) ranged from 0.006 to > 8 mg ml-1 and the minimum fungicidal concentrations (MFCs) from 0.06 to > 8 mg ml-1 . Extracts from S . mauritiana (both roots and flowers) exhibited no activity against Candida spp., but against Aspergillus spp., the MIC and MFC values ranged from 0.13 to 0.25 mg ml-1 and from 0.13 to 1 mg ml-1 respectively . It is concluded that the extracts contain compounds with high antifungal potency.

Mycoses, 1996 Jan-Feb, 39(1-2), 51 - 6
In vitro susceptibility of fungi to acyclic inhibitors of 2,3-oxidosqualene cyclases; Airaudi D et al.; In the present study we determine the antifungal properties of two acyclic inhibitors of 2,3-oxidosqualene cyclases: 22,23-epoxy-2-aza-2,3-dihydrosqualene (EAS) and azasqualene alcohol (ASA) . Fungistatic and fungicidal activity towards dermatophytes and other fungi involved in cutaneous and systemic infections was tested (48 isolates from 10 species) . The tests were carried out by inoculating 10 microliters of mycelial homogenate in 1 ml of Sabouraud glucose liquid medium containing serial dilutions of 100 to 0.25 micrograms ml-1 of the substance . For each isolate, the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of both compounds were determined . EAS was more active (MIC range 1.5-25 micrograms ml-1) than ASA (MIC range 3-50 micrograms ml-1) . At the highest concentration tested, EAS also showed fungicidal action towards some isolates of Trichophyton mentagrophytes, T . terrestre, Epidermophyton floccosum, Microsporum canis and Scopulariopsis brumptii . The most sensitive species was T . mentagrophytes, the most resistant T . rubrum.

Mycoses, 1996, 39 Suppl 1, 65 - 72
{Prerequisites for effective therapy of chronic recurrent vaginal candidiasis}; Kunzelmann V et al.; 67 women with chronic recurrent or persistent vaginal candidosis between 5-79 years of age were seen in our outdoor department . In 34 cases, yeasts could be isolated in a vaginal swab taken at the first consultation . On average the patients reported 5 episodes per year during the last years . Typical symptoms consisted of pruritus vulvae, local inflammation and a curdy vaginal discharge . Nearly all of the women had received local or systemic antimycotic treatment for several times . In 53% (18 patients), C . albicans had been isolated, in 29% (10 patients) C . glabrata and in 9% (3 patients) C . krusei . While candidosis due to C . albicans and C . krusei was frequently associated with distressing complaints, infections with C . glabrata caused only very few symptoms . Independent of the species, severe and persistent infections were characterized by long term persisting specific IgM-antibody-titers and remarkable lack of IgG-antibodies . The laboratory parameters of WBC, CRP and immunelectrophoresis were normal . The minimum inhibitory concentrations (MIC) of 60 Candida strains against fluconacole were determined by microdilution assay . The MIC for C . albicans (n = 35) were between 0.78 and 3.125 micrograms/ml, for C . glabrata (n = 20) between 8 and 32 micrograms/ml and for C . krusei (n = 5) between 25 and 128 micrograms/ml . In 7 cases, local antimycotic treatment was sufficient . Correlating to the sensitivity, 18 women were treated with 100-800 mg fluconacole/d for 10-20 days . In 13 of them, clearance of symptoms and yeasts was achieved . The treatment of fluconacole-resistant strains with itraconazole (100-200 ml/d for 10-20 days) together with local application of nystatin (2 x 1 Mio . IE for 10 days) was without any effect . Three women with C . albicans, C . glabrata and C . krusei infection received a candidin-vaccination (0.005 BE/ml-500 BE/ml) . In all of these cases, production of IgM-antibodies was induced . However, the clinical symptoms could not be influenced . Only in two cases it was not possible to reach a clearance of symptoms and yeasts . The results show the benefit of a precise differentiation before therapy . Serologic controls of antibody titers seem to be useful tools to control the efficacy of treatment.

Zhongguo Yao Li Xue Bao, 1996 Jan, 17(1), 55 - 8
Effects of tetrandrine on cytosolic free calcium in cultured rat myocardial cells; Li XT et al.; AIM: To study the effects of tetrandrine (Tet) on myocardium . METHODS: Using Fura 2-AM and AR-CM-MIC cation measurement system, cytosolic free calcium ({Ca2+}i) was examined in cultured rat single myocardial cells . RESULTS: The resting {Ca2+}i was 90 +/- 12 nmol.L-1 in the presence of Ca2+ 1.3 mmol.L-1 in Hanks' solution . Tet 1-100 mumol.L-1 had no effect on the resting {Ca2+}i, but 10-100 mumol.L-1 depressed the {Ca2+}i elevation when extracellular Ca2+ was 5 mmol.L-1 . Tet 1-100 mumol.L-1 inhibited KC1 (30 and 60 mmol.L-1) induced {Ca2+}i elevation in a concentration-dependent manner, the IC50 value was 8.8 mumol.L-1 (95% confidence limits: 3.3-23.7 mumol.L-1) and 6.9 mumol.L-1 (95% confidence limits: 2.8-17.4 mumol.L-1), respectively . Norepinephrine (NE) 10 mumol.L-1 caused a rapid increase in {Ca2+}i in the presence or absence of extracellular Ca2+, Tet 30-100 mumol.L-1 only decreased the former . Tet 10-100 mumol.L-1 also decreased ouabain (Oua)-induced elevation in {Ca2+}i . CONCLUSION: Tet had inhibitory effects on Ca2+ transmembrane movement, but it is not a selective calcium channel blocker in rat myocardial cells.

Ann Plast Surg, 1996 Jan, 36(1), 80 - 3
Treatment of chronic, nonhealing abdominal wound in a liquid environment; Eriksson E et al.; A 66-year-old woman with an abdominal wound caused by infected synthetic mesh had failed to heal in spite of many surgical attempts to close the wound . A sealed transparent vinyl chamber was glued to the periphery of the wound and antibiotics in high concentrations (up to 2,500 times the minimum inhibitory concentration) were delivered through the chamber . The wound fluid in the chamber was used for analysis of microbial activity, concentration of residual antibiotics, and growth factor activity . After 10 weeks of treatment, the wound was closed and has not recurred in 24 months.

J Appl Bacteriol, 1996 Jan, 80(1), 26 - 30
Minimum inhibitory concentrations of intestinal Escherichia coli from broiler chickens after oral administration of apramycin; Kobe A et al.; This study describes the influence of apramycin on minimum inhibitory concentrations (MIC) of intestinal Escherichia coli in young broiler chickens, after oral administration of the antibiotic at a dosage equivalent to a prophylactic course of treatment for 10 d . The bacteria were isolated from cloacal swabs and caecal contents . MICs were determined by agar dilution procedures . MIC of apramycin for the investigated strains ranged from 1 microgram ml-1 to 16 micrograms ml-1 . Strains obtained from undosed birds mainly had MIC values of 2 micrograms ml-1 . MIC values of 8 micrograms ml-1 or more were recorded only among isolates obtained from chickens which had received apramycin . Administration of apramycin resulted in a slight but statistically significant increase in the average MIC . Statistically higher average MICs were recorded among isolates from cloacal swabs 10 d after withdrawal until the end of the experiment . For strains from caecal contents, this was demonstrated only on one sampling occasion, 15 d after withdrawal.

Pathologe, 1996 Jan, 17(1), 6 - 17
{Pathology of Ewing sarcoma}; Roessner A et al.; Ewing's sarcoma is a very rare tumor which has, however, attracted much oncological interest since the dramatic improvement of its prognosis under chemotherapy . Its histogenesis has been discussed controversially for a long time, including a possible origin in immature reticulum, myogenous, endothelial and undifferentiated mesenchymal cells . Repeated reports have also suggested a possible neuroectodermal genesis . Convincing arguments, however, have only been brought forward during recent years, since it was found that Ewing's sarcoma and malignant peripheral neuroectodermal tumor share a common chromosome translocation 11;22 . In the meantime this hypothesis has been strengthened by numerous cell biological analyses . There seems to be no clear border between Ewing's sarcoma and malignant peripheral neuroectodermal tumors with definite neural differentiation . Histological differential diagnosis of Ewing's sarcoma has been improved by immunohistological methods . In most cases, they can be distinguished from lymphoma (leucocyte common antigen, B and T markers) and embryonal rhabdomyosarcoma (muscle specific actin, desmin) without problems . Apart from that, it is possible nowadays to obtain antibodies against the MIC 2-protein, which is preferably expressed in Ewing sarcoma . The diagnostics of Ewing's sarcoma and the malignant peripheral neuroectodermal tumor have considerably been enriched by the fact that the specific chromosome translocation t(11;22) can be proved molecular biologically . In contrast to the cytogenetic evidence, it is not necessary to establish cell cultures.

J Antimicrob Chemother, 1996 Jan, 37(1), 77 - 84
Activity of CP 99,219 (trovafloxacin) compared with ciprofloxacin, sparfloxacin, clinafloxacin, lomefloxacin and cefuroxime against ten penicillin-susceptible and penicillin-resistant pneumococci by time-kill methodology; Visalli MA et al.; Activity of CP 99,219 (trovafloxacin), clinafloxacin, ciprofloxacin, sparfloxacin, lomefloxacin and cefuroxime against 4 penicillin-susceptible, 2 penicillin-intermediate and 4 penicillin-resistant pneumococci was tested by MIC and time-kill methodology . Bacteriostatic values for all three groups did not differ significantly with all compounds tested except cefuroxime, and were lowest for trovafloxacin and clinafloxacin, followed by sparfloxacin, ciprofloxacin and lomefloxacin; cefuroxime yielded values which increased in line with those of penicillin G . The test compounds were bactericidal (i.e . they reduced original counts by > or = 3 log10 cfu/mL at one dilution above bacteriostatic levels) in most cases, though some strains showed slightly greater discrepancies between bacteriostatic and bactericidal levels of all compounds tested . Trovafloxacin, clinafloxacin and sparfloxacin yielded MIC and time-kill results which point to possible efficacy in treatment of penicillin-susceptible and -resistant pneumococcal infections.

Vet Res, 1996, 27(1), 23 - 32
{Bactericidal effect of colistin on Escherichia coli . Model and simulation or the pharmacokinetic-pharmacodynamic relation for prediction of efficacy in veterinary antibiotic therapy}; Renard L et al.; Pharmacodynamics studies consider three main parameters: the size of the bacterial population, the concentration of the antibiotic and the duration of its action . The pharmacodynamic characteristics of colistin were studied in vitro with Escherichia coli . The bacterial kinetics were fitted using differential equations . The mathematical model gave qualitative and quantitative information about the characteristics of the antibiotic-bacteria association . Above all, when linked to a pharmacokinetic model, the model permitted the prediction of the drug's efficiency . Simulations of various dosage levels in which the administration route, dose size, or interval between doses varied, permitted a more rational optimization than a prediction of efficacy based on the time taken to achieve antibiotic plasmatic concentrations above the minimal inhibitory concentration . Pharmacokinetic/pharmacodynamic modeling seems to be an interesting possibility for determining antibiotic dosing levels during the preclinical phase.

Cancer Chemother Pharmacol, 1996, 37(5), 496 - 8
Phase II study of mitomycin, ifosfamide and cisplatin in adenocarcinoma of the oesophagus; Allen SM et al.; We evaluated the effect of brief neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus . Two courses of mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2;MIC) were given followed by evaluation of response by barium swallow and computed tomography scan . Of 20 patients, 17 completed both courses and 4 (20%) showed a partial response . Toxicity was generally mild and consisted principally of nausea and vomiting . Altogether, 15 patients were surgically explored; resection was completed in 12 patients, 3 of whom died in hospital (25%) . Neoadjuvant therapy with MIC offers no advantage over surgery alone.

Berl Munch Tierarztl Wochenschr, 1996 Jan, 109(1), 14 - 7
{Furazolidone resistance of E . coli from chicken intestines after prophylactic treatment with bioptivet GB in animal feed}; Kobe A et al.; This study describes the influence of bioptivet GB on minimum inhibitory concentrations (MIC) for furazolidone of the intestinal E . coli flora of young broiler chickens after prophylactic treatment . From day 6 until day 15 one group of 50 birds received a diet containing 326 ppm furazolidone, another group of 75 birds served as non medicated control . Investigated E . coli had been isolated from cloacal swabs and from caecal contents . MIC of 1581 E . coli strains were determined by agar dilution test . MIC of furazolidone for the investigated strains ranged from 2 micrograms/ml to 64 micrograms/ml . For classification as "resistant" or "susceptible" limits of 16 micrograms/ml and 8 micrograms/ml respectively were used . Strains obtained from undosed birds mainly had MIC values of 4 micrograms/ml or 8 micrograms/ml, i.e . two or three times higher than MIC of E . coli ATCC 25 922, MIC values of 16 micrograms/ml or more were recorded only among isolates obtained from chickens which had received the drug . Administration of bioptivet GB resulted in a statistically significant increase in the average MIC . Statistically higher average MIC were recorded among isolates from cloacal swabs only during application of the drug . For strains from caecal contents, the effect became obvious only at the end of the experiment.

Int J Syst Bacteriol, 1996 Jan, 46(1), 35 - 40
Karyotyping of fluconazole-resistant yeasts with phenotype reported as Candida krusei or Candida inconspicua; Essayag SM et al.; The yeasts Candida krusei and Candida inconspicua have similar phenotypes, which may make discrimination of these organisms difficult . In this study we determined the karyotypes of 51 isolates of these two yeast species by contour-clamped homogeneous electric field electrophoresis . We found that the 43 isolates that had the C . krusei phenotype had three karyotype-specific characteristics . These isolates produced either two or three bands between 2,000 and 3,000 kb and no band between 1,300 and 2,000 kb, and there was either a single bright band at 1,300 or 1,200 kb or two separate bands at 1,300, 1,200, or 1,100 kb . Using this technique, we were able to distinguish 27 different C . krusei types on the basis of band variations . The seven isolates identified as C . inconspicua on the basis of phenotype differed in that they produced at least one band between 1,300 and 2,000 kb . These isolates produced six to nine bands, in contrast to C . krusei strains, which produced three to six bands . The MIC of fluconazole for all of the isolates was at least 12.5 mg/liter, as determined by a broth dilution method.

Med J Aust, 1996 Jan 1, 164(1), 39 - 42
Aminoglycoside dosing: one, two or three times a day?
McLean AJ, Ioannides-Demos LL, Spicer WJ, Christophidis N.
The safety and efficacy of conventional aminoglycoside dosing regimens have been proven in clinical trials . Higher doses at longer intervals may be more effective if they result in higher peak serum levels of the drug, but few trials of "once-a-day" dosing have shown improved clinical outcome . The clinical safety of allowing trough serum levels to fall below the minimum inhibitory concentration is not established . Literal "once-a-day" dosing will result in drug accumulation and toxicity in patients with reduced renal clearance, and in potential lack of efficacy and the emergence of antibiotic-resistant organisms in those with increased renal clearance . However, modified "once-a-day" dosing, with the interval determined by the individual's renal clearance rate (hence avoiding subtherapeutic trough levels), will avoid these problems.

Proc Natl Acad Sci U S A, 1995 Dec 19, 92(26), 12379 - 83
The BALB/c mouse B-cell response to pigeon cytochrome c initiates as a heteroclitic response specific for the self antigen mouse cytochrome c; Minnerath JM et al.; Direct evidence is presented in support of the longstanding but unproven hypothesis that B lymphocytes specific for self antigens (Ags) can be used in the immune response to foreign Ags . We show that the B cells in BALB/c mic responding early to pigeon cytochrome c (CYT) produce antibodies that recognize and bind the major antigenic site on mouse CYT with greater affinity than they bind pigeon CYT i.e., they are heteroclitic for the self Ag . Furthermore, these B cells express the same combination of immunoglobulin variable region (V) genes that are known to be used in B-cell recognition of mouse CYT . Over time, the response to pigeon CYT becomes more specific for the foreign Ag through the recruitment of B cells expressing different combinations of V genes and, possibly, somatic mutation of the mouse CYT specific B cells from early in the response . Cross-recognition of pigeon CYT by mouse CYT-specific B cells results from the sharing of critical amino acid residues by the two Ags . Although B-cell recognition of the self Ag, mouse CYT, is very specific, which limits the extent to which foreign Ags can cross-activate the autoreactive B cells, it is possible that polyreactive B cells to other self Ags may be used more frequently in response to foreign Ags.

Int J Obes Relat Metab Disord, 1995 Dec, 19(12), 841 - 5
The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects; Goto T et al.; OBJECTIVE: To determine whether fatty liver impairs insulin clearance and contributes to insulin resistance in obese and lean healthy non-diabetic men and women . DESIGN: Cross-sectional, descriptive . SETTING: Medical outpatient clinic; university hospital . SUBJECTS: Twenty-seven (14 men) non-diabetic obese (Body fat % = 31.5 +/- 9.3; mean +/- s.d.) and 19 (13 men) non-diabetic non-obese (body fat % = 19.0 +/- 6.8; P < 0.01 vs obese) healthy subjects aged 31-64 without liver disease . MAJOR OUTCOME MEASURES: Liver density relative to the spleen on CT scan (LFS), glucose infusion rate (GIR) and metabolic insulin clearance rate (MIC) during euglycemic hyperinsulinemic clamp; anthropometric (waist-hip ratio: WHR) and CT-determined (visceral fat area: VFA) measures of fat distribution . RESULTS: Fatty liver was inversely related to MIC (r = -0.39; P < 0.01) with a positive correlation with fasting p-insulin (r = 0.39; P < 0.01) . There were no statistically significant correlations between BMI, body fat % or WHR and MIC . GIR was inversely related to body fat % (r = -0.49; P < 0.01), VFA (r = -0.56; P < 0.01) and WHR (r = -0.36; P < 0.01) in all subjects, with an inverse relationship to fatty liver in men (r = -0.43; P < 0.05) . CONCLUSION: Increased steatosis of the liver is associated with reduced insulin clearance, contributing to insulin resistance in non-diabetic Japanese men and women.

J Antimicrob Chemother, 1995 Dec, 36(6), 987 - 96
Determination of the in vivo post-antibiotic effects of ciprofloxacin and rifampicin; Meng X et al.; A modified rabbit meningitis model is described for determining the PAE in vivo, which utilised a self-standing device for repeatedly sampling pure CSF . The model allowed the PAEs of ciprofloxacin and rifampicin on Escherichia coli ATCC 25922 to be determined following PAE induction in vitro, or in vivo in CSF after intrathecal injection or during the last 1.5 h of a 7 h iv continuous infusion . The estimated volumes of distribution of ciprofloxacin and rifampicin in CSF were 0.68 +/- 0.24 mL and 0.74 +/- 0.04 mL, respectively, and the terminal elimination half lives were 1.8 +/- 0.5 h and 2.2 +/- 0.3 h, respectively . PAEs of approximately 2 h were obtained in vivo and in vitro after exposing E . coli to 3 x MIC of ciprofloxacin in vitro and to 1 x MIC of drug in vivo . When the organism was exposed to rapidly declining concentrations in vivo, only a minimal PAE was observed for both antibiotics . Moreover, a PAE of 3.1 +/- 1.3 h of rifampicin was obtained in vivo, being smaller than the 4.8 h PAE observed in vitro, which might be explained by the binding of 45 +/- 6.5% rifampicin to proteins in the CSF.

Bone Marrow Transplant, 1995 Dec, 16(6), 849 - 53
Invasive Candida guilliermondii infection: in vitro susceptibility studies and molecular analysis; Vazquez JA et al.; Candida guilliermondii is rarely isolated from humans . We describe a case of disseminated C . guilliermondii with associated purulent pericarditis, despite high-dose amphotericin B (AmB), in a 19-year-old female with aplastic anemia who underwent BMT . In vitro susceptibility studies of the 13 clinical isolates, two control strains and one environmental isolate revealed a minimum inhibitory concentration (MIC) range of (0.19-1.56 micrograms/ml) for AmB and (1.25-10 micrograms/ml) for fluconazole . Pulsed-field gradient gel electrophoresis was performed to evaluate possible similarities between strains . This case is significant for several reasons, the high degree and prolonged duration of fungemia despite high-dose AmB and concomitant flucytosine, the change in in vitro susceptibility during therapy, the initial misidentification of the yeast isolate, and the invasiveness of the organism . The poor response to therapy may have been due to the severe and sustained neutropenia and the high MICs of C . guilliermondii to AmB.

Asian Pac J Allergy Immunol, 1995 Dec, 13(2), 81 - 5
Effect of inhaled corticosteroids on bronchial hyperresponsiveness in patients with mild asthma; Wongtim S et al.; We studied the effect of inhaled budesonide on bronchial hyperresponsiveness (BHR) in twenty mild asthmatic patients . The study was conducted as a randomized, double-blind, placebo-controlled study . Before entering the study, the patients performed methacholine inhalation challenge (MIC) using a reservoir method to assess BHR . Then, they were randomly allocated to receive budesonide turbuhaler (200 micrograms/dose) or placebo turbuhaler two inhalations, twice daily for eight weeks . During the study, each patient recorded daily asthma score and daily number of puffs of beta 2 agonist and they were assessed at weeks 4 and 8 . At the end of the treatment, MIC was repeated again . Patients receiving budesonide showed a significant improvement in airway responsiveness compared with those receiving placebo (p < 0.05) . They also showed a significant improvement in asthma severity score and a significant decrease in beta 2 agonist bronchodilator use . This study also suggested that inhaled corticosteroids may be the primary treatment in patients, even with mild asthmatic and well-controlled symptoms.

Eur J Clin Microbiol Infect Dis, 1995 Dec, 14(12), 1085 - 8
Endocarditis caused by Arcanobacterium haemolyticum; Alos JI et al.; A 33-year-old, active intravenous drug-abusing male infected with the human immunodeficiency virus developed endocarditis due to Arcanobacterium haemolyticum . Empirical treatment with ampicillin plus gentamicin failed to achieve a marked clinical improvement . When the results of antibiotic susceptibility were available (ampicillin MIC < or = 0.06 mg/l; ampicillin MBC 2 mg/l; MBC:MIC ratio > 32) therapy was changed to vancomycin plus gentamicin . During the following days progressive clinical and radiological improvement was observed . The patient received antibiotics for 30 days and no relapse occurred during a 14-month follow-up . The literature of endocarditis due to this uncommon bacterium is reviewed here.

Surg Laparosc Endosc, 1995 Dec, 5(6), 477 - 9
Minimally invasive colectomy in elderly patients; Peters WR et al.; The safety of minimally invasive colectomy (laparoscopic or laparoscopically assisted colectomy) has not been evaluated in the elderly patient . Therefore, a prospective study of the outcome of minimally invasive colectomy (MIC) in patients aged 65 years or older was undertaken . Between October 1991 and September 1993, 103 elderly patients underwent attempted MIC (right colectomy, 53; left colectomy, sigmoid colectomy, or anterior resection, 36; abdominoperineal resection, 12; and total proctocolectomy with ileostomy, 2); 81 procedures were successfully completed . Complications occurred in 23% of patients converted to laparotomy (including one death) and in 25% undergoing successful MIC (two deaths, p = ns) . The average length of postoperative stay was 5.3 days in the MIC group and 8.1 days for patients converted to laparotomy (p < 0.001) . These results compare favorably with published results of traditional colectomy for elderly patients . We conclude that MIC is safe in the elderly patient and that further studies are warranted.

Antimicrob Agents Chemother, 1995 Dec, 39(12), 2803 - 6
Postantibiotic effect of clarithromycin alone and combined with ethambutol against Mycobacterium avium complex; Ellis LC et al.; The postantibiotic effect (PAE) of clarithromycin alone and in combination with ethambutol was determined for two clinical blood isolates of Mycobacterium avium complex . An average PAE, ranging from 5.5 to 18.0 h, was noted for each isolate at each clarithromycin concentration except when isolate B was exposed to clarithromycin at the MIC . The addition of ethambutol did not enhance the PAE observed with clarithromycin alone . The clinical implications of the PAE of clarithromycin for M . avium complex remain to be determined.

Kokubyo Gakkai Zasshi, 1995 Dec, 62(4), 495 - 505
{Subgingival distribution of periodontopathic bacteria in periodontic patients and susceptibility of these bacteria to minocycline-HCl}; Hagiwara S et al.; The present study was carried out to examine the distribution of six periodontopathic bacteria in deep periodontal pockets and to reconfirm the effect of Periocline on these periodontopathic bacteria . Samples from sixty-two periodontal pockets were collected at pocket depths of over 4 mm in twenty-one periodontitis patients aged 43 to 75 years . After sampling, Periocline was applied topically to the selected pockets once a week for four weeks and reexamined . The detected rates of the periodontopathic bacteria were Capnocytophaga sputigena (37.1%), Prevotella intermedia (22.6%), Porphyromonas gingivalis (22.6%), Fusobacterium nucleatum (20.1%), Actinobacillus actinomycetemcomitans (9.7%) and Eikenella corrodens (4.8%) . The distribution of the bacteria was compound because two or three bacterial species were found to coexist . In view of the MIC of minocycline-HCI for these bacteria, increase of most of the measured bacteria was suppressed by the concentration of drugs, including Periocline . However, clinical strains of P . i . were considered to have low susceptibility to minocycline-HCl . In view of the effect of topical application of drugs, no significant differences were found . From these results, it was suggested that Periocline contained effective concentration of minocycline-HCl.

Microbiology, 1995 Dec, 141 ( Pt 12), 3133 - 40
The tellurite-resistance determinants tehAtehB and klaAklaBtelB have different biochemical requirements; Turner RJ et al.; The tehAtehB operon from the Escherichia coli chromosome (32.3 min) mediates resistance to potassium tellurite (K2TeO3) when expressed on a multicopy plasmid such as pUC8 (pTWT100) . An MIC of 128 micrograms ml-1 is observed when tehAtehB is expressed in a wild-type host and grown on rich media . In this study, the tehAtehB determinant was transformed into mutants deficient in electron transport processes and/or thiol redox coupling within E . coli . These mutants included ubi, nad, cys, nar, trx, grx, gsh and sod . MICs of tehAtehB transformed into these mutants ranged from 1-16 micrograms K2TeO3 ml-1 compared to 0.03-2 micrograms ml-1 for strains transformed with a control plasmid . The tellurite-resistance determinant locus kilA cloned from the IncP alpha plasmid RK2Ter (pDT1558) was also investigated in these strains . This tellurite-resistance determinant showed little or no dependency on the host genotype . The ability of tehAtehB to mediate resistance in wild-type hosts is limited to rich medium . Rich medium may provide a key unidentified cofactor required by TehATehB that is not provided under minimal conditions . Again, the ability of the kilA determinant to mediate tellurite resistance was independent of medium conditions . These data suggest that either a reducing environment or electron-reducing equivalents are required for tehAtehB to mediate high levels of resistance to potassium tellurite . Therefore, the two resistance determinants studied here possess two very different biochemical mechanisms of resistance . Our data also suggest a mechanism for endogenous resistance to tellurite which involves nitrate reductase, superoxide dismutase, and thiol redox processes.

Am J Trop Med Hyg, 1995 Dec, 53(6), 602 - 6
Rickettsia tsutsugamushi infection in cell culture: antibiotic susceptibility determined by flow cytometry; Kelly DJ et al.; Recent unpublished reports from northern Thailand of severe and sometimes fatal cases of scrub typhus, despite appropriate antibiotic therapy, suggest that resistance may occur . Current antibiotic susceptibility methods that use direct microscopic counts of Giemsa-stained cells or mouse protection assays are slow, labor-intensive, and expensive . We explored the use of flow cytometry to measure rickettsial infection in vitro in L-929 cells treated with and without doxycycline, ciprofloxacin, erythromycin, and chloramphenicol . It was possible to detect the rickettsiae down to a level of 83% of the cells infected, mean of 37 rickettsiae per cell, and 40% of cells with too many rickettsiae to count . This level of sensitivity was sufficient to determine the inhibitory effect of all four drugs at standard screening concentrations . At lower concentrations of doxycycline, flow cytometry detected inhibition of rickettsial growth at a concentration of 6.25 x 10(-2) micrograms/ml but not at 6.25 x 10(-3) micrograms/ml, suggesting that the minimum inhibitory concentration is somewhere between these two values . The data from this study show that flow cytometry permits the rapid screening of numerous rickettsial isolates for their susceptibility to a variety of antibiotics, but that visual counts of infected cells provide a more precise indication of rickettsial growth.

Pharmacol Res, 1995 Nov, 32(5), 315 - 9
Correlation between reduction of surface hydrophobicity of S . aureus and the decrease in its adhesiveness induced by subinhibitory concentrations of brodimoprim; Braga PC et al.; Hydrophobic interactions are involved in the mechanism of adhesion of a variety of bacteria to host tissues . Bacterial attachment to human cells is modulated by a change in interfacial free energy and this is correlated with surface hydrophobicity of bacterial cells . In S . aureus (one ATCC25923+four clinical isolates) hydrophobicity before and after incubation with subinhibitory concentrations (sub-MICs) of brodimoprim (BMP), a dimethyoxypyrimidine recently entered clinical practice, was measured by sessile drop technique as the contact angle . BMP is a new molecule derived from trimethoprim by substitution of the OCH3 group in position 4 of the benzyl-ring with a bromine atom . Bacterial adhesiveness of the same S . aureus strains was measured under the same experimental conditions . BMP significantly decreased the surface hydrophobicity of S . aureus strains at one-half MIC and one-quarter MIC . At sub-MICs concentrations BMP also reduced the adhesiveness to human epithelial buccal cells but this effect was significant down to one-sixteenth MIC . The two phenomena are correlated and hydrophobicity is involved in bacterial adhesiveness but the molecular mechanisms for the two phenomena do not completely overlap, with adhesiveness the more complex and based on a system involving both the bacteria and the epithelial cells with their specific surface characteristics.

J Med Vet Mycol, 1995 Nov-Dec, 33(6), 403 - 9
Evaluation of the susceptibility of dermatophytes to antifungal drugs: a new technique; Butty P et al.; The evaluation of the minimal inhibitory concentration (MIC) for pathogenic fungi is still a technically difficult assay . Insufficient standardization of the technique is often the basis of problems which appear . Culture characteristic of dermatophytes do not favour techniques usually used in bacteriology (Steers agar dilution method) . A study was undertaken to compare the Steers agar dilution method and a new culture method to evaluate the minimal inhibitory concentration of antifungal compounds on several species of dermatophytes . The new method involves dilution of the antifungal drug in solid medium in a Petri dish . Standardized agar cylinders are cut from the plates and filled with inocula of the same size cut from plates of dermatophyte cultures . Such inocula facilitate analysis of the fungus in its natural growth conditions in vitro without being submitted to a disruptive preparative technique . The MIC values were similar for the two methods of evaluation in spite of important differences between the inocula . The new technique is reliable, quick, and highly reproducible . It is more efficient than the Steers agar dilution method because it enables assays to be run on several strains simultaneously and avoids labour-intensive procedures for the preparation of the inocula.

J Med Vet Mycol, 1995 Nov-Dec, 33(6), 395 - 401
Ultrastructural alterations produced by sertaconazole on several opportunistic pathogenic fungi; Figueras MJ et al.; Sertaconazole is a new synthetic antifungal which has shown promising activity against numerous fungi . The morphological changes induced by the drug at two concentrations, the MIC and 10 times the MIC, during 24 and 48 h on the filamentous opportunistic fungi Aspergillus fumigatus, Chaetomium atrobrunneum and Scedosporium prolificans indicated that the intensity of the ultrastructural breakdown depended on the dose and not on the time of exposure . Common severe alterations of many fungal cells, which could be considered beyond repair, were seen at the cell wall, plasmalemma and cytoplasm levels . The results obtained underline the drug efficacy for those fungi and suggest its applicability as therapeutic agent in the human infections produced by them.

Eur J Clin Microbiol Infect Dis, 1995 Nov, 14(11), 972 - 8
Activity of beta-lactamase inhibitor combinations on Escherichia coli isolates exhibiting various patterns of resistance to beta-lactam agents; Vanjak D et al.; The efficacy of the clinically available beta-lactam/beta-lactamase inhibitor combinations (amoxicillin/clavulanic acid (CA), ticarcillin/CA, amoxicillin/sulbactam, and piperacillin/tazobactam) was evaluated on 300 amoxicillin-resistant Escherichia coli isolates having the main patterns of beta-lactam resistance . The patterns, which reflect the production of various beta-lactamase enzymes, were analyzed by a principal component analysis of susceptibility to 11 beta-lactam antibiotics or beta-lactam/beta-lactamase inhibitor combinations . Sixty-two percent of strains were not very susceptible to penicillins, cephalothin, or any beta-lactam/beta-lactamase inhibitor combinations except for piperacillin/tazobactam; these strains may represent high-level broad-spectrum beta-lactamase (so-called penicillinase) production phenotype or inhibitor-resistant TEM-like enzyme production phenotype . Of the strains, 14.7% were resistant to amoxicillin and ticarcillin compatible with low-level broad-spectrum beta-lactamase production phenotype; 5.7% were cefoxitin resistant and were postulated to present a high-level cephalosporinase production phenotype; and 2.6% were resistant to cephalothin only, attributable to a low-level cephalosporinase production phenotype . Three percent of strains were intermediate or resistant to cefotaxime and may produce an extended-spectrum beta-lactamase, and the remaining strains (12 %), resistant to all tested antibiotics except for cefotaxime and piperacillin/tazobactam, were hypothesized to produce both broad-spectrum beta-lactamase plus cephalosporinase . The minimal inhibitory concentration (MIC) for these phenotype patterns indicated that combinations of CA plus amoxicillin or ticarcillin, or sulbactam plus amoxicillin, restored the activity of penicillins against phenotype 1 strains, whereas these combinations remained inactive against the other phenotype strains . Piperacillin plus tazobactam showed the best in vitro effect against the strains of all resistance phenotypes.

J Clin Immunol, 1995 Nov, 15(6 Suppl), 22S - 25S
The role of superantigens in virus infection; Huber BT; Murine mammary tumor viruses are retroviruses which encode superantigens capable of stimulating T cells via superantigen-reactive T-cell receptor V beta chains . Murine mammary tumor viruses are transmitted to the suckling offspring through the milk . We have established that B cell-deficient pups which were foster-nursed by virus-secreting mice do not transfer infectious murine mammary tumor viruses to their offspring . No murine mammary tumor virus proviruses could be detected in the spleen and mammary tissue of these mic . We conclude that B cells are essential for the completion of the viral life cycle in vivo . This indicates that B cells are infected first and that viral amplification takes place only if infected B cells present the murine mammary tumor virus superantigen on their surface, which, in turn, results in activation of T cells expressing the appropriate T-cell receptor B beta chains . These activated T cells secrete factors which stimulate B cells, enabling viral replication.

Farmaco, 1995 Nov, 50(11), 783 - 6
2-(4-Pyridyl)-delta 2-1,3,4-oxadiazolines from isonicotinoylhydrazones and diazomethane as potential antimycobacterial and anti-HIV agents . V; Vigorita MG et al.; The 5-aryl-4-methyl-2-(4-pyridyl)-delta 2-1,3,4-oxadiazolines 3, previously synthesized along with isomer 4-aryl-1-methoxy-1-(4-pyridyl)-2,3-diaza-1,3-butadienes 2 from benzaldehyde isonicotinoylhydrazones and diazomethane, were tested for in vitro activity against both M . tuberculosis and some atypical mycobacterial strains as well as against human immunodeficiency virus (HIV-1) . Some halophenyl derivatives, 3e, 3g, 3i, 3j, were found to display MIC ranges from 1 to 10 (micrograms/ml against H 37 Rv and a clinical isolate tubercular strain, whereas against M . avium (MAC) the MICs were higher than 20 micrograms/ml . When the combinations of oxadiazolines with ethambutol, acting as inhibitor of cell wall synthesis, were assayed on MAC strain a synergistic effect was demonstrated for 3g and 3h trifluoromethyl derivatives . The antimycobacterial profiles of 2 and 3 analogues are compared and discussed . As shown by compounds 2, no substantial anti-HIV in vitro activity was found in selected delta 2-oxadiazolines; a moderate cytotoxicity, however, appears to be a common property.

Berl Munch Tierarztl Wochenschr, 1995 Nov, 108(11), 412 - 7
{Resistance to tetracycline of E . coli of chicken intestines after prophylactic treatment of animal feed with bioptivet GB}; Kobe A et al.; This study describes the influence of bioptivet GB on minimum inhibitory concentrations (MIC) for oxytetracycline (OTC) of the intestinal E . coli flora of young broiler chickens after oral administration at a dosage equivalent to a prophylactic course of treatment . From day 6 until day 15 one group of 50 birds received a diet containing 124 ppm OTC, another group of 75 birds served as non medicated control . Investigated E . coli had been isolated from cloacal swabs and from caecal contents . MIC of 1581 E . coli strains were determined by agar dilution test procedures . MIC of OTC for the investigated strains were either > or = 128 micrograms/ml (resistant) or < or = 4 micrograms/ml (susceptible) . Even from undosed birds resistant strains were isolated frequently, especially from samples of caecal contents . Administration of bioptivet GB resulted in a statistically significant increase in the average MIC . Statistically higher average MIC were recorded among isolates from cloacal swabs only during application of the drug . For strains from caecal contents this could be demonstrated until the end of the experiment.

Pharm Res, 1995 Nov, 12(11), 1791 - 5
Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert; Gurtler F et al.; PURPOSE . Gentamicin eye drop solutions have a short precorneal residence time . The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution . METHODS . In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution . Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively . The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria . A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff) . RESULTS . In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) {micrograms ml-1 h}) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) {micrograms ml-1 h}); the teff had a similar behavior: 6-15 {h} in dogs and 2-6 {h} in rabbits . In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) {micrograms ml-1 h} and 70-76 {h}, respectively . The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits . CONCLUSIONS . This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.

Antimicrob Agents Chemother, 1995 Nov, 39(11), 2520 - 2
Comparison of Etest and National Committee for Clinical Laboratory Standards broth macrodilution method for antifungal susceptibility testing: enhanced ability to detect amphotericin B-resistant Candida isolates; Wanger A et al.; The National Committee for Clinical Laboratory Standards (NCCLS) proposed macrobroth reference method (M27P) for susceptibility testing of yeasts is technically difficult . We evaluated Etest, a simple agar-based MIC methodology, as a possible alternative . In studies of six yeast quality control strains, Etest yielded results identical to those obtained by the NCCLS reference method for both amphotericin B and fluconazole . In studies of 91 clinical Candida isolates, agreement +/- 2 dilutions between the two methods was 95% for fluconazole with phosphate-buffered RPMI 1640 agar and 96 to 97% for amphotericin B with either MOPS (morpholinepropanesulfonic acid)-buffered RPMI 1640 agar or antibiotic medium 3 agar . While the two methods had excellent general agreement, testing of a collection of amphotericin B-resistant isolates demonstrated that, unlike the NCCLS reference method, Etest readily identified the resistant isolates and could do so with a defined medium . Etest is equivalent to the NCCLS proposed method for susceptibility testing of yeasts and superior in its ability to detect amphotericin B resistance.

Chem Pharm Bull (Tokyo), 1995 Nov, 43(11), 2019 - 20
Quantitative relation between surface active properties and antibiotic activity of 1-alkyl-3-alkylthiomethylimidazolium chlorides; Pernak J et al.; The critical micelle concentration (CMC) values were determined by surface tensiometry, and the hydrophobicity index (HI) was calculated . The quantitative relation between the minimum inhibitory concentration (MIC) and the CMC, and the HI was calculated.

J Clin Pathol, 1995 Nov, 48(11), 1064 - 6
Lack of correlation of P-glycoprotein expression with response to MIC chemotherapy in oesophageal cancer; Darnton SJ et al.; The multidrug resistance gene product P-glycoprotein (P-GP) was assessed immunohistochemically (by antibody JSB-1) in biopsy specimens from 27 oesophageal squamous carcinomas and 10 adenocarcinomas before treatment with mitomycin, ifosfamide and cisplatin (MIC) . Tumours were assessed following treatment and correlation with response sought . Of the squamous carcinomas, 74% (20/27) responded to MIC but only one expressed P-GP before and after treatment . Of the adenocarcinomas, 30% (three of 10) responded . Seven of the 10 adenocarcinomas expressed P-GP before treatment but all 10 were P-GP positive after chemotherapy . The difference in prevalence and induction of P-GP between the histological types was highly significant and may correlate with the greater response to MIC seen in squamous carcinomas compared with adenocarcinomas . P-GP cannot be used as a predictive marker of response as tumours express it inconsistently with response to MIC . Resistance to MIC may be due to other mechanisms.

Scand J Immunol, 1995 Nov, 42(5), 551 - 6
Calprotectin-mediated zinc chelation as a biostatic mechanism in host defence; Clohessy PA et al.; The S-100 Ca2+ binding protein, calprotectin, isolated from neutrophil lysates, has been reported to exhibit zinc reversible biostatic activity in vitro . We verified these findings with C . albicans and investigated whether the growth inhibition resulted from zinc deprivation due to chelation by calprotectin . Calprotectin concentrations of 250 micrograms/ml significantly inhibited the growth of C . albicans . This was reversed by supplementing culture medium with 10 microM ZnSO4 . Incubation of calprotectin in culture medium for 24 h prior to inoculation significantly reduced the minimum inhibitory concentration . When this latter medium was ultrafiltered to remove the calprotectin and then inoculated with C . albicans, significant growth inhibition was still present: again it was reversed by zinc . These findings implicate zinc chelation as a novel, potentially important host defence function of an abundant neutrophil protein.

Microb Pathog, 1995 Oct, 19(4), 257 - 72
Chemiluminescent analysis of Borrelia burgdorferi penicillin-binding proteins using ampicillin conjugated to digoxigenin; Norgard MV et al.; Knowledge of the penicillin-binding proteins (PBPs) of Borrelia burgdorferi is important for understanding both the targets of beta-lactams used therapeutically for Lyme borreliosis and the complex membrane biology of the distinctive spirochetal pathogen which causes Lyme disease . In this study, the PBPs of a number of B . burgdorferi strains and variants were examined using a rapid and sensitive chemiluminescent assay which employs ampicillin conjugated to digoxigenin (dig-amp) . The minimum inhibitory concentration of dig-amp for B . burgdorferi high-passage strain B31 (0.012 micrograms/ml) was essentially no different from that of free ampicillin (0.025 micrograms/ml) . Dig-amp bound specifically to B . burgdorferi B31 PBPs with molecular masses of 92, 80, 65, 46, 40, 34, 31, 29, 22, 20 and 13 kDa; the 31 kDa and 34 kDa PBPs were proven to be OspA and OspB, respectively . All of the borrelial PBPs were present in the cytoplasmic membrane fraction of B . burgdorferi, findings consistent with their activities as PBPs but inconsistent with OspA and OspB as surface-exposed outer membrane lipoproteins . Furthermore, among the PBP profiles of other high- and low-passage variants of B . burgdorferi strains Sh-2-82, HB19, and N40, which differed somewhat from one another, OspD (28 kDa) but not OspC (22-25 kDa) also was strongly implicated as a PBP; however, OspC possessed a gel mobility easily misconstrued as that of a 26 kDa PBP often expressed reciprocally with OspB . The ramifications of classifying OspA, OspB, and OspD as PBPs are discussed . While the current inability to genetically manipulate B . burgdorferi hinders determining which of the borrelial PBPs are essential for spirochetal viability (i.e., are the lethal targets of beta-lactams), a priori knowledge of the borrelial PBPs will facilitate the production and purification of recombinant derivatives whose activities can be assessed further in vitro.

Antimicrob Agents Chemother, 1995 Oct, 39(10), 2320 - 4
Antimycobacterial activity of a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9); Reddy VM et al.; The antimycobacterial activities of a new rifampin (RIF) derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (To), against 20 susceptible and multidrug-resistant strains of Mycobacterium tuberculosis and 20 Mycobacterium avium complex (MAC) strains were investigated . The radiometric MICs of T9 for M . tuberculosis were significantly lower than those of RIF . The MICs of T9 and RIF at which 90% of the RIF-susceptible strains were inhibited were < or = 0.25 and < or = 0.5 micrograms/ml, respectively . Interestingly, T9 had lower MICs against some RIF-resistant M . tuberculosis strains . T9 had better activity against MAC strains, and the MIC at which 90% of the MAC strains were inhibited was < or = 0.125 micrograms/ml, and that of RIF was < or = 2.0 micrograms/ml . T9 also showed high in vitro bactericidal and intracellular activities which were significantly superior to those of RIF against both M . tuberculosis, and MAC strains . More importantly, T9 showed excellent in vivo activity against M . tuberculosis H37Rv compared with that of RIF in both the lungs and spleens of C57BL/6 mice, indicating the potential therapeutic value of T9 in the treatment of mycobacterial infections.

Antimicrob Agents Chemother, 1995 Oct, 39(10), 2295 - 303
In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis; Hirata T et al.; The in vitro and in vivo activities of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium tuberculosis were studied . The MIC at which 50% of the isolates are inhibited (MIC50) and the MIC90 of KRM for 30 fresh isolates of M . tuberculosis measured by the BACTEC 460 TB System were 0.016 and 2 micrograms/ml, respectively . These values were much lower than those for rifampin (RMP), which were 4 and >128 micrograms/ml, respectively, and considerably lower than those for rifabutin (RBT), which were 0.125 and 8 micrograms/ml, respectively . A correlational analysis of the MICs of these drugs for the clinical isolates revealed the presence of cross-resistance of the organisms to KRM and either RMP or RBT although the MICs of KRM were distributed over a much lower range than were those of the other two drugs . KRM and RMP at concentrations of 1 to 10 micrograms/ml almost completely inhibited the bacterial growth of RMP-sensitive strains (H37Rv, Kurono, and Fujii) of M . tuberculosis phagocytosed in macrophage-derived J774.1 cells . KRM was more active than RMP in inhibiting the growth of the RMP-resistant (MIC = 8 micrograms/ml) Kurata strain but failed to show such an effect against the RMP-resistant (MIC >128 micrograms/ml) Watanabe stain . When KRM was given to M . tuberculosis-infected mice at dosages of 5 to 20 mg/kg of body weight by gavage, one daily six times per week from day 1 after infection, it was much more efficacious than RMP against infections induced in mice by the RMP-sensitive Kurono strain, as measured by a reduction of rates of mortality, a reduction of the frequency and extent of gross lung lesions, histopathological changes in lung tissues, and a decrease in the bacterial loads in the lungs and spleens of infected mice . KRM also displayed significant therapeutic efficacy against infection induced by the RMP-resistant Kurata strain, while neither KRM nor RMP was efficacious against infection by the RMP-resistant Watanabe strain . In the case of infection with the Kurono strain, the efficacy of the drugs in prolonging the time of survival was in the order KRM, RBT, RMP . KRM was much more efficacious than RMP, when given at 1- to 4-week intervals . These findings suggest that KRM may be useful for the clinical treatment of tuberculosis contracted through RMP-sensitive strains, even when it is administered at long intervals.

J Appl Bacteriol, 1995 Oct, 79(4), 379 - 83
Response of Saccharomyces cerevisiae strains to antineoplastic agents; Delitheos A et al.; The effect of several antineoplastic agents on Saccharomyces cerevisiae strains has been investigated . Minimum inhibitory concentration (MIC), minimum cytotoxic concentration (MCC) and median effective concentration (EC50) were determined to identify strains with inherent sensitivity to the agents tested . Several strains proved to be sensitive to the antimetabolites 5-fluorouracil and methotrexate as well as to doxorubicin and cis-platine . On the contrary m-amsacrine, procarbazine, vinca alcaloids, melphalan and hydroxyurea were inactive at concentrations up to 400 micrograms ml-1 . The strain ATCC 2366, the most relatively sensitive to the agents tested, was used for studying the effect of treatment duration and of drug concentration on cell survival . Methotrexate and cis-platine, which according to MIC and MCC tests seemed ineffective for this strain, reduced survival significantly after 6 h of treatment . A correlation of the shape of the survival curves with MIC and MCC values was attempted.

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