bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor
Authors: Barbhaiya R H , Shukla U A , Gleason C R , Shyu W C , Pittman K A
Published: June 2012

The objective of this study was to assess the effects of food on the pharmacokinetics of cefprozil and cefaclor. A group of 12 healthy male volunteers received a single 250-mg dose of cefprozil or cefaclor under fasting conditions as well as after the intake of food. There was a 1-week washout period between each treatment. Serial blood samples were collected and assayed for cefprozil or cefaclor by specific high-pressure liquid chromatographic methods. The mean +/- standard deviation peak concentration (Cmax) of cefprozil in plasma was 6.13 +/- 1.22 micrograms/ml under the fasting condition and 5.27 +/- 1.06 micrograms/ml after breakfast, and these values were not significantly different from each other. The corresponding median time to reach Cmax was prolonged after food intake, but this difference was not significant. The mean Cmax values of cefaclor decreased significantly from 8.70 +/- 2.72 micrograms/ml under the fasting condition to 4.29 +/- 1.52 micrograms/ml after breakfast, and the corresponding median times to reach Cmax were significantly prolonged. The mean half-lives of cefprozil and cefaclor were nearly identical for the two treatments, suggesting that the elimination kinetics of these cephalosporins remained unaltered when the drugs were administered with food. The area under the plasma-concentration-versus-time curves for fasted and fed conditions were not significantly different for both drugs. The results of this study indicate that the extent of absorption and rate of elimination of both cephalosporins remain unaltered in the presence of food. However, the absorption rate of cefaclor is significantly reduced in the presence of food, while that of cefprozil remains unaltered. As a result, the Cmax of cefaclor is significantly reduced in the presence of food, whereas that of cefprozil is not significantly affected. Cefprozil can be administered with a meal without markedly affecting levels in blood.
Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rhesus monkeys
Authors: Schinazi R F , Boudinot F D , Doshi K J , McClure H M
Published: June 2012

3'-Fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine are nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution of the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailability of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% +/- 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythymidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.
Dissemination of amikacin resistance gene aphA6 in Acinetobacter spp
Authors: Lambert T , Gerbaud G , Bouvet P , Vieu J F , Courvalin P
Published: June 2012

The distribution of the aphA6 gene, encoding a 3'-aminoglycoside phosphotransferase type VI, was studied by dot blot hybridization with 115 amikacin-resistant Acinetobacter strains from various geographical areas. Nucleotide sequences related to aphA6 were found in 109 strains belonging to seven species. As inferred from results of Southern hybridization, dissemination of amikacin resistance in Acinetobacter spp. is due to a gene rather than a strain or plasmid epidemic.
Effects of supraphysiologic temperature and broth dilution on serum protein binding
Authors: White R L , Kays M B , Armstrong T A , Friedrich L V
Published: June 2012

Pooled human serum, unheated (UU) and heated at 56 degrees C for 30 (HU-30) and 60 (HU-60) min, and these media diluted 1:1 with broth (UD, HD-30, and HD-60) were used to assess the effects of supraphysiologic temperature and broth dilution on the serum protein binding of ceftriaxone. Protein binding was determined by ultrafiltration and subsequent high-performance liquid chromatography analysis. Significant differences in protein binding between UU and HU-60 (P less than 0.05), UD and HD-60 (P less than 0.01), HD-30 and HD-60 (P less than 0.01), and all undiluted and diluted media (P less than 0.01) were found. These alterations in protein binding may influence the in vitro microbiologic testing of highly protein-bound antibiotics.
Evidence for a staphylococcal-like mercury resistance gene in Enterococcus faecalis
Authors: Zscheck K K , Murray B E
Published: June 2012

We investigated mercury resistance (Hgr) in 52 clinical isolates of Enterococcus faecalis from two different geographical regions. Eleven of the 52 strains were resistant to HgCl2, and plasmids from these enterococci hybridized with a staphylococcal mercury resistance gene probe. Hgr from 5 of the 11 transferred at frequencies ranging from approximately 2 X 10(-7) to 2 X 10(-3).
Pathogenicity for humans of human rhinovirus type 2 mutants resistant to or dependent on chalcone Ro 09-0410
Authors: Yasin S R , al-Nakib W , Tyrrell D A
Published: June 2012

Mutants of human rhinovirus type 2 (HRV-2) resistant to and dependent on the antirhinoviral compound chalcone Ro 09-0410 were selected in cell culture under clean laboratory conditions. A total of 42 volunteers were challenged with either the drug-resistant mutant [SR2-410(r)] (15 volunteers), the drug-dependent mutant [SR2-410(d)] (15 volunteers), or a wild-type HRV-2 which had a similar passage level in vitro as the mutants but without the drug (12 volunteers). Of volunteers challenged with the wild-type HRV-2, 33, 67, and 82% developed cold symptoms, shed virus, and showed serological evidence of infection, respectively. In contrast, only 13, 27, and 23% of volunteers challenged with the drug-resistant mutant developed colds, shed virus, and showed serological evidence of infection, respectively. None of the volunteers challenged with the drug-dependent virus became infected or had symptoms of colds. These results demonstrate that a drug-resistant rhinovirus was capable of infecting humans and producing disease, although its infectivity was reduced when compared with that of the wild type. In contrast, a drug-dependent virus had lost its ability to infect humans.
Liposome-encapsulated-gentamicin therapy of Mycobacterium avium complex infection in beige mice
Authors: Klemens S P , Cynamon M H , Swenson C E , Ginsberg R S
Published: June 2012

The efficacy of liposome-encapsulated gentamicin and free gentamicin was evaluated with the beige (C57BL/6J-bgj/bgj) mouse model of disseminated Mycobacterium avium complex infection. Approximately 10(7) viable M. avium complex cells were given intravenously. Seven days later, treatment with either encapsulated or free gentamicin at 20 mg/kg of body weight was started. Treatment was given daily for 5 consecutive days or twice weekly for 3 weeks. The mice were sacrificed 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined. An analysis of variance and subsequent Tukey honestly significant difference tests indicated that both encapsulated and free gentamicin reduced viable cell counts in each of the organs compared with no treatment. Encapsulated gentamicin significantly reduced viable cell counts in the spleen and liver compared with the free gentamicin. A dose-response experiment was performed with a daily dose of 0.2, 2, or 20 mg/kg. Dose-related reductions in viable cell counts were observed for spleens and livers, although none of the regimens resulted in sterilization of these organs. Liposome-encapsulated gentamicin should be considered for further evaluation in the treatment of M. avium complex infection in humans.
High-level chromosomal gentamicin resistance in Streptococcus agalactiae (group B)
Authors: Buu-Hoï A , Le Bouguenec C , Horaud T
Published: June 2012

This is the first report of high-level gentamicin resistance in a group B streptococcus. Strain B128 of serotype II was isolated from an infected leg wound in 1987. B128 was resistant to high levels of gentamicin as well as of all other available aminoglycosides and was also resistant to tetracyclines. No bactericidal synergism was found between ampicillin or vancomycin and any of these aminoglycosides. Gentamicin, kanamycin, streptomycin, and tetracycline resistance determinants transferred by conjugation into a plasmid-free group B streptococcus recipient at a frequency of 10(-8) to 10(-9) transconjugants per donor cell. No transconjugants were detected when streptococci of groups A, C, and G, Streptococcus sanguis, or Enterococcus faecalis was used as a recipient. No plasmids were detected in B128 or in any of the four transconjugants tested. By DNA-DNA hybridization, homology was detected between gene aac6/aph2, of E. faecalis origin, and a 2.4-kilobase HindIII chromosomal fragment of B128; homology to the genes aph3 and aadE, of E. faecalis origin, was found with HindIII chromosomal fragments of the same size (3.0 kilobases). Strains like B128, which potentially can be responsible for severe neonatal infections, are of great clinical concern, since there are to date no antibiotic combinations exhibiting bactericidal synergism against them.
In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and determination of the molecular basis of the antifungal property
Authors: Marcireau C , Guilloton M , Karst F
Published: June 2012

The effects of fenpropimorph on sterol biosynthesis and growth of Saccharomyces cerevisiae were examined to pinpoint the mode of action of fungicides that inhibit ergosterol biosynthesis. Taking advantage of sterol auxotrophy and sterol permeability in mutant strains, we show that growth inhibition is strongly correlated with inhibition of sterol biosynthesis. We confirm that in vivo and at low concentrations, fenpropimorph inhibits delta 8----delta 7-sterol isomerase, and in addition, when it is used at higher concentrations, it inhibits delta 14-sterol reductase. We show also that the fungistatic effect of fenpropimorph is not due to the accumulation of abnormal sterols in treated cells but is linked to the specific inhibition of ergosterol biosynthesis, leading to the arrest of cell proliferation in the unbudded G1 phase of the cell cycle.
Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with hepatic cirrhosis
Authors: Hayton W L , Kneer J , Blouin R A , Stoeckel K
Published: June 2012

The pharmacokinetics of orally administered cefetamet pivoxil and intravenously administered cefetamet were studied in 12 healthy subjects and 12 patients with hepatic cirrhosis without ascites. Cirrhosis had no detectable effect on the pharmacokinetics of cefetamet and on the bioavailability of cefetamet pivoxil. After intravenous cefetamet in control versus cirrhotic subjects, respectively, the following mean +/- standard deviation values were observed: total body clearance, 128 +/- 10.2 versus 123 +/- 28.8 ml/min; steady-state volume of distribution, 23.2 +/- 2.2 versus 22.7 +/- 4.6 liters; half-life, 2.42 +/- 0.21 versus 2.35 +/- 0.41 h. Renal and nonrenal clearances of cefetamet were similar in both groups, as were the mean residence times and areas under the plasma concentration-time curve. For oral cefetamet pivoxil, no differences were detected in the mean values of the percentage of dose absorbed: 44.6 +/- 9.1 versus 50.1 +/- 12.9. The rate of appearance of cefetamet in the plasma also was not affected by cirrhosis: similar mean values were found for the mean residence time and the maximum concentration in plasma and its time of occurrence.
Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis
Authors: Bell C A , Hall J E , Kyle D E , Grogl M , Ohemeng K A , Allen M A , Tidwell R R
Published: June 2012

The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) and Plasmodium falciparum clones W2 (Indochina III/CDC) and D6 (Sierra Leone I/CDC). Pentamidine and each of the analogs tested exhibited activity in vitro against L. m. amazonensis and P. falciparum. The pentamidine analogs were more effective against the P. falciparum clones than against L. m. amazonensis. P. falciparum was extremely susceptible to these compounds, with 50% inhibitory concentrations as low as 0.03 microM. While none of the analogs exhibited marked improvement in antileishmanial activity compared with pentamidine, 12 of the pentamidine analogs showed activity approximately equal to or greater than that of the parent compound. From the promising activity exhibited by the pentamidine analogs in this in vitro study and their potential for reduced toxicity relative to the parent drug, pentamidine-related compounds hold promise as new agents for the treatment of protozoal infections.
In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to six new oral cephalosporins
Authors: Hoppe J E , Müller J
Published: June 2012

Of six new oral cephalosporins, cefixime and cefpodoxime were the most active (MIC for 90% of isolates tested [MIC90], 16 micrograms/ml) against Bordetella pertussis, followed by cefetamet, cefprozil, and loracarbef (LY163892) (MIC90, 64 micrograms/ml) and ceftibuten (MIC90, 128 micrograms/ml). Against Bordetella parapertussis, loracarbef was more active (MIC90, 32 micrograms/ml) than the other compounds tested (MIC90s, 64 to greater than 128 micrograms/ml). The new oral cephalosporins are unlikely to play a role in pertussis treatment.
Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase
Authors: Bitonti A J , Byers T L , Bush T L , Casara P J , Bacchi C J , Clarkson A B , McCann P P , Sjoerdsma A
Published: June 2012

A structural analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxy adenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (tau 50, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 microM), and was apparently irreversible. The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of alpha-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.
Activities of clarithromycin, sulfisoxazole, and rifabutin against Mycobacterium avium complex multiplication within human macrophages
Authors: Perronne C , Gikas A , Truffot-Pernot C , Grosset J , Pocidalo J J , Vilde J L
Published: June 2012

The activities of clarithromycin, sulfisoxazole, and rifabutin against three virulent strains of Mycobacterium avium complex isolated from patients with acquired immunodeficiency syndrome were evaluated in a model of intracellular infection. Human monocyte-derived macrophages were infected at day 6 of culture with M. avium complex. Intracellular bacteria were counted 60 min after inoculation. Extra- and intracellular bacteria were counted at days 4 and 7 after inoculation. The concentrations used were 4 micrograms of clarithromycin per ml (MICs for the three strains, 4, 4, and 4 micrograms/ml), 50 micrograms of sulfisoxazole per ml (MICs, 50, 25, and 25 micrograms/ml), and 0.5 micrograms of rifabutin per ml (MICs, 2, 0.5, and 0.5 micrograms/ml). Compared with controls, clarithromycin and rifabutin slowed the intracellular replication of the three strains (at day 7 after inoculation, P was less than 0.01 for the first strain and less than 0.001 for the two others). Sulfisoxazole was ineffective against the three strains. Clarithromycin was as effective as rifabutin. Clarithromycin plus rifabutin was as effective as each single agent. Clarithromycin plus sulfisoxazole was as effective as clarithromycin alone.
Effects of incubation temperature, inoculum size, and medium on agreement of macro- and microdilution broth susceptibility test results for yeasts
Authors: Cook R A , McIntyre K A , Galgiani J N
Published: June 2012

We examined the effects of temperature and inoculum on the agreement of macro- and microdilution broth MICs of five antifungal agents against six isolates of Candida species or Torulopsis glabrata. Incubation temperature affected results with amphotericin B, flucytosine, fluconazole, and SCH 39304, producing better agreement at 35 degrees C than at 37 degrees C. Agreement between methods was better with an inoculum size of 10(2) than with one of 10(4) yeast cells per ml in testing fluconazole or SCH 39304, and the discrepancies seen with a higher incubation temperature and a larger inoculum appeared to be additive. However, inoculum size did not seem to affect agreement between methods in testing amphotericin B, flucytosine, or ketoconazole. Regardless of test conditions, macrodilution broth MICs of amphotericin B for different isolates were strikingly higher than microdilution test MICs, with mean differences being greater than ninefold under some test conditions. We conclude that for most currently available antifungal agents, an incubation temperature of 35 degrees C and a starting yeast inoculum of less than 10(4) cells per ml improve the agreement between macro- and microdilution broth tests.
OHIO-1 beta-lactamase is part of the SHV-1 family
Authors: Shlaes D M , Currie-McCumber C , Hull A , Behlau I , Kron M
Published: June 2012

The OHIO-1 beta-lactamase gene was subcloned in a 1.16-kilobase TaqI fragment in the 2.4-kilobase chimeric plasmid pSK04. After directional subcloning into M13, the DNA sequence of this fragment was determined. The results showed an open reading frame of 858 base pairs (bp) encoding a protein of 286 amino acids. The structural gene showed 95, 87, and 60% DNA sequence identity with SHV-1, LEN-1, and TEM-1, respectively, and 93, 85, and 62% predicted amino acid sequence identity, respectively. The 87 bp upstream of the OHIO-1 structural gene had 96% identity with the upstream flanking sequence of SHV-1, including the -35 and -10 consensus sequences and the putative ribosomal binding site. A 223-bp DNA probe derived from a PstI-HaeII fragment in the C-terminal sequence of OHIO-1 had predicted 96, 88, and 61% sequence identity with SHV-1, LEN-1, and TEM-1, respectively. This probe hybridized to SHV-1 and poorly to LEN-1, but not to TEM-1 or a variety of other plasmid-mediated beta-lactamase genes, under stringent conditions. Screening of plasmid DNA derived from 40 ampicillin-resistant clinical isolates by Southern hybridization with the 223-bp probe uncovered no strains encoding OHIO-1. Isoelectric focusing of the same collection did identify two strains producing enzymes resembling SHV-1, however. We have also performed a kinetic comparison of OHIO-1, SHV-1, and TEM-1. OHIO-1 and SHV-1 were indistinguishable from each other but could be distinguished from TEM-1. These data clearly place OHIO-1 within the SHV-1 family of beta-lactamases.
Enhanced action of amphotericin B on Leishmania mexicana resulting from heat transformation
Authors: Ramos H , Milhaud J , Cohen B E , Bolard J
Published: June 2012

A comparative study of the effect of the polyene antibiotic amphotericin B (AmB) on the viability of Leishmania mexicana promastigotes before and after their transformation by heat into amastigotelike forms was carried out. The kinetics of cell death were followed by spectrofluorometry with the nucleic acid-binding compound ethidium bromide. It was found that the rapid killing effect that is exerted by AmB on Leishmania promastigotes was even faster after their transformation into amastigotelike forms. Binding studies of AmB to Leishmania membranes by circular dichroism indicated that heat transformation modified it from noncooperative to cooperative binding, decreasing the amount of antibiotic that bound to the membranes. Thus, the increased rate of ethidium bromide incorporation into transformed cells was not related either to the amount of AmB bound or to an increased amount of ergosterol in the membrane (the ergosterol/phospholipid ratio was four times smaller after heat shock). An increase in the Mg2+ content of the external aqueous solution was able to prevent the AmB-induced incorporation of ethidium bromide into Leishmania promastigotes to a greater extent (Ki = 13.8 mM) than it was into heat-transformed cells (Ki = 64 mM), suggesting that there were significant changes at the Leishmania cell surface on heat transformation. The significance of these results for understanding the mechanism of action of AmB on sensitive organisms is discussed.
In vitro susceptibility of Ehrlichia sennetsu to antibiotics
Authors: Brouqui P , Raoult D
Published: June 2012

Antibiotic efficacies were evaluated by Diff-Quik (Dade, Düdingen, Federal Republic of Germany) staining of Ehrlichia sennetsu in P388D1 murine macrophages grown in 96-well microtiter plates. Sennetsu disease is generally cured with tetracyclines. In vivo, E. sennetsu is susceptible to doxycycline and is resistant to erythromycin, penicillin, and chloramphenicol. Our study confirmed, in vitro, the efficacy of doxycycline, which had an MIC of 0.125 micrograms/ml. E. sennetsu was found to be resistant to erythromycin, chloramphenicol, penicillin, gentamicin, and co-trimoxazole, while it was very susceptible to ciprofloxacin (MIC, 0.125 micrograms/ml) and rifampin (MIC, 0.5 micrograms/ml).
Activity of compound G2 isolated from alfalfa roots in experimental dermatophyte infection
Authors: Evron R , Guizie M , Zehavi U , Polacheck I
Published: June 2012

Compound G2 isolated from alfalfa roots was applied topically to skin lesions of guinea pigs experimentally infected with the dermatophyte Trichophyton mentagrophytes var. granulare. After 12 to 15 applications, 80% of the infected lesions were cured, as judged by clinical and microbial criteria, compared with 20% of the untreated lesions which healed spontaneously (P less than 0.01).
In vitro activities of fleroxacin, cefetamet, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanic acid against rare members of the family Enterobacteriaceae primarily of human (clinical) origin
Authors: Hohl P , Lüthy-Hottenstein J , Zollinger-Iten J , Altwegg M
Published: June 2012

Fleroxacin and cefetamet were evaluated in vitro against 38 infrequently encountered species (250 strains) of the family Enterobacteriaceae and compared with four established compounds. For all the strains tested, the fleroxacin MIC was less than or equal to 0.5 mg/liter, and for 98% of strains the cefetamet MIC was less than or equal to 8 mg/liter; even though the two new compounds did not quite reach the activities (on a weight-by-weight basis) of ciprofloxacin and ceftriaxone, respectively, they nonetheless clearly surpassed trimethoprim-sulfamethaxazole and amoxicillin-clavulanic acid. The very potent new oral compounds tested in this study appear to be promising for the treatment of clinically relevant infections due to uncommon species of Enterobacteriaceae.
Effect of rifabutin on disseminated Mycobacterium avium infections in thymectomized, CD4 T-cell-deficient mice
Authors: Furney S K , Roberts A D , Orme I M
Published: June 2012

Disseminated Mycobacterium avium infection is the major cause of bacteremia in patients with acquired immunodeficiency syndrome. We present here a new animal model of this disease, thymectomized C57BL/6 mice that were intravenously infused with monoclonal antibody to selectively deplete CD4+ T cells. The increased susceptibility of such animals to M. avium infection is comparable to that of C57BL/6 beige mice and thus may provide a viable alternative to the latter model. Further, using representative strains of acquired immunodeficiency syndrome-associated M. avium (serotypes 1, 4, and 8 and a rough isolate), we show that the course of such infections in thymectomized, CD4-deficient mice can be markedly restrained and in some cases the infections can be sterilized by treatment over a 120-day period with a regimen containing 40 mg of the new antimycobacterial agent rifabutin per kg (body weight).
In vitro selection of resistant Helicobacter pylori
Authors: Haas C E , Nix D E , Schentag J J
Published: June 2012

Four strains of Helicobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromycin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, although the MIC of amoxicillin was increased 4- to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.
Application of a modified bioassay for monitoring serum teicoplanin and vancomycin in febrile neutropenic patients
Authors: Kureishi A , Jewesson P J , Bartlett K H , Cole C D , Chow A W
Published: June 2012

Teicoplanin is a glycopeptide antibiotic with a mode of action and spectrum of activity similar to those of vancomycin. Its efficacy and tolerability as empiric therapy and its pharmacokinetic properties in neutropenic patients are being studied in a double-blinded, randomized trial in comparison with those of vancomycin. We report here a modified agar diffusion bioassay which is suitable for monitoring levels of either teicoplanin or vancomycin in serum during combination therapy with beta-lactams, aminoglycosides, and amphotericin B. Serum samples spiked with either teicoplanin or vancomycin gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, amphotericin B, or their combinations. Among 25 patients who received teicoplanin at a dosing schedule of 6 mg/kg every 24 h intravenously, steady state was reached after 14.2 +/- 4.0 days, and 1-h peak and trough concentrations of teicoplanin in serum at steady state were 40.8 +/- 15.0 and 12.5 +/- 3.2 mg/liter, respectively. In contrast, among 25 patients who received vancomycin at a dosing schedule of 15 mg/kg every 12 h intravenously, steady state was reached by 24 h, and the 1-h peak and trough concentrations in serum were 37.5 +/- 15.6 and 8.3 +/- 3.8 mg/liter, respectively. The elimination half-lives for teicoplanin estimated by two separate approaches agreed closely with each other: 80.5 +/- 21.5 h by an accumulation model (M. Gilbaldi and D. Perrier, Pharmacokinetics, 2nd ed., p. 121, 1982) and 87.3 +/- 19.3 h as predicted from the degree of renal function (M. Rowland, Clin. Pharmacokinetic 18:184-209, 1990). These values were 14- to 15-fold higher than that for vancomycin (5.6 +/- 1.8 h). Since considerable variability was noted in the pharmacokinetic parameters for both teicoplanin and vancomycin among the individual patients, our data further emphasized the need for frequent monitoring of these drugs during empiric therapy of the febrile neutropenic patient.
Detection of methicillin resistance in staphylococci by using a DNA probe
Authors: Archer G L , Pennell E
Published: June 2012

A DNA probe derived from the PBP 2a gene of the methicillin-resistant Staphylococcus aureus COL was compared with phenotypic microbiologic tests for its ability to identify methicillin-resistant and -susceptible staphylococci. Lysates were applied to nitrocellulose with a dot blot apparatus. Isolates tested were both S. aureus and coagulase-negative staphylococci that had been recovered from a variety of geographic and clinical sources. When compared with a spread plate phenotypic test, the DNA probe gave sensitivity, specificity, and predictive values for both positive and negative tests of 100% for 204 S. aureus isolates (103 positive, 101 negative) and 99, 95, 99, and 95%, respectively, for 249 coagulase-negative staphylococci (210 positive, 39 negative). The probe was more sensitive than broth microdilution and more specific than agar dilution in identifying methicillin-resistant and -susceptible coagulase-negative staphylococci; all tests were equally accurate in identifying the methicillin susceptibility of S. aureus. DNA probe analysis for determining the methicillin susceptibility of staphylococci was rapid, easily interpretable, and equally accurate with radioactive and nonradioactive probes, and it gave results equivalent to the most sensitive microbiologic test for all staphylococcus species studied.
Mathematical modeling of antimicrobial susceptibility data of Staphylococcus haemolyticus for 11 antimicrobial agents, including three experimental glycopeptides and an experimental lipoglycopeptide
Authors: Hunter P R , George R C , Griffiths J W
Published: June 2012

Antimicrobial MIC data were obtained for 96 strains of Staphylococcus haemolyticus and the following 11 antimicrobial agents: methicillin, gentamicin, rifampin, fusidic acid, ciprofloxacin, vancomycin, teicoplanin; three experimental glycopeptides, MDL 62,873, MDL 62,208, and MDL 62,224; and an experimental lipoglycopeptide, ramoplanin. Resistance to methicillin and gentamicin was present in over 50% of the strains, although resistance to the other agents was present in less than 10%. It is shown how application of mathematical modeling techniques can add to the understanding of such MIC data. MICs of methicillin and gentamicin were highly correlated, suggesting that evolutionary pressures for development of resistance to these agents were similar. The structural relationships among the glycopeptides were accurately reflected in their spatial relationships within the model. MICs of ramoplanin were negatively correlated with MICs of some other antimicrobial agents, particularly gentamicin, suggesting that this agent is more active against gentamicin-resistant strains. Methicillin-resistant strains were more tightly clustered than were methicillin-susceptible strains, suggesting that methicillin-resistant strains were more closely related to each other than were methicillin-susceptible strains. Mathematical modeling techniques enable more detailed analysis of MIC data.
Antistaphylococcal activity of pentamidine
Authors: Libman M D , Miller M A , Richards G K
Published: June 2012

Pentamidine isethionate was bacteriostatic against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus sanguis, Micrococcus sp., and Candida albicans. S. aureus was inhibited by concentrations of 16 to 64 micrograms/ml and killed by 64 to greater than or equal to 128 micrograms/ml. Staphylococcal killing was consistently greater in the presence of cations and was unaffected by methicillin resistance.
Efficacy of ampicillin versus trimethoprim-sulfamethoxazole in a mouse model of lethal enterococcal peritonitis
Authors: Chenoweth C E , Robinson K A , Schaberg D R
Published: June 2012

Lethal enterococcal peritonitis in mice was used to compare trimethoprim-sulfamethoxazole (TMP-SMX) therapy with ampicillin therapy. Peritoneal fluid showed a 10(3)-CFU decrease in enterococci with ampicillin compared with TMP-SMX. Mortality of the untreated mice was 100%, compared with 40% for ampicillin and 95% for TMP-SMX, despite adequately measured levels in serum and peritoneal fluid.
Comparative study of cephradine and amoxicillin-clavulanate in the treatment of recurrent urinary tract infections
Authors: Brumfitt W , Hamilton-Miller J M
Published: June 2012

Eighty-eight female patients with a history of recurrent urinary tract infections were treated according to a randomization scheme with either 1 g of cephradine every 12 h (47 patients) or 375 mg of amoxicillin-clavulanate every 8 h (41 patients) for 7 days. The treatments were equally effective (cure rates of 89% for cephradine and 88% for amoxicillin-clavulanate) and showed similar relapse rates (cephradine, 14%; amoxicillin-clavulanate, 11%). Adverse effects were similar in both groups (cephradine, 23%; amoxicillin-clavulanate, 22%).
Mode of action of GR69153, a novel catechol-substituted cephalosporin, and its interaction with the tonB-dependent iron transport system
Authors: Silley P , Griffiths J W , Monsey D , Harris A M
Published: June 2012

GR69153 is a novel cephalosporin incorporating a catechol-substituted 7-aminothiazolyl-oxime. The antibiotic is actively transported into gram-negative cells via iron-regulated outer membrane proteins regulated by the tonB product. This transport enhances bactericidal activity most significantly at low concentrations, essentially removing the permeability barrier for antibiotic uptake.
Endogenous colonization by gentamicin-resistant gram-negative bacilli elaborating aminoglycoside (3)-5-acetyltransferase
Authors: Barg N L , Cooper J F
Published: June 2012

Members of the family Enterobacteriaceae that elaborate aminoglycoside 3-5-acetyltransferase [AAC(3)-5] caused a nosocomial outbreak at the Vanderbilt University Medical Center and have persisted. To see whether the gene for AAC(3)-5 was present in the community, stool cultures of newly admitted patients and ambulatory persons were examined with a specific gene probe. AAC(3)-5-positive strains were present in the intestinal flora examined.
In vitro activities of ampicillin-sulbactam and cefoperazone-sulbactam against oxacillin-susceptible and oxacillin-resistant staphylococci
Authors: Barry A L , Jones R N
Published: June 2012

Ampicillin-sulbactam and cefoperazone-sulbactam were tested against staphylococci that were collected from 40 different medical centers throughout the United States. Oxacillin-resistant strains were resistant to both drug combinations, but oxacillin-susceptible strains were uniformly susceptible. The latter included strains with borderline susceptibility to oxacillin and methicillin.
Comparative in vitro activities of a new quinolone, WIN 57273, and piperacillin plus tazobactam against anaerobic bacteria
Authors: Venezia R A , Yocum D M , Robbiano E M , Echols R M
Published: June 2012

The in vitro activities of a new quinolone, WIN 57273, and the combination of piperacillin and tazobactam, a beta-lactamase inhibitor, were compared with those of cefoxitin, ceftizoxime, chloramphenicol, clindamycin, imipenem, metronidazole, and piperacillin for 123 clinical anaerobic isolates. Ceftizoxime and cefoxitin had equivalent activities, while metronidazole was active against gram-negative isolates. In the Bacteroides fragilis group, species other than B. fragilis were the most resistant. The combination of piperacillin with tazobactam in a ratio of 8 to 1 was more effective than piperacillin against B. fragilis group organisms when the MIC of piperacillin was greater than or equal to 64 micrograms/ml. Overall, WIN 57273 (i) and imipenem (ii) were the most active agents, with MICs for 50 and 90% of strains of (i) 0.25 and 0.5 and (ii) 0.125 and 2 microgram/ml, respectively.
Increasing resistance of Staphylococcus aureus to ciprofloxacin
Authors: Daum T E , Schaberg D R , Terpenning M S , Sottile W S , Kauffman C A
Published: June 2012

We demonstrated the marked emergence of resistance to ciprofloxacin among Staphylococcus arueus strains isolated at the Ann Arbor Veterans Administration Medical Center. All S. aureus isolates tested from 1984 to 1985 were susceptible, whereas 55.1% of methicillin-resistant and 2.5% of methicillin-susceptible strains from 1989 had high-level resistance to ciprofloxacin.
In vitro antibacterial activity of KP-736, a new cephem antibiotic
Authors: Maejima T , Inoue M , Mitsuhashi S
Published: June 2012

KP-736, a new cephen antibiotic with a broad antibacterial spectrum and potent antipseudomonal activity, was evaluated for in vitro antibacterial activity in comparison with ceftazidime, cefotaxime, and cefpirome. KP-736 was significantly more active than the test compounds against gram-negative bacteria, including the Pseudomonas group and ceftazidime-, cefotaxime-, or imipenem-resistant strains, but less active against gram-positive bacteria. KP-736 had very high affinities for penicillin-binding protein 3 (PBP 3) of Escherichia coli K-12 and PBP 1A and PBP 3 of Pseudomonas aerugiosa NCTC 10490 and showed potent bactericidal activities against these two strains. It was stable to hydrolysis by penicillinases and cephalosporinases but was slightly hydrolyzed by oxyiminocephalosporinases and type II penicillinase.
Differential inhibition of chitin synthetases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and nikkomycins
Authors: Cabib E
Published: June 2012

Polyoxin D, nikkomycin X, and nikkomycin Z are all competitive inhibitors of chitin synthetase 2 (Chs2), the essential enzyme for primary septum formation in Saccharomyces cerevisiae, and of Chs1, a repair enzyme. However, Chs2 is more resistant to these antibiotics than Chs1. When Co2+, the best stimulator of Chs2, was used in the assay for this enzyme, the differences in the Ki values for nikkomycins between the two isozymes reached 3 orders of magnitude. These results point to differences in the active sites of the two isozymes. Polyoxin D was much more effective than nikkomycin Z in inhibiting cell growth. This underlines the importance of the choice of enzyme and of assay conditions when cell wall-synthesizing enzymes are used in screens for possible antifungal agents.
Novel method for measurement of outer membrane permeability to new beta-lactams in intact Enterobacter cloacae cells
Authors: Bellido F , Pechère J C , Hancock R E
Published: June 2012

The ability of five new beta-lactams to permeate the outer membrane of intact Enterobacter cloacae beta-lactamase-overproducing cells was measured by using a high-pressure liquid chromatography (HPLC)-based technique that avoided certain possible artifacts of the traditional methods. Low concentrations of antibiotics were mixed with bacterial suspensions, and at different times, the cells were removed from the medium by filtration. Residual beta-lactam concentrations in the medium were then assessed by HPLC and UV detection. The assay was performed under conditions in which no beta-lactamase activity was detected in the filtrate and the number of viable cells remained constant during the experiment. Outer membrane permeability was assessed with the Zimmermann-Rosselet equation, in which outer membrane permeability was rate limiting for hydrolysis of the beta-lactam by periplasmic beta-lactamase. Thus, the rate of disappearance of beta-lactam was equal to the rate of outer membrane permeation. Preincubation of bacterial suspensions with 300 micrograms of cloxacillin per ml inhibited the hydrolysis of beta-lactams by intact cells, demonstrating that beta-lactam hydrolysis by periplasmic beta-lactamase was essential in order to allow measurement of outer membrane permeability by this method. Permeability coefficients (P) were calculated from the Zimmermann-Rosselet equation and were independent of the external concentration of antibiotic over a 100-fold concentration range. Cefepime and cefpirome exhibited rates of outer membrane permeation 5- to 20-fold higher than those of carumonam, ceftriaxone, and cefotaxime. Thus, the presence of a positive charge in the 3-lateral chain increased the permeation ability of beta-lactam molecules considerably.
Novel method for measuring growth of Treponema hyodysenteriae and its application for monitoring susceptibility of clinical isolates to antimicrobial agents
Authors: Weber F H , Earley D L
Published: June 2012

A microdilution assay method was developed to determine MICs of antibiotics for Treponema hyodysenteriae and to estimate the bacterial burden of mice colonized by this swine pathogen. Hemolysis of bovine erythrocytes in broth was correlated with growth of the spirochete, and growth inhibition by drugs could be determined by measuring hemolysis. MICs of 10 antibiotics for eight clinical isolates of T. hyodysenteriae measured by this method were similar to values obtained by an agar dilution method and to values reported in the literature. This method was also used to demonstrate the elimination of T. hyodysenteriae from the ceca of infected mice following oral treatment with carbadox. The procedure described in this paper provides a rapid and simple method for determining MICs of antibiotics for T. hyodysenteriae and may be adapted for the purpose of determining the presence of this veterinary pathogen in cecal contents of experimentally infected mice.
Pyrimethamine-clarithromycin combination for therapy of acute Toxoplasma encephalitis in patients with AIDS
Authors: Fernandez-Martin J , Leport C , Morlat P , Meyohas M C , Chauvin J P , Vilde J L
Published: June 2012

Clarithromycin, a new macrolide, is effective in treating experimental Toxoplasma gondii infection. A pyrimethamine-clarithromycin combination was evaluated for the treatment of acute Toxoplasma encephalitis in 13 AIDS patients. The scheduled regimen was 2 g of clarithromycin per day and 75 mg of pyrimethamine per day for 6 weeks. The protocol was completed in eight patients and stopped in five patients (because of voluntary withdrawal by two patients, deterioration of neurological condition and thrombocytopenia in two patients, and suspicion of liver toxicity in one patient). The clinical and computed tomography scan responses at week 6 of treatment were 80 and 50%, respectively. Two patients died, one of toxoplasmic encephalitis and the other of cerebral bleeding due to pyrimethamine-induced thrombocytopenia. Adverse events related to therapy were nausea and/or vomiting (38%), skin rash (38%), significant increase of liver tests (24%), hearing loss (15%), and severe hematological abnormalities (31%). In this pilot study, a pyrimethamine-clarithromycin combination was shown to be comparable to the conventional regimen for the treatment of acute Toxoplasma encephalitis in AIDS patients.
Shell-vial assay: evaluation of a new technique for determining antibiotic susceptibility, tested in 13 isolates of Coxiella burnetii
Authors: Raoult D , Torres H , Drancourt M
Published: June 2012

Coxiella burnetii is a strictly intracellular bacterium. Bacteriostatic effects have been described previously on a few isolates in embryonated eggs (A. J. Spicer, M. G. Peacock, and J. C. Williams, p. 375-383, in W. Burgdorfer and R. L. Anacker, ed., Rickettsiae and rickettsial diseases, 1981). We used the shell-vial technique (D. Raoult, G. Vestris, and M. Enea, J. Clin. Microbiol. 28:2482-2484, 1990) to determine the susceptibility of C. burnetii to amoxicillin, amikacin, erythromycin, co-trimoxazole, pefloxacin, ofloxacin, ciprofloxacin, chloramphenicol, tetracycline, doxycycline, minocycline, and rifampin antibiotics at a single dilution. Human embryonic lung fibroblast monolayers in shell vials were seeded with 13 different C. burnetii isolates, including 3 reference strains (Nine Mile, Q212, and Priscilla) and 10 new isolates, in order to obtain 30% infected cells 6 days later. After inoculation, antibiotics were added, shell vials were incubated for 7 days, and immunofluorescence was revealed and compared with that of the positive controls. Strain Nine Mile was more susceptible than strains Q212 and Priscilla were. The heterogeneity of susceptibility to fluoroquinolones, chloramphenicol, and erythromycin was noted among the strains; all were resistant to amoxicillin and amikacin, and all were susceptible to rifampin, co-trimoxazole, tetracycline, and tetracycline analogs.
Single daily dosing of antibiotics: importance of in vitro killing rate, serum half-life, and protein binding
Authors: Potel G , Chau N P , Pangon B , Fantin B , Vallois J M , Faurisson F , Carbon C
Published: June 2012

The relative importance of pharmacokinetic and pharmacodynamic parameters for the feasibility of a single daily dose (SDD) of antibiotics remains to be established. Therefore, we studied the relationship between in vitro bacteriological parameters (MIC, MBC, and killing rate [KR], defined as the reduction in the inoculum within 3 h), pharmacokinetic parameters (t1/2 and protein binding [PB], and in vivo antibacterial effect of a single antibiotic dose in an experimental rabbit model of Escherichia coli endocarditis. Nine antibiotics were investigated: two aminoglycosides, two quinolones, and five beta-lactams. For each drug, the minimal effective dose (MED) (in milligrams per kilogram) was defined as the lowest dose able to achieve a significant difference (P less than 0.05) of CFU in the vegetations in comparison with controls 24 h after a single intravenous injection. Aminoglycosides and quinolones had the lowest MEDs, followed by beta-lactams. Univariate regression analysis showed that KR was the major determinant of MED. A stepwise regression analysis showed that t1/2 significantly improved the predictive value of KR, while PB, MIC, and MBC did not. The final equation was MED = 1,586-238 KR-297 t1/2 (r = 0.90, P = 0.01). We concluded that the pharmacodynamic parameters (especially the high KR) of aminoglycosides and quinolones explained their low MEDs and might allow SDD. In contrast, the low KR of beta-lactams emphasized the critical importance of a long t1/2, as for ceftriaxone, allowing the use of this beta-lactam alone in SDD.