bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro susceptibilities and beta-lactamase production of 53 clinical isolates of Branhamella catarrhalis
Authors: Alvarez S , Jones M , Holtsclaw-Berk S , Guarderas J , Berk S L
Published: June 2012

We tested 53 clinical isolates of Branhamella catarrhalis recovered from patients with respiratory symptoms to determine the susceptibility of the isolates to 25 antimicrobial agents, including the newer beta-lactam antibiotics. Of the 53 strains, 46 (86.7%) were beta-lactamase producers. All the strains were susceptible to the majority of the new penicillins and cephalosporins. The combinations of amoxacillin-clavulanic acid and ticarcillin-clavulanic acid were also very active against the beta-lactamase-producing strains.
Inhibitory effect of cephalosporins on gamma-aminobutyric acid receptor binding in rat synaptic membranes
Authors: Hori S , Kurioka S , Matsuda M , Shimada J
Published: June 2012

Cephalosporins inhibited gamma-aminobutyric acid receptor binding in a concentration-dependent manner in vitro. Scatchard analysis revealed that cefazolin decreased the binding capacity but did not change the affinity of the receptor. It is suggested that this inhibition of gamma-aminobutyric acid receptor binding may be involved in the induction of convulsions by cephalosporins.
Comparison of single-dose tetracycline hydrochloride to conventional therapy of urinary tract infections
Authors: Rosenstock J , Smith L P , Gurney M , Lee K , Weinberg W G , Longfield J N , Tauber W B , Karney W W
Published: June 2012

Sixty-two women with signs and symptoms compatible with lower urinary tract infections were randomized to receive single-dose tetracycline (2 g), multi-dose tetracycline (500 mg four times per day for 10 days), or single-dose amoxicillin (3 g). Urine cultures were obtained upon entry into the study and on days 4, 14, and 28 after therapy. Single-dose tetracycline cured 12 of 16 (75%) of women with documented urinary tract infections, compared with 15 of 16 (94%) in the multi-dose tetracycline group and 7 of 13 (54%) receiving single-dose amoxicillin. Mild nausea in 3 of 20 patients (15%) was the only complication in the single-dose tetracycline group. Two grams of single-dose tetracycline is as effective as other reported regimens regardless of the susceptibility of the initial pathogen and has minimal toxicity.
Evaluation of the in vitro activity of BMY-28142, a new broad-spectrum cephalosporin
Authors: Fuchs P C , Jones R N , Barry A L , Thornsberry C
Published: June 2012

The in vitro activity of BMY-28142, a new cephalosporin, was tested by a broth microdilution system and compared with those of cefotaxime, ceftazidime, cefoperazone, moxalactam, and HR 810 against 747 bacterial isolates, one-third of which were resistant to one or more third-generation cephalosporins. BMY-28142 was the most active drug tested against 326 Enterobacteriaceae with an MIC for 90% of the organisms tested (MIC90) of 1.0 micrograms/ml. Against these Enterobacteriaceae the relative activities were: BMY-28142 greater than HR 810 greater than moxalactam and ceftazidime greater than cefotaxime greater than cefoperazone. For cefotaxime- and cefoperazone-resistant strains, the MIC90 of BMY-28142 was 4.0 micrograms/ml (compared with 0.13 micrograms/ml for susceptible strains). BMY-28142, with an MIC90 of 8.0 micrograms/ml for Pseudomonas aeruginosa, was about half as active as ceftazidime. The relative activities against P. aeruginosa were: ceftazidime greater than BMY-28142 greater than HR 810 greater than cefoperazone greater than moxalactam and cefotaxime. The MIC90 of BMY-28142 against staphylococci was 2.0 micrograms/ml, which was fourfold less active than HR 810, slightly less active than cefotaxime and cefoperazone, and fourfold more active than ceftazidime and moxalactam. BMY-28142 was very active against beta-lactamase-positive and -negative Haemophilus influenzae (MIC90, 0.06 micrograms/ml), Neisseria gonorrhoeae (MIC90, 0.015 micrograms/ml),aand nonenterococcal streptococci. Its activity against Streptococcus faecalis was poor (MIC90, 64 micrograms/ml). BMY-28142 was stable against the several beta-lactamases tested but exhibited little beta-lactamase inhibitory effect.
Effects of aminoglycoside antibiotics on polymorphonuclear leukocyte function in vivo
Authors: Venezio F R , DiVincenzo C A
Published: June 2012

In vitro incubation of aminoglycoside antibiotics with human polymorphonuclear leukocytes (PMNs) has been shown to induce abnormalities in cell function. This study was designed to determine whether there are similar abnormalities in leukocyte function after exposure to the action of these agents in vivo. Four aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) were tested. In vitro incubation did not induce a chemotactic defect when measured by an under-agarose method. However, inhibition of candidacidal activity was reproducible after in vitro incubation of all aminoglycosides tested. Nevertheless, when the aminoglycosides were administered intravenously to normal volunteers, PMN function, including adherence to nylon wool columns, chemotaxis, phagocytosis, and killing of Candida albicans, was unimpaired at 1, 3, and 24 h postinfusion. Therefore, we conclude that aminoglycoside antibiotic administration does not induce PMN dysfunction in vivo.
Development of two DNA probes for differentiating the structural genes of subclasses I and II of the aminoglycoside-modifying enzyme 3'-aminoglycoside phosphotransferase
Authors: Young S A , Tenover F C , Gootz T D , Gordon K P , Plorde J J
Published: June 2012

Two DNA probes were developed to screen for the genes encoding 3'-aminoglycoside phosphotransferase activity in gram-negative bacilli. The 3'-I phosphotransferase [APH(3')I] probe was subcloned from Tn903; the APH(3')II probe was subcloned from Tn5. Each probe proved to be specific for genes corresponding to its own APH(3') subclass and did not hybridize with DNA from other classes when tested at high stringency by either Southern hybridization or dot-blot hybridization methods. The APH(3')I probe hybridized to DNA obtained from organisms demonstrating APH(3')I activity as measured by the phosphocellulose paper binding assay (PPBA) as well as to DNA from organisms reported to have both APH(3')I and APH(3')II activity by PPBA. This probe did not hybridize to DNA from organisms showing only APH(3')II activity by PPBA. The APH(3')II probe demonstrated homology with DNA from organisms showing APH(3')II activity by PPBA but not with DNA from organisms showing APH(3')I activity or both APH(3')I and APH(3')II activity by PPBA. We conclude that organisms previously believed to contain both APH(3')I and APH(3')II genes based on PPBA contain in fact only the APH(3')I gene.
Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency
Authors: Klein R J , Friedman-Kien A E
Published: June 2012

The effect of topical and systemic treatment with 9-(1,3-dihydroxy-2-propoxymethyl)guanine on the evolution of herpes simplex virus-induced skin infection in hairless mice was investigated. Systemic (subcutaneous) treatment with a 10-mg/kg dose and topical applications with a 5% cream started up to 48 h after infection prevented the development of severe skin lesions and a fatal outcome. However, the establishment of latent infections was prevented only by topical treatment started at 6 h after infection. Systemic (50 mg/kg) and topical treatments started 48 h after infection reduced virus titers in the skin and ganglia and promoted rapid clearance of virus from these sites. The clearance of infectious virus from ganglia during the acute phase of infection was followed by early establishment of latency. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (0.03 microgram/ml) significantly inhibited the synthesis of infectious virus in explant cultures of latently infected ganglia, and at concentrations higher than 8 micrograms/ml no infectious virus was detectable in ganglia explant cultures.
Analysis of amifloxacin in plasma and urine by high-pressure liquid chromatography and intravenous pharmacokinetics in rhesus monkeys
Authors: McCoy L F , Crawmer B P , Benziger D P
Published: June 2012

An analytical method for the quantitation of amifloxacin, 6-fluoro-1,4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid, in plasma and urine has been developed. The method involves extraction with chloroform, back-extraction into 0.1 M sodium hydroxide, and subsequent analysis by reverse-phase high-pressure liquid chromatography with UV detection. The precision of the assay calculated as the overall standard deviation was +/- 4.9% in plasma and +/- 1.1% in urine. The range of mean percent differences from the nominal values was used as an estimate of accuracy and was 93.6 to 103% of the nominal values in plasma and 95.2 to 107% of the nominal values in urine. The minimum quantifiable levels were 0.032 micrograms/ml in plasma and 2.7 micrograms/ml in urine. The methods were employed in a pharmacokinetic analysis of amifloxacin after intravenous administration to rhesus monkeys. The decline in drug plasma levels was described by a biexponential process with mean rates of 8.4 h-1 and 0.32 h-1 with corresponding half-lives of ca. 5 min and 2.2 h. Amifloxacin was rapidly excreted, with ca. 53% of the dose appearing in the urine within 48 h after medication. The mean renal clearance +/- standard deviation was 4.4 +/- 1.0 ml X kg-1 X min-1 and is compatible with passive glomerular filtration in this species.
Determination of inhibitory concentrations of antiviral agents in cell culture by use of an enzyme immunoassay with virus-specific, peroxidase-labeled monoclonal antibodies
Authors: van Tiel F H , Boere W A , Harmsen T , Kraaijeveld C A , Snippe H
Published: June 2012

An enzyme immunoassay (EIA) to determine 50% inhibitory concentrations of drugs which suppress Semliki Forest virus replication is described. Inhibition of virus replication was measured in L-cells, seeded as monolayers in 96-well plates by use of horseradish peroxidase-labeled monoclonal antibodies directed against the E1 glycoprotein of Semliki Forest virus. The antiviral agents tested were cycloheximide, tunicamycin, NH4Cl, and disodium cromoglycate. The 50% inhibitory concentration of these antiviral agents was arbitrarily defined as the concentration of drug, in culture medium, associated with 50% reduction of the control absorbance value measured on Semliki Forest virus-infected cells without drug in the culture fluid. Twenty-two hours after infection the 50% inhibitory concentrations of the drugs were 0.2 microgram/ml for cycloheximide, 0.8 microgram/ml for tunicamycin, 0.3 mg/ml for NH4Cl, and 4.9 mg/ml for disodium cromoglycate. These values are similar to those determined by others with conventional methods of virus quantification. This test is sensitive and easy to perform and therefore is suited for large-scale experiments.
Forecasting cephalosporin and monobactam antibiotic half-lives in humans from data collected in laboratory animals
Authors: Mordenti J
Published: June 2012

The postdistribution half-lives of 10 cephalosporin and 2 monobactam antibiotics in humans were predicted from data obtained in other mammals. This forecasting was accomplished with the allometric equation t1/2 = aWb, where a is the y intercept and b is the slope obtained from the log-log plot of antibiotic half-life (t1/2) versus body weight (W). Dimensionless similarity criteria were used to produce a biological clock for ceftizoxime elimination. The creation of the biological clock, which measured physiologic time (heartbeats) rather than chronologic time (minutes), demonstrated that ceftizoxime half-life was identical in five mammals. This methodology will contribute to infectious disease research through a greater understanding of pharmacokinetic scaling in mammals.
Attenuation of experimental tobramycin nephrotoxicity by ticarcillin
Authors: English J , Gilbert D N , Kohlhepp S , Kohnen P W , Mayor G , Houghton D C , Bennett W M
Published: June 2012

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.
Concentrations of fusidic acid, cloxacillin, and cefamandole in sera and atrial appendages of patients undergoing cardiac surgery
Authors: Bergeron M G , Desaulniers D , Lessard C , Lemieux M , Després J P , Métras J , Raymond G , Brochu G
Published: June 2012

The concentrations of cefamandole, cloxacillin and fusicid acid were measured in the serum and heart tissue of 100 recipients of these drugs before cardiac surgery. During cardiopulmonary bypass, mean (+/- standard deviation) peak concentrations in serum of all patients were 63.0 +/- 34.0 micrograms of cefamandole per ml, 30.8 +/- 17.7 micrograms of cloxacillin per ml, and 32.4 +/- 10.8 micrograms of fusidic acid per ml. Mean (+/- standard deviation) concentrations in atrial appendages taken 1 h (+/- 15 min) after infusion were 21.3 +/- 11.0 micrograms of cefamandole per g, 23.8 +/- 17.3 micrograms of cloxacillin per g, and 10.7 +/- 4.2 micrograms of fusidic acid per g. No cloxacillin could be detected in 5 of 39 heart specimens. Mean tissue-to-serum ratios at 1 h for cefamandole, cloxacillin, and fusidic acid were respectively 0.35, 0.73, and 0.33. Fusidic acid, a drug which is highly effective in vitro against both methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, was detectable in heart tissue in concentrations which were 12 times higher than the MICs of this agent against these resistant microorganisms.
Plasmid-borne or chromosomally mediated resistance by Tn7 is the most common response to ubiquitous use of trimethoprim
Authors: Steen R , Sköld O
Published: June 2012

The folic acid analog trimethoprim has been in clinical use for more than 10 years. The use of it in Sweden has doubled in the last 6 to 7 years, and from the distribution statistics it can be calculated that during 1 year 4 to 5% of the population in Sweden are given this drug. The bacterial resistance mechanisms to be found in response to such a selection pressure were investigated in a relatively isolated population in northern Sweden (the county of Jämtland), in which one centrally located bacteriological laboratory serves the area. Trimethoprim-resistant strains were collected during an 8-month period from consecutive specimens of bacteria from the urinary tracts of patients. Among the highly resistant strains of enteric bacteria, trimethoprim resistance mediated by transposon-borne dihydrofolate reductase of type I was found to dominate. The corresponding Tn7-like transposon was found to be localized both on the chromosome of isolated Escherichia coli strains and also on a 50-kilobase IncI transferable plasmid which was found in several different serotypes of E. coli. In two enterobacterial strains, resistance to more than 10(3) micrograms of trimethoprim per ml was furthermore found to be caused by a ca. 80-fold increase in the formation of chromosomal dihydrofolate reductase.
Antimicrobial susceptibility patterns and R plasmid-mediated resistance of the fish pathogen Yersinia ruckeri
Authors: De Grandis S A , Stevenson R M
Published: June 2012

Fifty strains of Yersinia ruckeri, the causative agent of enteric redmouth disease of salmonid fish, were tested for susceptibility to 23 antimicrobial agents by using an agar dilution procedure. The MICs were generally uniform for all serological varieties. Two of the 50 strains carried a 36-megadalton plasmid which determined resistance to tetracyclines and sulfonamides and was transferable to both Escherichia coli and Y. ruckeri recipients. The serovars did differ in their response to polymyxin B. Strains of serovars II, III, and V were highly resistant (MICs of 128 to 512 micrograms/ml), whereas most serovar I strains were susceptible to less than or equal to 2.0 micrograms/ml. Of 33 serovar I strains, 6 were highly resistant to polymyxin B, which is a characteristic that may divide serovar I (Hagerman) strains into two distinct subgroups.
Reverse inoculum effect in bactericidal activity and other variables affecting killing of group B streptococci by penicillin
Authors: Jokipii L , Brander P , Jokipii A M
Published: June 2012

Variables of the effect of penicillin G on the numbers of viable group B streptococci in broth cultures were studied. One-fourth of the MIC was the lowest concentration that reduced the viable count compared with antibiotic-free controls. The rate of killing increased with the concentration of penicillin up to 4 X MIC, but no further. During the first 2 or 3 h, the bactericidal activity was more rapid than later on. The MIC and supraoptimal concentrations of penicillin killed an inoculum of 10(6) organisms more rapidly than an inoculum of 10(4) organisms. The MIC was not inoculum dependent. The reverse inoculum effect was revealed by the killing curves but not by the MBC. There were reproducible differences among strains as to the rate of killing by penicillin; these did not correlate with the rate of multiplication, which also varied among strains. Among the 11 strains tested, there were no tolerant ones.
Activity of a peptidyl prodrug, alafosfalin, against anaerobic bacteria
Authors: Grappel S F , Giovenella A J , Nisbet L J
Published: June 2012

Alafosfalin, an antibacterial phosphonodipeptide requiring peptide transport for activity, was tested for activity against clinical strains of anaerobic bacteria in peptide-free Roche Sensitivity Test Medium no. 5 agar. It was active against Bacteroides spp., Fusobacterium nucleatum, and Clostridium perfringens but not against Clostridium difficile. Alafosfalin activity was antagonized by appropriate peptides. Synergy was obtained with other cell wall-active antibiotics.
Simultaneous determination of dacarbazine, its photolytic degradation product, 2-azahypoxanthine, and the metabolite 5-aminoimidazole-4-carboxamide in plasma and urine by high-pressure liquid chromatography
Authors: Fiore D , Jackson A J , Didolkar M S , Dandu V R
Published: June 2012

A high-pressure liquid chromatographic method has been developed that allows for the simultaneous analysis of dacarbazine (DTIC), 5-aminoimidazole-4-carboxamide (AIC), and 2-azahypoxanthine (2-AZA) in plasma or urine. Plasma samples were prepared by ultrafiltration, whereas urine samples were filtered and diluted for analysis. Chromatography was done with a C18 mu Bondapak column along with gradient elution of the drugs. The mobile phase consisted of 100% 0.5 M sodium acetate (pH 7.0) and 25% acetonitrile in 0.05 M sodium acetate (pH 5.5) with detection at 280 nm. Linearity was observed up to 500 micrograms/ml for DTIC and up to 53 micrograms/ml for AIC and 2-AZA. The assay methodology was reproducible, with a lower limit of detection of 5.0, 0.5, and 0.5 micrograms/ml for DTIC, AIC, and 2-AZA, respectively. Interday and intraday coefficients of variation ranged between 4 to 14% and 2 to 16%, respectively. The analytical method was applied to the analysis of plasma and urine samples resulting from the isolation perfusion chemotherapy of an extremity with 57 mg of DTIC per kg in a patient with melanoma.
Chemical parameters, antimicrobial activities, and tissue toxicity of 0.1 and 0.5% sodium hypochlorite solutions
Authors: Cotter J L , Fader R C , Lilley C , Herndon D N
Published: June 2012

ffe chemical parameters, antimicrobial activity, and tissue toxicity of two sodium hypochlorite (NaOCl) solutions buffered to a physiologic pH were studied. Initially, a 0.5% NaOCl solution buffered with 3 g of NaH2PO4 per liter was examined. The solution had a pH of 7.49 and an osmolality of 352 mOsmol/liter. When compared with unbuffered and NaHCO3-buffered 0.5% NaOCl solutions, the NaH2PO4-buffered solution was significantly more effective in killing Staphylococcus aureus in vitro. However, the pH of the NaH2PO4-buffered solution decreased over time with a concomitant decrease in antibacterial activity. A freshly prepared solution decontaminated human cadaveric skin colonized by S. aureus, Pseudomonas aeruginosa, or Candida albicans in vitro within 10 min of exposure, whereas a 24-h-old solution cleared the skin of organisms within 15 min. When gauze soaked with 0.5% NaOCl was applied to guinea pig skin for 2 weeks, a 15% decrease in basal cell viabilities was noted. Because of the pH instability and basal cell toxicity, a 0.1% NaOCl solution buffered with NaH2PO4-Na2HPO4 was evaluated. This solution had an osmolality of 386 mOsmol/liter and a pH of 7.4 that was stable over 1 week. A freshly prepared 0.1% NaOCl solution decontaminated skin colonized with S. aureus, C. albicans, and P. aeruginosa within 10, 20, and 30 min, respectively. A 24-h-old solution did not completely decontaminate the colonized skin but significantly reduced the number of microorganisms on the skin surface (P less than 0.001). Application of this solution of guinea pig skin for 2 weeks produced no significant effect on basal cell viabilities. These solutions may serve as alternative topical agents for use in burn therapy.
Difference in blister fluid penetration after single and multiple doses of ceftriaxone
Authors: LeBel M , Grégoire S , Caron M , Bergeron M G
Published: June 2012

Plasma and suction skin blister fluid concentrations of ceftriaxone were studied in 12 subjects after intravenous administration of 1 g of ceftriaxone every 12 h (q12h) and 2 g every 24 h (q24h) after single and multiple doses. Ceftriaxone concentrations were determined by high-pressure liquid chromatography. Mean peak plasma concentrations (at the end of the 5-min infusion) were 254.0 and 374.8 micrograms/ml after administration of 1 g q12h after single and multiple doses, respectively. Similarly, with 2 g q24h, maximum levels were 409.6 and 443.5 micrograms/ml. Forty-eight hours after the last dose of ceftriaxone, plasma concentrations were still detectable: 1.2 micrograms/ml after 1 g q12h and 3.0 micrograms/ml after 2 g q24h. Higher ceftriaxone concentrations were observed in blister fluid after multiple doses than after a single dose. Peak concentrations almost doubled in the blister fluid after multiple doses: 36.0 versus 67.0 micrograms/ml and 38.6 versus 68.9 micrograms/ml for 1 g q12h and 2 g q24h, respectively. Elimination half-life of ceftriaxone in the blister (8.3 and 11.5 h) was longer than plasma half-life (6.3 h). With the area under the concentration-time curve ratio, a 113% increase in tissue penetration was observed after multiple doses for the 1 g q12h regimen. The free plasma and blister fluid ceftriaxone concentrations observed at the end of the dosing interval of the 2 g q24h regimen were higher than the MIC for 90% of the susceptible microorganisms and justified the once-a-day use of ceftriaxone.
Susceptibility of Legionella pneumophila to ofloxacin in vitro and in experimental Legionella pneumonia in guinea pigs
Authors: Saito A , Sawatari K , Fukuda Y , Nagasawa M , Koga H , Tomonaga A , Nakazato H , Fujita K , Shigeno Y , Suzuyama Y
Published: June 2012

The antimicrobial activity of ofloxacin was tested against 15 standard strains and 37 clinical and environmental strains of Legionella pneumophila by agar dilution susceptibility studies with a new growth medium. The ofloxacin MICs were inoculum dependent and ranged from 0.03 to 0.125 microgram/ml. The antibacterial activities of other agents tested relative to ofloxacin were rifampin greater than ofloxacin greater than josamycin greater than pipemidic acid. Ofloxacin, at concentrations equal to or greater than 0.05 microgram/ml, inhibited the growth of L. pneumophila grown in human monocytes. The therapeutic efficacy of ofloxacin in experimental guinea pig L. pneumophila pneumonia was greater than that observed with erythromycin or josamycin therapy; it was less effective than was rifampin. Ofloxacin was very active against intracellular L. pneumophila in these experiments and should be studied in the therapy of human Legionnaires disease.
Plasmid-mediated fosfomycin resistance is due to enzymatic modification of the antibiotic
Authors: Llaneza J , Villar C J , Salas J A , Suarez J E , Mendoza M C , Hardisson C
Published: June 2012

The molecular mechanism of plasmid-mediated resistance to fosfomycin is described. The antibiotic was inactivated intracellularly and remained inside the cells. Modification was also obtained from cell extracts and was not energy dependent. The modifying enzyme seems to have sulfhydryl groups in its active center.
Penetration of sulbactam-ampicillin and clavulanic acid-amoxicillin into the pelvic peritoneum
Authors: Houang E T , Colley N , Chapman M
Published: June 2012

Sixteen patients were given single intravenous injections of ampicillin (0.5 g) with sulbactam (0.5 g), and 15 patients were given amoxicillin (1 g) with clavulanic acid (0.2 g) before elective laparoscopy. At 2 h after dosing, the concentrations of the four compounds in serum and in the peritoneal fluid from the Pouch of Douglas and the ratio of each combination reached levels shown to be effective for antimicrobial activity in vitro.
Genetic analysis of spontaneous resistance to ampicillin in Neisseria gonorrhoeae
Authors: Jones F , Cunningham E J , Shockley T E , Jackson J H
Published: June 2012

Step-wise intrinsic resistance to ampicillin in Neisseria gonorrhoeae was analyzed genetically by DNA-mediated transformation experiments. A first-step ampicillin-resistant (Ampr1) mutant and a second-step ampicillin-resistant (Ampr2) mutant generated during sequential selection were used in these studies. Each selection step was accompanied by an approximate twofold increase in resistance. Four amp alleles were found to account for full resistance of the Ampr2 phenotype. All four amp alleles lie among a cluster of genes which code for ribosomal functions. This region has the map order rif str fus tet cam. First-step resistance was caused by two amp alleles, ampA2 and ampB1, neither of which independently caused detectable ampicillin resistance. Outcrossing of the ampA2 or the ampB1 mutation resulted in wild-type susceptibility to ampicillin. Mapping studies indicate that ampB1 lies between str and fus, whereas ampA2 lies to the right of cam. Second-step resistance required two mutations, ampC3 and ampD4, in addition to ampB1 and ampA2. Transformation of ampC3 to ampC3+ in an Ampr2 mutant resulted in the Ampr1 phenotype. Both ampC3 and ampD4 showed transformation linkage to rif and str. ampC3 was positioned at a site between rif and str. ampD4 apparently occupied a site, outside of the rif-str region, proximal to rif and distal to str. We postulate the gene order to be ampD rif ampC str ampB fus tet cam ampA.
Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia
Authors: Cone L A , Woodard D R , Stoltzman D S , Byrd R G
Published: June 2012

A prospective, randomized study was undertaken to compare the efficacy and safety of ceftazidime with those of a combination of ticarcillin and tobramycin in the treatment of 40 nonneutropenic patients with pneumonia or bacteremia. Altogether, 93% of the patients receiving ceftazidime for pneumonia were cured, and 87% of those with bacteremia responded favorably. Of the subjects who were treated with ticarcillin and tobramycin ceftazidime developed significant superinfection, and one individual treated with the aminoglycoside and carboxypenicillin developed reversible azotemia. Ceftazidime appears to be as efficacious as the ticarcillin-tobramycin combination and is probably safer with regard to oto-and nephrotoxicity; however, superinfections did occur more frequently in the group treated with ceftazidime.
In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum
Authors: Conrad D A , Scribner R K , Weber A H , Marks M I
Published: June 2012

The antibacterial activity of BMY-28142, a new aminothiazole cephalosporin, was measured by standardized broth microdilution and agar dilution methods against 450 gram-positive and gram-negative bacteria isolated from pediatric infections, including acute pulmonary exacerbations of cystic fibrosis. BMY-28142 activity was compared with that of aminoglycosides, beta-lactams, chloramphenicol, trimethoprim-sulfamethoxazole, vancomycin, and clindamycin. The activity of BMY-28142 in combination with other antimicrobial agents against Pseudomonas aeruginosa was also determined. Furthermore, the effects of inoculum and pH on BMY-28142 activity were evaluated. BMY-21842 was active against most of the gram-positive and gram-negative isolates, with the exception of methicillin-resistant Staphylococcus aureus and Pseudomonas cepacia. The combination of BMY-28142 with tobramycin was often synergistic, and combinations of BMY-28142 with either polymyxin B or imipenem were usually antagonistic. BMY-28142 antibacterial activity could be adversely affected at extremes of medium pH and by high inoculum densities.
Impact of netilmicin regimens on the activities of ceftazidime-netilmicin combinations against Pseudomonas aeruginosa in an in vitro pharmacokinetic model
Authors: Blaser J , Stone B B , Groner M C , Zinner S H
Published: June 2012

The antibacterial activities of ceftazidime and netilmicin were studied in a two-compartment in vitro model. Pseudomonas aeruginosa cultures were exposed to changing drug concentrations that mimic human pharmacokinetics. Netilmicin alone reduced the numbers of organisms in cultures of the susceptible strains by more than 99% within 4 h; however, regrowth occurred after 8 h. Although ceftazidime alone killed more slowly than netilmicin, only one of the five strains regrew within 28 h. When both drugs were combined, rapid initial killing occurred without subsequent regrowth. Studied after 24 h in combination with ceftazidime, netilmicin was as effective when given as a single daily dose as when administered in three daily doses that provided 50% more aminoglycoside per day. Decreased bacterial susceptibility was seen after ceftazidime exposure for one strain and after netilmicin exposure for all originally netilmicin-susceptible strains. No such reduction in susceptibility was observed during exposure to the combination. The results of standard in vitro checkerboard tests for synergism were predictive of the initial (4 to 8 h) but not the final (24 to 28 h) assessment of drug interaction in the pharmacokinetic model.
Antiviral and antimetabolic activities of neplanocins
Authors: De Clercq E
Published: June 2012

Of a series of carbocyclic analogs of adenosine, in which the ribose moiety was replaced by a cyclopentenyl ring, neplanocin A, or (-)-9-[trans-2, trans-3-dihydroxy-4-(hydroxymethyl)cyclopent-4-enyl]adenine proved particularly effective in inhibiting the multiplication of DNA viruses (i.e., vaccinia), (-)RNA viruses (i.e., parainfluenza, measles, and vesicular stomatitis), and double-stranded RNA viruses (i.e., reo) in vitro in cell culture. Depending on the cells used, the MIC of neplanocin A for these viruses ranged from 0.01 to 4 micrograms/ml, and depending on the parameter used to assess toxicity for the host cell, the specificity index of neplanocin A ranged from 50 to 4,000. As postulated before for other adenosine analogs, neplanocin A may owe its antiviral action to inhibition of S-adenosylhomocysteine hydrolase, hence perturbation of transmethylation reactions. In vivo, neplanocin A afforded only marginal protection against a lethal infection of mice with vesicular stomatitis virus.
Membrane permeability changes associated with DNA gyrase inhibitors in Escherichia coli
Authors: Dougherty T J , Saukkonen J J
Published: June 2012

Inhibition of DNA synthesis in Escherichia coli B/r by a DNA gyrase inhibitor results in cell death after a 50-min lag period. Examination of the cells under phase-contrast and electron microscopes revealed that they appeared to undergo plasmolysis coincident with the onset of cell death. The inhibited cells were also found to become susceptible to low levels of detergent at this time. With a fluorescent membrane probe, the level of membrane permeability was assessed and found to increase concurrently with the decrease in culture viability. Analysis of the cell envelope constituents revealed that, other than a shift in the protein/lipid ratio, the compositions of the cell membranes were unperturbed.
Use of an enzyme-linked immunosorbent assay performed directly on fixed infected cell monolayers for evaluating drugs against varicella-zoster virus
Authors: Berkowitz F E , Levin M J
Published: June 2012

An in situ enzyme-linked immunosorbent assay (ELISA), performed directly on fixed varicella-zoster virus-infected monolayers, was used to quantitate viral antigen, and by color reduction it was used to evaluate the activity of drugs against varicella-zoster virus. Color production in the ELISA (optical density) was directly related to the dose of input virus. Antigen representing 5 to 10 plaques could be detected 3 days after infection. The ELISA was specific and reproducible, as shown by absorption and repeat experiments, respectively. A color-reduction test by ELISA was compared with the conventional plaque-reduction assay for its ability to measure the antiviral activity of acyclovir, bromovinyldeoxyuridine, trifluorothymidine, and vidarabine against four strains of varicella-zoster virus. In all cases but one the 50% inhibitory doses were lower when measured by ELISA than by the plaque-reduction assay. This in situ ELISA color reduction method had the following advantages over the conventional plaque-reduction assay: the endpoint was an objective measurement; there was less well-to-well variation; the assay was sensitive to changes in plaque size as well as plaque number; it was less labor intensive.
Genesis of a complex transposon encoding the OXA-1 (type II) beta-lactamase gene
Authors: Tanaka M , Matsushita K , Yamamoto T
Published: June 2012

Plasmid R753-1-encoded resistance to ampicillin (by production of OXA-1 [type II] beta-lactamase), streptomycin, and sulfonamide was analyzed functionally and physically. The OXA-1 beta-lactamase gene on R753-1 could not transpose, whereas on some plasmids this gene was capable of transposition as part of transposon Tn2603. By using the nontransposable gene on R753-1 with Tn21 on a separate plasmid, we observed the genesis of a complex transposon with a structure similar to that of Tn2603. This finding confirms our previous hypothesis that Tn2603 has evolved directly from Tn21 through acquisition of the OXA-1 beta-lactamase gene by substitution of DNA segments. Furthermore, the mechanism of mobilization of pACYC184 derivatives by RecA-dependent homologous recombination was demonstrated.
Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers
Authors: Gonzalez M A , Moranchel A H , Duran S , Pichardo A , Magana J L , Painter B , Forrest A , Drusano G L
Published: June 2012

We administered multiple doses of ciprofloxacin intravenously over 30 min every 12 h for 1 week to nine healthy volunteers. Three volunteers received a placebo (vehicle) intravenously. Doses of 100, 150, and 200 mg were evaluated with a 1-week wash-out period intervening between each dose level. Terminal excretion half-lives averaged 3.67 +/- 0.65, 3.60 +/- 0.26, and 4.00 +/- 0.69 h for the 100-, 150-, and 200-mg doses, respectively. Serum clearances were 30.1 +/- 3.4, 29.8 +/- 4.0, and 26.9 +/- 4.1 liters/h per 1.73 m2 for these doses. Urine concentrations remained in excess of the MIC for 90% of the relevant urinary tract pathogens for the full 12-h dosing interval at each dose. Renal clearance accounted for 56 to 71% of the serum clearance. However, because a microbiologic assay was used and biologically active, renally excreted metabolites were identified, the renal clearance determinations are likely to be in excess of the true values. The doses of ciprofloxacin administered intravenously were well tolerated, and the drug concentrations appeared adequate for the treatment of the vast majority of cases of nosocomially acquired sepsis and urinary tract infections. For patients with serious Pseudomonas infections and perhaps staphylococcal infections, either an 8-h dosing schedule or larger doses on a 12-h schedule should be considered.
In vitro interaction of aminoglycosides with beta-lactam penicillins
Authors: Wallace S M , Chan L Y
Published: June 2012

The aminoglycosides are used clinically in combination with beta-lactam antibiotics. The combined use, however, produces an interaction and inactivation of the antibiotics. A study was designed to investigate the kinetics of the interaction in vitro. Four concentrations of aminoglycosides (5 to 20 micrograms of gentamicin and tobramycin per ml) and penicillins (100 to 600 micrograms of carbenicillin and ticarcillin per ml) were incubated in plasma (3 days, 37 degrees C). Samples taken at 12-h intervals were analyzed for both aminoglycosides (radioimmunoassay) and penicillin (high-pressure liquid chromatography). In controls, degradation of all four antibiotics were by first-order reactions. In incubation mixtures of two antibiotics, the rate of loss of the aminoglycosides was greater than that in the controls, whereas the rate of loss of penicillins was not significantly increased. The loss of penicillins in incubation mixtures still appeared to be by first-order reactions. However, semilogarithmic plots of aminoglycoside concentrations were curvilinear, suggesting a second-order reaction. Aminoglycoside concentrations in incubation mixtures were fitted by computer to a model incorporating a second-order interaction between aminoglycosides and penicillins and the first-order loss of penicillin from the mixture. The interaction rate constant averaged 2.2 X 10(-4) (micrograms/ml h)-1 for interaction of both carbenicillin and ticarcillin with gentamicin and 1.6 X 10(-4) (micrograms/ml h)-1 for interaction of the penicillins with tobramycin. The effect of the interaction in vivo was examined by computer simulation using the kinetic parameters determined in vitro.
Tolerance of Haemophilus influenzae to beta-lactam antibiotics
Authors: Bergeron M G , Lavoie G Y
Published: June 2012

Two hundred clinical isolates of Haemophilus influenzae were tested for tolerance (MBC/MIC greater than or equal to 32) to ampicillin and cefotaxime by broth dilution tests. Of 200 strains, 9 were tolerant to ampicillin, and 10 were tolerant to cefotaxime. Tolerant organisms were identified in both systemic and nonsystemic infections and among different biotypes and serotypes of H. influenzae. These tolerant isolates were compared with nontolerant isolates by broth dilution and killing curves with log-phase and stationary-phase inocula. Both tolerant and nontolerant bacteria in log phase were killed more rapidly by antibiotics than bacteria in stationary-phase growth. When tested against 11 different beta-lactams, several patterns of tolerance were observed. Six of the ten strains were tolerant to aztreonam, four were tolerant to cefuroxime, three were tolerant to cefamandole, and two were tolerant to cefoxitin. Strain H130 was tolerant to all beta-lactam antibiotics studied. None of the 10 tolerant H. influenzae isolates were tolerant to chloramphenicol, rifampin, tobramycin, ciprofloxacin, enoxacin, and trimethoprim-sulfamethoxazole. Although the clinical significance of tolerance is not determined, this study suggests that the bactericidal activity (MBC) of beta-lactam antibiotics against H. influenzae should be determined in cases of severe infections in which clinical response is slow or unsatisfactory.
Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis
Authors: Yim C W , Flynn N M , Fitzgerald F T
Published: June 2012

Five patients with laboratory evidence of latent or neurosyphilis were treated orally with doxycycline (200 mg) twice a day for 21 days. After the seventh dose, the mean level of doxycycline in serum was 5.8 micrograms/ml, with a mean drug level in cerebrospinal fluid of 1.3 micrograms/ml. The mean penetration into cerebrospinal fluid was 26%. These preliminary findings suggest that doxycycline, administered orally at a dose of 200 mg twice a day, reaches a sufficient concentration in cerebrospinal fluid to be worthy of further evaluation as an alternative regimen to penicillin therapy for latent or neurosyphilis.
Norfloxacin penetration into human renal and prostatic tissues
Authors: Bergeron M G , Thabet M , Roy R , Lessard C , Foucault P
Published: June 2012

Concurrent norfloxacin concentrations in serum, kidney, and prostatic tissue were determined in 14 patients. Mean ratios of norfloxacin concentration in tissue over concentration in serum were 6.6 +/- 2.8 for the kidney and 1.7 +/- 0.2 for the prostate samples. The levels were above the MICs of most urinary pathogens.
Antimicrobial susceptibilities of food-isolated strains of Yersinia enterocolitica, Y. intermedia, Y. frederiksenii, and Y. kristensenii
Authors: Ahmedy A , Vidon D J , Delmas C L , Lett M C
Published: June 2012

The in vitro antimicrobial susceptibility of Yersinia enterocolitica and newly related species isolated from foods was examined. Only 4 of 375 isolates displayed resistance to non-ss-lactam antibiotics. MICs of ampicillin and carbenicillin determined by agar dilution with respect to 125 isolates showed the high susceptibility of Y. kristensenii and biovar 3 of Y. enterocolitica to carbenicillin (MIC for 90% of the strains, less than or equal to 8 micrograms/ml).
In vitro susceptibility of pathogenic Vibrio species to norfloxacin and six other antimicrobial agents
Authors: Morris J G , Tenney J H , Drusano G L
Published: June 2012

The in vitro activity of norfloxacin and six other antimicrobial agents was tested against 93 vibrio strains representing the currently described pathogenic Vibrio species. Norfloxacin had excellent activity against all species, with the following MICs for 90% of the strains: 0.016 micrograms/ml for Vibrio cholerae (including tetracycline-resistant V. cholerae O1 strains), 0.25 micrograms/ml for V. parahaemolyticus, and 0.063 micrograms/ml for V. vulnificus.
Double-blind, placebo-controlled study of oxacillin combined with rifampin in the treatment of staphylococcal infections
Authors: Van der Auwera P , Klastersky J , Thys J P , Meunier-Carpentier F , Legrand J C
Published: June 2012

A total of 101 patients with proven Staphylococcus aureus infection were included in a double-blind, placebo-controlled study; this study compared oxacillin (12 g/day, intravenously) or vancomycin (2 g/day, intravenously) plus rifampin (1,200 mg/day, orally) with oxacillin or vancomycin plus placebo. We evaluated 65 patients. Of the patients tested, 33 received oxacillin plus rifampin (13 bacteremias), and 32 received oxacillin plus placebo (16 bacteremias). Clinical cure was achieved in 61% of the patients treated with oxacillin plus rifampin and in 56% of the patients treated with oxacillin plus placebo. Improvement was noted in 27 and 25%, respectively, and failure occurred in 9 and 18%, respectively. These differences were not statistically significant. Bacteriological failure occurred in 3 and 28%, respectively (P less than 0.05). None of the failures within the rifampin-treated group was associated with the emergence of a rifampin-resistant mutant. The rates of superinfection were similar in both groups. The geometric means of the serum bactericidal activity after 1, 6, and 11 h were, respectively, 22, 17, and 9 after treatment with oxacillin plus rifampin and 25, 3.4, and 2.3 after treatment with oxacillin plus placebo. It was suggested that the addition of rifampin to oxacillin or vancomycin might only be beneficial to severely ill patients.
Pharmacokinetics of cephalosporins in normal and septicemic rabbits
Authors: Ganzinger U , Haslberger A
Published: June 2012

The differences in the pharmacokinetics of cefotaxime, moxalactam, and CPW 86-363, a new expanded-spectrum cephalosporin, were studied in healthy rabbits and in rabbits infected intravenously with Streptococcus pneumoniae. The pharmacokinetic analysis of concentration-time courses in the sera of infected animals according to a two compartment-model evidenced a clear decrease of drug fractions in the central compartment but enhanced drug fractions in the peripheral compartment. The shift was more pronounced in animals which received CPW 86-363 (60%; P less than 0.05) than in those which received cefotaxime (20%) or moxalactam (5%). Corresponding increases in drug concentration were observed in soft tissue interstitial fluid; therefore, the areas under the curve and mean residence times in the soft tissue interstitial fluid of infected rabbits were prolonged. The shift of drug fractions from the central compartment to other body fluid compartments during infection was thought to be due to cardiovascular changes associated with fever. No changes in serum binding of the three drugs were found during the course of the infection. The quantitative differences in the extent of altered distribution properties of the drugs might be due to variations in the physicochemical properties of the drugs.
Effects of morphine on the disposition of ampicillin in mice
Authors: Garty M , Hurwitz A
Published: June 2012

Morphine raised the levels of intravenously administered ampicillin in the plasma of mice. Despite higher ampicillin levels in plasma after administration of morphine, levels of this antibiotic in bile and urine were not elevated. After ligation of the common bile duct, ampicillin levels in plasma were elevated. Morphine caused a further rise in drug levels in plasma of duct-ligated mice. Ampicillin levels in plasma were higher in mice made anephric by prolonged ligation of their external urethras. In such animals, morphine also caused ampicillin levels in plasma to be even higher. These experiments suggest that morphine impairs both renal and hepatobiliary elimination of ampicillin. These effects of morphine were completely reversed by naloxone. In contrast to effects on intravenously administered ampicillin, morphine markedly reduced drug levels in plasma when ampicillin was given by gastric intubation. This resulted from delayed absorption because of retardation of gastric emptying by morphine.