bluuebunny/crossref_metadata_2025 huggingface dataset:
Homology of a transferable tetracycline resistance determinant of Clostridium difficile with Streptococcus (Enterococcus) faecalis transposon Tn916
Authors: Hächler H , Kayser F H , Berger-Bächi B
Published: June 2012

In several tetracycline-resistant (Tetr) Clostridium difficile strains, homology with the Tn916 part of plasmid pAM120 DNA was observed. This 15-kilobase transposon, carrying a Tetr determinant, was originally found in Streptococcus (Enterococcus) faecalis. Hybridization experiments revealed that at least six of seven HincII fragments of Tn916, representing greater than 95% of its length, showed homology with DNA of Tetr C. difficile strains. Therefore, a close relationship of the C. difficile Tetr-determining element with the entire Tn916 transposon can be assumed, although differences were observed concerning the number of HindIII cleavage sites within the transposon. In addition to strong hybridization of Tetr determinants of C. difficile with Tn916, weak signals were detected when DNA of Tets C. difficile was hybridized with Tn916. These weak signals could be attributed to a single internal HincII fragment of Tn916.
Pharmacokinetics and tissue penetration of roxithromycin after multiple dosing
Authors: Wise R , Kirkpatrick B , Ashby J , Andrews J M
Published: June 2012

The pharmacokinetics of the macrolide roxithromycin (RU 28965) were studied during and after administration of 150 mg every 12 h for 3 days (five doses) in six volunteers. The concentrations in serum, blister fluid, and urine were measured. Mean levels in serum taken at 1.5 h after the morning dose increased from 4.4 micrograms/ml on day 1 to 5.9 micrograms/ml on day 2 and 7.4 micrograms/ml on day 3. The mean serum and blister fluid elimination half-lives on day 3 were 13.2 and 12.5 h, respectively. Roxithromycin penetrated blister fluid well; the mean percent penetration (as measured by the ratio of areas under the curve) was 85%. After the final dose, a mean of 10.5% of that dose was recovered in 12 h as microbiologically active compound.
Serum bactericidal activity and postantibiotic effect in serum of patients with urinary tract infection receiving high-dose amikacin
Authors: Van der Auwera P , Klastersky J
Published: June 2012

Ten patients received a 30-min infusion of amikacin (30 mg/kg) on day 1 and 15 mg/kg on day 2. Mean serum creatinine was 1.1 +/- 0.3 (standard deviation) mg/dl before and 1.0 +/- 0.3 mg/dl 3 days after the second infusion. Mean serum amikacin concentrations before, at the end of infusion, and 1, 6, 12, and 24 h after 30 and 15 mg/kg were 0, 157, 79, 31, 16, 5, 5, 85, 51, 19, 12, and 5 mg/liter, respectively. Five strains each of Staphylococcus aureus, Staphylococcus epidermidis susceptible and resistant to oxacillin, Streptococcus (Enterococcus) faecalis, corynebacterium sp. strain JK, Listeria monocytogenes, Mycobacterium fortuitum (three strains), Klebsiella pneumoniae, Serratia marcescens, Acinetobacter calcoaceticus, and Pseudomonas aeruginosa were tested. Serum bactericidal activities (SBAs) were greater than or equal to 1:8 in greater than or equal to 80% of the sera 1 and 6 h after 30 mg/kg and in greater than or equal to 60% of the sera 1 and 6 h after 15 mg/kg against Staphylococcus aureus and Staphylococcus epidermidis susceptible to oxacillin, A. calcoaceticus, and K. pneumoniae. L. monocytogenes, Serratia marcescens, and P. aeruginosa had lower SBAs. Very low or no activity was observed against oxacillin-resistant staphylococci and Streptococcus faecalis. The study of the killing rate in serum confirmed these results. Postantibiotic effect was studied by incubating a strain from each species in serum samples obtained 1 and 6 h after both regimens for 0.5, 1, or 2 h. The duration of postantibiotic effect depended on the duration of contact and the concentration of amikacin for the following organisms: oxacillin-susceptible staphylococci, L. monocytogenes, P. aeruginosa, A. calcoaceticus, K. pneumoniae, and Serratia marcescens. M. fortuitum was killed after 30 min of contact. No postantibiotic effect was observed with Streptococcus faecalis, Corynebacterium sp. strain JK, or oxacillin-resistant staphylococci. Amikacin at 30 mg/kg provided high levels and SBAs against susceptible pathogens. Prolonged postantibiotic effects were observed. No signs of nephrotoxicity occurred.
Interaction of (2,3)-methylenepenams with penicillin-binding proteins
Authors: Georgopapadakou N H , Russo D A , Liebman A , Burger W , Rossman P , Keith D
Published: June 2012

A series of (2,3)-methylenepenams were examined with respect to binding to essential penicillin-binding proteins (PBPs) in Escherichia coli and Staphylococcus aureus. The compounds were also examined with respect to their interaction with Streptomyces strain R61 DD-carboxypeptidase. The alpha isomer of (2,3)-methylene penicillin G bound to PBP 3 of E. coli and other enterobacteria at 0.1 to 10 micrograms/ml. The beta isomer bound to PBP 3 at 100 micrograms/ml. Either isomer bound to PBPs 1b and 2 of E. coli only at 100 micrograms/ml. The alpha, but not the beta, isomer also bound to PBP 2 of S. aureus at 0.1 micrograms/ml. Binding studies with radiolabeled compounds indicated the binding to be covalent and revealed no additional binding proteins. (2,3)-Methylenepenams active against E. coli bound to PBP 3 and induced filamentation. The compounds also inhibited Streptomyces strain R61 DD-carboxypeptidase with apparent 50% inhibitory concentrations as low as 10(-7) M. The two (2,3)-methylene penicillin G isomers bound to the enzyme covalently, most likely at the same site as penicillin G since partial proteolysis after binding radiolabeled compounds produced similar peptide patterns. The bound beta isomer was released with a half-time similar to that of penicillin G (70 min at 30 degrees C), while the alpha isomer was released with a longer half-time (13 h at 30 degrees C). With either isomer, the major release product was phenylacetylglycine, suggesting C-5-C-6 cleavage.
In vitro susceptibility of Coxiella burnetii to antibiotics, including several quinolones
Authors: Yeaman M R , Mitscher L A , Baca O G
Published: June 2012

Antibiotic susceptibility testing of the rickettsial Q fever agent Coxiella burnetii was performed by using persistently infected L929 fibroblast cells. The efficacies of a variety of antibiotics with different metabolic targets were tested and compared. The most effective antibiotics in bringing about the elimination of the parasite from infected cells included several quinolone compounds and rifampin. Of the quinolone compounds tested, difloxacin (A-56619) was the most effective, followed by ciprofloxacin and oxolinic acid. These three quinolones were apparently rickettsiacidal. After 48 h of exposure to microgram amounts of the compounds (ranging from 2 micrograms of difloxacin per ml to 5 micrograms of the other two antibiotics per ml), the number of intracellular parasites markedly declined; after 10 days of treatment, very few intracellular rickettsiae were detected. Rifampin (1 microgram/ml) was also very effective in eliminating the parasites. Some of the 13 other antibiotics tested that were somewhat effective included chloramphenicol, doxycycline, and trimethoprim. The persistently infected L929 cells were found to provide a convenient system for the relatively rapid determination of the susceptibility of C. burnetii to antibiotics.
Treatment of Clostridium difficile colitis in hamsters with a lipopeptide antibiotic, LY146032
Authors: Dong M Y , Chang T W , Gorbach S L
Published: June 2012

LY146032, an acidic lipopeptide antibiotic which inhibits the biosynthesis of cell wall peptidoglycan, was found to be effective in delaying death in a hamster model of pseudomembranous colitis. A dose of 0.05 mg/day was effective. The equivalent protection with vancomycin required a dose 100-fold higher, i.e., 5 mg/day.
Pentamidine aerosol in prophylaxis and treatment of murine Pneumocystis carinii pneumonia
Authors: Girard P M , Brun-Pascaud M , Farinotti R , Tamisier L , Kernbaum S
Published: June 2012

The efficacy and tolerance of pentamidine aerosol were evaluated in the prophylaxis and therapy of murine Pneumocystis carinii pneumonia. P. carinii pneumonia was induced in rats by corticosteroid immunosuppression. Pentamidine was administered three times weekly via a Bird micronebulizer. The actual amount of pentamidine inhaled was estimated by monitoring the ventilation of the rats during the aerosol administration. Pentamidine levels in blood, lung, liver and kidney samples were determined by high-pressure liquid chromatography after completion of the treatment. Efficacy was evaluated by examination of lung imprints. In the prophylactic treatment, 4.8- and 8.6-mg/kg doses of aerosolized pentamidine administered three times weekly for 7 weeks were effective in preventing P. carinii pneumonia in 80 and 100% of the rats, respectively. In the therapeutic studies, a 14.6-mg/kg dose of aerosolized pentamidine administered three times weekly for 3 weeks was effective both in curing the pneumonia and in clearing P. carinii cysts in 70% of the rats. In the remaining animals, although the pneumonia was cured, the cysts persisted. A dose-dependent effect of the drug was demonstrated in both prophylactic and therapeutic treatments. High lung/kidney and lung/liver ratios of pentamidine levels were demonstrated and were associated with good clinical, biological, and histologic tolerance.
Evaluation of (+)-cyclaradine-5'-esters as prodrugs for (+)-cyclaradine in animals
Authors: Lim J , Schwartz J , Loebenberg D , Miller G H , Symchowicz S , Lin C
Published: June 2012

Both (+)-cyclaradine-5'-methoxyacetate (CM) and (+)-cyclaradine-5'-ethoxypropionate (CE) were converted to (+)-cyclaradine (C) in squirrel monkey and human sera at 37 degrees C. CE was more stable than CM. After oral administration (20 mg base equivalent per kg) of either CM or CE, no unchanged esters were observed in serum of squirrel monkeys, rabbits, or rats. Instead, C was detected, indicating conversions of CM and CE to C in vivo. In squirrel monkeys, the areas under the curve (AUCs) of C obtained from oral dosing with CM were 61% higher than those obtained from dosing with C, indicating that CM may be a good prodrug for C. In squirrel monkeys, rabbits, and rats, CE resulted in a 20 to 90% higher AUC of C than did CM, indicating that CE was better absorbed than CM.
Comparative in vitro activity of CGP 31608, a new penem antibiotic
Authors: Eliopoulos G M , Wennersten C , Reiszner E , Moellering R C
Published: June 2012

The in vitro activity of a new penem antimicrobial agent, CGP 31608, was compared with those of imipenem, SCH 34343, and several other antimicrobial agents against approximately 600 bacterial isolates. CGP 31608 was active against gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MIC for 90% of the isolates [MIC90], 0.25 microgram/ml) and penicillin-susceptible streptococci (MIC90s, less than or equal to 2 micrograms/ml). Penicillin-resistant streptococci (including enterococci) and methicillin-resistant S. aureus were more resistant to the penem. Activities of CGP 31608 against members of the family Enterobacteriaceae were remarkably uniform, with MIC90s of 8 to 16 micrograms/ml. CGP 31608 was at least as active as imipenem and ceftazidime and more active than piperacillin against Pseudomonas aeruginosa. Drug activity was not influenced by the presence of any of 10 plasmid-mediated beta-lactamases. Against strains of Serratia marcescens, Enterobacter cloacae, and P. aeruginosa with derepressible chromosomally mediated beta-lactamases, the presence of cefoxitin did not induce increased resistance to CGP 31608. The new drug was also active against anaerobes (MIC90s, 0.25 to 8 micrograms/ml), Haemophilus influenzae (MIC90s, 0.5 to 1.0 micrograms/ml), and Legionella spp. (MIC90, 2 micrograms/ml). CGP 31608 showed an antibacterial spectrum similar to those of imipenem and SCH 34343 (except that the latter is not active against P. aeruginosa) but was generally less potent than these drugs. However, CGP 31608 demonstrated more activity (MIC90) than imipenem against P. aeruginosa, Pseudomonas cepacia, and methicillin-resistant Staphylococcus epidermidis and S. aureus.
Ranking of prophylactic efficacy of poly(ICLC) against Rift Valley fever virus infection in mice by incremental relative risk of death
Authors: Kende M , Lupton H W , Rill W L , Gibbs P , Levy H B , Canonico P G
Published: June 2012

The prophylactic efficacy of poly(ICLC) (stabilized, synthetic, double-stranded polyriboinosinic-polyribocytidylic acid) against Rift Valley fever virus infection in Swiss-Webster mice was dependent on the treatment schedule. The treatment schedule was optimized by ranking the results of various treatments by the Cox proportional-hazard model based on the incremental relative risk of death. With this ranking procedure, the schedule of choice was three doses of 20 micrograms each given 5 days apart. This regimen yielded a 90% survival rate. Additional parameters were determined, including the timing of the first and second drug dose, the temporal relationship of these treatments to the day of challenge, and the minimal effective dose (1 microgram per mouse).
Antimicrobial substance from a human Lactobacillus strain
Authors: Silva M , Jacobus N V , Deneke C , Gorbach S L
Published: June 2012

Lactobacillus sp. strain GG, which was isolated from the feces of a normal person, produced a substance with potent inhibitory activity against a wide range of bacterial species. It inhibited anaerobic bacteria (Clostridium spp., Bacteroides spp., Bifidobacterium spp.), members of the family Enterobacteriaceae, Pseudomonas spp. Staphylococcus spp., and Streptococcus spp., as demonstrated by a microbiological assay; however, it did not inhibit other lactobacilli. The inhibitory activity occurred between pH 3 and 5 and was heat stable. Bactericidal activity against Escherichia coli was demonstrated at a dilution of 1:128. The inhibitory substance was distinct from lactic and acetic acids. It had a low molecular weight (less than 1,000) and was soluble in acetone-water (10:1). Because of these characteristics, the inhibitory material could not be considered a bacteriocin; it most closely resembled a microcin, which has been associated previously with members of the family Enterobacteriaceae.
Detection of a second mechanism of resistance to gentamicin in animal strains of Escherichia coli
Authors: Chaslus-Dancla E , Gerbaud G , Martel J L , Lagorce M , Lafont J P , Courvalin P
Published: June 2012

One mechanism of plasmid-mediated resistance to gentamicin in Escherichia coli strains isolated from animals is due to the synthesis of the aminoglycoside 3-N-acetyltransferase type IV. A second mechanism of plasmid-mediated resistance to gentamicin was detected in animal strains of E. coli in France and is due to the production of the aminoglycoside 3-N-acetyltransferase type II. The molecular relationships among plasmids encoding this enzyme were studied.
Cloning and expression of a tetracycline resistance determinant from Campylobacter jejuni in Escherichia coli
Authors: Tenover F C , LeBlanc D J , Elvrum P
Published: June 2012

The tetracycline resistance gene (tet) from the Campylobacter jejuni plasmid pFKT1025 was cloned into both pUC18 and pBR322 and was expressed when the chimeric plasmids were introduced into Escherichia coli. The location of the tet determinant on the chimeric plasmids was determined by BAL 31 deletion mapping within a 2.25-kilobase (kb) RsaI-HincII fragment. A protein of approximately 70 kilodaltons was consistently produced by E. coli maxicells harboring the cloned tet determinant. A 500-base-pair restriction fragment from within the 2.25-kb tet region was shown to hybridize only to DNA from tetracycline-resistant strains of C. jejuni and C. coli, but not to the DNA of organisms known to carry the streptococcal tetM determinant. No homology was noted between the DNA of 10 tetracycline-resistant isolates of campylobacter and the streptococcal tetL, tetM, or tetN determinants when tested under conditions of high stringency. However, homology was noted between a 5.0-kb HincII restriction fragment containing the tetM determinant and two C. jejuni tet R factors under conditions of reduced stringency.
Relationship between cefamandole and cefuroxime activity against oxacillin-resistant Staphylococcus epidermidis and oxacillin resistance phenotype
Authors: Woods G L , Knapp C C , Washington J A
Published: June 2012

The activity of cefamandole and cefuroxime against oxacillin-resistant staphylococcus epidermidis was studied in vitro to determine whether there was any relationship between oxacillin resistance phenotypes and cephalosporin activity. Oxacillin resistance phenotypes were determined by efficiency-of-plating studies on Mueller-Hinton agar containing oxacillin, with and without NaCl, and incubated at 30 and 35 degrees C. On the basis of MIC and MBC determinations, cefamandole was more active than cefuroxime against oxacillin-resistant S. epidermidis. Although temperature had minimal effect on the activity of either cefamandole or cefuroxime, NaCl significantly decreased the activity of cefuroxime but not of cefamandole. Neither cephalosporin consistently produced greater than or equal to 99.9% bactericidal activity within 24 h in timed killing-curve studies. No consistent relationship was observed between cefamandole or cefuroxime activity and oxacillin resistance phenotype.
Pharmacokinetics of ofloxacin after parenteral and oral administration
Authors: Lode H , Höffken G , Olschewski P , Sievers B , Kirch A , Borner K , Koeppe P
Published: June 2012

In 10 volunteers, the pharmacokinetics of ofloxacin [HOE 280, DL 8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid] was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open two- and three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at greater than 0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.
Accumulation of enoxacin by Escherichia coli and Bacillus subtilis
Authors: Bedard J , Wong S , Bryan L E
Published: June 2012

Several methods were used to determine enoxacin uptake in Escherichia coli strains because washing of cells removed all or most cell-associated enoxacin whereas no washing was associated with large amounts of cell-bound enoxacin. Washing after up to 40 to 45 min of exposure to enoxacin followed by suspension in drug-free medium prevented a significant effect of enoxacin on cell growth. Cell uptakes obtained with different methods showed no difference in the shape of the timed uptake curves but did show significant quantitative differences. These results are consistent with cell-associated enoxacin comprising a freely exchangeable pool of drug. Lineweaver-Burk plots of uptake were consistent with uptake of enoxacin by simple diffusion. No saturability and no competition with ciprofloxacin were observed. Low temperature (4 degrees C) was associated with decreased uptake. Arsenate, carbonyl cyanide m-chlorophenylhydrazone, sodium fluoride, sodium azide, and 2,4-dinitrophenol had no effect on uptake. We conclude that the mechanism of transport of enoxacin into cells is by simple diffusion. Mutants of E. coli with deficiency of outer membrane proteins F and C and an enoxacin-resistant mutant selected by serial passage with increasing enoxacin concentrations demonstrated that F porins play a significant role in enoxacin uptake and influence susceptibility to enoxacin. Uptake was shown to be similar in a strain of Bacillus subtilis.
Polysaccharides as antiviral agents: antiviral activity of carrageenan
Authors: González M E , Alarcón B , Carrasco L
Published: June 2012

A number of polysaccharides showed good antiviral activity against several animal viruses. At 5 micrograms/ml, carrageenan prevented the cell monolayer from destruction by herpes simplex virus type 1 (HSV-1) growth. At 10 micrograms/ml, carrageenan reduced the formation of new infectious HSV-1 by almost five logs. No cytotoxic effects were detected with concentrations of carrageenan up to 200 micrograms/ml. When 10 micrograms of carrageenan per ml was added at the beginning of HSV-1 infection of HeLa cells, there was potent inhibition of viral protein synthesis, and the cells continued synthesizing cellular proteins. This did not occur if carrageenan was added 1 h after HSV-1 infection. The use of [35S]methionine-labeled virions to analyze the entry of HSV-1 or Semliki Forest virions into cells indicated that carrageenan had no effect on virus attachment or virus entry. Moreover, carrageenan did not block the early permeabilization of cells to the toxic protein alpha-sarcin. These results suggest that this sulfated polysaccharide inhibits a step in virus replication subsequent to viral internalization but prior to the onset of late viral protein synthesis.
Single- and combination-antibiotic therapy for experimental endocarditis caused by methicillin-resistant Staphylococcus aureus
Authors: Rodríguez A , Vicente M V , Olay T
Published: June 2012

The efficacy of fosfomycin in combination with vancomycin or gentamicin was evaluated in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. After 5 days of therapy, both combinations proved to be highly effective since all rabbits had sterile vegetations.
New tetracycline resistance determinant on R plasmids from Vibrio anguillarum
Authors: Aoki T , Satoh T , Kitao T
Published: June 2012

Two classes of tetracycline resistance determinants on R plasmids were detected in Vibrio anguillarum strains isolated from ayu (sweat fish; Plecoglossus altivelis) farms in Japan. Tetracycline resistance genes categorized as class B were prevalent from 1973 to 1977; however, a new tetracycline resistance gene, which was not classified into tetracycline resistance determinant class A, B, C, or D, has been prevalent since 1981.
Purification of Citrobacter freundii DNA gyrase and inhibition by quinolones
Authors: Aoyama H , Sato K , Fujii T , Fujimaki K , Inoue M , Mitsuhashi S
Published: June 2012

DNA gyrase is a bacterial enzyme which catalyzes the ATP-dependent negative supercoiling of DNA. It is the accepted target of quinolones. The enzyme from Citrobacter freundii IID976 was purified by affinity chromatography on novobiocin-Sepharose and heparin-Sepharose. It had two subunits, designated A and B, which closely resembled those of the enzyme from Escherichia coli and Micrococcus luteus in enzymatic requirements. The inhibitory effects of the quinolones on the supercoiling activities of the enzyme correlated with their antibacterial activities. New quinolones were better inhibitors of DNA gyrase than nalidixic acid and pipemidic acid. We also purified DNA gyrase from a spontaneous nalidixic acid-resistant mutant (M2-5). The gyrases from IID976 and M2-5 were defined as mixtures of subunits As+Bs (s, susceptible) and Ar+Br (r, resistant), respectively. The supercoiling activities of reconstituted Ar+Br and Ar+Bs were more resistant to quinolones than As+Bs and As+Br. These findings indicate that one mechanism of C. freundii resistance against quinolones is resistance modification of the A subunit protein.
Effect of protein binding on drug penetration into blister fluid
Authors: Shyu W C , Quintiliani R , Nightingale C H , Dudley M N
Published: June 2012

The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ratio. Both the area under the concentration-time curve ratio and the concentration ratio (by the disk method) for cefonicid were statistically lower than the ratios for ceftizoxime and cefotaxime. The high degree of protein binding of cefonicid results in the availability of less drug for diffusion to blister fluid than with the low-protein-binding ceftizoxime and cefotaxime.
LY146032 compared with penicillin G in experimental aortic valve endocarditis caused by group G streptococci
Authors: Bayer A S , Yih J , Hirano L
Published: June 2012

Rabbits with group G streptococcal aortic endocarditis received no therapy (controls); repeated doses of procaine penicillin G, 300 mg/kg (body weight) per day, administered intramuscularly; or LY146032, a new peptolide antibiotic, 20 mg/kg per day, administered intravenously. Penicillin G and LY146032 reduced mean intravegetation group G streptococcal densities significantly below those observed in controls at both day 3 and day 6 of therapy. Penicillin G effected a more rapid clearance of intravegetation streptococci than LY146032 by day 3, but not by day 6, of therapy.
In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents
Authors: Sears S D , O'Hare J
Published: June 2012

We determined the susceptibilities of five strains of Trichomonas vaginalis, one of which was metronidazole resistant, to 50 antimicrobial agents. For the metronidazole-susceptible strains, the most active agents were metronidazole, tinidazole, mebendazole, furazolidone, and anisomycin. Against the resistant strain mebendazole, furazolidone, and anisomycin were the most active. Antifungal agents, beta-lactams, macrolides, aminoglycosides, and folic acid antagonists were ineffective against all strains.
Susceptibility of dysgonic fermenter 2 to antimicrobial agents in vitro
Authors: Verghese A , Hamati F , Berk S , Franzus B , Berk S , Smith J K
Published: June 2012

Dysgonic fermenter 2 (DF-2) is a fastidious, gram-negative organism well recognized as a cause of fulminant septicemia in patients without spleens or patients with alcoholic cirrhosis. In vitro antibiotic susceptibility testing of eight strains with a Schaedler broth dilution technique revealed DF-2 to be susceptible to all of the antibiotics tested except aztreonam. Previous reports that DF-2 is aminoglycoside resistant were based on disk diffusion or agar dilution assays that may be less reliable given the slow growth of the organism and its requirement for CO2 incubation. Penicillin is commonly used as prophylaxis after dog bites and has excellent activity against DF-2.
Laboratory- and species-specific interpretive breakpoints for disk diffusion tests of chloramphenicol susceptibility of Haemophilus influenzae
Authors: Kronvall G , Ringertz S , Karlsson I , Göransson E , Dornbusch K
Published: June 2012

A total of 601 clinical isolates of Haemophilus influenzae isolated in six different regions of Sweden were tested for chloramphenicol susceptibility by using agar dilution MIC determinations and disk diffusion tests. For seven strains MICs were 4 micrograms/ml or higher, and for one strain the MIC was 2 micrograms/ml. All eight strains produced chloramphenicol acetyltransferase. For the remaining 593 strains, MICs were less than or equal to 1 microgram/ml, and the MICs for 50% and 90% of the strains were both 0.5 microgram/ml. Disk diffusion tests carried out by using revised interpretive criteria introduced in 1984 by the Swedish Reference Group for Antibiotics correctly identified the 593 strains as susceptible and the 8 strains as resistant. Quality assessments were performed in 29 clinical microbiology laboratories. The revised criteria for chloramphenicol disk diffusion testing gave rise to false resistance results in some laboratories. The interpretive accuracy improved when the interlaboratory variation was compensated for by using adjusted breakpoints. Such revision was possible through peak correction, single-strain regression analysis, and standard curve regression analysis. Peak-corrected breakpoints improved the accuracy from an overall incidence of false-resistant isolates of 4.4% to 2.3%. Single-strain regression analysis and standard curve regression analysis provided laboratory- and species-specific breakpoints which reduced false resistance rates of 0.14% and 0%, respectively.
Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin
Authors: Jones R N , Barry A L
Published: June 2012

The antimicrobial activity and spectrum of ceftibuten (7432-S; SCH 39720) was determined on a wide variety of bacterial species selected for resistance to oral and parenteral beta-lactam antimicrobial agents. Ceftibuten was found to be the most active beta-lactam tested against members of the family Enterobacteriaceae, inhibiting 81.6% of strains at less than or equal to 8.0 micrograms/ml compared with 75.0 and 54.8% of strains inhibited by cefixime and cefuroxime, respectively. All strains of Haemophilus influenzae (MIC for 90% of strains [MIC90], less than or equal to 0.06 microgram/ml), Branhamella catarrhalis (MIC90, 3.0 micrograms/ml), and pathogenic Neisseria spp. (MIC90, less than or equal to 0.06 and 0.019 microgram/ml) were susceptible to ceftibuten. Beta-hemolytic Streptococcus spp. (serogroups A, B, C, and G) were also inhibited by ceftibuten, but penicillin-resistant pneumococci were generally resistant to cefixime and ceftibuten. The activity and spectrum of ceftibuten seem most applicable to infections of the respiratory and urinary tract plus those infections caused by pathogenic Neisseria spp. Ceftibuten disks (30 micrograms) were evaluated and found to have an acceptable correlation (r = 0.88) with ceftibuten MICs. Preliminary zone size interpretive criteria for MIC breakpoints of less than or equal to 4.0 and less than or equal to 8.0 micrograms/ml were calculated.
In vitro activity of carumonam (Ro 17-2301; AMA-1080) versus enteropathogenic and nonfermentative gram-negative rods and Legionella pneumophila
Authors: Hohl P , von Graevenitz A , Zollinger-Iten J
Published: June 2012

The in vitro activity of carumonam (Ro 17-2301; AMA-1080) was tested against 355 single-patient isolates, by and large enteropathogenic or nonfermentative rods. The new monobactam was inhibitory and bactericidal against the majority of diarrhea-causing members of the family Enterobacteriaceae at concentrations of less than and equal to 8 micrograms/ml. Although known to be active against Pseudomonas aeruginosa, it generally did not exhibit clinically useful activity against other nonfermenters or against Legionella pneumophila, thus confirming its narrow spectrum of activity.
Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs
Authors: Hoffman H E , Gaylord J C , Blasecki J W , Shalaby L M , Whitney C C
Published: June 2012

We studied the pharmacokinetics and metabolism of rimantadine hydrochloride (rimantadine) following single-dose oral and intravenous administration in mice and dogs. Absorption of the compound in mice was rapid. Maximum concentrations in plasma occurred at less than 0.5 h after oral administration, and the elimination half-life was 1.5 h. Peak concentrations in plasma following oral administration were markedly disproportional to the dose (274 ng/ml at 10 mg/kg, but 2,013 ng/ml at 40 mg/kg). The bioavailability after an oral dose of 40 mg/kg was 58.6%. Clearance was 4.3 liters/h per kg, and the volume of distribution was 7.6 liters/kg at 40 mg/kg. In contrast to the results observed in mice, absorption of the compound in dogs was slow. Maximum concentrations in plasma occurred at 1.7 h after oral administration, and the elimination half-life was 3.3 h. A further difference was that peak concentrations in plasma were approximately proportional to the dose. Following administration of a single oral dose of 5, 10, or 20 mg/kg, maximum concentrations in plasma were 275,800, and 1,950 ng/ml, respectively. The bioavailability after an oral dose of 5 mg/kg was 99.4%. The clearance was 3.7 liters/h per kg, and the volume of distribution was 13.8 liters/kg at 5 mg/kg. Mass balance studies in mice, using [methyl-14C]rimantadine, indicated that 98.7% of the administered dose could be recovered in 96 h. Less than 5% of the dose was recovered as the parent drug in dog urine within 48 h. Finally, gas chromatography-mass spectrometry studies, done with mouse plasma, identified the presence of two rimantadine metabolites. These appeared to be ring-substituted isomers of hydroxy-rimantadine.
Temocillin efficacy in experimental Klebsiella pneumoniae meningitis after infusion into rabbit plasma to simulate antibiotic concentrations in human serum
Authors: Woodnutt G , Catherall E J , Kernutt I , Mizen L
Published: June 2012

An infusion system was developed to simulate in the plasma of rabbits the concentrations of temocillin in human serum measured after administration of a 2-g intravenous bolus dose. The efficacy of therapy with this infusion against experimental Klebsiella pneumoniae meningitis was compared with that of a conventional bolus dose to the animals. The marked difference between the elimination half-life (t1/2) of temocillin in rabbit plasma and human serum (0.3 and 5 h, respectively) was reflected in concentrations in cerebrospinal fluid (CSF). The mean peak concentration after infusion occurred 3.5 h later than after bolus dosing, and levels were more prolonged (t1/2 in CSF was 6.3 h compared with 0.83 h following the bolus dose). After infusion, the mean viable count in CSF decreased by 4 log10 CFU/ml, whereas the bolus dose was ineffective because of the rapid fall to subinhibitory concentrations. These results suggest that the infusion system used is valuable for experimental studies with antibacterial agents whose elimination kinetics differ markedly between animals and humans.
Antiherpesvirus activity and mechanism of action of indolo-(2,3-b)quinoxaline and analogs
Authors: Harmenberg J , Wahren B , Bergman J , Akerfeldt S , Lundblad L
Published: June 2012

The antiherpesvirus activity of 14 derivatives of indoloquinoxaline was tested. The most active was 2,3-dimethyl(dimethylaminoethyl)5H-indolo-(2,3-b)quinoxaline, also called B-220. The antiherpesvirus mechanism of B-220 was sought. The compound inhibited replication of herpes simplex virus type 1, cytomegalovirus, and varicella-zoster virus in tissue culture at concentrations of 1 to 5 microM, depending on the cell type used for assay and the amount of virus. Cellular toxicity was seen at a concentration of 10 to 30 microM, and antiviral activity in the human bladder cancer and human embryonic lung fibroblast cell lines tested was found at concentrations 3 to 15 times lower than the concentrations causing cellular toxicity. Viral DNA synthesis, as well as production of early and late viral proteins, was inhibited at 0.5 to 4.5 microM B-220, but viral DNA polymerases tested in vitro were not inhibited at these concentrations. There was no interaction with the pyrophosphate analog foscarnet, and no reversal of the antiviral activity of B-220 occurred with naturally occurring nucleosides. We conclude that the antiviral effect depends on the multiplicity of infection and may occur at the level of viral DNA synthesis and that no interference occurs with pyrophosphate analogs or nucleosides. The more potent activity against viral DNA than against cellular DNA may be caused by a true selectivity for herpesvirus DNA or by the higher metabolism of viral DNA in infected cells.
Rapid isoelectric focusing of plasmid-mediated beta-lactamases with Pharmacia PhastSystem
Authors: Huovinen S
Published: June 2012

A modified isoelectric focusing method for rapid semiquantitative identification of plasmid-mediated beta-lactamases by use of the Pharmacia PhastSystem (Uppsala, Sweden) is described. Sonication of bacterial colonies collected directly from growth plates decreased the time required for the procedure. With sonic extracts of known beta-lactamase-producing strains used as controls, the assay could be completed in less than 2 h.
In vitro activities of ofloxacin and four other new quinoline-carboxylic acids against Chlamydia trachomatis
Authors: Nagayama A , Nakao T , Taen H
Published: June 2012

The in vitro activities of five new quinoline-carboxylic acids against 2 reference strains and 45 clinical isolates of Chlamydia trachomatis of genital origin were compared with the activities of minocycline and doxycycline. Ofloxacin was the third most active agent (after the two tetracyclines), followed by ciprofloxacin, NY-198, and AM-833.
Role of beta-lactamase and different testing conditions in oxacillin-borderline-susceptible staphylococci
Authors: Sierra-Madero J G , Knapp C , Karaffa C , Washington J A
Published: June 2012

A group of staphylococcal isolates for which oxacillin MICs were intermediate (1 to 4 micrograms/ml) were studied to establish the role of beta-lactamase in this phenomenon. MICs and MBCs of oxacillin and penicillin with and without clavulanic acid or sulbactam (4 or 16 micrograms/ml, respectively) were determined for 11 Staphylococcus aureus and 2 coagulase-negative Staphylococcus isolates for which oxacillin MICs were 1 to 4 micrograms/ml. The susceptibility studies were done with incubation at 35 and 30 degrees C, and the MICs were read at 24 and 48 h. Of the 13 isolates, 4 became resistant when longer incubation or 30 degrees C incubation was used, and the MICs for 9 remained in the intermediate range. Only three of these strains were susceptible to penicillin, and beta-lactamase was not detected. For 6 of 10 beta-lactamase-positive strains, there was a greater-than-twofold-dilution reduction in oxacillin MICs with the addition of clavulanic acid or sulbactam. Of the four strains that became resistant with incubation at the lower temperature, a clavulanic acid effect was observed in three but only at 35 degrees C. The oxacillin MIC for one of the beta-lactamase-negative strains was also reduced with clavulanic acid; however, this strain was inhibited by 1 microgram of clavulanic acid per ml alone. Bactericidal activity was observed with two or four times the oxacillin MIC in eight strains tested at both temperatures, and the combination with clavulanic acid was bactericidal at higher than four times the MIC in five of the strains at 30 degrees C. Our results suggest that oxacillin intermediate MICs for staphylococcal isolates are due not only to beta-lactamase hyperproduction but also some other unidentified factor. The reduction in oxacillin MIC observed when clavulanic acid was added to one strain was probably due to the intrinsic inhibitory activity of clavulanic acid.
Differential effects of DNA gyrase inhibitors on the genetic transformation of Neisseria gonorrhoeae
Authors: Parham C , Cunningham E , McGinnis E
Published: June 2012

Inhibitors of DNA gyrase in Escherichia coli exerted differential effects on the genetic transformation of Neisseria gonorrhoeae. When competent cells of the gonococcus were exposed to novobiocin before the uptake of transforming antibiotic resistance DNA, there was a 50 to 60% reduction in the number of transformants compared with the number of control untreated cells. Norfloxacin, a more potent inhibitor of DNA gyrase and an analog of nalidixic acid, nearly abolished the production of transformants by recipient cells. On the contrary, exposure of competent cells to nalidixic acid had no effect on transformant yield. The target of these inhibitors appears to be at the level of recombination. Possible mechanisms are discussed.
Comparative efficacies of amoxicillin-clavulanic acid and ampicillin-sulbactam against experimental Bacteroides fragilis-Escherichia coli mixed infections
Authors: Gisby J , Beale A S
Published: June 2012

Amoxicillin-clavulanic acid was compared with ampicillin-sulbactam in preventing the development of mixed infections produced in mice by subcutaneous inoculation of amoxicillin-resistant strains of Bacteroides fragilis and Escherichia coli. At doses designed to produce concentrations in mouse plasma similar to those obtained in humans, both amoxicillin-clavulanic acid and ampicillin-sulbactam were effective in preventing an infection caused by B. fragilis VPI 8908 mixed with E. coli E96, both strains being susceptible in vitro to each combination. However, ampicillin-sulbactam failed to arrest the progression of infections involving a more potent beta-lactamase-producing strain, E. coli 41548, even when a comparatively low inoculum was tested. In contrast, amoxicillin-clavulanic acid therapy effectively reduced the bacterial numbers at the site of infection. These data illustrate the need to treat polymicrobial infections with agents effective against the responsible aerobic as well as anaerobic bacteria.
Mechanism of action of cephalosporins and resistance caused by decreased affinity for penicillin-binding proteins in Bacteroides fragilis
Authors: Yotsuji A , Mitsuyama J , Hori R , Yasuda T , Saikawa I , Inoue M , Mitsuhashi S
Published: June 2012

The susceptibilities of 52 clinical isolates of Bacteroides fragilis to five monoanionic cephalosporins were examined. Cefoperazone showed the highest antibacterial activity, followed by ceftezole, cefazolin, cefamandole, and cephalothin. There were two groups of resistant strains: one group (ca. 15%), of which B. fragilis G-232 was a typical sample, was resistant to ceftezole (MIC, 100 micrograms/ml), cefazolin (MIC, 100 micrograms/ml), and cephalothin (MIC, 200 micrograms/ml) but not cefoperazone (MIC, 6.25 micrograms/ml) or cefamandole (MIC, 25 micrograms/ml). On the basis of studies of stability to beta-lactamase, outer membrane permeation, and affinity for penicillin-binding proteins (PBPs), we conclude that decreased affinity for PBP 3 may play an important role in the resistance to ceftezole, cefazolin, and cephalothin in B. fragilis G-232. Another group (also ca. 15%), of which B. fragilis G-242 was a representative, was resistant to all five cephalosporins (MIC, 100 to 400 micrograms/ml) and produced a high amount of beta-lactamase. Similar broad-spectrum resistance was seen in a mutant of strain G-232 that had a greater-than-30-fold increase in beta-lactamase production.
Activities of fluconazole (UK 49,858) and ketoconazole against ketoconazole-susceptible and -resistant Candida albicans
Authors: Hughes C E , Bennett R L , Tuna I C , Beggs W H
Published: June 2012

We have compared the activities of fluconazole and ketoconazole against ketoconazole-susceptible and -resistant strains of Candida albicans in a neutropenic-site rabbit model. Oral treatment with fluconazole resulted in much higher serum and extravascular concentrations of this antifungal agent than did comparable doses of ketoconazole. Fluconazole had no additional in vivo activity against the ketoconazole-susceptible strains; no fungicidal activity was observed with peak drug levels as high as approximately 75 micrograms/ml in the infection sites. Significant fungistatic activity against the ketoconazole-resistant strains was observed with fluconazole treatment (80 mg/kg), but not with less fluconazole (20 mg/kg) or with ketoconazole (approximately 67 mg/kg). In vitro susceptibility tests separated the ketoconazole-susceptible strains from the ketoconazole-resistant strains, but the results were variable when the resistant strains were tested with fluconazole.
Toxicity trial of prophylactic 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (ganciclovir) after marrow transplantation in dogs
Authors: Appelbaum F R , Meyers J D , Deeg H J , Graham T , Schuening F , Storb R
Published: June 2012

The effects of 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine, or ganciclovir, administered during the immediate posttransplant period to dogs given total-body irradiation and autologous marrow transplants were studied. Doses of ganciclovir of 3.0 mg/kg (body weight) per day were well tolerated without detectable delay in hematopoietic recovery, whereas doses of 5.0 mg/kg per day were associated with delayed platelet recovery.
Effect of oral activated charcoal on tobramycin clearance
Authors: Davis R L , Koup J R , Roon R A , Opheim K E , Smith A N
Published: June 2012

To evaluate the effect of activated charcoal on aminoglycoside pharmacokinetics, six healthy volunteers received tobramycin intravenously with and without multiple oral doses of activated charcoal. Activated charcoal did not have a statistically significant effect on any pharmacokinetic parameter. We conclude that activated charcoal does not enhance tobramycin clearance in subjects with normal renal function when concentrations in serum are within the therapeutic range.
Involvement of glucose catabolism in avermectin production by Streptomyces avermitilis
Authors: Ikeda H , Kotaki H , Tanaka H , Omura S
Published: June 2012

The addition of glucose in the early stage of fermentation suppressed not only avermectin production but also the activity of 6-phosphogluconate dehydrogenase in the pentose phosphate pathway. On the other hand, when glucose was added at the late stage of fermentation, suppression of avermectin formation and 6-phosphogluconate dehydrogenase activity was not observed but avermectin formation was increased and about a twofold-higher content of avermectins than that of the control fermentation was accumulated.
Chloramphenicol, gentamicin, and ciprofloxacin against murine scrub typhus
Authors: McClain J B , Joshi B , Rice R
Published: June 2012

Ciprofloxacin (120 mg/kg of body weight per day), chloramphenicol (300 mg/kg per day), and gentamicin (30 mg/kg per day) were compared with placebo in a BALB/cj mouse model of scrub typhus. All animals treated with ciprofloxacin and chloramphenicol survived. All animals treated with gentamicin or placebo died. All surviving animals showed evidence of seroconversion. Ciprofloxacin and chloramphenicol were statistically more effective in preventing death than gentamicin or placebo.