bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro investigation of BK-218, a new oral and parenteral cephalosporin
Authors: Szabó I , Barabás J , Tar A , Kiss L , Filep M , Schmidt T , Marossy K , Tóth-Martinez B , Barabás G , Hernádi F
Published: June 2012

The antibacterial activity of BK-218 was similar to that of cefamandole when it was tested against several laboratory strains. The inhibiting effect of BK-218 was greater than that of cephalexin and cefoxitin on penicillin-binding proteins of Escherichia coli HB101. This result was in close correlation with the relative inhibition of radiolabeled glucosamine incorporation (greatest with BK-218) and with the lytic effect (most intensive with BK-218). BK-218 proved to be a good inhibitor for all five of the beta-lactamases that were investigated, although two enzymes (Enterobacter cloacae P99 and Pseudomonas aeruginosa Cilote) hydrolyzed it to some extent.
Induction potential of fluconazole toward drug-metabolizing enzymes in rats
Authors: Lavrijsen K L , Van Houdt J M , Van Dyck D M , Meuldermans W E , Heykants J J
Published: June 2012

The induction of drug-metabolizing enzymes in rat liver was studied after subchronic administration of the new triazole antifungal agent fluconazole. The administered doses were 10, 40, and 160 mg/kg per day for 7 days. Fluconazole behaved as a high-magnitude inducer and significantly increased cytochrome P-450 concentrations already at 10 mg/kg (+42%). Cytochrome P-450 induction by fluconazole was dose dependent and reached a value of 302% of the control value at the dose of 160 mg/kg. The induction effects on cytochrome P-450 were also reflected in the drug-metabolizing enzyme activities in hepatic microsomes of pretreated rats. Fluconazole (160 mg/kg per day) preferentially induced the demethylase activities of N,N-dimethylaniline and p-nitroanisole to 258 and 281% of the control values, respectively. The detoxification enzyme UDP-glucuronosyltransferase was significantly lowered by fluconazole at the highest dose. A possible link between the induction potential and the pharmacokinetic properties of triazole antifungal agents is discussed.
Double-blind, dose-range-finding study of fleroxacin (RO 23-6240; AM-833) for treatment of complicated urinary tract infections
Authors: Wolfhagen M J , Hoepelman A I , Verhoef J
Published: June 2012

In a double-blind randomized trial, we evaluated the efficacy and safety of three oral dosage regimens of fleroxacin, a new fluoroquinolone, once daily in 62 patients for the treatment of complicated urinary tract infections. The regimens compared were 200 mg for 10 days (n = 20), 400 mg for 10 days (n = 21), and 600 mg for 10 days (n = 21). Forty-five patients were evaluable for efficacy. A clinical cure was reached in 78% of the patients. Overall, a favorable bacteriological response (negative culture or reinfection at 4 to 6 weeks) was obtained in 36 of 45 (80%) patients. No significant difference could be found among the three dosage groups. During therapy, one Klebsiella ozaenae strain became resistant and one Pseudomonas aeruginosa strain became less susceptible to fleroxacin. In 13 patients, therapy had to be discontinued due to major adverse events (oliguria [n = 1], psychosis [n = 1], photosensitivity [n = 1], insomnia [n = 1], and nausea [n = 9]). Minor side effects were seen in 13 other patients. Increased dosage correlated significantly (P less than 0.01) with total number of adverse events.
Role of protonated and neutral forms of macrolides in binding to ribosomes from gram-positive and gram-negative bacteria
Authors: Goldman R C , Fesik S W , Doran C C
Published: June 2012

Erythromycin binds to a single site on the bacterial 50S ribosomal subunit and perturbs protein synthesis. However, erythromycin contains desosamine and thus exists in both protonated (greater than 96%) and neutral (less than 4%) forms at physiological pH because of the pKa of the dimethylamino group. We therefore examined the relative roles of both forms in binding to ribosomes isolated from two species each of gram-positive and gram-negative bacteria. We developed a system to directly measure the forward (association) rate constant of formation of the macrolide-ribosome complex, and we have measured both the forward and reverse (dissociation) rate constants as a function of pH. Forward rate constants and binding affinity did not correlate with pH when the interaction of erythromycin with ribosomes from both gram-positive and gram-negative bacteria was examined, demonstrating that the protonated form of this macrolide binds to ribosomes. Conversely, the neutral form of macrolide cannot be the sole binding species and appears to bind with the same kinetics as the protonated form. Forward rate constants were 3- to 4-fold greater at physiological pH, and binding affinity calculated from rate constants was 5- to 10-fold greater than previously estimated. Similar results were obtained with azithromycin, a novel 15-membered macrolide that contains an additional tertiary amine in the macrolide ring. Ribosome- and macrolide-specific kinetic parameters were demonstrated at neutral pH and may be related to the potency of the two macrolides against gram-positive and gram-negative bacteria.
Multiple-dose pharmacokinetics of concurrent oral ciprofloxacin and rifampin therapy in elderly patients
Authors: Chandler M H , Toler S M , Rapp R P , Muder R R , Korvick J A
Published: June 2012

The purpose of this clinical study was to investigate the influence of concomitant drug therapy with ciprofloxacin and rifampin on the individual pharmacokinetic profile of each agent in elderly patients. Twelve nursing home patients (age, 74 +/- 7 years), colonized with methicillin-resistant Staphylococcus aureus, were randomized to receive 14-day therapy with oral ciprofloxacin (750 mg every 12 h) (group A; n = 6) or ciprofloxacin (750 mg every 12 h) and oral rifampin (300 mg every 12 h) (group B; n = 6). Serial blood samples were obtained from 0 to 12 h following ciprofloxacin doses 1 and 13 and from 0 to 36 h after the last ciprofloxacin dose. No significant differences (P greater than 0.05) were found between or within groups in any pharmacokinetic parameter. The mean ciprofloxacin oral clearance values were 0.35 +/- 0.06, 0.41 +/- 0.15, and 0.38 +/- 0.11 liter/h per kg for doses 1, 13, and 28, respectively, in group A patients. The mean oral clearance values in group B patients for the respective doses were 0.53 +/- 0.36, 0.32 +/- 0.13, and 0.36 +/- 0.17 liter/h per kg. Likewise, no significant differences (P greater than 0.05) in rifampin pharmacokinetic parameters were found when compared with historical controls. These data suggest that ciprofloxacin and rifampin may be given concomitantly in standard clinical dosing regimens. The combination results in therapeutic levels of both drugs and appears to be safe for administration to elderly nursing home patients.
Evaluation of Bay R 3783 in rodent models of superficial and systemic candidiasis, meningeal cryptococcosis, and pulmonary aspergillosis
Authors: Hector R F , Yee E
Published: June 2012

The triazole Bay R 3783 was compared with fluconazole, itraconazole, ketoconazole, and amphotericin B in rodent models of superficial and systemic candidiasis, meningocerebral cryptococcosis, and pulmonary aspergillosis. Overall, Bay R 3783 was comparable or slightly superior to fluconazole and markedly superior to itraconazole and ketoconazole in both survival and short-term organ load experiments in models of candidiasis and cryptococcosis but was less effective than amphotericin B. Of the antifungal agents tested, only Bay R 3783 and itraconazole showed any efficacy in the model of pulmonary aspergillosis.
Inhibitory effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on woodchuck hepatitis virus replication in chronically infected woodchucks
Authors: Fourel I , Hantz O , Watanabe K A , Jacquet C , Chomel B , Fox J J , Trepo C
Published: June 2012

The treatment of woodchuck hepatitis virus infections with 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), given intraperitoneally, caused complete and permanent decrease of serum virus endogenous DNA polymerase and viral DNA in all treated woodchucks but was associated with severe toxicity. By contrast 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU) induced a sustained, although less dramatic, decrease of viral replication without apparent toxic effect. FEAU was also effective when given orally. However, in both cases this inhibitory effect was transient.
Hemodialysis clearance of intravenously administered ribavirin
Authors: Kramer T H , Gaar G G , Ray C G , Minnich L , Copeland J G , Connor J D
Published: June 2012

A patient with an implanted artificial heart, acute, anuric renal failure, and disseminated influenza virus type A infection received intravenous ribavirin. Drug elimination by hemodialysis was measured. Plasma dialysis clearance averaged 93.9 +/- 8.6 ml/min. The maximum amount of ribavirin removed from the body during one period of hemodialysis was 79.1 mg. Ribavirin is not removed in important quantities by hemodialysis.
Recent advances in the diagnosis, treatment, and prevention of Pneumocystis carinii pneumonia
Authors: Davey R T , Masur H
Published: June 2012

In summary, recent advances in our ability to diagnose, treat, and prevent recurrences of pneumocystis pneumonia have significantly improved the clinical management of this infection, especially in HIV-1-infected individuals. As current investigations allow our therapeutic armamentarium in this disease to be strengthened even further, it is likely that pneumocystis pneumonia will pose a diminishing threat to those patients currently most susceptible to this infection.
Emergence of resistant fecal Escherichia coli in travelers not taking prophylactic antimicrobial agents
Authors: Murray B E , Mathewson J J , DuPont H L , Ericsson C D , Reves R R
Published: June 2012

Fecal specimens from individuals traveling to Mexico were examined before, during, and after travel for the presence of Escherichia coli resistant to ampicillin, chloramphenicol, gentamicin, kanamycin, streptomycin, sulfonamides, trimethoprim (TMP), and TMP-sulfamethoxazole (TMP-SMX). None of these individuals took prophylactic antibiotics, although 4 of 13 took short courses of an antimicrobial agent for therapy of traveler's diarrhea. With an average of 9.3 E. coli per sample, resistance to all agents tested except gentamicin was shown to increase during the time in Mexico (P less than 0.001 to P less than 0.05). For example, no TMP-resistant (Tmpr) E. coli isolates were found by this method before travel, whereas 57% of the individuals had Tmpr and Tmpr-Smxr E. coli by the final week in Mexico. This increase in resistance occurred regardless of whether an individual took a short course of antimicrobial therapy. This study shows that travel itself, even without the use of prophylactic or therapeutic antimicrobial agents, is associated with the acquisition of resistant E. coli. Travel to developing nations may rival other sources of resistant organisms.
Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus, and Lactobacillus species
Authors: Swenson J M , Facklam R R , Thornsberry C
Published: June 2012

Eighty-five strains of vancomycin-resistant gram-positive bacteria from three genera, Leuconostoc, Pediococcus, and Lactobacillus, were tested to determine susceptibility to 24 antimicrobial agents by broth microdilution and to 10 agents by disk diffusion. The MICs of vancomycin and teicoplanin ranged from 64 to greater than 512 micrograms/ml; however, the MICs of daptomycin, a new lipopeptide, were all less than or equal to 0.25 micrograms/ml. None of the organisms were resistant to imipenem, minocycline, chloramphenicol, gentamicin, or daptomycin. The MICs of penicillin were in the moderately susceptible range for all but three strains. Susceptibility to the other agents varied by genus and, in some cases, by species. When disk diffusion results were compared with MICs for drugs recommended for streptococci by the National Committee for Clinical Laboratory Standards, Villanova, Pa., few very major or major errors were obtained, but the number of minor errors was 19.3%. Therefore, we recommended that MIC testing be used instead of disk diffusion testing for these organisms.
Autobacteriographic studies of clarithromycin and erythromycin in mice
Authors: Kohno Y , Ohta K , Suwa T , Suga T
Published: June 2012

The antimicrobial activity of clarithromycin was compared with that of erythromycin in experimentally infected mice by whole-body autobacteriography. In mice with systemic staphylococcal infections, the number of vital microbes in the body was relatively low in the early period after oral administration of erythromycin, but increased thereafter to the levels found in nonmedicated control mice. On the other hand, with clarithromycin treatment, a significantly smaller number of microbes was evident throughout the body. The microbes were scarcely seen in the parenchyma of any organs during the examination period. This potent antimicrobial activity of clarithromycin compared with that of erythromycin was further demonstrated in mice with respiratory infections. On the other hand, to examine the distribution properties of both antibiotics in the whole body, an autoradiographic study was carried out with [N-methyl-14C]clarithromycin and [N-methyl-14C]erythromycin. Both labeled antibiotics were distributed widely throughout the body after oral administration in both uninfected control mice and mice with systemic infections. However, the radioactivity was more marked and persistent for [14C]clarithromycin than it was for [14C]erythromycin, particularly in the lungs. The observations described above indicate the superior in vivo antimicrobial activity of clarithromycin compared with that of erythromycin and suggest that the superiority of clarithromycin is largely attributed to its favorable distribution properties. The advantages of whole-body autobacteriography, coupled with whole-body autoradiography, are discussed.
In vitro and in vivo activities of a new quinolone, WIN 57273, possessing potent activity against gram-positive bacteria
Authors: Sedlock D M , Dobson R A , Deuel D M , Lesher G Y , Rake J B
Published: June 2012

The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was less than or equal to 0.002 micrograms/ml; for the coagulase-negative strains the MIC90 was 0.008 micrograms/ml. Against enterococci the MIC90 was 0.06 micrograms/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were less than or equal to 1 micrograms/ml. Exceptions were Serratia marcescens (MIC90, 16 micrograms/ml), Citrobacter freundii (MIC90, 4 micrograms/ml), and Pseudomonas aeruginosa (MIC90, 8 micrograms/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 micrograms/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 micrograms/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylocci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2- to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30- to 300-fold).
Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis
Authors: Hector R F , Zimmer B L , Pappagianis D
Published: June 2012

Nikkomycins X and Z, competitive inhibitors of fungal chitin synthase, were evaluated as therapeutic agents in vitro and in mouse models of coccidioidomycosis, histoplasmosis, and blastomycosis. In vitro, the nikkomycins were found to be most effective against the highly chitinous, dimorphic fungi Coccidioides immitis and Blastomyces dermatitidis, were less effective against yeasts, and were virtually without effect on the filamentous fungus Aspergillus fumigatus. Additionally, by transmission electron microscopy, nikkomycin Z was highly disruptive to the cell wall and internal structure of the spherule-endospore phase of C. immitis in vitro. In vivo, nikkomycin Z was more effective than nikkomycin X, was also found to be superior on a milligram per milligram basis to the majority of azoles tested in the models of coccidioidomycosis and blastomycosis, and was moderately effective in histoplasmosis. A study of the pharmacokinetics in mice showed that nikkomycin Z was rapidly eliminated after intravenous infusion but that absorption after oral administration was sufficiently slow to allow inhibitory levels to persist for more than 2 h. Results of limited toxicology tests suggest that nikkomycin Z was well tolerated at the dosages employed.
3'-Azido-3'-deoxythymidine prevents induction of murine acquired immunodeficiency syndrome in C57BL/10 mice infected with LP-BM5 murine leukemia viruses, a possible animal model for antiretroviral drug screening
Authors: Ohnota H , Okada Y , Ushijima H , Kitamura T , Komuro K , Mizuochi T
Published: June 2012

Adult C57BL/10 mice (H-2b Fv-1b) inoculated with LP-BM5 murine leukemia virus develop a disease which has many features in common with human acquired immunodeficiency syndrome (AIDS), in particular abnormal lymphoproliferation and severe immunodeficiency. In the present study, we examined the possibility that this murine AIDS (MAIDS) model would be useful for evaluating antiretrovirus drugs in vivo through the use of a well-defined antiretrovirus drug, the reverse transcriptase (RT) inhibitor (H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. St. Claire, S. Nusinoff-Lehrman, R.C. Gallo, D. Bolognesi, D.W. Barry, and S. Broder, Proc. Natl. Acad. Sci. USA 82:7096-7100, 1985) 3'-azido-3'-deoxythymidine (AZT). We evaluated the effect of AZT treatment on de novo virus infection as well as on the induction of immunodeficiency by various parameters, including RT activity in serum, splenomegaly, proliferative responses against alloantigens and mitogens, soluble-antigen-presenting cell activity, and immunoglobulin G levels in serum. Our results demonstrated that AZT treatment of C57BL/10 mice infected with LP-BM5 murine leukemia virus efficiently prevented the induction of immunodeficiency if started at the time of virus inoculation. Starting AZT treatment 1 week later provided only a partial protective effect. Starting AZT treatment 2 weeks later was associated with suppression of RT activity in serum but no prevention of immunosuppression. This MAIDS model may allow rapid and cost-effective screening for antiretrovirus drugs targeted against retroviral functions shared between human AIDS and MAIDS, such as those encoded by gag, pol, or env.
Influence of beta-lactam antibiotics on serum resistance of K1-positive blood culture isolates of Escherichia coli
Authors: Suerbaum S , Leying H , Meyer B , Opferkuch W
Published: June 2012

The K1-positive strains of Escherichia coli are a group with considerable clinical importance, serum resistance being a common virulence factor of these strains. In the present paper, the influences of cephaloridine, imipenem, and ceftazidime on the serum resistance of eight serum-resistant K1-positive E. coli blood culture isolates with smooth-type lipopolysaccharide were studied. All strains were rendered more serum sensitive by treatment with subinhibitory concentrations of antibiotics. The amount of the reduction of serum resistance was dependent on the concentration of the antibiotic. Amounts of K1 produced under the influence of the antibiotics were measured and were found to be reduced for almost all strains tested. To further test the hypothesis that antibiotic-induced reduction of serum resistance is mediated by inhibition of K1 expression, isogenic mutants of one strain were produced by selection for resistance against infection with K1-specific bacteriophages. These mutants were found to be highly serum sensitive. We conclude from this study that beta-lactam antibiotics can render K1-positive serum-resistant strains of E. coli highly serum sensitive and that this effect is mediated by inhibition of K1 expression.
Antifungal activity in human cerebrospinal fluid and plasma after intravenous administration of Allium sativum
Authors: Davis L E , Shen J K , Cai Y
Published: June 2012

Commercial Allium sativum (garlic) extract was given intravenously to two patients with cryptococcal meningitis and three patients with other types of meningitis. Plasma titers of anti-Cryptococcus neoformans activity rose twofold over preinfusion titers. Anti-C. neoformans activity was detected in four of five cerebrospinal fluid samples but not in pooled normal cerebrospinal fluid.
Susceptibilities of Bacteroides and Fusobacterium spp. from foot rot in goats to 10 beta-lactam antibiotics
Authors: Piriz Duran S , Valle Manzano J , Cuenca Valera R , Vadillo Machota S
Published: June 2012

The agar dilution method was used to determine the bacteriostatic activities of 10 beta-lactam antibiotics against 132 strains belonging to the genus Bacteroides and 25 strains belonging to the genus Fusobacterium, all isolated from clinical cases of caprine foot rot. The three ureidopenicillins studied proved to be the most effective antimicrobial agents.
Randomized, controlled trial of a 10-day course of amifloxacin versus trimethoprim-sulfamethoxazole in the treatment of acute, uncomplicated urinary tract infection. Amifloxacin Multi-Center Trial Group
Authors: Boyko E J , Iravani A , Silverman M H , Schelling D J , Wright R A
Published: June 2012

We conducted a randomized controlled trial of orally administered amifloxacin versus trimethoprimsulfamethoxazole (TMP-SMX) as treatments of acute uncomplicated urinary tract infection in women. Amifloxacin at a dosage of 200 mg twice a day appeared as safe and effective as TMP-SMX, but amifloxacin at 400 mg twice a day tended to cause adverse events more frequently than did TMP-SMX.
Continuation of chloroquine-susceptible Plasmodium falciparum parasitemia in volunteers receiving chloroquine therapy
Authors: Murphy J R , Clyde D F , Herrington D A , Baqar S , Davis J R , Palmer K , Cortese J
Published: June 2012

Volunteers infected with a chloroquine-susceptible line of Plasmodium falciparum were administered standard oral chloroquine therapy at the first detection of parasites in the blood. Parasitemias progressed in the face of therapy for up to 5 days and to levels up to 100-fold greater than those at the initiation of treatment. Thereafter, infections cleared without a requirement for additional chemotherapy. This course of infection and response to treatment has not been previously reported and may have been detected because volunteers were exposed to an unusually large number of sporozoites. The observations are consistent with the hypothesis that prolonged parasitemia resulted from the continued release of merozoites from liver.
Comparative effects of cilofungin and amphotericin B on experimental murine candidiasis
Authors: Morrison C J , Stevens D A
Published: June 2012

The effectiveness of cilofungin (LY121019, referred to hereafter as LY), a lipopeptide, was studied in a murine candidiasis model. CD-1 mice (5 weeks old) were injected intravenously with 3 x 10(5) Candida albicans yeast cells. Intraperitoneal LY or amphotericin B (AmB) therapy was begun 4 days after infection and was continued daily for 2 weeks. LY and AmB were compared at 62.5, 6.25, and 0.625 mg/kg per day, with the LY dose split into two treatments per day. Mice were observed for 30 days postinfection, and survivors were necropsied. AmB at 62.5 mg/kg per day was lethal in the absence of infection. Cumulative mortality for infected controls was 94% (17 of 18). Survival of mice treated with the control diluent for LY was the same as survival with no treatment. Survival after 0.625 mg of LY per kg per day was the same as that of the controls, and 6.25 or 62.5 mg of LY per kg per day was significantly superior. AmB treatment at 0.625 or 6.25 mg/kg per day was protective and superior to the same LY doses. Atrophied kidneys were common in AmB-treated mice, and mice treated with 6.25 mg of AmB per kg per day appeared ill during therapy. The number of CFU recovered from kidneys and spleens of surviving mice reflected the same relationships between drugs and doses as those described for mortality. C. albicans was not cleared from the kidneys of mice in any group, and only in the 6.25-mg/kg-per-day AmB treatment group was not detectable C. albicans found in the spleens. These data indicate that LY or AmB suppresses candida infection but neither is curative in this model.
Biochemical characterization of a beta-lactamase that hydrolyzes penems and carbapenems from two Serratia marcescens isolates
Authors: Yang Y J , Wu P J , Livermore D M
Published: June 2012

Reexamination of Serratia marcescens isolates obtained in 1982 revealed two organisms that were resistant to the penem FCE 22101 (MIC, 512 micrograms/ml) and imipenem (MIC, 16 micrograms/ml) and that had slightly reduced susceptibilities to meropenem (MIC, 0.12 micrograms/ml). MICs of these agents for typical S. marcescens isolates were 1 to 8, 0.25 to 0.5, and 0.03 micrograms/ml, respectively. The two isolates were fully susceptible to broad-spectrum cephalosporins, and only one was highly resistant to ampicillin and carbenicillin (MICs, greater than 1,024 micrograms/ml). Both isolates had beta-lactamases that focused at pIs 8.2 and 9.7. The penicillin-resistant isolate additionally produced the TEM-1 enzyme. The enzymes with pIs of 8.2 and 9.7 were separated by cation-exchange chromatography. The pI 8.2 beta-lactamase was a class I enzyme of the type found in most S. marcescens isolates. It was almost inactive against carbapenems and penems, as was the class I enzyme from another S. marcescens strain. The pI 9.7 enzyme hydrolyzed penems and carbapenems rapidly: kcat (turnover number) values for FCE 22101, imipenem, and meropenem were 3.4, 26, and 1% of the kcat value for cephaloridine, respectively; kcat/Km values were 140, 915, and 150% of the kcat/Km value for cephaloridine, respectively. Otherwise, the pI 9.7 enzyme had predominantly penicillinase activity. It was inhibited more readily by clavulanate than by tazobactam and was inactivated by the chelating agents EDTA and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Expression of the pI 9.7 enzyme was not associated with any plasmid, and production was not transferred to Escherichia coli K-12 recipients, even after the mobilizing plasmid pUZ8 was inserted into the S. marcecens donor strains.
Vancomycin pharmacokinetics in burn patients and intravenous drug abusers
Authors: Rybak M J , Albrecht L M , Berman J R , Warbasse L H , Svensson C K
Published: June 2012

The pharmacokinetics of vancomycin were evaluated in 34 patients (10 burn patients, 14 intravenous drug abusers [IVDA], and 10 controls). Multiple serum samples were drawn following a 1-h vancomycin infusion at steady state over an 8- to 12-h dosing interval. Pharmacokinetic parameters were derived by noncompartmental analysis. There were no significant differences among the groups with respect to age, weight, serum creatinine, volume of distribution, or protein binding. Burn patients had a significantly higher creatinine clearance than did IVDA or controls. Vancomycin clearances averaged 142.8, 98.0, and 67.7 ml/min in burn patients, IVDA, and controls, respectively. The renal clearance of vancomycin was also higher in burn patients than in the other groups. IVDA tended to have a higher vancomycin clearance (31% higher) than did controls, but the difference was not statistically significant. Vancomycin clearance was much higher in burn patients requiring dosage individualization and close monitoring. A considerable amount of vancomycin was eliminated through renal tubular secretion, making dosage predictions based on creatinine clearance more difficult. Further work with IVDA will be needed to determine if they represent a group requiring aggressive vancomycin dosages.
Bacitracin-induced proteins in Bacillus subtilis and Bacillus thuringiensis and their relationship with resistance
Authors: García-Patrone M
Published: June 2012

Bacitracin induced one protein (bacitracin-induced protein [BIP]) in Bacillus thuringiensis and two proteins (BIP1 and BIP2) in Bacillus subtilis that were localized in the membrane. Divalent cations acted as cofactors for induction in all three cases. Growth was initially inhibited by the antibiotic, but following induction of proteins growth resumed. B. subtilis cells possessing BIPs were able to duplicate at a normal rate in the presence of bacitracin. The amount of B. subtilis BIPs diminished markedly after a few divisions in the absence of the antibiotic and the organism simultaneously reverted to the susceptible state. Induction of the proteins did not take place after the fourth or fifth hour of the stationary phase. The B. thuringiensis BIP was also induced by vancomycin. Bacitracin did not induce the synthesis of specific proteins in susceptible (Micrococcus lysodeikticus) or outer membrane-possessing resistant bacteria (Escherichia coli).
In vitro activity of Bay v 3522, a new cephalosporin, compared with activities of other agents
Authors: Wise R , Andrews J M , Ashby J P , Thornber D
Published: June 2012

The in vitro activity of Bay v 3522, a new aminobenzothiazol cephem, was compared with those of other oral beta-lactams. Bay v 3522 displayed high activity against Staphylococcus spp. (MICs for 90% of strains tested [MIC90S], 0.5 micrograms/ml), Streptococcus pneumoniae (MIC90, 0.06 micrograms/ml), and Haemophilus influenzae and Branhamella catarrhalis (MIC90S, 2 micrograms/ml). There was limited activity against members of the family Enterobacteriaceae, with the MIC90S being between 4 and greater than 128 micrograms/ml. The stability of Bay v 3522 to hydrolysis by the SHV-1 and TEM-1 enzymes was intermediate to those of cephalexin (least hydrolyzed) and cefaclor, but it was markedly more stable than amoxicillin. There was high affinity to the chromosomally mediated P99 enzyme. The protein binding of Bay v 3522 was 45%. The primary target of Bay v 3522 was penicillin-binding protein 3.
Purification of a glutathione S-transferase that mediates fosfomycin resistance in bacteria
Authors: Arca P , Hardisson C , Suárez J E
Published: June 2012

The enzyme that modifies fosfomycin by formation of an adduct with glutathione was purified 12-fold with a 56% activity yield by passage through DEAE Sephacel and high-performance liquid chromatography molecular exclusion columns. Its functional form was a homodimer of two 16,000-dalton polypeptides, which possibly showed an antiparallel alpha tertiary structure and which lacked marked hydrophobic regions. Visualization of the reaction was achieved by precolumn derivatization of glutathione and the adduct, separation by high-performance liquid chromatography, and fluorescence detection of both compounds. Temperature and pH optima were 20 to 30 degrees C and 8.25, respectively; Mn2+, Fe2+, and Co2+ enhanced the rate of modification; and Km values were 9.4 and 11 mM for fosfomycin and glutathione, respectively. Phosphoenolpyruvate did not interfere with fosfomycin modification. The enzyme was stable at 4 degrees C for at least 6 months but progressively lost its activity upon being heated for 60 min at temperatures over 30 degrees C.
In vitro tumor necrosis factor induction assay for analysis of febrile toxicity associated with amphotericin B preparations
Authors: Chia J K , McManus E J
Published: June 2012

Amphotericin B can stimulate macrophages to produce tumor necrosis factor alpha (TNF alpha), one of the inflammatory mediators that may be responsible for the febrile toxicity associated with drug administration. The purpose of this study was to compare the in vitro TNF-inducing activity of one recalled lot of an amphotericin B preparation which was associated with more frequent febrile reactions in patients with a preparation not associated with a greater incidence of febrile reaction. We found that the former preparation induced significantly more TNF than the latter preparation, and the in vitro data correlated with the results of rabbit pyrogen testing. The in vitro TNF induction assay may serve as a screening tool for the selection of the least pyrogenic lots of amphotericin B preparation.
Fluconazole levels in plasma and vaginal secretions of patients after a 150-milligram single oral dose and rate of eradication of infection in vaginal candidiasis
Authors: Houang E T , Chappatte O , Byrne D , Macrae P V , Thorpe J E
Published: June 2012

Mean peak concentrations of fluconazole in plasma and vaginal secretions of females after a 150-mg single oral dose were shown to be 2.82 micrograms/ml and 2.43 micrograms/g, respectively. Our results indicate that clinically efficacious concentrations of fluconazole in vaginal secretions are easily achieved after this single oral dose.
Pharmacokinetics of FCE 22891, a new oral penem
Authors: Saathoff A , Lode H , Hampel B , Deppermann K M , Borner K , Koeppe P
Published: June 2012

FCE 22891 is the oral prodrug of FCE 22101, a new broad-spectrum penem. The pharmacokinetics of FCE 22891 after single-dose administration, its absolute bioavailability, and the effect of food intake on its absorption were investigated in three different randomized crossover studies in healthy volunteers. Drug levels in blood and urine were measured by high-pressure liquid chromatography and bioassay. For optimal comparison of the results of all studies, and since there was good agreement of both methods, only the high-pressure liquid chromatography results are included. The pharmacokinetics of the penem were linear, and its bioavailability after oral administration was 42 +/- 11%. Food intake increased the total area under the curve from 0 h to infinity from 11.9 +/- 3.5 to 14.1 +/- 2.4 mg.h/liter. A specific side effect, i.e., bladder complaints, was registered in some volunteers taking FCE 22891 at doses greater than or equal to 1.0 g.
Role of sodium in protection by extended-spectrum penicillins against tobramycin-induced nephrotoxicity
Authors: Sabra R , Branch R A
Published: June 2012

Salt depletion is known to potentiate aminoglycoside nephrotoxicity, while salt replacement attenuates it. Recent studies have shown that ticarcillin protects against tobramycin and gentamicin nephrotoxicity. It has been suggested that this protection is due to an interaction between ticarcillin and the aminoglycoside. However, it can also be explained by the salt load associated with ticarcillin administration. This study was conducted to examine this question. Tobramycin was administered to eight groups of rats at 100 mg/kg per day intraperitoneally for 10 days. Group 1 rats were salt depleted, while group 2 rats were on a normal salt diet. Rats in groups 3 through 8 were also salt depleted but received, in addition, the following interventions intraperitoneally: group 3, ticarcillin, 300 mg/kg per day (0.37 to 0.39 meq of Na supplement per day); group 4, ticarcillin, 300 mg per day (1.56 meq of Na supplement per day); group 5, ticarcillin, 300 mg/kg per day, and NaCl supplement (1.17 to 1.19 meq/day), resulting in a total load of 1.56 meq/day; group 6, piperacillin, 400 mg/day (0.76 meq of Na supplement per day and equimolar to the ticarcillin dose [300 mg/day] in group 4 rats); group 7, piperacillin, 400 mg/day, and NaCl supplement (0.8 meq/day) for a total Na load of 1.56 meq/day; and group 8, 1.56 meq of Na per day as NaCl. Rats in groups 2, 4, 5, 7, and 8, which received a normal salt diet or its equivalent Na supplement, had no significant change in creatinine clearance (CLCR) over the 10-day period. The remaining groups sustained significant reductions in CLCR, as follows: group 1, -53.0% (P < 0.05); group 3, -66.2% (P < 0.05); group 6, -79.8% (P < 0.05). A positive correlation was found between the concentration of tobramycin in the kidneys and the percent change in CLCR at the end of the study. Concentrations of drugs in plasma were highest in group 1 rats, lowest in the rats in groups in which protection was observed, and moderately elevated in the remaining groups of rats. The results of this study suggest the following: (i) that the protective effect of ticarcillin against tobramycin nephrotoxicity is secondary to the obligatory sodium load associated with it, (ii) pharmacokinetic and pharmacodynamic interactions between salt and tobramycin are proposed to explain this effect, (iii) the nephrotoxicity of tobramycin is probably related to the degree of accumulation of the drug in the kidney, and (iv) an in vivo interaction between tobramycin and ticarcillin does not contribute to the protective effect of the penicillin but may influence concentrations in plasma, especially under conditions of severe renal impairment.
Effect of renal function on the bioavailability of ciprofloxacin
Authors: Plaisance K I , Drusano G L , Forrest A , Weir M R , Standiford H C
Published: June 2012

The effect of renal function on the bioavailability of ciprofloxacin was studied in 21 subjects with measured creatinine clearances ranging from 0 to 8.99 liters/h per 1.73 m2. Each subject received ciprofloxacin, 200 mg intravenously and 750 mg orally, separated by at least 1 week. Serial (12 to 15) blood samples were obtained over 24 to 48 h. Concentrations in serum were assayed by high-pressure liquid chromatography. Area under the curve was calculated by the trapezoidal rule with extrapolation to infinity. Bioavailability was calculated as the ratio between the dose-normalized area under the curve of oral and intravenous administrations. The overall mean (standard deviation) bioavailability observed was 63.4% (14.6%), similar to that observed in those with normal renal function (69.0% [15.7%]). The mean bioavailability in the subgroup of subjects with renal insufficiency was 59.9% (13.3%). The observed range in bioavailability was 33.9 to 91.4%. Linear regression did not reveal a correlation between creatinine clearance and bioavailability. Renal insufficiency does not appear to affect ciprofloxacin bioavailability.
Activities of 3'-azido-3'-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1
Authors: Schinazi R F , Sommadossi J P , Saalmann V , Cannon D L , Xie M Y , Hart G C , Smith G A , Hahn E F
Published: June 2012

The relative antiviral potencies of five nucleotide heterodimers of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-3'-deoxythymidilyl-(5',5')-2'-3'-dideoxy-5'-adenylic acid (AZT-P-ddA), 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI), and the corresponding 2-cyanoethyl congeners AZT-P(CyE)-ddA and AZT-P(CyE)-ddI, were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The homodimer 3'-azido-3'-deoxythymidilyl-(5',5')-3'-azido-3'-deoxythymidilic acid (AZT-P-AZT) was also included for comparison. The potencies of the compounds were AZT-P-ddA greater than or equal to AZT-P-ddI greater than AZT-P(CyE)-ddA greater than or equal to AZT-P(CyE)-ddI greater than or equal to AZT greater than AZT-P-AZT. Whereas AZT-P-ddA and AZT-P-ddI had in vitro therapeutic indices greater than that of AZT, the homodimer of AZT had a low therapeutic index. AZT-P-ddI exhibited the lowest toxicity in peripheral blood mononuclear, Vero, or CEM cells. Combination studies between AZT and 2',3'-dideoxyinosine (ddI) at nontoxic concentrations indicated a synergistic interaction at a drug ratio of 1:100. At higher ratios (1:500 and 1:1,000), the interactions were synergistic only at concentrations that produced up to 75% virus inhibition. At higher levels of antiviral effects, this combination was antagonistic, as determined by the multiple drug effect analysis method. AZT-P-ddI was about 10-fold less toxic than AZT to human granulocyte-macrophage progenitor cells. However, no significant difference was apparent when the compounds were evaluated against cells of the erythroid lineage. The greater antiviral activity and lower toxicity of this compound could not be attributed to the extracellular decomposition of the dimer in media at physiological temperature and pH. However, in acidic solutions, AZT-P-ddI decomposed in a pH-dependent manner. Advanced preclinical studies with this heterodimer of two clinically effective antiretroviral agents should be considered.
Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil
Authors: Borin M T , Hughes G S , Spillers C R , Patel R K
Published: June 2012

The single-dose and steady-state pharmacokinetics of cefpodoxime were assessed in plasma and skin blister fluid (SBF) after oral dosing of 200 mg (n = 8) and 400 mg (n = 8) of cefpodoxime proxetil (doses are expressed as cefpodoxime equivalents) in healthy subjects in an open-label, parallel-design study. Skin blisters were formed by air suction on the midvolar forearm by a previously validated method. After single-dose administration, serial plasma and SBF samples were collected over 24 h for measurement of cefpodoxime by microbiological assays. After a 1-week washout, subjects received the same doses of antibiotic every 12 h for 5 days, with plasma and SBF sampling on day 5. After 200 mg of cefpodoxime proxetil, average peak concentrations (Cmax) in plasma and SBF were 2.18 +/- 0.52 and 1.55 +/- 0.59 micrograms/ml, respectively, after a single dose and 2.33 +/- 0.74 and 1.56 +/- 0.55 micrograms/ml, respectively, at steady state. After 400 mg of cefpodoxime proxetil, Cmax in plasma and SBF averaged 4.16 +/- 1.04 and 2.94 +/- 0.71 micrograms/ml, respectively, following a single dose and 4.10 +/- 0.95 and 2.84 +/- 0.88 micrograms/ml, respectively, at steady state. Cmax occurred 1.1 to 1.6 h later in SBF than in plasma. There was no accumulation of cefpodoxime in plasma or SBF when dosing was done every 12 h. Cefpodoxime blister fluid penetration was estimated to be 67 to 101%, consistent with the relatively low serum protein binding of the drug. Cefpodoxime levels exceeding the MIC for 90% of many skin pathogens, such as Streptococcus species (<1 microgram/ml) or Staphylococcus species (2 to 4 micrograms/ml), were achieved in plasma and SBF following the 200- and/or 400-mg dosing regimens.
Antibacterial activity of lomefloxacin in a pharmacokinetic in vitro model
Authors: Rustige C , Wiedemann B
Published: June 2012

An in vitro model simulating two-compartment pharmacokinetics was used to study the antibacterial activity of lomefloxacin after single oral doses of 200 and 400 mg. Lomefloxacin produced reliable bactericidal activity against gram-negative aerobic bacteria and staphylococci. Bacterial strains for which MICs were less than 0.5 microgram/ml were inhibited with both dosing schedules. Doubling the dose from 200 to 400 mg increased the bactericidal activity only against Pseudomonas aeruginosa. Against Enterococcus faecalis lomefloxacin showed no effect. Selection of resistant variants during the simulation of treatment was observed with Staphylococcus aureus and P. aeruginosa.
Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides
Authors: Mamber S W , Brookshire K W , Forenza S
Published: June 2012

A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (beta-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddI) induced cell filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at less than 100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 micrograms/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT greater than ddA greater than or equal to ddI greater than or equal to ddG greater than ddT = D4T greater than ddC. ddA and ddI had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit Bacillus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.
Activities of (-)-carbovir and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro
Authors: Carter S G , Kessler J A , Rankin C D
Published: June 2012

(-)-Carbovir, the minus optical isomer of carbocyclic-2',3'-didehydro-2',3'-dideoxyguanosine, has been shown to be the biologically active form for the inhibition of human immunodeficiency virus type 1 replication. The concentration of (-)-carbovir required to reduce reverse transcriptase activity by 50% compared with the control was 0.8 microM in H9 cells infected with the HTLV-IIIb strain; the 50% inhibitory concentration for cytotoxicity was greater than 2 mM in these cells. The effect of the timing of drug addition, pre- and postinfection, and the effect of increasing amounts of virus on the antiviral activities of (-)-carbovir and 3'-azido-3'-deoxythymidine were determined.