bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and ex vivo susceptibility of cefpodoxime proxetil in patients receiving continuous ambulatory peritoneal dialysis
Authors: Johnson C A , Ateshkadi A , Zimmerman S W , Hughes G S , Craig W A , Carey P M , Borin M T
Published: June 2012

Pharmacokinetics of cefpodoxime, an extended-spectrum cephalosporin, were determined for eight noninfected patients on continuous ambulatory peritoneal dialysis (CAPD) and eight healthy volunteers. Subjects were matched for sex, age (+/- 6 years), and body weight (+/- 10 kg, except for one pair) and received a single 200-mg (cefpodoxime equivalents) oral dose of the prodrug cefpodoxime proxetil in an open-label, paired-design fashion. Dialysate (CAPD group only), plasma, and urine samples were collected and assayed for cefpodoxime by a microbiologic method. In addition, mean bactericidal titers of the effluent dialysate against selected bacterial strains often associated with CAPD-related peritonitis were determined at 6 and 24 h after the dose. There was a significant difference (P < 0.05) in all pharmacokinetic parameters between healthy and CAPD subjects, except for lag time to absorption. The mean peak plasma cefpodoxime concentration of 1.88 +/- 0.6 micrograms/ml occurred at 2.44 +/- 0.5 h for healthy volunteers, while the peak concentration of 3.25 +/- 1.4 micrograms/ml occurred at 12.0 +/- 4.2 h for patients on CAPD. The average elimination half-life in CAPD patients was approximately 12 times greater than that seen in healthy volunteers. Peritoneal dialysis had a minimal effect on cefpodoxime clearance. In healthy volunteers, 24.2% +/- 13% of the dose was recovered from the urine, in contrast to only 5.59% +/- 6.9% for CAPD patients. The mean bactericidal titers for all CAPD patients, at 6 and 24 h, were mostly less than 1:2 and did not exceed 1:4 for any of the isolates. Because of the decreased renal clearance and negligible dialysate clearance of cefpodoxime, and delayed drug absorption, the dosage interval for cefpodoxime proxetil may need to be extended in CAPD patients.
In vitro activity of novobiocin against multiresistant strains of Enterococcus faecium
Authors: French P , Venuti E , Fraimow H S
Published: June 2012

Sixty strains of vancomycin- and ampicillin-resistant Enterococcus faecium were evaluated for their susceptibilities to novobiocin in vitro. In Mueller-Hinton broth, novobiocin inhibited all strains when it was used at a concentration of < or = 2 microgram/ml and 40 of 60 strains when it was used at a concentration of < or = 0.5 micrograms/ml. MICs were 8- to 16-fold higher in 50% serum. Novobiocin alone resulted in 2-log-unit killing at 24 h. Combinations of novobiocin and a fluoroquinolone (either ciprofloxacin or ofloxacin) were additive and bactericidal for quinolone-susceptible strains in either broth or 50% serum. Gentamicin did not affect novobiocin activity, and rifampin and doxycycline were antagonistic.
Efficacy of cefuroxime axetil suspension compared with that of penicillin V suspension in children with group A streptococcal pharyngitis
Authors: Gooch W M , McLinn S E , Aronovitz G H , Pichichero M E , Kumar A , Kaplan E L , Ossi M J
Published: June 2012

The bacteriological and clinical efficacies of cefuroxime axetil suspension (20 mg/kg of body weight per day in two divided doses) were compared with those of penicillin V suspension (50 mg/kg/day in three divided doses) in a multicenter, randomized, evaluator-blinded study. Children aged 2 to 13 years with clinical signs and symptoms of acute pharyngitis and a positive throat culture for group A beta-hemolytic streptococci (GABHS) were eligible. Patients were assessed and samples from the throat for culture were obtained at the time of diagnosis, 3 to 7 days after the initiation of treatment, and 4 to 8 days and 19 to 25 days after the completion of 10 days of therapy. Of the 385 evaluable patients, GABHS were eradicated from 244 of 259 (94.2%) cefuroxime-treated patients and 106 of 126 (84.1%) penicillin-treated patients (P = 0.001). Complete resolution of the signs and symptoms present at the time of diagnosis was achieved in 238 of 259 (91.9%) cefuroxime-treated patients and 102 of 126 (81.0%) penicillin-treated patients (P = 0.001). Potential drug-related adverse events were reported in 7.0 and 3.2% of the cefuroxime- and penicillin-treated patients, respectively (P = 0.078). In the present study, cefuroxime axetil suspension given twice daily resulted in significantly greater bacteriological and clinical efficacies than those of penicillin V suspension given three times daily to pediatric patients with acute pharyngitis and a positive throat culture for GABHS.
Pharmacokinetics of nevirapine: initial single-rising-dose study in humans
Authors: Cheeseman S H , Hattox S E , McLaughlin M M , Koup R A , Andrews C , Bova C A , Pav J W , Roy T , Sullivan J L , Keirns J J
Published: June 2012

Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.
Sequences of wild-type and mutant ampD genes of Citrobacter freundii and Enterobacter cloacae
Authors: Kopp U , Wiedemann B , Lindquist S , Normark S
Published: June 2012

The ampD gene product regulates the expression of AmpC beta-lactamase in gram-negative bacteria and is proposed to be involved in peptidoglycan metabolism. In this study, we sequenced the ampD wild type and three mutant genes of Enterobacter cloacae and Citrobacter freundii. They exhibited a high degree of homology with the corresponding gene of Escherichia coli except in the carboxy termini, where, in the wild-type genes of E. cloacae and C. freundii, four additional amino acids yielding the Ser-X-X-Lys motif were found. Evidence that this C-terminal region of the ampD gene product is necessary for activity was shown by constructing a deletion of the last 16 amino acids. The spontaneous mutation of ampD02 is an out-of-frame insertion and yields an inactive AmpD protein. The single-base-pair substitution of Gly for Asp-121 in ampD05 is responsible for a hyperinducible phenotype. These results demonstrate regions of the ampD gene and the corresponding protein which have functional importance for the induction of AmpC beta-lactamase in E. cloacae.
Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women
Authors: Dan M , Weidekamm E , Sagiv R , Portmann R , Zakut H
Published: June 2012

Fleroxacin was administered to seven lactating women as a single oral dose of 400 mg. Plasma, urine, and milk samples were collected for up to 48 h after administration. Drug concentrations were determined by a reversed-phase high-pressure liquid chromatography method and were used for the pharmacokinetic evaluation. At approximately 2 h after oral administration, a maximum concentration of 5.6 mg/liter was determined in plasma; the area under the plasma concentration-time curve (AUC) amounted to 70.3 mg.h/liter, and the elimination half-life in the postdistributive phase was 8 h. Total systemic clearance was 97.3 ml/min, and urinary excretion was 38% of the dose within 48 h. In addition, 8.6% of the N-demethyl metabolite and 4.4% of the N-oxide metabolite were recovered from urine. In comparison with previous results obtained with healthy male volunteers, the time to reach maximum concentrations in plasma was twice as long in the nursing women, and total clearance as well as urinary elimination were reduced by 25%. In breast milk, the mean maximum concentration was 3.5 mg/liter, which was reached 2.6 h after drug administration. The elimination half-life of fleroxacin in milk was identical to that in plasma, and the AUC reached 43.3 mg.h/liter. On the basis of the comparison of the AUC in milk versus the AUC in plasma, the proportion of fleroxacin penetration into milk was 62%. The cumulative excretion in milk amounted to only 0.219 mg within 48 h. On the basis of an average daily intake of milk of a breast-fed child of 150 ml/kg of body weight, the maximum daily ingested fleroxacin dose would not exceed 10 mg. However, quinolones are known to induce arthropathy in juvenile animals, and therefore, administration of fleroxacin to breast-feeding women cannot be allowed.
New turbidimetric assay for quantitation of viable bacterial densities
Authors: Li R C , Nix D E , Schentag J J
Published: June 2012

A turbidimetric assay was developed and validated against Escherichia coli for the quantitation of viable bacterial densities. The Abbott MS-2 research system was employed for continuous 5-min measurements of optical density. A linear standard curve was obtained by regressing the initial bacterial density (log CFU per milliliter) against the time required for bacterial growth causing a 5% decrease in optical transmittance. Slope and intercept values obtained from eight standard curves showed excellent assay reproducibility. Results obtained by the turbidimetric assay compared favorably to those obtained by the conventional pour plate assay. Prior to the application of the new assay, possible interferences of postantibiotic effect induced by the test antibiotics were excluded. The turbidimetric assay, which is presumably more efficient and less expensive, was implemented for the time-kill studies of three different beta-lactams against E. coli.
Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine
Authors: Brown S T , Edwards F F , Bernard E M , Tong W , Armstrong D
Published: June 2012

Azithromycin, rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 10(7) CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 10(4) organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections.
Multiple-dose pharmacokinetics of 12 milligrams of trimethoprim and 60 milligrams of sulfamethoxazole per kilogram of body weight per day in healthy volunteers
Authors: Stevens R C , Laizure S C , Sanders P L , Stein D S
Published: June 2012

The disposition of 12 mg of trimethoprim and 60 mg of sulfamethoxazole per kg of body weight in six healthy male volunteers is described. The daily dose was evenly divided and administered orally every 6 h for 13 consecutive doses. Individual drug components were assayed by high-performance liquid chromatography. Steady-state concentrations in serum for trimethoprim and sulfamethoxazole were within the purported therapeutic ranges for treating Pneumocystis carinii pneumonia. Co-trimoxazole was well tolerated, and no subject withdrew from the study because of toxicity. Comparison of the pharmacokinetic parameters in this study with those of our previous findings indicates that the elimination of trimethoprim-sulfamethoxazole follows a first-order process within the dose ranges assessed. Administration of 15- to 20-mg/kg trimethoprim and 75- to 100-mg/kg sulfamethoxazole in four evenly divided doses for the first 24 h followed by 12 and 60 mg/kg/day, respectively, for the remainder of therapy rapidly attains concentrations in serum within the proposed P. carinii pneumonia therapeutic range. Clinical trials are indicated to evaluate this dosing scheme, which may decrease exposure to potentially excessive concentrations of trimethoprim and sulfamethoxazole.
Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration
Authors: Kinowski J M , de la Coussaye J E , Bressolle F , Fabre D , Saissi G , Bouvet O , Galtier M , Eledjam J J
Published: June 2012

The pharmacokinetic parameters of amikacin and ceftazidime were assessed in four patients undergoing hemofiltration for septic shock. The parameters were assessed during hemofiltration and in the interim period. The concentration-time profiles of these two drugs in plasma, urine, and ultrafiltrate were investigated after intravenous perfusion (30 min). In all cases a 1-g dose of ceftazidime was administered; for amikacin, the dosage regimen was adjusted according to the patient's amikacin levels (250 to 750 mg). Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection for ceftazidime and by enzyme multiplied immunoassay for amikacin. The elimination half-life (t1/2) and the total clearance of amikacin ranged from 31.1 to 138.2 h and from 5.4 to 8.9 ml/min, respectively, during the interhemofiltration period in anuric patients. Hemofiltration substantially decreased the t1/2 (3.5 +/- 0.49 h) and increased the total clearance (89.5 +/- 11.8 ml/min). The hemofiltration clearance of amikacin represented 71% of the total clearance, and the hemofiltration process removed, on average, 60% of the dose. During hemofiltration, the elimination t1/2 of ceftazidime (2.8 +/- 0.69 h) was greatly reduced and the total clearance increased (74.2 +/- 11.2 ml/min) compared with those in the interhemofiltration period (9 to 43.7 h and 7.4 to 16.8 ml/min, respectively). About 55% of the administered dose was recovered in the filtrate, and the hemofiltration clearance of ceftazidime was 46 +/- 14.3 ml/min. A redistribution phenomenon (rebound) in the amikacin and ceftazidime concentrations in plasma (35 and 28%, respectively) was reported after hemofiltration in two patients. The MICs for 90% of the most important pathogens were exceeded by the concentrations of the two drugs in plasma during the whole treatment of these patients.
Safety, tolerance, and pharmacokinetics of systemic ribavirin in children with human immunodeficiency virus infection
Authors: Connor E , Morrison S , Lane J , Oleske J , Sonke R L , Connor J
Published: June 2012

Eleven pediatric patients, aged 1 to 10 years and with symptomatic human immunodeficiency virus infection, were treated with 6 or 10 mg of oral ribavirin per kg of body weight daily for 60 days. Safety and pharmacokinetic parameters were monitored; five children had comprehensive pharmacokinetic evaluations. The children tolerated the drug well, and treatment was not associated with any clinically significant adverse effects. Peak concentrations in plasma of 2.5 and 3.0 microM were reached at 90 min after single oral doses of 6 and 10 mg/kg, respectively. The mean systemic availability of oral ribavirin was 42.3%. After 60 days of ribavirin administration, mean trough concentrations in plasma of 2.6 and 4.1 microM were obtained. Ribavirin penetrated well into the cerebrospinal fluid, achieving 70% of the concentration in plasma at steady state.
Mechanisms of action of cephalosporin 3'-quinolone esters, carbamates, and tertiary amines in Escherichia coli
Authors: Georgopapadakou N H , Bertasso A
Published: June 2012

Cephalosporin 3'-quinolone esters, carbamates, and tertiary amines are potent antibiotics whose antibacterial activities reflect the action of both the beta-lactam and the quinolone components. The biological properties of representative compounds from each class were compared in Escherichia coli. All compounds bound to the essential PBP 3, inhibited DNA gyrase, and caused filamentation in growing cells. To distinguish between cephalosporin- and quinolone-induced filaments, nucleoid segregation was also examined, as quinolones disrupt nucleoid segregation while the beta-lactams do not (N. H. Georgopapadakou and A. Bertasso, Antimicrob. Agents Chemother. 35:2645-2648, 1991). The cephalosporin quinolone esters Ro 23-9424 and Ro 24-6392, at concentrations causing filamentation in E. coli ATCC 25922, did not affect nucleoid segregation after 1 h of incubation (cephalosporin response) but did not affect it after 2 h (quinolone response), indicating the release of free quinolone. Accordingly, only the quinolone response was produced in a strain possessing TEM-3, an expanded-spectrum beta-lactamase. The cephalosporin carbamate Ro 24-4383 and the tertiary amine Ro 24-8138 produced a quinolone response in E. coli ATCC 25922, though they produced a cephalosporin response in a quinolone-resistant strain. Carbamate and tertiary amine linkages are chemically more stable than the ester linkage, and both cephalosporin 3'-quinolone carbamates and tertiary amines are more potent inhibitors of DNA gyrase than are the corresponding esters. The results suggest that, while intact cephalosporin 3'-quinolone esters act as cephalosporins, carbamates and amines may possess both cephalosporin and quinolone activity in the intact molecule.
Efficacy of ampicillin-sulbactam versus that of cefoxitin for treatment of Escherichia coli infections in a rat intra-abdominal abscess model
Authors: Rice L B , Carias L L , Shlaes D M
Published: June 2012

We examined the efficacy of ampicillin-sulbactam (2:1) and cefoxitin in the treatment of infections caused by Escherichia coli strains exhibiting increasing levels of beta-lactamase-mediated resistance to ampicillin-sulbactam in the rat intra-abdominal abscess model. Cefoxitin was superior to ampicillin-sulbactam in the treatment of infections caused by all strains. Treatment with ampicillin-sulbactam resulted in a statistically significant decrease in CFU per gram of abscess in comparison with treatment with ampicillin alone for both the moderately resistant and the resistant strains, with an inverse correlation between the MIC and the absolute decrease in CFU per gram of abscess.
Antimicrobial strategies in the care of organ transplant recipients
Authors: Rubin R H , Tolkoff-Rubin N E
Published: June 2012

Since the early days of transplantation, infection has been a major consequence of antirejection immunosuppressive therapy. Increasingly effective prophylactic and preemptive strategies are being developed to prevent the infectious consequences of immunosuppressive therapy. Although the data base is incomplete and there remains a compelling need for well-designed, randomized, comparative trials, the potential for controlling life-threatening viral, bacterial, fungal, and protozoal infections exists. The cornerstone of this effort is the recognition that effective immunosuppressive strategies require an antimicrobial program to make them safe and that such an antimicrobial program needs to be individualized in order to be appropriately matched with the needs of the antirejection program. Thus, escalation and de-escalation of the antimicrobial program should be carried out to match the immunosuppressive program. Infection and rejection remain closely intertwined, linked by the immunosuppressive program that is prescribed.
The Pseudomonas cepacia 249 chromosomal penicillinase is a member of the AmpC family of chromosomal beta-lactamases
Authors: Proenca R , Niu W W , Cacalano G , Prince A
Published: June 2012

Pseudomonas cepacia 249 produces an inducible beta-lactamase with penicillinase activity. The nucleotide sequence of the penA gene, which encodes this beta-lactamase, was determined and found to include regions with a significant homology to the ampC-encoded beta-lactamases of members of the family Enterobacteriaceae and Pseudomonas aeruginosa. The predicted amino acid sequence of the PenA beta-lactamase contained 17 amino acids immediately preceding the putative active-site serine which were highly conserved among the enzymes of the AmpC family. Although the penA-coding sequence had a total GC content of 60%, the predicted codon usage was more characteristic of Escherichia coli ampC-encoded beta-lactamase, with 53% of the codons having G or C in the third position, in contrast to the values for the P. aeruginosa ampC (88.5%) or Pseudomonas cepacia (88 to 92%) metabolic genes. The inducible expression of penA can be regulated by the E. coli gene product AmpD. A putative P. cepacia AmpR homolog was associated with the positive regulation of both Enterobacter cloacae ampC and P. cepacia penA expression, as confirmed by gel retardation studies. The E. cloacae AmpR did not regulate penA expression. Thus, by homology studies, codon usage, and genetic analysis, the P. cepacia penA beta-lactamase appears to have been acquired from members of the family Enterobacteriaceae and belongs to the class C group of beta-lactamases.
In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine
Authors: Kageyama S , Mimoto T , Murakawa Y , Nomizu M , Ford H , Shirasaka T , Gulnik S , Erickson J , Takada K , Hayashi H
Published: June 2012

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.
In vitro antimicrobial susceptibilities of Nocardia species
Authors: Khardori N , Shawar R , Gupta R , Rosenbaum B , Rolston K
Published: June 2012

The in vitro activities of various quinolones, two new aminoglycosides, a new cephamycin analog (cefmetazole) and a new spectinomycin analog (trospectomycin), imipenem, and trimethoprim-sulfamethoxazole against 26 isolates of Nocardia asteroides, 7 isolates of N. brasiliensis, and 6 isolates of N. caviae were determined by a broth microdilution method. The three new quinolones, PD 117558, PD 117596 and PD 112739, inhibited 90% of N. asteroides at 1 to 2 micrograms/ml, and two new aminoglycosides, SCH 21420 and SCH 22591, inhibited 90% of N. asteroides at 2 to 4 micrograms/ml. Among the beta-lactams, cefmetazole was more active than imipenem. N. brasiliensis and N. caviae isolates were also very susceptible to the three quinolones (MICs for 50% of the isolates, 0.25 to 1 microgram/ml) and the two aminoglycosides (MICs for 50% of the isolates, 1 to 2 micrograms/ml). Cefmetazole was moderately active against N. brasiliensis, whereas imipenem showed poor activity against both of these species.
Kill kinetics and regrowth patterns of Escherichia coli exposed to gentamicin concentration-time profiles simulating in vivo bolus and infusion dosing
Authors: Bastone E B , Li S C , Ioannides-Demos L L , Spicer W J , McLean A J
Published: June 2012

The relative influence of peak concentration (Cmax) versus the area under the antibiotic concentration-time curve (AUC) on the bactericidal effect of gentamicin against Escherichia coli NCTC 10418 was studied. Bacteria in the lag phase were exposed to an in vitro gentamicin concentration series which mirrored the concentrations determined in patients after 80-mg intravenous bolus (1 min) and 80-mg intravenous infusion (30 min) doses. Bacterial viable cell counts and gentamicin concentrations were measured before and during antibiotic exposure. Both the Cmax and AUC were shown to be factors determining antibacterial activity; however, the Cmax was an independent determinant of effect. These findings indicate that bolus intravenous dosing with gentamicin could maximize bactericidal activity. Increased efficacy could result at any given daily antibiotic dose if delivered via bolus with long intervals (12 to 24 h) between doses if appropriate precautions to avoid toxicity are taken.
Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: evidence for enhanced resistance resulting from the coexistence of two different resistance mechanisms
Authors: Rice L B , Carias L L , Etter L , Shlaes D M
Published: June 2012

We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbactam against an isogenic series of Klebsiella pneumoniae strains. Both cefoperazone and cefoperazone-sulbactam were active in vitro against a susceptible clinical strain, and the combination was highly effective in the treatment of rat intra-abdominal abscesses. Loss of expression of a 39-kDa outer membrane protein resulted in at least a fourfold increase in the MICs of cefoperazone and cefoperazone-sulbactam but did not appreciably affect the in vivo efficacy of either regimen. Introduction of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the susceptible strain resulted in the loss of in vitro activity and in vivo efficacy for cefoperazone. The in vitro activity of cefoperazone-sulbactam against this strain was diminished, but the antibiotic combination remained highly active in vivo. Introduction of RP4 into the strain lacking the 39-kDa outer membrane protein resulted in a fourfold increase in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a loss of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanisms, neither of which alone results in substantially diminished cefoperazone-sulbactam efficacy in vivo, can cause in vivo resistance to the beta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.
Serum protein-binding characteristics of vancomycin
Authors: Sun H , Maderazo E G , Krusell A R
Published: June 2012

A synthesis of studies of serum protein binding of vancomycin and its reported abnormal binding in serum with very high concentrations of immunoglobulin A (IgA) suggests that this antibiotic may be bound to more than one serum protein. Using an ultrafiltration method for separating free from bound drug and high-performance liquid chromatography to measure drug concentration, we studied the binding characteristics of vancomycin for alpha-1 acid glycoprotein, IgG, IgM, IgA, and albumin. The results showed that vancomycin does not bind to alpha-1 acid glycoprotein, IgG, or IgM. Major binding to albumin and IgA occurs, and total drug binding to serum proteins can be fully explained by binding to these two proteins. We calculated an N (number of binding sites per molecule) of 1.3 +/- 0.4 and a K (association constant) of 3.3 x 10(5) +/- 6.3 x 10(4) M-1 (NK = 4.3 x 10(5) M-1) for binding to IgA, whereas the corresponding NK value for albumin was only 527.5 M-1, indicating that vancomycin preferentially binds to IgA. Very high concentrations of IgA in serum (i.e., grams per deciliter), such as in patients with IgA myeloma, may result in the paradox of high (total) concentrations of vancomycin in serum that may be clinically ineffective.
In vitro susceptibility of Streptococcus mutans to chlorhexidine and six other antimicrobial agents
Authors: Järvinen H , Tenovuo J , Huovinen P
Published: June 2012

The susceptibility of Streptococcus mutans to chlorhexidine and to six commonly used, systemic antibacterial agents (amoxicillin, cefuroxime, penicillin, sulfamethoxazole-trimethoprim, tetracycline, and erythromycin) was studied for 424 clinical isolates from 116 children and students. The MIC of chlorhexidine for all isolates was < or = 1 micrograms/ml. No resistance to the other antimicrobial agents was detected. Although widely exposed to various antimicrobial agents, S. mutans has remained susceptible to common antimicrobial agents, most importantly to chlorhexidine.
Antimicrobial resistance of Salmonella isolates in a Spanish hospital
Authors: Muńoz P , Díaz M D , Rodríguez-Créixems M , Cercenado E , Peláez T , Bouza E
Published: June 2012

We studied 961 clinical Salmonella isolates (one per patient) seen in one Spanish hospital from 1988 to 1991. The incidence of non-Salmonella typhi Salmonella infections per 100,000 admissions increased from 3.93 to 5.98. Overall rates of resistance to ampicillin, chloramphenicol, and co-trimoxazole were 32, 11, and 2%, respectively. Resistance to chloramphenicol increased from 9 to 16% during the study period, while resistance to each of the other drugs remained stable. Variations related to serogroups were observed.
Characterization of a novel extended-spectrum beta-lactamase from Pseudomonas aeruginosa
Authors: Nordmann P , Ronco E , Naas T , Duport C , Michel-Briand Y , Labia R
Published: June 2012

A clinical isolate of Pseudomonas aeruginosa RNL-1 showed resistance to extended-spectrum cephalosporins which was inhibited by clavulanic acid. Although this strain contained three plasmids ca. 80, 20, and 4 kb long, the resistance could not be transferred by mating-out assays with P. aeruginosa or Escherichia coli. Cloning of a 2.1-kb Sau3A fragment from P. aeruginosa RNL-1 into plasmid pACYC184 produced pPZ1, a recombinant plasmid that encodes a beta-lactamase. This beta-lactamase (PER-1) had a relative molecular mass of 29 kDa and a pI of 5.4 and was biosynthesized by P. aeruginosa RNL-1 along with a likely cephalosporinase with a pI of 8.7. PER-1 showed a broad substrate profile by hydrolyzing benzylpenicillin, amoxicillin, ticarcillin cephalothin, cefoperazone, cefuroxime, HR 221, ceftriaxone, ceftazidime, and (moderately) aztreonam but not oxacillin, imipenem, or cephamycins. Vmax values for extended-spectrum cephalosporins were uncommonly high, and the affinity of the enzyme for most compounds was relatively low (i.e., high Km). PER-1 activity was inhibited by clavulanic acid, sulbactam, imipenem, and cephamycins but not by EDTA. A 1.1-kb SnaBI fragment from pPZ1 failed to hybridize with plasmids that encode TEM-, SHV-, OXA-, or CARB/PSE-type beta-lactamase or with the ampC gene of P. aeruginosa. However, the same probe appeared to hybridize with chromosomal but not plasmid DNA from P. aeruginosa RNL-1. This study reports the properties of a novel extended-spectrum beta-lactamase in P. aeruginosa which may not be derived by point mutations from previously known enzymes of this species.
9-Anilinoacridines as potential antileishmanial agents
Authors: Mauël J , Denny W , Gamage S , Ransijn A , Wojcik S , Figgitt D , Ralph R
Published: June 2012

A number of 1'-substituted 9-anilinoacridines were evaluated for their activities against promastigote and amastigote forms of Leishmania major and for their toxicities to human Jurkat leukemia cells. Several compounds possessing 1'-NH-alkyl substituents produced more than 80% growth inhibition of macrophage-infected L. major amastigotes at or below a concentration of 1 microM. 1'-Hexylamino-9-anilinoacridine (compound 14) was the least toxic compound to human Jurkat cells, while it retained strong antileishmanial activity. There was a general trend for the more lipophilic compounds to show the greatest antileishmanial activity, whereas 3,6-di-NH2 substitution of the acridine nucleus reduced or eliminated activity. Some structure-activity relationships of the various compounds are discussed.
Inhibition of intracellular growth of Mycobacterium avium by one pulsed exposure of infected macrophages to clarithromycin
Authors: Mor N , Heifets L
Published: June 2012

A single 2-h pulsed exposure of either human monocyte-derived macrophages or J774 cells infected with Mycobacterium avium to clarithromycin at 3.0 micrograms/ml completely inhibited the intracellular bacterial growth during the first four days of observation, and then only a slight increase in the number of CFU per milliliter took place between the fourth and seventh days. These data suggest that in vivo the intracellular bacteria can be effectively inhibited after a short period when the concentration of the drug in blood reaches its maximum. On the basis of these data, the assumptions that the elimination of bacteremia observed in clarithromycin clinical trials is a result of the activity of the drug not only against bacteria in blood but in macrophages as well and that the peak concentration attainable in blood is essential for these effects can be made.
Characterization of the gene for chromosomal trimethoprim-sensitive dihydrofolate reductase of Staphylococcus aureus ATCC 25923
Authors: Dale G E , Then R L , Stüber D
Published: June 2012

The gene for the trimethoprim-sensitive (Tmps) chromosomal dihydrofolate reductase (DHFR) of Staphylococcus aureus ATCC 25923 was cloned and characterized. The structural gene encodes a polypeptide of 159 amino acid residues and has a calculated molecular weight of 18,251. The amino acid sequences of this Tmps DHFR and those of the trimethoprim-resistant type S1 DHFR encoded by transposon Tn4003 are 80% identical. In contrast to the trimethoprim-resistant enzyme, the Tmps DHFR can be highly overexpressed in Escherichia coli, with most of the recombinant protein occurring in a soluble and an active form.
Evaluation of bacterial interference and beta-lactamase production in management of experimental infection with group A beta-hemolytic streptococci
Authors: Brook I , Gilmore J D
Published: June 2012

The in vivo effects of penicillin and cefprozil therapy on the interaction between organisms commonly recovered from inflamed tonsils were studied by using a subcutaneous abscess model in mice. These organisms were group A beta-hemolytic streptococci (GABHS), Streptococcus salivarius (which is capable of interfering with GABHS), and Staphylococcus aureus. In mice infected with GABHS and S. salivarius alone or in combination, penicillin eliminated both organisms and cefprozil eliminated GABHS and S. aureus but not S. salivarius. Penicillin did not, however, reduce the number of GABHS or S. salivarius in the presence of S. aureus. The present study demonstrated the ability of beta-lactamase-producing S. aureus to protect GABHS from penicillin. However, no such protection was present following the administration of cefprozil. Furthermore, the preservation of S. salivarius that interferes with GABHS growth may provide protection from reinfection with GABHS. This study supports and provides an explanation for the increased efficacies of cephalosporins administered orally over that of penicillin when treating patients with acute GABHS pharyngitis or tonsillitis.
Characterization of the aac(6')-Ib gene encoding an aminoglycoside 6'-N-acetyltransferase in Pseudomonas aeruginosa BM2656
Authors: Galimand M , Lambert T , Gerbaud G , Courvalin P
Published: June 2012

Pseudomonas aeruginosa BM2656 was resistant to tobramycin and susceptible to gentamicin and amikacin by disk diffusion testing. This unusual resistance was not transferable by conjugation to Escherichia coli or P. aeruginosa PAO38, and plasmid DNA was not detected in this strain. A 0.9-kb fragment harboring the tobramycin resistance gene was cloned from BM2656 into pUC18, generating pAT129. Analysis for aminoglycoside-modifying activity in extracts of BM2656 and E. coli harboring pAT129 indicated that tobramycin resistance was due to synthesis of an aminoglycoside 6'-N-acetyltransferase type I [AAC(6')-I] enzyme which modified amikacin and tobramycin. Although amikacin was acetylated, the bactericidal synergism of this aminoglycoside with ceftazidime against BM2656 was minimally affected. The sequence of the DNA fragment was determined. It contained an aac (6')-Ib-like gene and was located downstream from a conserved region related to Tn21. The translated sequence of this aac(6')-Ib gene possessed 99.2% identity with the putative products of the aac(6')-Ib gene cassettes from Serratia marcescens and Klebsiella pneumoniae and 69% identity with the putative aacA(6')-II gene product from P. aeruginosa. We conclude that an aac(6')-Ib gene has spread to the chromosome of P. aeruginosa, probably by transposition.
In vitro antibacterial activity and beta-lactamase stability of CP-70,429 a new penem antibiotic
Authors: Minamimura M , Taniyama Y , Inoue E , Mitsuhashi S
Published: June 2012

In in vitro susceptibility tests, the new penem CP-70,429 showed potent antibacterial activity against gram-positive and gram-negative bacteria except Pseudomonas aeruginosa and Xanthomonas maltophilia. CP-70,429 was stable to various types of beta-lactamases except for the enzyme from X. maltophilia and was 16- to 128-fold more active than the other compounds against beta-lactamase-producing strains of Enterobacter cloacae and Citrobacter freundii.
Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis
Authors: Friedland I R , Paris M , Ehrett S , Hickey S , Olsen K , McCracken G H
Published: June 2012

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.
Method for detection of picornavirus capsid binders with soluble intercellular adhesion molecule 1
Authors: Last-Barney K , Marlin S D , Pal K , Cahill-Feehan C , McNally E J , Jeanfavre D D , Merluzzi V J
Published: June 2012

A method utilizing immobilized major group rhinoviruses and biotinylated soluble intercellular adhesion molecule 1 has been developed for the detection of capsid binders. Binding measurements indicate a loss in relative affinity of biotinylated soluble intercellular adhesion molecule 1 for rhinoviruses by capsid binders. This method and a new class of capsid binders are discussed.
Antibiotic susceptibility of group A streptococci: a 6-year follow-up study
Authors: Betriu C , Sanchez A , Gomez M , Cruceyra A , Picazo J J
Published: June 2012

The susceptibility patterns of group A streptococci over the last 6 years in our hospital were determined. Since our last study, carried out in 1987, all isolates have remained very susceptible in vitro to penicillin and all of the other beta-lactam agents tested. We observed resistance to erythromycin, clindamycin, tetracycline, and ofloxacin. The prevalence of erythromycin-resistant group A streptococci did not change appreciably throughout the study period.
The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodeficiency virus type 1 reverse transcriptase
Authors: Wilson J E , Martin J L , Borroto-Esoda K , Hopkins S , Painter G , Liotta D C , Furman P A
Published: June 2012

The (-) enantiomer of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine is a potent inhibitor of human immunodeficiency virus type 1 in vitro. The 5'-triphosphates of the (-) and (+) enantiomers equally inhibited the production of full-length minus-strand DNA in an endogenous reverse transcriptase reaction, each competitively inhibited DNA synthesis, and each was used as a chain-terminating substrate.
Isolation of moderately penicillin-susceptible strains of Neisseria meningitidis in Argentina
Authors: Lopardo H A , Santander C , Ceinos M C , Rubeglio E A
Published: June 2012

Four strains that were moderately susceptible to penicillin and/or ampicillin were found among 54 consecutive isolates of meningococci recovered from patients in one pediatric hospital in Argentina from October 1991 to December 1992. Disk diffusion tests performed with 2 U of penicillin failed to detect one strain. These findings suggest that attention should be paid to changes in the susceptibility patterns of meningococci in order to anticipate therapeutic failures in the future.
Involvement of inhibitory and excitatory neurotransmitters in levofloxacin- and ciprofloxacin-induced convulsions in mice
Authors: Akahane K , Kato M , Takayama S
Published: June 2012

We studied the effects of gamma-aminobutyric acid (GABA)-benzodiazepine receptor agonists and glutamate receptor antagonists on levofloxacin (LVFX)- and ciprofloxacin (CPFX)-induced convulsions using intrathecal (i.t.) injections in mice. We also studied the effects of these agonists and antagonists on exacerbated convulsions induced by coadministration of the quinolone with 4-biphenylacetic acid (BPAA). The agonists or antagonists were injected i.t. 5 min and BPAA was administered orally 30 min before a single i.t. injection of the quinolone (10 microliters per animal). The animals were observed for clonic convulsion and death, and latency times to the appearance of convulsion were determined. Among the agonists, baclofen showed marked inhibition of both LVFX- and CPFX-induced convulsions, while other compounds such as GABA, muscimol, diazepam, and 3-aminopropylphosphonic acid had slight effects. Among the antagonists, kynurenic acid showed the strongest inhibition of convulsions caused by all doses of LVFX and CPFX and prolonged latency times; gamma-glutamyl-aminomethylsulfonic acid (GAMS) also markedly inhibited convulsions. The antagonists D-AP-5, AP-7, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) had slight effects. Additionally, GAMS, DNQX, and MK-801 significantly lowered the incidence of death in the groups treated with CPFX. The enhanced convulsive activities of LVFX or CPFX by pretreatment with BPAA were clearly blocked by baclofen, kynurenic acid, GAMS, and DNQX. D-AP-5 and AP-7 also showed clear effects on the activity of LVFX. These results suggest that LVFX has fewer effects on the brains than CPFX and that convulsions induced by these quinolones alone and by these quinolones administered with BPAA may be mediated largely through glutamate and GABA(B) rather than GABA(A) receptors in mice.
Anti-Mycobacterium avium activity of quinolones: structure-activity relationship studies
Authors: Klopman G , Wang S , Jacobs M R , Ellner J J
Published: June 2012

The structures and inhibitory activities of 88 quinolones, previously studied as potential in vitro inhibitors of 14 selected strains of Mycobacterium avium complex, were examined in an effort to identify a quinolone with optimal activity towards all strains. A MULTICASE structure-activity relationship analysis of the inhibitory activities of these 88 quinolones against 14 strains of M. avium was performed and led to the identification of a number of structural constraints required to overcome the resistance of most of the strains. Our data suggested that the increased resistance of the strains was probably not due to a specific resistance mechanism but rather due to gradual limitation of the constraints imposed on the structure of the quinolones. This increasing structural selectivity could be produced either at the level of cell membrane penetration or at the level of interaction with the DNA gyrase receptor site. On the basis of these findings, a number of new quinolones holding the promise of superior activity are currently being evaluated in vitro and in vivo to determine the clinical relevance of our observations.