bluuebunny/crossref_metadata_2025 huggingface dataset:
Bactericidal activity and killing rate of serum from volunteers receiving pefloxacin alone or in combination with amikacin
Authors: Van der Auwera P , Klastersky J , Lieppe S , Husson M , Lauzon D , Lopez A P
Published: June 2012

Serum bactericidal activities (SBAs) were studied after intravenous administration of pefloxacin (8 mg/kg) and amikacin (7.5 mg/kg) alone or in combination to 15 human volunteers. About 10 strains each of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested. The serum levels of pefloxacin were measured microbiologically by using E. coli KP 1976-712 as the test organism at 0, 30, 60, 120, and 720 min after infusion; at 0, 30, 60, and 720 min these levels were 7 +/- 1.4, 5 +/- 0.8, 4.5 +/- 0.7, and 2.1 +/- 0.6 mg/liter (mean +/- standard deviation), respectively, with a terminal half-life of 10 h. The serum levels of pefloxacin in the presence of amikacin were measured similarly; 1% sodium polyanethol sulfonate was added to the agar to inactivate amikacin. Treatment with pefloxacin alone resulted in high SBAs against E. coli, K. pneumoniae strains susceptible to cephalothin, and Staphylococcus aureus at the peak concentration; 81 to 100% of the sera had SBAs of greater than or equal to 1:8. However, treatment with pefloxacin alone resulted in low SBAs against K. pneumoniae strains resistant to cephalothin and P. aeruginosa; only 34% of the sera had SBAs of greater than or equal to 1:8. At trough concentrations the percentages of sera with SBAs greater than or equal to 1:8 were 75 to 83% (E. coli), 9 to 27% (K. pneumoniae), 0% (P. aeruginosa), and 10% (S. aureus). The combination of pefloxacin plus amikacin was most often additive; the peak activity was due to amikacin, and the trough activity was due to pefloxacin. Occasionally antagonism occurred with P. aeruginosa, K. pneumoniae, and S. aureus strains. These observations were confirmed by the killing curves in pooled serum obtained at peak and trough levels. Regrowth was observed for seven strains of P. aeruginosa treated with pefloxacin alone; amikacin seemed to prevent this phenomenon.
Pharmacokinetics and dose proportionality of cefpimizole in normal humans after intramuscular administration
Authors: Lakings D B , Novak E , Friis J M , Lunan C M , Paxton L M
Published: June 2012

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were evaluated after intramuscular administration of single doses (dose range, 100 to 1,000 mg) and multiple doses (dose range, 500 to 2,000 mg) given b.i.d. for 6 or 11 days. The kinetics after intramuscular administration correspond to a one-compartment model with first-order input. The apparent volume of distribution of the absorbed dose averaged 18.6 +/- 3.4 (standard deviation) liters for 58 individuals; the absorption-phase and elimination-phase rate constants averaged 2.53 +/- 1.16 h-1 (half-life, 0.27 h) and 0.338 +/- 0.041 h-1 (half-life, 2.05 h), respectively; and the mean residence time was 3.43 +/- 0.43 h. The total body clearance of the absorbed dose after single-dose intramuscular administration was 102 +/- 13 ml/min. The primary route of elimination was renal with 73 to 83% of the administered dose excreted in the urine as unchanged drug. Renal clearance averaged 81 +/- 13 ml/min. Dose proportionality was obtained from area under the plasma curve, concentration maximum in plasma, and cumulative urinary excretion levels. Multiple-dose evaluation of intramuscular administration of cefpimizole indicated no apparent change in the absorption or elimination phases after b.i.d. dosing for 6 or 11 days. The kinetic parameters determined from multiple-dose plasma and urine levels were in close agreement with the same parameters calculated from single-dose results. No apparent accumulation of cefpimizole occurred, and nondetectable levels of drug were observed in the 24-h plasma and 24- to 48-h urine specimen after administration of the last dose. The kinetics of cefpimizole after intramuscular administration were similar to the kinetics obtained after intravenous infusion.
A 19F nuclear magnetic resonance study of uptake and metabolism of 5-fluorocytosine in susceptible and resistant strains of Candida albicans
Authors: Di Vito M , Podo F , Torosantucci A , Carpinelli G , Whelan W L , Kerridge D , Cassone A
Published: June 2012

The metabolism of the antifungal drug 5-fluorocytosine (5-FC) was studied in intact viable cells of Candida albicans by 19F nuclear magnetic resonance (NMR). The uptake of the drug and its conversion to the deaminated product 5-fluorouracil (5-FU) were easily observed by NMR analysis of both the cells and the supernatants of the incubation mixture. In the 5-FC-resistant mutant D14 of C. albicans, which lacked cytosine deaminase activity, the resonance peak of 5-FU was not observed. In intact cells of all 5-FC-susceptible strains the metabolism of 5-FU progressed to the formation of other fluorinated derivatives which were visualized as a single, broad resonance band at a lower field with respect to 5-FC and 5-FU. This band was resolved into three distinct peaks in the acid extract of treated cells, one of these peaks being attributable to 5-fluoro-dUMP (5-FdUMP). In strain 72R of C. albicans, which is 5-FC resistant because of a low level of UMP-pyrophosphorylase activity, the broad, low-field resonance band was detected later and with much less intensity than in the 5-FC-sensitive strains. This suggests that, besides 5-FdUMP, this band is also contributed to by 5-FUMP and possibly other phosphorylated derivatives. 19F NMR analysis also revealed that a significant amount of 5-FU is secreted into the external medium, the rate of secretion being higher in 5-FC-resistant strain 72R than in 5-FC-sensitive strain 72S. Although not all resonances were definitely identified, this study shows that 19F NMR spectroscopy may be an important tool for noninvasive analysis of the metabolism of fluorinated drugs in yeasts.
Cloning and molecular epidemiology of plasmid-determined fosfomycin resistance
Authors: Villar C J , Hardisson C , Suárez J E
Published: June 2012

The plasmid determinant of resistance to fosfomycin (For) was cloned into pBR322 and located in a 0.7-kilobase segment of DNA by transposon mutagenesis and in vitro deletion analysis. It encodes an 18-kilodalton protein located in the cytoplasm of resistant cells. Its synthesis is constitutive. The For genetic determinant is common to all plasmids isolated since 1975 in an hospital environment as determined by DNA-DNA hybridization. However, plasmids which carry For can be divided into two groups on the basis of size, pattern of antibiotic resistances, incompatibility specificity, and restriction and hybridization properties.
Polymyxin B nonapeptide inhibits mating in Saccharomyces cerevisiae
Authors: Boguslawski G
Published: June 2012

Polymyxin B nonapeptide enhanced susceptibility of yeast cells to various hydrophobic antibiotics and to mating pheromones. At much lower concentrations, the nonapeptide severely inhibited mating. The inhibition was caused by interference with sexual agglutination.
In vitro activity of A-56619 and A56620, two new aryl-fluoroquinolone antimicrobial agents
Authors: Smith B R , LeFrock J L , Donato J B , Joseph W S , Weber S J
Published: June 2012

The in vitro antimicrobial activity of two new aryl-fluoroquinolone antibiotics, A-56619 and A-56620, was compared with those of norfloxacin and several other antibiotics against 448 bacterial isolates. A-56620 was the most active agent tested. The usual 90% MIC of A-56620 was less than or equal to 2 micrograms/ml, except for enterococci, gentamicin-resistant Serratia marcescens, and gentamicin-resistant Pseudomonas aeruginosa, for which the 90% MIC was 4 micrograms/ml. A-56619 and norfloxacin were generally severalfold less active than A-56620. Cross resistance was observed between the quinolone antibiotics and other unrelated antibiotic classes.
Comparative in vitro activity of seven quinolones against 100 clinical isolates of Clostridium difficile
Authors: Delmee M , Avesani V
Published: June 2012

The in vitro activity of seven quinolone derivatives against 100 clinical isolates of Clostridium difficile was determined. CI934 was the most active, inhibiting 90% of the strains at 4 micrograms/ml and 100% at 8 micrograms/ml. Ofloxacin and ciprofloxacin had moderate activity (16 and 32 micrograms/ml) whereas enoxacin, pefloxacin, norfloxacin, and nalidixic acid had poor activity (128 micrograms/ml).
Reduction of cephamycin concentrations at the infection site in mice with experimental peritoneal infection caused by cephalosporinase-producing bacteria
Authors: Minami S , Araki H , Watanabe Y , Yasuda T , Takai A , Saikawa I , Mitsuhashi S
Published: June 2012

In an experimental model of peritoneal infection by cephalosporinase- (Ia and Ic) producing bacteria in mice, the reduction of cefoxitin, cefmetazole, and cefazolin concentrations in peritoneal fluid was observed in the mice infected with the Ia enzyme producer, whereas cefbuperazone concentrations were not reduced.
Comparative in vitro activities of ciprofloxacin and other 4-quinolones against Mycobacterium tuberculosis and Mycobacterium intracellulare
Authors: Fenlon C H , Cynamon M H
Published: June 2012

The in vitro activity of ciprofloxacin, ofloxacin, amifloxacin, and norfloxacin against 22 clinical isolates of Mycobacterium tuberculosis was evaluated by agar dilution. The MICs for 90% of the isolates of ciprofloxacin and ofloxacin were 0.5 and 1 microgram/ml, respectively. Amifloxacin and norfloxacin were less active. The MICs for 90% of the isolates of ciprofloxacin and ofloxacin against 20 clinical isolates of Mycobacterium intracellulare were determined by agar dilution to be 2 and 8 micrograms/ml, respectively.
Evaluation of pefloxacin in experimental Escherichia coli meningitis
Authors: Shibl A M , Hackbarth C J , Sande M A
Published: June 2012

The therapeutic efficacy of the fluoroquinolone pefloxacin mesylate was compared with those of cefotaxime and chloramphenicol in a rabbit model of Escherichia coli meningitis. The mean percent penetration (+/- the standard deviation) of pefloxacin (range, 1 to 30 mg/kg per h) into cerebrospinal fluid of infected rabbits was 51.3 +/- 14.0 compared with 11.1 +/- 1.0 for cefotaxime (100 mg/kg per h) and 22.3 +/- 1.5 for chloramphenicol (60 mg/kg per h). The rate of bacterial killing (delta log10 CFU/ml per h) did not change over a dosage range of 1 to 15 mg/kg per h (-0.37 +/- 0.15, 20% sterile). At 30 mg/kg per h, the rate achieved (-0.77 +/- 0.18, 100% sterile) was comparable to that of cefotaxime (-0.88 +/- 0.23, 100% sterile) and superior to that of chloramphenicol (-0.10 +/- 0.14, 0% sterile).
Imipenem coadministered with cilastatin compared with moxalactam: integration of serum pharmacokinetics and microbiologic activity following single-dose administration to normal volunteers
Authors: Standiford H C , Drusano G L , Bustamante C I , Rivera G , Forrest A , Tatem B , Leslie J , Moody M
Published: June 2012

We administered 1 g of imipenem along with equal amounts of cilastatin (a dehydropeptidase I inhibitor) or 2 g of moxalactam intravenously over a period of 30 min to six volunteers in a crossover manner 1 week apart. The antibiotic concentrations and pharmacokinetics for each drug were determined and integrated with the microbiologic activity by measuring the duration of time that the free drug concentrations remained above the MICs for 90% of 581 clinical isolates and by measuring serum bactericidal activities against organisms which commonly infect granulocytopenic cancer patients. Moxalactam produced serum levels at 1 h after infusion of 99.9 micrograms/ml; these levels were four times greater than the plasma levels of imipenem (22.8 micrograms/ml). The trough (5.5-h) moxalactam serum levels were 10 times greater than those of imipenem (18.5 and 1.7 micrograms/ml, respectively). Essentially all of the imipenem was unbound to protein, whereas 36 to 42% of the moxalactam was unbound. Moxalactam produced free antibiotic concentrations that were above the MIC for 90% of the strains tested for more than 6 h against all of the species tested except Staphylococcus aureus (5.3 h), Enterobacter hafnia (1.6 h), and Pseudomonas aeruginosa (0 h). The imipenem concentrations were above the MIC for 90% of the strains tested for 5.6 h or more against all of the bacteria tested except Proteus spp. and Pseudomonas aeruginosa (4.5 h). The geometric mean peak bactericidal titers from volunteers receiving imipenem were more than 1:8 against all bacteria and were significantly higher than the titers from volunteers receiving moxalactam against S. aureus (1:7.3) and Pseudomonas aeruginosa (1:4.5). These data, in addition to information obtained from animal models, indicate that imipenem is a promising new candidate for carefully controlled clinical trials as a single agent for therapy of serious infections, including empiric therapy for fever in granulocytopenic cancer patients.
Discrepancies between MBC and actual killing of viridans group streptococci by cell-wall-active antibiotics
Authors: Meylan P R , Francioli P , Glauser M P
Published: June 2012

We determined the MBC of amoxicillin and vancomycin, two antibiotics advocated for treatment and prophylaxis of bacterial endocarditis, for 24 strains of viridans group streptococci isolated from patients with endocarditis. We found that the MIC of amoxicillin for all strains was less than or equal to 0.25 micrograms/ml and the MBC was either low (less than 0.5 micrograms/ml) in 6 nontolerant strains or high (greater than 128 micrograms/ml) in 18 tolerant strains. The MIC of vancomycin for the 24 strains was less than or equal to 1 microgram/ml, and the MBC was either low (less than 1 microgram/ml) for 3 nontolerant strains or high (greater than 128 micrograms/ml) for 21 tolerant strains. In addition to the MBC, we determined the actual reduction of the viable bacterial counts in each tube dilution after 24 h of incubation. This determination was made by subtracting the number of colonies observed on the subculture plate from the number of bacteria contained in the initial inoculum. For both antibiotics we found that the maximal reduction in viable counts was achieved at or very close to the MIC and did not increase with increasing antibiotic concentrations (up to 128 micrograms/ml). As expected, the six strains for which the amoxicillin MBC was less than 0.5 micrograms/ml and the three strains for which the vancomycin MBC was less than 1 microgram/ml had a reduction of viable counts of more than 3 log10 (greater than 99.9% killing). In contrast, among the strains defined as tolerant to amoxicillin and vancomycin, there were wide variations in the actual reduction of bacterial counts, ranging from 3 log10 to less than 1 log10. Therefore our observations suggest that the reduction of viable streptococcal counts reflects more accurately the bactericidal effect of amoxicillin and vancomycin than does the MBC, which artificially divides the strains into sensitive or tolerant strains.
Properties of a novel carbenicillin-hydrolyzing beta-lactamase (CARB-4) specified by an IncP-2 plasmid from Pseudomonas aeruginosa
Authors: Philippon A M , Paul G C , Thabaut A P , Jacoby G A
Published: June 2012

CARB-4, a novel carbenicillin-hydrolyzing beta-lactamase with an isoelectric point of 4.3, was discovered in a strain of Pseudomonas aeruginosa from France. It was determined by a multiresistant transmissible plasmid belonging to the P-2 incompatibility group.
Recipient characteristics in the transduction of methicillin resistance in Staphylococcus epidermidis
Authors: Blanchard T J , Poston S M , Reynolds P J
Published: June 2012

Methicillin resistance (Mecr) was transduced into a methicillin-susceptible variant of the Mecr donor Staphylococcus epidermidis BS10. UV irradiation of phage stimulated Mecr transduction frequency. If loss of Cd and Hg ion resistance occurred in this recipient, or if the three markers Mecr, Cdr, and Hgr were co-eliminated from the donor, neither strain acted as a recipient for Mecr.
Reduction of oral flora with rifampin in healthy volunteers
Authors: Appelbaum P C , Spangler S K , Potter C R , Sattler F R
Published: June 2012

The effect of a short course of rifampin on the oral microflora was evaluated in 17 healthy volunteers. Salivary specimens were collected before and after two 600-mg doses of rifampin administered 6 h apart. Salivary bacteria were identified to species, and total quantitative colony counts were determined for each isolate. For all 17 subjects, treatment with rifampin led to a reduction in total bacterial colony counts; the mean inhibitory activity was 85.8% (range, 48.3 to 99.8%). Both aerobic and anaerobic bacteria were inhibited in every case: 45.5 to 99.8% for aerobic bacteria, mean inhibitory activity of 85.8%; 40.9 to 100% inhibition for anaerobic bacteria, mean inhibitory activity of 87.6%. However, total counts were reduced by greater than or equal to 2 logarithms in only 18% of individuals; for aerobes, in 29%; and for anaerobes, in 41%. All classes of bacteria were inhibited, with mean inhibitory activities ranging from 8.4 to 99.9%. However, only streptococci, Haemophilus spp., Bacteroides spp., and aerobic and anaerobic gram-positive nonsporeforming rods were reduced in counts close to 2 logarithms after treatment with rifampin. Clinical studies are needed to clarify the significance of these in vitro data and to delineate a possible role for rifampin in preoperative prophylaxis of patients undergoing head and neck cancer surgery.
Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and candida pyelonephritis in rabbits
Authors: Perfect J R , Savani D V , Durack D T
Published: June 2012

Itraconazole and fluconazole, two new triazoles, were examined for their antifungal activity in rabbits. Fluconazole easily crossed the blood-cerebrospinal fluid barrier, and active drug was eliminated in high concentrations in the urine. On the other hand, itraconazole did not cross the blood-cerebrospinal fluid barrier in measurable amounts, and urine concentrations were variable. Despite differences in pharmacokinetics at the site of infection, both agents were equally effective in treating cryptococcal meningitis and candida pyelonephritis in animals. By using a ketoconazole-resistant strain of Candida albicans, we showed that there was cross-resistance in vivo between these two new triazole compounds.
Sensitive high-pressure liquid chromatographic assay for amphotericin B which incorporates an internal standard
Authors: Granich G G , Kobayashi G S , Krogstad D J
Published: June 2012

We developed a rapid, sensitive, high-pressure liquid chromatographic (HPLC) procedure which incorporates a commercially available internal standard, 1-amino-4-nitronaphthalene, to measure amphotericin B in serum. Recovery was quantitative (greater than or equal to 90%), and the standard curve was linear from 0.04 to at least 10.0 micrograms/ml. The reproducibility of the assay was good, with intrarun coefficients of variation from 2.0 to 6.8% and interrun coefficients of variation from 4.9 to 10.0%. Comparison by linear regression analysis of the HPLC assay with an agar well diffusion bioassay gave a correlation coefficient of 0.942, with the HPLC assay exhibiting greater precision and sensitivity. No interference was encountered from over 20 drugs and three amphotericin B analogs. However, serum specimens that contained high concentrations of conjugated bilirubin (greater than 3 mg/dl) produced interfering peaks in both this assay and other previously reported HPLC assays for amphotericin B. We also describe a solid-phase extraction procedure which effectively removes this interference and uses an alternative internal standard (N-acetyl amphotericin B).
In vitro comparison of ampicillin-chloramphenicol and ampicillin-cefotaxime against 284 Haemophilus isolates
Authors: Lapointe J R , Lavallée C , Michaud A , Chicoine L , Joncas J H
Published: June 2012

Since November 1982 at the Sainte-Justine Hospital in Montreal, ampicillin and cefotaxime were used in association as initial treatment (greater than or equal to 48 h) for childhood bacterial meningitis. In this report is described the in vitro interaction of the new regimen in comparison with that of the previous ampicillin-chloramphenicol combination against 284 Haemophilus isolates. Among the 156 ampicillin-susceptible, beta-lactamase-negative isolates, synergy was detected in 13 with ampicillin-cefotaxime, and antagonism was detected in only 1; in contrast, synergy was found in only 2 strains with ampicillin-chloramphenicol, and antagonism was found in 15. These differences were statistically significant (P less than 0.01). Such significant differences were not observed among the 128 ampicillin-resistant, beta-lactamase-positive Haemophilus isolates. The synergy of ampicillin-cefotaxime did not contribute to a decrease of the MIC of cefotaxime for 90% of isolates tested, whereas the antagonism of ampicillin-chloramphenicol did not contribute to increase the MIC of ampicillin for 90% of isolates tested.
Serum bactericidal activity of rifampin in combination with other antimicrobial agents against Staphylococcus aureus
Authors: Hackbarth C J , Chambers H F , Sande M A
Published: June 2012

Because rifampin-resistant strains of Staphylococcus aureus emerge during monotherapy with this drug, a search was made for potentially useful companion drugs. Bactericidal titers of spiked serum were determined, and time kill studies were performed for 10 strains of methicillin-susceptible S. aureus. We tested rifampin in combination with nafcillin, vancomycin, clindamycin, pefloxacin, ciprofloxacin, trimethoprim, teicoplanin, or erythromycin. The bactericidal activity of nafcillin, vancomycin, and teicoplanin was significantly reduced (P less than 0.05) when rifampin was added to the drug regimen. In contrast, the addition of rifampin to clindamycin or erythromycin significantly increased bactericidal activity as measured by both bactericidal titers in serum and 6-h killing rates (P less than 0.02). Bactericidal activity in serum was also increased by the addition of rifampin to trimethoprim, but rifampin-resistant strains emerged with this combination.
Cerebrospinal fluid penetration of imipenem and cilastatin (primaxin) in children with central nervous system infections
Authors: Jacobs R F , Kearns G L , Brown A L , Longee D C
Published: June 2012

Cerebrospinal fluid (CSF) penetration of imipenem-cilastatin was evaluated in 20 children (aged 4 months to 11 years) with central nervous system infections. A total of 10 children received a single 25-mg/kg intravenous dose, and 10 received three 25-mg/kg intravenous doses at 6-h intervals. Blood and CSF were obtained 1.5 to 2.5 h after the last dose during the early (days 1 to 3) and the late (days 7 to 10) stages of infection. Imipenem concentrations after single-dose infusion in serum and CSF during the early phase of treatment (8.59 +/- 0.95 and 1.36 +/- 0.32 micrograms/ml, respectively) were similar to those during the late phase (9.96 +/- 2.36 and 2.08 +/- 1.14 micrograms/ml, respectively). Concentrations of imipenem in serum and CSF after multiple-dose infusion during the early phase (11.97 +/- 2.03 and 1.87 +/- 0.29 micrograms/ml, respectively) were similar to those during the late phase (9.57 +/- 1.76 and 1.22 +/- 0.11 micrograms/ml, respectively). There were no significant differences in the serum or CSF imipenem concentrations between the single- and multiple-dose groups during the early or late treatment stages. Cilastatin concentrations in serum and CSF were similar in all groups with the exception of the multiple-dose, early- versus late-phase evaluation of CSF cilastatin concentration. There was no correlation between age or absolute CSF neutrophil count and the serum or CSF concentrations of imipenem or cilastatin. We found a mean CSF penetration of 15 to 27% for imipenem and 16 to 66% for cilastatin in children. These findings suggest that imipenem-cilastatin sufficiently penetrates into CSF in children to warrant further investigation of this compound in pediatric central nervous system infections.
Vancomycin hypersusceptibility in Neisseria gonorrhoeae isolated from patients involves diverse mutations
Authors: Koelbl J A , Catlin B W
Published: June 2012

We investigated the genetic determinants of hypersusceptibility to vancomycin and erythromycin found in Neisseria gonorrhoeae strains isolated from patients. In terms of resistance (highest concentration of antibiotic permitting growth), the levels of vancomycin resistance of six strains ranged from 0.2 to 1.0 microgram/ml, and the level of erythromycin resistance of these strains was 0.02 or 0.05 micrograms/ml. DNA from these strains was used to introduce their hypersusceptibility determinants into partially isogenic derivatives of N. gonorrhoeae 89 which initially had wild-type levels of resistance to vancomycin (greater than or equal to 3.0 micrograms/ml) and erythromycin (greater than or equal to 0.1 microgram/ml). The recombination frequencies found in reciprocal transformation tests of six isogenic strains indicated that the mutations responsible for vancomycin hypersusceptibility were located at different sites. The transformants selected for increased resistance to vancomycin were also resistant to erythromycin. This evidence, together with DNA concentration-response curves, indicated that the mutations affected either one gene locus or closely linked loci. The recombination indices obtained in crosses between our hypersusceptible strains and DNAs from reference strains carrying the envelope mutations env-1, env-2, env-3, and env-10 showed that the mutation (designated env-12) responsible for erythromycin hypersusceptibility in one strain (89-954) was located in close proximity to env-2. The determinant of vancomycin hypersusceptibility in strain 89-954 was distinct from env-12, but the two were linked. In the other five isogenic strains, the hypersusceptibilities to both vancomycin and erythromycin could be annulled by spontaneous mutations in a locus provisionally designated vel because of its likely effects on the envelope. Vel+ mutants obtained by selection with either vancomycin alone or erythromycin alone gained increased resistance to both antibiotics.
Comparative antibacterial activity of an arylglycyl oral cephalosporin, LY164846
Authors: Chin N X , Neu H C
Published: June 2012

LY164846 is a semisynthetic arylglycyl cephalosporin which can be absorbed orally. It had in vitro activity comparable to that of cefaclor against beta-hemolytic streptococcal species and was two- to fourfold more active than cephalexin. Enterococci and Listeria species were resistant, and its activity against staphylococci was similar to that of other oral cephalosporins. Although some Bacteroides species were inhibited, the MICs for 25% were greater than or equal to 16 micrograms/ml. LY164846 was hydrolyzed by Staphylococcus aureus beta-lactamase and by cephalosporinases, but it was more stable than cefaclor.
Mutation of Escherichia coli capable of expressing gene(s) for beta-lactamase production of Citrobacter freundii
Authors: Murayama S Y , Yamamoto T , Suzuki I , Sawai T
Published: June 2012

A mutation in a chromosomal gene of Escherichia coli, designated reb, acted in trans to increase the expression of the cloned beta-lactamase gene of Citrobacter freundii. The reb gene was located around 99 min. Deletion mutants in the cloned gene(s) which had lost the regulatory region for induction were also constructed.
In vitro activity of clavulanic acid, amoxicillin, and ticarcillin against Chlamydia trachomatis
Authors: Bowie W R
Published: June 2012

In vitro, growth of Chlamydia trachomatis was not entirely eliminated by 960 micrograms of ticarcillin per ml, 64 micrograms of amoxicillin per ml, 32 micrograms of clavulanic acid per ml, a combination of ticarcillin (480 micrograms/ml) and clavulanic acid (32 micrograms/ml), and a combination of amoxicillin (32 micrograms/ml) and clavulanic acid (8 micrograms/ml). However, a greater than or equal to 99% decrease in the number of inclusions was obtained at concentrations readily attainable in serum.
Complementation analysis of resistance to 5-fluorocytosine in Candida albicans
Authors: Whelan W L , Markie D , Kwon-Chung K J
Published: June 2012

A complementation test was devised to study allelism among the genetic determinants of resistance to 5-fluorocytosine in Candida albicans. Complementation was demonstrated in control hybrids produced by crossing a resistant strain that was deficient in cytosine deaminase activity with four other resistant strains deficient in UMP pyrophosphorylase activity. This complementation test was used to test allelism of the resistance determinants present in five clinical isolates. All were found to bear recessive alleles of the locus (FCY1) that determined 5-fluorocytosine resistance associated with low levels of UMP pyrophosphorylase activity.
In vitro activity of CI-934, a new quinolone, compared with that of other quinolones and other antimicrobial agents
Authors: Mandell W , Neu H C
Published: June 2012

The in vitro activity of CI-934, a new 4-quinolone, was determined against gram-positive and gram-negative bacteria. The MICs for 90% of the isolates tested were 0.25 microgram/ml for Streptococcus pneumoniae, 0.5 microgram/ml for Streptococcus faecalis, 0.25 microgram/ml for staphylococci, including methicillin-resistant strains, and less than or equal to 1.0 microgram/ml for Escherichia coli, Salmonella and Shigella spp., Klebsiella spp., Proteus spp., and Citrobacter spp. CI-934 had activity superior to that of other quinolones against streptococci by four- to eightfold. Against members of the family Enterobacteriaceae, ciprofloxacin was 2- to 18-fold more active; ofloxacin and norfloxacin were twofold more active or similar to CI-934. CI-934 inhibited ampicillin-cephalothin-resistant urinary isolates of E. coli, Klebsiella pneumoniae, and Proteus mirabilis and cefoxatime-resistant Acinetobacter spp., Citrobacter freundii, Enterobacter cloacae, Proteus vulgaris, and Morganella morganii. The medium, inoculum size, and oxygen concentration, as well as the addition of serum, had not major effect on the activity of CI-934. Magnesium at a concentration of 9 mM increased MICs and MBCs four- to eightfold, and testing at pH 6 increased MICs as much as 32- to 64-fold for some organisms in comparison with MICs at pH 7. The frequency of spontaneous mutation to resistance was comparable to that for other new quinolones, but resistant isolates could be selected by repeated subculture.
Susceptibility to other antiherpes drugs of pathogenic variants of herpes simplex virus selected for resistance to acyclovir
Authors: Larder B A , Darby G
Published: June 2012

Cross-resistance data for a group of nine acyclovir-resistant variants of herpes simplex virus type 1 are reported. These mutants, which express either altered thymidine kinase (TK) or DNA polymerase, were all derived from the same wild-type (wt) strain after exposure to acyclovir in tissue culture. Furthermore, all variants have pathogenic properties similar to the wt parental strain as assessed using mouse model systems (G. Darby, H.J. Field, and S.A. Salisbury, Nature (London) 289:81-83, 1981; B.A. Larder and G. Darby, Virology 146:262-271, 1985). Two groups of antiherpes compounds were used: those requiring activation by TK and those whose action is independent of that enzyme. The TK substrate-specificity mutants were generally resistant to the TK-activated drugs but showed wt susceptibility to phosphonoacetic acid, 9-beta-D-arabinofuranosyladenine, and aphidicolin. The DNA polymerase mutants were relatively susceptible to most TK-activated drugs, although two were resistant to 5-(trifluoromethyl)-2'-deoxyuridine. The polymerase mutants showed a more complex pattern of susceptibility, however, to those compounds whose mode of action is independent of TK. In general, these variants showed similar responses to phosphonoacetic acid, phosphonoformate, and 9-beta-D-arabinofuranosyladenine, a particular variant being either resistant, susceptible, or hypertensive to all three. The response of each variant to aphidicolin, however, appeared to be the inverse of its response to the other three drugs. The cross-resistance patterns are discussed, and their implications for combined or successive therapies are considered.
Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi
Authors: Sirawaraporn W , Yuthavong Y
Published: June 2012

Dihydrofolate reductase was partially purified from a pyrimethamine-sensitive Plasmodium chabaudi clone and a pyrimethamine-resistant clone derived from it and used in a study of the inhibitory effect of pyrimethamine and sulfadoxine, both alone and in combination. Kinetic analysis of the inhibitory effect of sulfadoxine against the enzyme from pyrimethamine-sensitive and -resistant parasites revealed that the drug inhibited the former enzyme competitively, with an inhibition constant (Kis) of 0.7 +/- 0.4 mM, but inhibited the latter enzyme noncompetitively, with Kis and Kii of 8.9 +/- 1.2 and 4.1 +/- 1.2 mM, respectively. Previous studies also showed competitive inhibition by pyrimethamine on the former enzyme and noncompetitive inhibition on the latter enzyme, with some 200-fold-lower affinity. Sulfadoxine and pyrimethamine exhibited a mutually potentiating effect on the enzyme activity, as revealed by the concave isoboles and the fractional inhibitions of less than unity. A potentiating effect was observed for the enzymes from both sources and was not dependent on the degree of the purification of the enzyme. Our results can be explained by assuming simultaneous binding of two inhibitors on the enzyme.
Vidarabine-associated encephalopathy and myoclonus
Authors: Vilter R W
Published: June 2012

A 24-year-old man with disseminated herpes zoster, which occurred 9 months after bone marrow transplantation for chronic myeloid leukemia, developed encephalopathy and immobilizing myoclonus after 7 days of vidarabine treatment (10 mg/kg of body weight per day). Only mild hepatic dysfunction was a risk factor for a toxic reaction. After the vidarabine therapy was stopped, the symptoms worsened until treatment with hydration, large doses of chlordiazepoxide, and protective care gave symptomatic relief.
Comparative evaluation of a new beta-lactamase inhibitor, YTR 830, combined with different beta-lactam antibiotics against bacteria harboring known beta-lactamases
Authors: Gutmann L , Kitzis M D , Yamabe S , Acar J F
Published: June 2012

YTR 830, a new beta-lactamase inhibitor, combined with amoxicillin or carbenicillin, showed a synergistic effect similar to that observed with clavulanic acid, and generally better than that with sulbactam, against strains harboring chromosome-encoded penicillinases and broad-spectrum beta-lactamases or plasmid-determined beta-lactamases. With ampicillin, YTR 830 showed the best synergistic activity of the inhibitors against Proteus morganii, Citrobacter freundii, and Enterobacter cloacae and their mutants with a derepressed chromosome-encoded cephalosporinase.
Influence of human monocytes on the antibacterial activity of kanamycin and gentamicin for Staphylococcus aureus
Authors: van den Broek P J , Buys L F , van den Barselaar M T , Leijh P C , van Furth R
Published: June 2012

The present study was performed to compare the antibacterial activities of kanamycin and gentamicin on Staphylococcus aureus phagocytosed by human monocytes and on nonphagocytosed S. aureus. The method used permitted the measurement of the effect of antibiotics on intracellular bacteria independent of phagocytosis and intracellular killing by the monocytes. A morphological assay with lysostaphin established the intracellular localization of about 70% of the cell-associated S. aureus in the monocyte-bacterium suspension. After 1 h of incubation, the antibacterial activity of both aminoglycosides was greater against intracellular than against nonphagocytosed S. aureus, but after 3 h, the reverse was true. The maximal effect on phagocytosed S. aureus, i.e., killing of about 98% of the bacteria, was reached in the first hour of incubation at kanamycin and gentamicin concentrations of 5 and 1 microgram/ml, respectively. A cell-free medium in which monocytes had been incubated increased the antibacterial activity of kanamycin, indicating that monocytes secrete a factor that enhances the antibacterial activity of aminoglycosides.
Ciprofloxacin in the treatment of pneumonia
Authors: Ernst J A , Sy E R , Colon-Lucca H , Sandhu N , Rallos T , Lorian V
Published: June 2012

The use of ciprofloxacin as the sole agent in the treatment of 25 patients with pneumonias caused by susceptible organisms resulted in rapid cure. No side effects, superinfections, or recurrences were observed.
Previously undescribed 6.6-kilobase R plasmid in penicillinase-producing Neisseria gonorrhoeae
Authors: Gouby A , Bourg G , Ramuz M
Published: June 2012

A penicillin-resistant Neisseria gonorrhoeae strain was isolated. The resistance was due to the production of TEM-1 beta-lactamase encoded by a plasmid. This 6.6-kilobase plasmid was compared with the previously known 7.4- and 5.3-kilobase penicillin R plasmids of N. gonorrhoeae.
Canine model for the simultaneous measurement of antibiotic levels in tissues and bacterial killing rate
Authors: Wagner D S , Salstrom S J , File T M , Tan J S
Published: June 2012

Antibiotic levels in serum are commonly used to guide antibiotic therapy. The antibiotic levels in interstitial fluid are a more accurate reflection of the efficacy of antibiotic penetration into the tissues. Although there are experimental models for determining interstitial fluid levels, there is no model for measuring the in vivo killing of bacteria, which is the endpoint of antibiotic therapy. We developed an accurate, reliable animal model which allows measurement of the in vivo killing of bacteria along with a determination of antibiotic levels in tissues. Modified Sykes-Moore chambers were applied to the dissected external oblique muscle of 14 dogs. The chambers were inoculated with clinical isolates of Staphylococcus aureus or Escherichia coli. The dogs were treated with cefoxitin or gentamicin. Quantitative cultures were performed, and the antibiotic levels in interstitial fluid were determined.
Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli
Authors: Jacobs M R , Aronoff S C , Johenning S , Shlaes D M , Yamabe S
Published: June 2012

The in vitro synergistic activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam, combined with ampicillin, ticarcillin, mezlocillin, azlocillin, piperacillin, and apalcillin, were determined against 34 strains of members of the Enterobacteriaceae family, Pseudomonas aeruginosa, Aeromonas hydrophila, and Haemophilus influenzae with characterized plasmid or chromosomal beta-lactamases or both. Strains were tested against fixed concentrations of beta-lactamase inhibitors (8 micrograms/ml) combined with doubling dilutions of beta-lactams. Synergy was defined as a fourfold or greater decrease in the MIC of the beta-lactam. Against Enterobacteriaceae producing Richmond and Sykes class III and V plasmid-mediated beta-lactamases, synergy was obtained against most strains with YTR 830- and clavulanate-beta-lactam combinations, with sulbactam being less effective. Against Enterobacteriaceae producing class I chromosomal beta-lactamases, combinations containing YTR 830 or sulbactam were more synergistic than combinations containing clavulanate. Against strains producing class V PSE enzymes, all three inhibitors were synergistic with piperacillin and apalcillin against strains producing PSE-1, -3, and -4 enzymes, while the PSE-2-producing strain was resistant to all inhibitors. YTR 830-beta-lactam combinations were also synergistic against strains producing the novel beta-lactamases OHIO-1, TLE-1, AER-1, and ROB-1. Overall, YTR 830 with piperacillin or apalcillin was the most effective combination.
In vitro evaluation of various antifungal agents alone and in combination by using an automatic turbidimetric system combined with viable count determinations
Authors: Van der Auwera P , Ceuppens A M , Heymans C , Meunier F
Published: June 2012

A new method combining automatic turbidimetry and sequential viable count determinations was developed to evaluate the in vitro activity of various antifungal agents alone and in combination against three clinical isolates of Candida spp. (two Candida albicans and one C. tropicalis) at two inocula (10(-5) and 10(-6) CFU/ml). Specific parameters were derived from the time-kill curves: the maximal rate of killing, the lowest biomass, and the overnight biomass. Their intra-assay and between-assay reproducibilities were high, with respective standard deviations of 0.4 and 0.25 to 1.4 log CFU/ml. Amphotericin B alone showed a linear relationship between rate of killing or lowest biomass and the log of concentration from 0.03 to 4 mg/liter that was similar for the three strains tested. 5-Fluorocytosine (flucytosine) alone showed a dose-related reduction of overnight biomass for concentrations up to 8 mg/liter with no further increase at higher concentrations for one strain of C. albicans and a paradoxical decrease for one strain of C. tropicalis. Ketoconazole alone was found to be only fungistatic with no increased activity at concentrations up to 16 mg/liter. Amphotericin B plus flucytosine interacted synergistically in 46 to 60% of the combinations tested against C. tropicalis depending on the initial inoculum. Indifference was observed for the two strains of C. albicans. Amphotericin B or flucytosine plus ketoconazole was usually indifferent against the three tested strains.
Plants as sources of antimalarial drugs: in vitro antimalarial activities of some quassinoids
Authors: O'Neill M J , Bray D H , Boardman P , Phillipson J D , Warhurst D C , Peters W , Suffness M
Published: June 2012

Fourteen quassinoids, obtained from simaroubaceous plants, were tested for in vitro antimalarial activity. All of these inhibited the incorporation of [3H]hypoxanthine into Plasmodium falciparum in vitro at concentrations below 0.41 microgram ml-1. The two most potent quassinoids, bruceantin and simalikalactone D, showed 50% inhibitory concentration values of 0.0008 and 0.0009 microgram ml-1, respectively. The results are compared with the antiamoebic, antileukemic, and cytotoxic activities of these compounds reported in the literature.
Tellurite susceptibility and non-plasmid-mediated resistance in Escherichia coli
Authors: Tomás J M , Kay W W
Published: June 2012

Tellurite (TeO3(2-)) is highly toxic toward Escherichia coli (MIC, approximately 1 microgram ml-1). Mutants (Tel) that were resistant to low levels of TeO3(2-) (MIC, approximately 10 micrograms ml-1) and collaterally resistant to arsenate were isolated. These Tel mutants were unable to grow on media containing low levels of Pi, which supported growth of the parent strain. When grown at much higher Pi levels they exhibited depressed levels of the outer membrane phoE protein and the periplasmic phoS protein, as well as several other proteins indicative of Pi starvation. Tel mutants were markedly defective in 32Pi transport, and TeO3(2-) was shown to be a potent competitive inhibitor of 32Pi transport in the parent strain. The Tel phenotype could be complemented by an F' plasmid harboring the phoR, phoB, and phoA loci, and curing of the F' plasmid completely restored TeO3(2-) resistance. Of a variety of well-characterized Pi transport mutants, only phoB mutants were equally resistant to TeO3(2-), and susceptibility could also be restored in strains carrying an F' plasmid for the phoB region and lost once more after F' curing. The tel and phoB loci were equally cotransducible with lac. Tel mutants still synthesized alkaline phosphatase, the phoA gene product, after Pi starvation, suggesting that the phoB locus per se was not involved because phoB is a positive regulatory gene for phoA expression. The results indicate that TeO3(2-) is transported into E. coli by a phosphate transport system and that resistance to TeO3(2-) specifically selects for as yet uncharacterized mutants in the phoB-phoA region of the chromosome.
Polycationic biocides with pendant active groups: molecular weight dependence of antibacterial activity
Authors: Ikeda T , Hirayama H , Yamaguchi H , Tazuke S , Watanabe M
Published: June 2012

Two types of polycations with pendant active groups were synthesized: one is polymethacrylate containing pendant biguanide units, and the other is poly(vinylbenzyl ammonium chloride). The two polycations were found to exhibit higher bactericidal activity against Staphylococcus aureus than the corresponding monomers. Fractionation of the polycations was successfully performed on gel filtration chromatography, and examination of the antibacterial activity against S. aureus of the well-characterized polymer samples with various molecular weights (MW) revealed that the activity was strongly dependent on the MW of the polycations and that there existed an optimal MW range for the cidal action of the polymeric biocides. Experiments on the lysis of protoplasts of Bacillus subtilis in contact with the polycations have shown that target sites of the polycationic biocides are cytoplasmic membranes of bacteria.
Inhibition of electron transfer and uncoupling effects by emodin and emodinanthrone in Escherichia coli
Authors: Ubbink-Kok T , Anderson J A , Konings W N
Published: June 2012

The anthraquinones emodin (1,3,delta-trihydroxy-6-methylanthraquinone) and emodinanthrone (1,3,8-trihydroxy-6-methylanthrone) inhibited respiration-driven solute transport at micromolar concentrations in membrane vesicles of Escherichia coli. This inhibition was enhanced by Ca ions. The inhibitory action on solute transport is caused by inhibition of electron flow in the respiratory chain, most likely at the level between ubiquinone and cytochrome b, and by dissipation of the proton motive force. The uncoupling action was confirmed by studies on the proton motive force in beef heart cytochrome oxidase proteoliposomes. These two effects on energy transduction in cytoplasmic membranes explain the antibiotic properties of emodin and emodinanthrone.
Pharmacokinetics of single-dose oral ciprofloxacin in patients undergoing chronic ambulatory peritoneal dialysis
Authors: Shalit I , Greenwood R B , Marks M I , Pederson J A , Frederick D L
Published: June 2012

The prevention and treatment of peritonitis in patients undergoing peritoneal dialysis is often complicated by several factors, including nephrotoxicity, requirement for hospitalization, parenteral antibiotic therapy, and infection caused by resistant microorganisms. Ciprofloxacin, a new carboxyquinolone derivative, may offer the advantages of oral administration, a broad spectrum of antibacterial activity, and safety for the management of these patients. The pharmacokinetics of ciprofloxacin in serum and peritoneal fluid of eight adult patients undergoing chronic ambulatory peritoneal dialysis (CAPD) were investigated. Each patient ingested a single 750-mg dose of ciprofloxacin, and drug concentrations were measured by high-pressure liquid chromatography in serum and peritoneal fluid for 48 h after the dose. Serum concentrations reached a mean peak of 3.6 micrograms/ml 1 to 2 h after the oral dose. The mean terminal serum half-life was 16.8 h, and the mean peritoneal fluid/serum concentration ratio was 0.64. The mean peak ciprofloxacin concentration in peritoneal fluid was 1.3 micrograms/ml, and the bioactivity of the drug in peritoneal fluid was confirmed. These data indicated that therapeutic concentrations of ciprofloxacin against bacterial pathogens commonly associated with peritonitis in CAPD patients may be achievable in the peritoneal fluid after oral administration to patients undergoing CAPD. In addition, the pharmacokinetic data provide guidelines for further clinical studies of oral ciprofloxacin in CAPD patients.