bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative effect of granulocytes on antibiotic treatment of experimental staphylococcal infection
Authors: Hoogeterp J J , Mattie H , Krul A M , van Furth R
Published: June 2012

The quantitative relation between granulocytopenia and antibiotic treatment was established for a short-term Staphylococcus aureus infection in the thighs of mice, using rifampin, benzylpenicillin, and erythromycin. Granulocytopenia was induced by total-body irradiation; the number of granulocytes decreased gradually during the first 5 days after irradiation to 10% of the number in normal mice. Experimental infections were established on each of the 5 days after irradiation. In animals not treated with antibiotics, the number of granulocytes in peripheral blood and the number of CFU at the site of infection exhibited a strong negative correlation. The influence of granulocytes on the effect of antibiotics on the number of CFU differed for the three antibiotics. For erythromycin the slope of the dose-effect relation was rather flat, but a decrease in the number of granulocytes caused a significant, nearly parallel, shift in the dose-effect relation, resulting in an increase in the number of CFU. For benzylpenicillin the slope of the dose-effect relation for normal mice was also flat, but as the number of granulocytes decreased the slope became significantly steeper, resulting in a diminishing influence of granulocytes at higher dosages. For rifampin the slope of the dose-effect relation, which was already steep for nonirradiated animals, increased significantly. Here too the effect of granulocytes decreased as the dose increased.
Comparative susceptibilities of Campylobacter pylori to norfloxacin and other agents
Authors: Shungu D L , Nalin D R , Gilman R H , Gadebusch H H , Cerami A T , Gill C , Weissberger B
Published: June 2012

Twenty-one strains of Campylobacter pylori (Campylobacter pyloridis) were tested for susceptibility to norfloxacin and other agents by the serial agar dilution method. Ampicillin (MIC for 90% of isolates [MIC90], 0.016 micrograms/ml) and famotidine (MIC90, greater than 1,024 micrograms/ml) were, respectively, the most and the least active of the agents tested. Norfloxacin (MIC90, 1 microgram/ml) and imipenem (MIC90, 0.125 micrograms/ml) were substantially active against this organism.
Effect of dose size on bioavailability of ciprofloxacin
Authors: Plaisance K I , Drusano G L , Forrest A , Bustamante C I , Standiford H C
Published: June 2012

We evaluated the bioavailability of ciprofloxacin at two dose sizes in eight healthy volunteers. Each volunteer was given 200 mg of ciprofloxacin both orally and intravenously in a randomized crossover fashion and 750 mg orally. Bioavailability at the two doses was similar: 69 and 69.1% for the 200- and 750-mg doses, respectively. However, the bioavailability observed with the 750-mg dose was significantly more variable than that observed with the 200-mg dose. Between 375 and 700 mg of ciprofloxacin reached the systemic circulation after administration of the 750-mg dose, with no evidence of adverse reactions.
Prevention and treatment of experimental herpes simplex virus encephalitis with human immune serum globulin
Authors: Erlich K S , Dix R D , Mills J
Published: June 2012

Pooled human immunoglobulin suitable for intravenous administration (IGIV) was evaluated in the prophylaxis and treatment of herpes simplex virus (HSV) type 1 encephalitis in a murine model. Four-week-old BALB/c mice received a single intraperitoneal injection of IGIV or saline 24 h before or up to 24 h after intranasal infection with 10(4.6) PFU of HSV type 1. Treatment with IGIV was protective against death, and the protective effects were dose and time dependent. Treatment with IGIV blocked the production of HSV antibody by infected mice and reduced the number of trigeminal ganglia containing latent virus. Removal of neutralizing antibody from the IGIV pool did not eliminate the protective effect, whereas F(ab)2 fragments of IGIV, which had virus-neutralizing activity that was identical to that of native IGIV, conferred no protection against death. Pooled human IGIV was effective for the prevention and treatment of HSV encephalitis in mice. Antibody-mediated protection required the Fc portion of the immunoglobulin molecule but did not require the direct neutralization of virus.
Synergistic activity of granulocyte-macrophage colony-stimulating factor and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro
Authors: Hammer S M , Gillis J M
Published: June 2012

The ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) and 3'-azido-3'-deoxythymidine (AZT) to inhibit human immunodeficiency virus (HIV) in the U-937 monocytic cell line was examined. Acutely HIV-infected U-937 cells were exposed to GM-CSF (0.03, 0.3, 3.0, or 30.0 U/ml) and AZT (0.1, 1.0, or 10.0 microM) alone and in combination for 14 to 17 days. Reverse transcriptase activity in the supernatant, the percentage of cells expressing viral antigens by indirect immunofluorescence, and the 50% tissue culture infectious dose per milliliter of supernatant were determined to assess the level of viral replication in treated and control cultures. By the fractional-product method of analysis, nearly all combinations of GM-CSF and AZT synergistically inhibited HIV replication by these three measurements. The most effective combinations were 30 U of GM-CSF per ml with 0.1, 1.0, or 10.0 microM AZT. These treatments resulted in no reverse transcriptase activity in the supernatants, less than 1% immunofluorescent positive cells, and less than 8 50% tissue culture infectious doses per ml in the absence of cytotoxicity. Despite this degree of suppression, productive viral replication returned in all cultures within 4 to 10 days after drug removal. Combined therapy with GM-CSF and AZT merits consideration in the approach to HIV-associated illnesses.
Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance
Authors: Blaser J , Stone B B , Groner M C , Zinner S H
Published: June 2012

An in vitro pharmacokinetic model was used to study the comparative antibacterial activities of multiple-dose regimens of enoxacin and netilmicin. Strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus were exposed to changing drug concentrations, mimicking human two-compartment pharmacokinetics. Oral administration was simulated for the quinolone, and intravenous administration was simulated for the aminoglycoside. Similar ratios of peak concentration to MIC resulted in similar changes in bacterial concentrations over time with both compounds. Following the initial dose, a rapid bactericidal effect occurred, with a greater than 99% reduction of the bacterial counts within 4 h at peak concentrations more than three times the MIC. However, bacterial regrowth occurred within 24 h unless the peak concentration/MIC ratio exceeded 8:1 (P less than 0.01). For the regrowing bacteria, MICs were four- to eightfold higher, and little or no bactericidal effect occurred following the second and subsequent doses. These data demonstrate the equally potent bactericidal activity of orally administered enoxacin and intravenously administered netilmicin. Selection of resistant subpopulations was similar with each drug. The peak concentration/MIC ratio may be an important parameter in the clinical use of quinolone and aminoglycoside antibiotics.
Altered pharmacokinetic disposition of ciprofloxacin and vancomycin after single and multiple doses in rabbits
Authors: Barriere S L , Kaatz G W , Schaberg D R , Fekety R
Published: June 2012

The pharmacokinetic disposition of vancomycin and ciprofloxacin was assessed in rabbits before the efficacy of these compounds in experimental staphylococcal endocarditis was compared. Ciprofloxacin was given in single intravenous bolus doses of 25 and 35 mg/kg and also in a multiple-dose regimen of 35 mg/kg every 6 h. Vancomycin was given in a similar manner in single doses of 17.5 and 25 mg/kg and in a multiple-dose regimen of 17.5 mg/kg every 6 h. Serum was sampled frequently after injections and analyzed by microbiologic assay for drug concentration. The pharmacokinetic parameters of clearance and steady-state volume of distribution were calculated by compartment-independent methods. These studies revealed that clearance of ciprofloxacin was reduced significantly after multiple doses (7.42 +/- 0.85 [standard deviation] versus 6.09 +/- 0.71 liters/h, P less than 0.01). Although the half-life and volume of distribution increased after multiple dosing, the differences were not statistically significant. The disposition of vancomycin following single doses was significantly altered after the 25-mg/kg dose compared with the 17.5-mg/kg dose. Half-life, clearance, and volume of distribution changed from 1.27 +/- 0.2 to 1.60 +/- 0.21 h (P less than 0.05), 0.54 +/- 0.05 to 0.39 +/- 0.04 liters/h (P less than 0.01), and 0.37 +/- 0.04 to 0.31 +/- 0.03 liters/kg (P less than 0.05), respectively. The disposition of ciprofloxacin was not altered with increases in dose size, and the disposition of vancomycin was not altered after multiple doses. If such alterations in the pharmacokinetic disposition of antimicrobial agents are unanticipated, the higher and more prolonged than expected serum concentrations may have an effect on the outcome of experimental infections.
Therapy of genital herpes with topically applied interferon
Authors: Eron L J , Toy C , Salsitz B , Scheer R R , Wood D L , Nadler P I
Published: June 2012

Ninety-four patients with recurrences of genital herpes were randomized in a double-blind trial to receive topical therapy for 5 days with either alpha-2a interferon at 30 X 10(6) IU/ml or 10 X 10(6) IU/ml or placebo six times daily. No differences were noted between either interferon dose and placebo with respect to the duration of viral shedding, the time to crusting, or the time to healing of herpetic lesions. Aqueous solutions of alpha-2a interferon applied topically to unroofed vesicles do not appear to be clinically useful in the treatment of recurrences of genital herpes.
Pharmacokinetics of a single dose of rimantadine in young adults and children
Authors: Anderson E L , Van Voris L P , Bartram J , Hoffman H E , Belshe R B
Published: June 2012

Single doses of rimantadine were given to children and young adults to evaluate the safety and pharmacokinetics of this antiviral compound. The half-life of rimantadine in young adults was 27.7 +/- 4.9 h for tablets and 27.8 +/- 8.0 h for syrup preparations. A total of 10 children, 5 to 8 years old, received a syrup preparation of rimantadine. The half-life of rimantadine in children was 24.8 +/- 9.4 h. A single dose of rimantadine was well tolerated in young adults and children.
Effect of roxithromycin on acute toxoplasmosis in mice
Authors: Chang H R , Pechere J C
Published: June 2012

Roxithromycin effectively treated acute peritoneal murine toxoplasmosis. After five doses, starting 24 h after challenge, the 100 and 50% survival doses were 540 and 336 mg/kg per day, respectively. After 14 doses, starting 3 h after challenge, the 50% survival dose was 360 mg/kg per day. Toxoplasma gondii was recovered from the brain in 59 and 28% of surviving mice treated with 5 and 14 doses, respectively.
Leakage of beta-lactamase: a second mechanism for antibiotic potentiation by amdinocillin
Authors: Sanders C C , Sanders W E , Goering R V , McCloskey R V
Published: June 2012

Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.
Activity of LY146032 compared with that of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxacin, and vancomycin against staphylococci as determined by kill-kinetic studies
Authors: Stratton C W , Liu C , Weeks L S
Published: June 2012

Kill-kinetic methods were used to provide data on the bactericidal activity of subinhibitory (0.5x MIC), inhibitory (1x MIC), and suprainhibitory (4x MIC) concentrations of LY146032 against methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis. These bactericidal activities were compared with those of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxacin, and vancomycin. LY146032 was among the most active of the antistaphylococcal agents tested, as determined by broth microdilution methods, with all strains being inhibited at concentrations of less than or equal to 1 microgram/ml. Time kill-kinetic studies demonstrated that at 4x MIC, LY146032 was rapidly bactericidal against all strains of staphylococci. Our data show that LY146032 has significant bactericidal activity against staphylococci in comparison with other antistaphylococcal agents. Further evaluation of LY146032 against serious staphylococcal infections is warranted.
Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL 39123) in cell culture
Authors: Boyd M R , Bacon T H , Sutton D , Cole M
Published: June 2012

The activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against several herpesviruses was compared with that of acyclovir (ACV). In plaque reduction tests with clinical isolates of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus, mean 50% inhibitory concentrations (IC50S) (n = number tested) for BRL 39123 were 0.4 (n = 17), 1.5 (n = 13), and 3.1 (n = 5) micrograms/ml, respectively. Corresponding IC50S for ACV were 0.2, 0.6, and 3.8 micrograms/ml. Cytomegalovirus was relatively resistant to BRL 39123 (IC50, 51 micrograms/ml), but equid herpesvirus 1, bovid herpesvirus 2, and felid herpesvirus 1 were susceptible (IC50S, 1.6, 1.2, and 0.9 micrograms/ml, respectively). BRL 39123 was inactive against an HSV-1 strain which does not express thymidine kinase activity, but a DNA polymerase mutant selected for resistance to ACV was sensitive to BRL 39123 (IC50, 1.5 micrograms/ml). In contrast to the results from plaque reduction tests, BRL 39123 was more active than ACV against HSV-1 and of equal activity against HSV-2 in virus yield reduction assays in MRC-5 cells. After treatment of HSV-infected cultures for short periods, BRL 39123 was considerably more effective than ACV at reducing virus replication, and furthermore, after removal of extracellular BRL 39123, virus replication remained depressed for long periods, whereas such persistent activity was not observed with ACV. Neither compound significantly affected MRC-5 cell replication at 100 micrograms/ml, but at 300 micrograms/ml BRL 39123 was more inhibitory than ACV.
Class D tetracycline resistance determinants of R plasmids from the fish pathogens Aeromonas hydrophila, Edwardsiella tarda, and Pasteurella piscicida
Authors: Aoki T , Takahashi A
Published: June 2012

Tetracycline resistance determinants of R plasmids from the fish pathogens Aeromonas hydrophila, Edwardsiella tarda, and Pasteurella piscicida were classified as class D by their expression of resistance to tetracycline and minocycline and through their DNA structure.
Changing antibiotic susceptibility of Neisseria gonorrhoeae in Franceville, Gabon
Authors: Peeters M , Frost E H , Collet M , Ossari S , Yvert F , Ivanoff B
Published: June 2012

Susceptibilities to penicillin, cefotaxime, kanamycin, tetracycline, and spectinomycin were measured for 5 reference strains and 302 Neisseria gonorrhoeae isolates collected between 1980 and 1985. After an initial rise, the number of penicillinase-producing strains decreased. A gradual decrease in susceptibility to spectinomycin and the appearance of tetracycline-resistant strains were also documented.
Cefotetan-induced disulfiram-type reactions and hypoprothrombinemia
Authors: Kline S S , Mauro V F , Forney R B , Freimer E H , Somani P
Published: June 2012

A double-blind, placebo-controlled study in eight healthy male volunteers was conducted to study possible disulfiram-type reactions and hypoprothrombinemia associated with cefotetan administration. Three doses of cefotetan (2 g) or of placebo were administered at 12-h intervals. Ethanol (0.5 g/kg of total body weight) was ingested 1 h after the third dose. Blood ethanol, serum acetaldehyde, and prothrombin times were measured throughout the study. Heart rate, blood pressure, and clinical signs as well as symptoms suggestive of a disulfiram-type reaction were also noted. Five of eight volunteers that received cefotetan showed significant flushing. A significant increase in heart rate also was noted. No change in mean arterial pressure was observed during the cefotetan phase, and no one experienced nausea or vomiting. No statistical differences were observed between phases with respect to ethanol area under the time-concentration curve, elimination rate, or serum acetaldehyde concentrations. A slight but statistically significant increase in prothrombin time also was observed with cefotetan. This study suggests that patients receiving cefotetan might be at risk to develop disulfiram-type reactions and hypoprothrombinemia.
Antifungal activity of the allylamine derivative terbinafine in vitro
Authors: Petranyi G , Meingassner J G , Mieth H
Published: June 2012

Terbinafine, an allylamine derivative, represents the most effective of this new chemical class of antimycotic compounds. Under in vitro conditions, terbinafine proved to be highly active against dermatophytes (MIC range, 0.001 to 0.01 microgram/ml), aspergilli (MIC range, 0.05 to 1.56 micrograms/ml), and Sporothrix schenckii (MIC range, 0.1 to 0.4 microgram/ml) and also exerted good activity against yeasts (MIC range, 0.1 to greater than 100 micrograms/ml). The growth of Malassezia furfur was inhibited also (MIC range, 0.2 to 0.8 microgram/ml). Terbinafine displays a primary fungicidal action against dermatophytes, other filamentous fungi, and S. schenckii. The type of action against yeasts is species dependent and can be primarily fungicidal (Candida parapsilosis) or fungistatic (Candida albicans). The in vitro activity of terbinafine is pH dependent and rises with increasing pH value.
Visna virus as an in vitro model for human immunodeficiency virus and inhibition by ribavirin, phosphonoformate, and 2',3'-dideoxynucleosides
Authors: Frank K B , McKernan P A , Smith R A , Smee D F
Published: June 2012

Inhibition of visna virus replication in vitro by several compounds previously reported to inhibit replication of human immunodeficiency virus (HIV) was examined. Ribavirin concentrations as high as 1 mM reduced virus production by less than 50% relative to controls. The concentration of phosphonoformate reducing virus replication by 50% was 80 microM. 2',3'-Dideoxynucleosides were potent inhibitors of visna virus replication. The 50% inhibitory concentrations for dideoxyguanosine, dideoxyadenosine, and dideoxycytidine were 0.1, 0.2, and 0.3 microM, respectively. In contrast, weak inhibition was produced by 100 microM dideoxythymidine. These results are consistent with the reported susceptibility of HIV replication to inhibition by these compounds in vitro. The interaction of visna virus reverse transcriptase with several inhibitors was also examined. Reverse transcriptase was inhibited by phosphonoformate, ribavirin 5'-triphosphate, ddATP, ddCTP, ddGTP, and ddTTP. The last four compounds inhibited incorporation of homologous 2'-deoxynucleoside 5'-triphosphates into polynucleotides by a competitive mechanism. In view of the biological similarities between visna virus and HIV and the similar in vitro susceptibility of visna virus replication to known inhibitors of HIV, visna virus may provide a good model for studying the inhibition of HIV replication in vitro. Because visna virus is not pathogenic to humans, this model may facilitate the identification of compounds for further investigation into the treatment of HIV-induced disease.
Cefotaxime stability during in vitro microbiological testing
Authors: Marchbanks C R , Yost R L , White R L
Published: June 2012

Cefotaxime is a broad-spectrum cephalosporin which is metabolized or degraded to less active or inactive metabolites by serum esterases, elevated temperatures, or a pH outside of its stability range. Cefotaxime instability during in vitro microbiological susceptibility tests may lead to an underestimation of the antibacterial activity of the compound. Cefotaxime and desacetylcefotaxime solutions were studied under MIC and serum inhibitory titer testing conditions. Cefotaxime concentrations, as measured by high-performance liquid chromatography, decreased 20 to 30% over the incubation period in various systems tested; the greatest decline occurred in systems containing serum in the media. Changes in the results of microbiological susceptibility tests interpreted after 6 and 18 h of incubation were consistent with changes observed in the high-performance liquid chromatography analysis. This study demonstrates cefotaxime instability under conditions of in vitro microbiological testing.
Mechanism of Pseudomonas aeruginosa persistence during treatment with broad-spectrum cephalosporins of lung infections in patients with cystic fibrosis
Authors: Schryvers A B , Ogunariwo J , Chamberland S , Godfrey A J , Rabin H R , Bryan L E
Published: June 2012

Beta-lactam resistance in Pseudomonas aeruginosa detected only during ceftazidime therapy of cystic fibrosis patients was studied. Evaluation of resistant and susceptible isolates from one patient and resistant laboratory derivatives indicated that elevated beta-lactamase levels were the primary determinant of resistance. Susceptible isolates outgrew resistant isolates on antibiotic-free medium.
In vitro activities of LY163892, cefaclor, and cefuroxime
Authors: Knapp C C , Washington J A
Published: June 2012

The in vitro activity of LY163892, a synthetic oral cephalosporin, was compared with those of cefaclor and cefuroxime against 1,193 clinical isolates. MIC ranges and MICs for 50 and 90% of isolates of the three cephalosporins were comparable. The activities of LY163892 and cefaclor were, however, highly inoculum dependent against beta-lactamase-positive Haemophilus influenzae and Staphylococcus aureus; that of cefuroxime was not. LY163892 and cefuroxime appeared stable in microdilution trays stored at 5 and -20 degrees C for 5 weeks, in contrast to cefaclor which remained stable for more than a week only at -5 degrees C.
Susceptibilities of Hong Kong isolates of multiply resistant Shigella spp. to 25 antimicrobial agents, including ampicillin plus sulbactam and new 4-quinolones
Authors: Ling J , Kam K M , Lam A W , French G L
Published: June 2012

Seventy-two percent of 129 shigella isolates from two Hong Kong hospitals were Shigella flexneri. Twenty-six percent were S. sonnei, and there was only one isolate each of S. dysenteriae and S. boydii. Ninety-six percent of the isolates were resistant to two or more antibiotics, and up to 11 resistances were seen in a single isolate. Fifty-seven percent or more of these isolates were resistant to ampicillin, streptomycin, tetracycline, chloramphenicol, and sulfamethoxazole; and up to twenty-three percent were resistant to kanamycin, trimethoprim, trimethoprim-sulfamethoxazole, and gentamicin. All the isolates were susceptible to amikacin, nalidixic acid, and the newer 4-quinolone agents; and all but one were susceptible to the cephalosporins tested. Only three isolates remained resistant to ampicillin in the presence of sulbactam. Ampicillin plus sulbactam or the newer 4-quinolone agents may be alternatives for the treatment of severe infections caused by multiply resistant shigellas.
In vitro selection of bacteria resistant to LY146032, a new cyclic lipopeptide
Authors: Liebowitz L D , Saunders J , Chalkley L J , Koornhof H J
Published: June 2012

Isolates of Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, and coagulase-positive and -negative staphylococci were investigated for their abilities, in vitro, to develop resistance to LY146032. Exposure of the organisms to incremental concentrations of LY146032 resulted in MICs 8- to 32-fold higher than those for the original isolates. After three passages on antibiotic-free medium, the high MICs were maintained for the coagulase-negative staphylococci and pneumococci, with a twofold decrease observed for the enterococci and a fourfold decrease observed for Staphylococcus aureus. The frequency of spontaneous emergence of resistance was highest with S. pneumoniae (1.2 X 10(-6) at 16 times the original MIC) and lowest with S. aureus (7.0 X 10(-10) at 8 times the original MIC). For bacteria For bacteria surviving time-kill studies MICs were also higher than were those for the original isolates. Exposure to LY146032 in vitro selected for strains with decreased susceptibilities to the antimicrobial agent. However, the emergence of resistance in vivo is unpredictable and can be evaluated only after prolonged clinical use of the drug.
Oral ciprofloxacin treatment for Salmonella typhimurium infection of normal and immunocompromised mice
Authors: Brunner H , Zeiler H J
Published: June 2012

Oral treatment of Salmonella typhimurium infection with ciprofloxacin was compared with conventional chemotherapy with ampicillin or chloramphenicol in normal (CFW1) and immunocompromised (C57BL/6) mice. Administration of the antibiotics for 12 days reduced the number of bacteria in livers and the mortality of C57BL/6 mice significantly. Ciprofloxacin was considerably more effective than ampicillin in prolongation of the mean survival time of these mice. Similar to conventional chemotherapeutic agents, ciprofloxacin did not prevent fatal disease in most C57BL/6 mice when the treatment lasted 12 days only. On the other hand, ciprofloxacin cured lethal S. typhimurium illness in immunocompromised mice after long-term oral chemotherapy for 26 days at a dosage of 100 mg/kg twice a day. This was not achieved by either ampicillin or chloramphenicol. In normal mice, 12 days of therapy with ciprofloxacin was sufficient for a significant decrease in both the number of viable bacteria in livers and the mortality of lethally infected mice. The results provide a basis for an alternative antibiotic treatment by the oral route in immunocompromised hosts with systemic infections.
Comparison of cefazolin, cefamandole, vancomycin, and LY146032 for prophylaxis of experimental Staphylococcus epidermidis endocarditis
Authors: Wheat L J , Smith J W , Reynolds J , Bemis A T , Treger T , Norton J A
Published: June 2012

We evaluated antibiotic prophylaxis in the rabbit model of experimental endocarditis with three strains of Staphylococcus epidermidis of differing susceptibility patterns. For the first strain, which was highly susceptible to methicillin and cephalosporins, vegetations grew S. epidermidis for all 15 untreated rabbits compared with 1 of 20 rabbits receiving cefazolin, 3 of 20 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the second strain, which was methicillin resistant but cephalosporin susceptible, vegetations were positive for 14 of 15 untreated controls, 4 of 20 receiving cefazolin, 5 of 22 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the third strain, which was methicillin resistant and only intermediately susceptible to cephalosporin antibiotics, vegetation cultures were positive for 15 of 17 untreated controls, 14 of 21 receiving cefazolin, 11 of 20 receiving cefamandole, 5 of 20 receiving vancomycin, and 0 of 22 receiving LY146032. In conclusion, these studies in the endocarditis model indicate that cefazolin and cefamandole have some protective value against certain strains of S. epidermidis. Vancomycin and LY146032, however, were more active than cephalosporins for all three strains included in this analysis. These findings support the need for trials of vancomycin and LY146032 prophylaxis in patients undergoing placement of prosthetic heart valves.
Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens
Authors: Panneton A C , Bergeron M G , LeBel M
Published: June 2012

The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.
Bactericidal activity of oxacillin against beta-lactamase-hyperproducing Staphylococcus aureus
Authors: Woods G L , Yam P
Published: June 2012

The bactericidal activity of oxacillin against beta-lactamase-hyperproducing strains of Staphylococcus aureus for which the MIC by MicroScan was 1 or 2 micrograms/ml after incubation for 24 h was evaluated by MBC studies and kill kinetics methods. MBC and kill kinetics tests were both performed using Mueller-Hinton broth (MHB), with and without 2% NaCl supplementation, and incubation at 30 and 35 degrees C. When MBC testing was performed with salt-supplemented MHB, the oxacillin MBC/MIC ratio was greater than 8 for 17 and 16 of 17 S. aureus isolates at 30 and 35 degrees C, respectively. With unsupplemented MHB, the MBC/MIC ratio was greater than 8 for nine and six strains at 30 and 35 degrees C, respectively. Five representative strains were selected for kill kinetics studies under the four different test conditions. Oxacillin appeared more bactericidal by the kill kinetics method than by MBC testing. Moreover, salt supplementation did not affect the results of kill kinetics studies as dramatically as it did the MBC results. Thus, bactericidal testing results are markedly influenced by the technique employed, and further in vivo studies are necessary to fully evaluate the efficiency of oxacillin against beta-lactamase-hyperproducing strains of S. aureus.
Efficacies of four antifungal agents in experimental murine sporotrichosis
Authors: Kan V L , Bennett J E
Published: June 2012

Four antifungal agents, amphotericin B, SDZ 89-485, itraconazole, and terbinafine, were tested for efficacy in a murine model of systemic sporotrichosis. Survival in the groups treated with amphotericin B, SDZ 89-485, and itraconazole was significantly better than that of control infected mice. However, these agents did not wholly protect the infected mice, as tail and paw lesions, whole-body radiographs, and positive cultures from survivors showed evidence of dissemination. Terbinafine-treated mice had the same or poorer survival as control infected mice, despite documented drug absorption.
Protective effect of amdinocillin against emergence of resistance to ceftazidime in Enterobacter cloacae
Authors: Yourassowsky E , van der Linden M P , Lismont M J , Crokaert F , Glupczynski Y
Published: June 2012

Enterobacter cloacae infections have been shown clinically to respond less reliably to monotherapy with broad-spectrum cephalosporins than was initially expected. Selection of populations producing high levels of beta-lactamase has been shown to be the most frequent reason for treatment failure, and the use of these agents with another active antibiotic is recommended. In this study, E. cloacae strains from clinical specimens susceptible to ceftazidime and amdinocillin by broth dilution and disk tests were examined. In the presence of ceftazidime at 10 micrograms/ml, in vitro selection of resistant organisms was demonstrated for 3 of 11 strains. Selection was prevented when amdinocillin was added in combination. A more rapid killing was also demonstrated with this combination. At inocula of 10(8) CFU/ml, ceftazidime-resistant populations were isolated from 6 of 11 strains in vitro, and the emergence of this resistance was prevented by amdinocillin. The enhanced killing effect noted for amdinocillin with ceftazidime may have resulted in part from complementary activity of the antibiotics on penicillin-binding proteins. The ceftazidime-amdinocillin combination offers an interesting prospect for the therapy of infections caused by E. cloacae strains which are initially susceptible to both antibiotics.
Pharmacodynamic evaluation of ofloxacin and trimethoprim-sulfamethoxazole in vaginal fluid of women treated for acute cystitis
Authors: Tartaglione T A , Johnson C R , Brust P , Opheim K , Hooton T M , Stamm W E
Published: June 2012

Vaginal colonization with Escherichia coli is an integral step in the development of acute cystitis, and persistent vaginal coliform colonization may also be a predisposing step to recurrent urinary tract infections. For this reason, we evaluated antibiotic concentrations in the vaginal fluid, serum, and urine and the vaginal colonization by E. coli of 56 women receiving either ofloxacin (200 mg orally twice a day) or trimethoprim-sulfamethoxazole (TMP-SMX) (160/800 mg orally twice a day) for the treatment of acute cystitis. Ofloxacin and trimethoprim both penetrated into vaginal fluid to a considerably greater extent than sulfamethoxazole. Among 33 patients given ofloxacin, the concentration of the drug in vaginal fluid during one dosage interval ranged from 1.6 to 21.6 micrograms/ml. In 21 women given TMP-SMX the range of drug concentrations in vaginal fluid was 2.6 to 32.5 micrograms/ml for TMP and 1.0 to 6.2 micrograms/ml for SMX. Treatment with both ofloxacin and TMP-SMX remarkably reduced vaginal colonization by E. coli during and up to 30 days after therapy. For the ofloxacin-treated women, eradication of vaginal E. coli was associated with a high ratio of drug concentration in vaginal fluid to that in serum. We conclude that ofloxacin and TMP both achieve high concentrations in vaginal fluid and are equally successful in eradicating E. coli from the vagina.
Comparative study of a novel plasmid-mediated beta-lactamase, CAZ-2, and the CTX-1 and CAZ-1 enzymes conferring resistance to broad-spectrum cephalosporins
Authors: Chanal C M , Sirot D L , Labia R , Petit A , Morand A , Sirot J L , Cluzel R A
Published: June 2012

Infections caused by strains of Klebsiella pneumoniae resistant to broad-spectrum cephalosporins have been observed recently in hospitals in Clermont-Ferrand, France. beta-Lactam resistance resulted primarily from the plasmid-mediated, expanded-spectrum CTX-1 beta-lactamase. Furthermore, since 1987 some K. pneumoniae isolates more resistant to ceftazidime than to other cephalosporins have been observed. This new resistance phenotype was the result of the production of ceftazidimase CAZ-1 and, more recently, CAZ-2. As in CTX-1-producing strains, resistance to beta-lactams resulting from CAZ-2 was associated with resistance to aminoglycosides except gentamicin, sulfonamide, and tetracycline and was transferable to Escherichia coli by conjugation. Agarose gel electrophoresis of plasmid DNA from wild-type strains and transconjugants indicated that CAZ-2 production was mediated by a plasmid of 85 kilobases highly related to plasmid pCFF04 coding for CTX-1 beta-lactamase. The isoelectric point, close to 6.0, of this novel enzyme differed from those of CTX-1 and CAZ-1. Like CAZ-1, the CAZ-2 enzyme efficiently hydrolyzed ceftazidime and aztreonam, but as with CTX-1, cefotaxime gave the maximal reaction rate. For each expanded-spectrum beta-lactamase, the activity of broad-spectrum cephalosporins was restored by clavulanic acid or sulbactam.
RSF1010 and a conjugative plasmid contain sulII, one of two known genes for plasmid-borne sulfonamide resistance dihydropteroate synthase
Authors: Rådström P , Swedberg G
Published: June 2012

The nucleotide sequence of the type II sulfonamide resistance dihydropteroate synthase (sulII) gene was determined. The molecular weight determined by maxicells was 30,000, and the predicted molecular weight for the polypeptide was 28,469. Comparison with the sulI gene encoded by Tn21 showed 57% DNA similarity. The sulII-encoded polypeptide has 138 of 271 amino acids in common with the polypeptide encoded by sulI. The sulII gene is located on various IncQ (broad-host-range) plasmids and other small nonconjugative resistance plasmids. Detailed restriction maps were constructed to compare the different plasmids in which sulII is found. The large conjugative plasmid pGS05 and the IncQ plasmid RSF1010 contained identical nucleotide sequences for the sulII gene. This type of sulfonamide resistance is very frequently found among gram-negative bacteria because of its efficient spread to various plasmids.
Pharmacokinetics of LY163892 in infants and children
Authors: Nelson J D , Shelton S , Kusmiesz H
Published: June 2012

Two dosages (7.5 and 15 mg/kg of body weight) of LY163892 were given to infants and children, and five plasma specimens were collected for antibiotic assay during the ensuing 4 h. Peak concentrations of 12.6 and 18.7 micrograms/ml occurred at 45 min. The mean half-lives were 0.85 and 0.78 h, and the mean areas under the curve were 24.4 and 38.0 micrograms.h/ml.
Sulfated polysaccharides are potent and selective inhibitors of various enveloped viruses, including herpes simplex virus, cytomegalovirus, vesicular stomatitis virus, and human immunodeficiency virus
Authors: Baba M , Snoeck R , Pauwels R , de Clercq E
Published: June 2012

Several sulfated polysaccharides (dextran sulfate, pentosan polysulfate, fucoidan, and carrageenans) proved to be potent inhibitors for herpes simplex virus, human cytomegalovirus, vesicular stomatitis virus, Sindbis virus, and human immunodeficiency virus. They were moderately inhibitory to vaccinia virus but not inhibitory to adenovirus, coxsackievirus, poliovirus, parainfluenza virus, and reovirus. These results indicate that, with the exception of parainfluenza virus, enveloped viruses are specifically susceptible to the inhibitory activity of sulfated polysaccharides.
In vitro and in vivo activities of macrolides against Mycobacterium leprae
Authors: Franzblau S G , Hastings R C
Published: June 2012

We previously demonstrated the potent in vitro activity of erythromycin against Mycobacterium leprae as determined by its effect on ATP pools and rates of palmitate oxidation and phenolic glycolipid I synthesis. In the present study, the relative in vitro activities of a number of new macrolides with superior pharmacokinetic properties were assessed. In addition, for the most active compounds, concentrations in serum were determined by bioassay during continuous administration in the feed of mice, and in vivo activity against M. leprae was assessed by the kinetic mouse footpad technique. Both clarithromycin and roxithromycin were more potent than erythromycin in vitro, with the former showing the highest activity in accelerating rates of ATP decay and reducing rates of palmitate oxidation. In mice, concentrations of clarithromycin in serum were higher than those of roxithromycin and erythromycin, with the latter undetectable even when administered at 0.1% (wt/wt) in the diet. When administered at 0.01% (wt/wt) in the diet, erythromycin and roxithromycin were unable to inhibit growth of M. leprae in mouse footpads whereas clarithromycin demonstrated bactericidal-type activity. On the basis of these data and other properties of macrolides, a clinical trial of clarithromycin in leprosy is warranted.
Antimicrobial susceptibility patterns of Nocardia asteroides
Authors: Wallace R J , Steele L C , Sumter G , Smith J M
Published: June 2012

Testing of the susceptibility to 12 antimicrobial agents, including beta-lactams, aminoglycosides, ciprofloxacin, and erythromycin, was performed by broth microdilution on 78 consecutive clinical isolates of Nocardia asteroides. Surprisingly, a limited number of patterns of susceptibility were identified that included all drug classes, with 95% of isolates exhibiting one of five patterns. One group (17%) exhibited resistance to the broad-spectrum cephalosporins, one group (18%) was susceptible to both ampicillin and erythromycin, one group (17%) was susceptible to ampicillin and carbenicillin but intermediate in susceptibility to imipenem, and the most common group (35%) was resistant to ampicillin but susceptible to the broad-spectrum cephalosporins and imipenem. The most active parenteral agents were amikacin (95%), imipenem (88%), ceftriaxone (82%), and cefotaxime (82%), while the most active oral agents were the sulfonamides (100%), minocycline (100%), and ampicillin (40%). Additional studies are needed to determine whether differences in beta-lactamases relate to varying beta-lactam resistance and whether taxonomic differences that correlate with the different susceptibility groups can be identified.
Multiple-dose pharmacokinetics of rimantadine in elderly adults
Authors: Tominack R L , Wills R J , Gustavson L E , Hayden F G
Published: June 2012

To assess the possible effect of aging on rimantadine hydrochloride pharmacokinetics, single- and multiple-dose kinetics were determined in 18 healthy adults with ages between 51 and 79 years. Subjects ingested single 100-mg oral doses of rimantadine after an overnight fast, followed after 5 days by a dosage of 100 mg twice a day for 9.5 days. No differences were observed among the age-stratified groups in measured or derived pharmacokinetic parameters. Peak concentrations in plasma (mean +/- standard deviation) following the single- and multiple-dose regimens, respectively, were 89 +/- 25 and 417 +/- 129 ng/ml for subjects who were 50 to 60 years of age (group 1), 92 +/- 24 and 401 +/- 84 ng/ml for those 61 to 70 years of age (group 2), and 100 +/- 14 and 538 +/- 51 for those 71 to 79 years of age (group 3). The elimination half-life in plasma following multiple doses averaged 33.5 h for group 1, 32.5 h for group 2, and 38.6 h for group 3. Steady-state concentrations in nasal mucus developed by day 5 of dosing (1.5-fold higher than concentrations in plasma), and rimantadine remained detectable in secretions for 5 days after the last dose in 65% of subjects. Stepwise regression analysis suggested that changes in maximum concentration in plasma and area under the concentration-time curve at steady state may be related to creatinine clearance. The results indicate that no important differences in rimantadine multiple-dose pharmacokinetics exist among healthy elderly adults with ages between 51 and 79 years.
Analogs of 5-methylthioribose, a novel class of antiprotozoal agents
Authors: Riscoe M K , Ferro A J , Fitchen J H
Published: June 2012

Since drug resistance and toxicity limit the use of available antiprotozoal agents, it is important that new drugs be developed as soon as possible. In this study, the method by which several protozoa degrade 5'-methylthioadenosine (MTA) was shown to differ from MTA catabolism in human cells. To exploit this metabolic difference, two analogs of methylthioribose (MTR), an MTA catabolite, were synthesized and found to be cytocidal to Plasmodium falciparum, Giardia lamblia, and Ochromonas malhamensis in vitro. In contrast, these analogs had no effect on cultured mammalian cells. Analogs of MTR represent a potential new class of antiprotozoal drugs.
Simple spectrophotometric assay for measuring protein binding of penem antibiotics to human serum
Authors: Gootz T D , Subashi T A , Lindner D L
Published: June 2012

The binding of antibiotics to plasma (serum) proteins through hydrogen bonding can significantly influence the biological characteristics of these drugs. A rapid spectrophotometric assay has been developed that measures the level of free (unbound) penem antibiotic in serum ultrafiltrates. Whole human serum was adjusted to a standard concentration of antibiotic and then filtered by centrifugation through a Centrifree (Amicon Corp., Lexington, Mass.) filter that retained greater than 99.9% of serum protein. The degree of penem protein binding was determined spectrophotometrically by measuring the level of unbound drug in the ultrafiltrate at 322 nm. At this wavelength, no interfering absorption from residual protein was detected in the ultrafiltrate, and penem absorption was linear over a wide concentration range. The method gave protein-binding values comparable to those obtained by a high-pressure liquid chromatography assay but was more rapid, since it did not require solvent extraction and high-pressure liquid chromatography calibration procedures. The spectrophotometric assay has been used to assay over 100 penems to determine the structure-activity relationships that are involved with the high serum protein binding of these agents. As with penicillins and some cephalosporins, the nonpolar nature of the penem side chain at the C-2 position strongly influenced the degree of penem binding to serum proteins.