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 res