bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and tissue penetration of single-dose cefotetan used for antimicrobial prophylaxis in patients undergoing colorectal surgery
Authors: Martin C , Portet C , Lambert D , Bruguerolle B , Sastre B , De Micco P , Gouin F
Published: June 2012

The pharmacokinetics and tissue penetration of cefotetan were studied after a single injection of 2 g given intravenously for antimicrobial prophylaxis to 16 consecutive patients undergoing colorectal surgery. Concentrations in tissue greater than or equal to the MIC for 90% of the main pathogens tested were considered adequate. The elimination half-life at beta phase was 4.6 +/- 1.4 h, the total body clearance was 0.75 +/- 0.19 ml/kg/min, and the volume of distribution was 260 +/- 71 ml/kg. At the time of incision (33 +/- 16 min after the injection), cefotetan concentrations were 14.2 +/- 7 micrograms/g in abdominal-wall fat, 16.4 +/- 1 micrograms/g in epiploic fat, and 163 +/- 62 mg/liter in serum. At the time of surgical anastomosis (151 +/- 54 min), cefotetan concentrations were 33.3 +/- 6 micrograms/g in the colonic wall and 73 +/- 34 mg/liter in serum. Upon closure of the abdomen (216 +/- 76 min), cefotetan concentrations were 6.3 +/- 3 micrograms/g in abdominal-wall fat, 6.1 +/- 4 micrograms/g in epiploic fat, and 64 +/- 38 mg/liter in serum. Cefotetan tissue penetration was 10% into abdominal and epiploic fat and 46% into the colonic wall. Levels in tissue were compared with the MIC for 90% of the most frequently encountered pathogenic germs (Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli). Adequate concentrations in tissue were obtained up to anastomosis but not upon closure. The authors therefore recommend the injection of an additional dose of 1 g before closure in order to ensure optimal efficacy throughout the surgical procedure.
Isolation of a beta-lactamase-producing, aminoglycoside-resistant strain of Enterococcus faecium
Authors: Coudron P E , Markowitz S M , Wong E S
Published: June 2012

Beta-Lactamase-producing, aminoglycoside-resistant strains of Enterococcus faecalis have been isolated from different geographic areas and are endemic at our institution. We report the isolation of a beta-lactamase-producing, aminoglycoside-resistant strain of E. faecium. The beta-lactamase was plasmid mediated and transferable with high frequency into a plasmid-free E. faecalis recipient strain. MICs suggested that the E. faecium strain also contained intrinsic (chromosomal) resistance to penicillins.
Comparative activity of ciprofloxacin, ofloxacin, sparfloxacin, temafloxacin, CI-960, CI-990, and WIN 57273 against anaerobic bacteria
Authors: Goldstein E J , Citron D M
Published: June 2012

The in vitro activities of seven fluoroquinolones against 290 anaerobes were determined by agar dilution. CI-960 and WIN 57273 inhibited greater than 95% of the strains at less than or equal to 2 micrograms/ml. CI-990 required less than or equal to 16 micrograms/ml. Clustering around 2 to 4 micrograms/ml was noted for Bacteroides fragilis group organisms with CI-990, sparfloxacin, and temafloxacin. Temafloxacin and sparfloxacin inhibited most strains at less than or equal to 2 micrograms/ml. B. fragilis was more susceptible to all quinolones than were the other B. fragilis group strains.
Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro
Authors: Fuhr U , Anders E M , Mahr G , Sörgel F , Staib A H
Published: June 2012

Inhibition of cytochrome P450IA2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P450IA2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 microM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 microM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.0%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.0%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose- and bioavailability-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy.
Therapy of experimental murine brucellosis with streptomycin, co-trimoxazole, ciprofloxacin, ofloxacin, pefloxacin, doxycycline, and rifampin
Authors: Shasha B , Lang R , Rubinstein E
Published: June 2012

Mice infected with Brucella melitensis were treated with streptomycin, co-trimoxazole, ciprofloxacin, doxycycline, and rifampin intraperitoneally and with ciprofloxacin, ofloxacin, pefloxacin, doxycycline, and rifampin orally for 14 to 21 days. Doxycycline- and rifampin-treated animals (either route) demonstrated a cure rate significantly better than that of controls. Longer therapy periods were associated with a significantly better outcome. Therapy failure was observed in all mice treated with ciprofloxacin, ofloxacin, and pefloxacin administered orally as well as in mice treated intraperitoneally with ciprofloxacin. Our findings demonstrate that treatment of experimental brucellosis in mice with doxycycline and rifampin yields therapeutic results that are superior to those yielded by treatment with quinolones.
In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1
Authors: Arruda E , Crump C E , Marlin S D , Merluzzi V J , Hayden F G
Published: June 2012

We studied the in vitro antirhinovirus activity of a soluble form of intercellular adhesion molecule-1 (sICAM-1). sICAM-1 inhibited the cytopathic effect of 10 representative human rhinovirus (HRV) serotypes of the major receptor group with, 50% effective concentrations (EC50s) of 0.1 to 7.9 micrograms/ml. Cell type-dependent variation in the inhibitory activity of sICAM-1 was observed for two major receptor group serotypes in HeLa cells (EC50, greater than 32 micrograms/ml), and no inhibitory effect was observed for two serotypes which use different cell receptors. Yield reduction assays showed that sICAM-1 inhibited the replication of HRV serotype 39 (HRV-39) in human adenoid explants in a concentration-dependent manner. No direct inactivation of infectivity of HRV-39 (EC50, 0.5 microgram/ml) was observed after incubation with sICAM-1 (32 micrograms/ml) for up to 24 h. Single-cycle-of-replication experiments with the addition of sICAM-1 at 10 micrograms/ml at different times showed that the inhibitory effect occurs only when sICAM-1 is added within 30 min after infection. In experiments in which absorption was carried out at 4 degrees C and then a single cycle of replication incubation was carried out at 33 degrees C, it was found that sICAM-1 at 10 micrograms/ml was inhibitory only when it was present during the absorption period. Our data show that sICAM-1 is inhibitory for representative major receptor group serotypes of HRV in two cell lines and human respiratory epithelium, that the interaction of sICAM-1 with HRV is readily reversible by dilution, and that the inhibitory effect of sICAM-1 on virus replication is present early in the infection cycle.
Efficacy of erythromycin lactobionate for treating Pseudomonas aeruginosa bacteremia in mice
Authors: Hirakata Y , Kaku M , Tomono K , Tateda K , Furuya N , Matsumoto T , Araki R , Yamaguchi K
Published: June 2012

We induced endogenous Pseudomonas aeruginosa bacteremia by administering cyclophosphamide and ampicillin to specific pathogen-free mice fed P. aeruginosa. Using this model, we evaluated the efficacy of erythromycin lactobionate (EML) in treating P. aeruginosa bacteremia. Treatment with EML at 50 and 100 mg/kg of body weight per day twice a day for 14 days significantly increased the survival rate. The most effective dose was 100 mg/kg/day, with a survival rate of 80% compared with a 20% survival rate in the control. However, the administration of EML at 500 mg/kg/day rather decreased the survival rate. In a model of intravenous infection, treatment with EML at 100 mg/kg/day twice a day for 7 days before the bacterial challenge also enhanced the survival rate. EML levels in serum, liver, and stool were apparently lower than the MIC (512 micrograms/ml). These observations suggest that EML is effective against P. aeruginosa bacteremia despite a lack of specific activity for this pathogen. Although the protective mechanism is still unclear, it is possible that a subinhibitory level of EML may affect the virulence of P. aeruginosa and enhance the host defense system.
Effect of antacid on absorption of the quinolone lomefloxacin
Authors: Shimada J , Shiba K , Oguma T , Miwa H , Yoshimura Y , Nishikawa T , Okabayashi Y , Kitagawa T , Yamamoto S
Published: June 2012

The effect of antacid on the absorption of lomefloxacin (LFLX) in humans was studied. When LFLX was orally administered concomitantly with aluminum- and magnesium-containing antacids under fasting conditions, its level in plasma decreased by one-half and its area under the concentration-time curve was reduced by 40% compared with the levels observed after treatment with LFLX alone. The urinary recovery value also decreased by 40%. No such effects were noted after coadministration of LFLX and a nonmetallic antacid. This study confirmed the existence of chelate complexes of LFLX with Al3+ and Mg2+ and examined the chelating strength. The stability constants of LFLX with Al3+ and Mg2+ were measured and compared with those of ofloxacin and norfloxacin; little difference was observed among them. LFLX was found to bind more strongly with Al3+ than with Mg2+. Further, the existence of chelate formation was proven by 13C-nuclear magnetic resonance spectroscopy. The decrease in the LFLX level in plasma in humans could be explained by a reduced absorption of the Al(3+)- and Mg(2+)-LFLX chelate complexes.
Combined effect of fluconazole and recombinant human interleukin-1 on systemic candidiasis in neutropenic mice
Authors: Kullberg B J , van 't Wout J W , Poell R J , van Furth R
Published: June 2012

The aim of the present study was to investigate the efficacy of treatment with a combination of fluconazole and human recombinant interleukin-1 alpha (IL-1 alpha) in normal or neutropenic mice with systemic Candida albicans infection. Six hours after intravenous injection of 5 x 10(4) CFU of C. albicans organisms, oral treatment twice daily with 2.5 or 10 mg of fluconazole per kg of body weight, a single intraperitoneal injection of 80 ng of IL-1, or a combination of the two was started. IL-1 had no influence on the antifungal activity of fluconazole in vitro or on the pharmacokinetics of fluconazole. For both normal and neutropenic mice, the number of C. albicans organisms cultured from the kidneys after 36 h of treatment was significantly lower in mice treated with IL-1 alone than in untreated animals. Treatment with fluconazole alone also significantly lowered the number of C. albicans organisms in the kidneys compared with that in untreated controls. In normal mice, the combination of fluconazole and IL-1 was not better than fluconazole alone. In neutropenic mice, combined treatment with IL-1 and 10 mg of fluconazole per kg led to significantly lower numbers of C. albicans organisms in the kidneys and the spleen than treatment with either agent alone. Although the precise mechanism by which IL-1 enhances resistance to infection is not clear, the additive effect of IL-1 and fluconazole in vivo indicates that combined therapy with immunomodulators and antifungal drugs is beneficial in immunocompromised mice with systemic fungal infections.
Mycolic acid synthesis: a target for ethionamide in mycobacteria?
Authors: Quémard A , Lanéelle G , Lacave C
Published: June 2012

Striking structural analogies exist between the two specific antimycobacterial drugs ethionamide (ETH) and isoniazid (INH), and they share several inhibitory properties in susceptible species of mycobacteria. The effect of ETH on mycolic acid synthesis was studied in whole cells and in cell extracts of various species, since this synthesis is one direct target for INH, as we recently demonstrated in cell extracts of Mycobacterium aurum. It was shown in the present study that there is not a direct relationship between ETH susceptibility and mycolic acid inhibition. This observation could explain the lack of cross-resistance between the two drugs. The presence of ETH disturbed mycolic acid synthesis in both resistant and susceptible mycobacteria. Synthesis of oxygenated species of mycolic acid was inhibited, while that of diunsaturated acids was either slightly altered or even increased. In contrast, INH inhibited the synthesis of all kinds of mycolic acids in the same way in all susceptible strains and had no effect on mycolic acid synthesis in resistant strains. In the presence of ETH, the unsaturated mycolic acid molecules presented a methyl end different from the usual one. These data strongly suggest that the normal unsaturated mycolic acid species are not the precursors of the oxygenated types. Moreover, they show that ETH probably acts early in the pathway leading to oxygenated mycolic acid.
In vitro and in vivo activities of SCE-2787, a new parenteral cephalosporin with a broad antibacterial spectrum
Authors: Iwahi T , Okonogi K , Yamazaki T , Shiki S , Kondo M , Miyake A , Imada A
Published: June 2012

SCE-2787, a new cephalosporin having a condensed azolium moiety in the 3 position and an aminothiadiazolyl group in the 7 beta side chain, was evaluated for its in vitro and in vivo activities in comparison with those of ceftazidime, flomoxef, cefpirome, and E1040. Against methicillin-susceptible strains of Staphylococcus aureus and Staphylococcus epidermidis, SCE-2787 was more active than ceftazidime and E1040 and was as active as flomoxef and cefpirome, with MICs for 90% of strains tested (MIC90s) being 1.56 micrograms/ml or less. SCE-2787 was also active against Pseudomonas aeruginosa, for which the MIC90 was 6.25 micrograms/ml, which was lower than that of cefpirome and comparable to that of ceftazidime. SCE-2787 was marginally active against methicillin-resistant strains of staphylococci and Enterococcus faecalis, although its MIC90s were the lowest among those of the antibiotics tested. The activities of SCE-2787 against Streptococcus species, most members of the family Enterobacteriaceae, and Haemophilus influenzae exceeded those of ceftazidime and flomoxef and were comparable to those of cefpirome. Furthermore, MIC90s of SCE-2787 were significantly lower than those of ceftazidime for ceftazidime-resistant isolates of Citrobacter freundii and Enterobacter cloacae. SCE-2787 was resistant to hydrolysis by various types of beta-lactamases, including the Bush group 1 beta-lactamases, and had low affinities for these enzymes, with Km or Ki values of greater than 100 microM. The in vitro activity of SCE-2787 was reflected in its efficacy in mouse protection tests. Thus, SCE-2787 appears to be a promising cephalosporin that should be further evaluated in clinical trials.
Vancomycin resistance in Enterococcus gallinarum
Authors: Vincent S , Minkler P , Bincziewski B , Etter L , Shlaes D M
Published: June 2012

The vancomycin resistance expressed by several strains of Enterococcus gallinarum was studied. Resistance was expressed constitutively, as demonstrated by analysis of growth and inhibition of peptidoglycan synthesis. E. gallinarum strains were moderately resistant to vancomycin (MIC, 16 micrograms/ml) but were as susceptible as vancomycin-susceptible enterococci to the glycopeptides, teicoplanin, A35512B, A47934, A4103A, and A41030E and the glycopeptide actaplanins A1, B2, and C1. Vancomycin resistance in E. gallinarum was inhibited by beta-lactam antibiotics at concentrations that saturated penicillin-binding protein 6 (PBP 6), as demonstrated by binding competition experiments. Spontaneous mutants (frequency, 10(-8)) were two- to fourfold more resistant to beta-lactam inhibition of vancomycin resistance than the parent strain. PBP binding competition experiments suggested that PBP 6 in the mutants bound less cefotaxime, while binding of penicillin and cefoxitin was unaffected. Both a bioassay method and high-performance liquid chromatography showed that E. gallinarum membranes have enzymatic activity which modifies a model pentapeptide yielding a product that is thought to be a tetrapeptide. This activity could be a D,D-carboxypeptidase. In both the parent E. gallinarum strain and its derivatives that were resistant to the synergistic drug combination, the activity was inhibited by beta-lactams at concentrations which correlated with those that inhibit vancomycin resistance and those that saturate PBP 6. These results suggest the possibility that PBP 6 may be involved in the vancomycin resistance of E. gallinarum and that the putative D,D-carboxypeptidase activity seen in E. gallinarum membranes may be attributable to PBP 6.
Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability
Authors: Bressolle F , de la Coussaye J E , Ayoub R , Fabre D , Gomeni R , Saissi G , Eledjam J J , Galtier M
Published: June 2012

Pharmacokinetic studies on ceftazidime, an aminothiazole cephalosporin with a wide spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa, were performed in patients with nosocomial pneumonia. The concentration-time profiles of ceftazidime in plasma, urine, and bronchial secretions of 12 patients were investigated after intravenous (i.v.) (n = 12), endotracheal (n = 10), and aerosol (n = 5) administrations. In all cases a 1-g dose was administered. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection. The elimination of the drug from the blood followed a biexponential (i.v. administration) or a monoexponential (endotracheal and aerosol administrations) decay, with an elimination half-life of 6 h and a total body clearance of 4.2 liters/h. The apparent volume of distribution was 0.36 liter/kg of body weight. Renal clearance of the drug accounted for 58% of the total clearance; 66% +/- 17.7%, 33.5% +/- 17.3%, and 6.59% +/- 3.45% of the administered dose were eliminated in urine as parent drug after i.v., endotracheal, and aerosol administrations, respectively. The absolute bioavailabilities were 0.47 and 0.08 for endotracheal and aerosol administrations, respectively. Very high concentrations were found in bronchial secretions after local administration. The MICs for 90% of the most important pathogens responsible for nosocomial infections were exceeded by concentrations in bronchial secretion for up to 12 h after i.v. infusion and for up to 24 h after endotracheal and aerosol administrations.
Aerosolized liposomal amphotericin B for treatment of pulmonary and systemic Cryptococcus neoformans infections in mice
Authors: Gilbert B E , Wyde P R , Wilson S Z
Published: June 2012

Cryptococcus infections of the lung and central nervous system have become major problems in immuno-compromised patients, leading to the need for additional treatment protocols. We have utilized a Cryptococcus-mouse model that mimics human cryptococcal disease to evaluate the efficacy of amphotericin B-liposomes (AmpB-Lip) when delivered by small-particle aerosol (SPA). In the model, initial intranasal inoculation leads to a pulmonary infection that spreads after 2 to 3 weeks to distant organs, including the brain. Aerosols of AmpB-Lip that were generated by a Collison nebulizer had mass median aerodynamic diameters of 1.8 microns and contained 10.3 micrograms of AmpB per liter. When AmpB-Lip SPA was begun at 24 h postinoculation, a single 2-h treatment (0.3 mg of AmpB per kg of body weight) was effective in reducing pulmonary Cryptococcus infection. This regimen was more effective than intravenous administration of AmpB-Lip given for 3 continuous days. This single 2-h exposure to AmpB-Lip also was effective in reducing pulmonary Cryptococcus infection when treatment was delayed for 7 or 14 days. At day 21, when organisms had spread to the brain in all animals, the single 2-h aerosol treatment reduced the number of cryptococci in the brain as well as in the lungs. AmpB-Lip SPA administered once for 2 h on days 7, 14, and 21 also was effective in increasing the duration of survival of infected animals. These results demonstrate that aerosolized AmpB-Lip can be effective in treating both local, pulmonary Cryptococcus disease and systemic disease.
Antimicrobial activity of DU-6859, a new potent fluoroquinolone, against clinical isolates
Authors: Sato K , Hoshino K , Tanaka M , Hayakawa I , Osada Y
Published: June 2012

DU-6859, (-)-7-[(7S)-amino-5-azaspiro(2,4)heptan-5-yl]-8-chloro-6- fluoro-1-[(1R,2R)-cis-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinol one-3- carboxylic acid, is a new fluoroquinolone with antibacterial activity which is significantly better than those of currently available quinolones. The MICs for 90% of methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis clinical isolates (MIC90s) were 0.1, 3.13, 0.1, and 0.39 microgram/ml, respectively. MIC50s of DU-6859 against quinolone-resistant, methicillin-resistant S. aureus were 8-, 32-, 64-, and 128-fold lower than those of tosufloxacin and sparfloxacin, ofloxacin and fleroxacin, ciprofloxacin, and lomefloxacin, respectively. DU-6859 inhibited the growth of all strains of Streptococcus pneumoniae and Streptococcus pyogenes at 0.1 and 0.2 microgram/ml, respectively, and was more active against enterococci than the other quinolones tested. Although the activity of DU-6859 against Pseudomonas aeruginosa was roughly comparable to that of ciprofloxacin at the MIC50 level, it was fourfold more active than ciprofloxacin at the MIC90 level. DU-6859 was also more active against other glucose-nonfermenting bacteria, Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, than the other drugs tested. Strains of Bacteroides fragilis and Peptostreptococcus spp. were susceptible to DU-6859; MIC90s were 0.39 and 0.2 microgram/ml, respectively. DU-6859 generally showed activities twofold or greater than those of ciprofloxacin and the other drugs against almost all members of the family Enterobacteriaceae. The action of DU-6859 against the clinical isolates was bactericidal at concentrations near the MICs. DU-6859 activity was not affected by different media, pH, inoculum size, or human serum but was decreased in human urine.
Use of an enzyme-linked immunosorbent assay to assess penetration of amoxicillin into lung secretions
Authors: Hill S L , Burnett D , Lovering A L , Stockley R A
Published: June 2012

An enzyme-linked immunosorbent assay (ELISA) was developed to measure total amoxicillin concentrations penetrating lung secretions, which were compared with "active" concentrations measured by conventional bioassay. An antibody was raised in rabbits to amoxicillin conjugated to bovine serum albumin and used in a competitive binding ELISA (sensitivity, 10 ng/ml; precision [coefficient of variation], 9%). The measurement of amoxicillin in lung secretions by using the ELISA method was verified by high-performance liquid chromatography. Amoxicillin concentrations were found to be similar in both whole sonicated sputum and sol-phase sputum obtained by ultracentrifugation following single oral doses of 3 g (4.6 mg/liter for sonicated and 4.7 mg/liter for sol-phase preparations) and 250 mg (0.23 mg/liter for both preparations). Eight patients with bronchiectasis received 500 mg of amoxicillin three times daily. On the second day of therapy (4 h after the morning dose), the mean concentration of amoxicillin in sputum was 0.88 mg/liter (standard error of the mean [SEM], 0.11) by ELISA and 0.40 mg/liter (SEM, 0.05) by bioassay, suggesting a significant degree of local inactivation. This difference between total and active amoxicillin levels was found to correlate significantly (r = 0.693; P less than 0.05) with beta-lactamase levels (mean, 29.5 mU/ml; SEM, 9.4). A pharmacokinetic study on day 3 revealed maximum levels in secretions 2 to 4 h after dosing (mean, 1.36 mg/liter; SEM, 0.26). At the end of successful therapy (day 14), total and active levels were lower (mean, 0.48 mg/liter; SEM, 0.11 [total]; mean, 0.21 mg/liter; SEM, 0.06 [active]); this result was associated with a reduction in lung inflammation (decreased serum-derived albumin in the lung secretions). In conclusion, antibiotic penetration is partly dependent on the degree of lung inflammation. The differences observed in total and active levels of amoxicillin and the relationship to beta-lactamase activity in sputum suggest why higher doses of antibiotic may be required to produce a therapeutic response in some patients.
Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro
Authors: Eron J J , Johnson V A , Merrill D P , Chou T C , Hirsch M S
Published: June 2012

The combination of zidovudine (AZT) and 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro with AZT-sensitive and AZT-resistant clinical isolates and HIV-1IIIB. Synergy was determined by the median-effect principle and isobologram techniques. Cytotoxicity of the agents was not observed. Clinical trials are ongoing to define the combination's role in HIV-1 therapy.
Comparative in vitro activities of teicoplanin, daptomycin, ramoplanin, vancomycin, and PD127,391 against blood isolates of gram-positive cocci
Authors: Shonekan D , Mildvan D , Handwerger S
Published: June 2012

The in vitro activities of teicoplanin, daptomycin, ramoplanin, and PD127,391, a new quinolone, were compared with that of vancomycin. Teicoplanin showed the lowest MICs against Enterococcus faecalis. Ramoplanin was slightly more active than the other peptide antibiotics against oxacillin-resistant Staphylococcus aureus. The MICs of the four peptide antibiotics were similar for the oxacillin-susceptible S. aureus. Daptomycin had good activity against staphylococci but was the least active agent against E. faecalis. The MICs of vancomycin against all isolates were in general higher than those of the new antibiotics, with the exceptions of the MICs of daptomycin against E. faecalis and teicoplanin against oxacillin-resistant Staphylococcus epidermidis. PD127,391 was the most active agent against all staphylococcal isolates.
Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I
Authors: Fukasawa M , Sumita Y , Harabe E T , Tanio T , Nouda H , Kohzuki T , Okuda T , Matsumura H , Sunagawa M
Published: June 2012

The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.
Quinolone accumulation in Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus
Authors: McCaffrey C , Bertasso A , Pace J , Georgopapadakou N H
Published: June 2012

The accumulation of quinolones by Escherichia coli JF568, Pseudomonas aeruginosa PAO1, and Staphylococcus aureus ATCC 29213 was measured by a modified fluorometric assay (J. S. Chapman and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:27-29, 1989). The quinolones examined were fleroxacin, pefloxacin, norfloxacin, difloxacin, A56620, ciprofloxacin, ofloxacin, and Ro 09-1168. In all three organisms, uptake was complete in less than 5 min and was proportional to extracellular quinolone concentrations between 2 and 50 micrograms/ml, which is consistent with simple diffusion. Washing cells with quinolone-free buffer decreased accumulation by up to 70% in E. coli and P. aeruginosa but not in S. aureus. Similarly, incubation with the uncouplers 2,4-dinitrophenol and carbonyl cyanide m-chlorophenylhydrazone increased accumulation up to fourfold in E. coli and P. aeruginosa, though not in S. aureus, suggesting endogenous, energy-dependent efflux. High quinolone hydrophobicity was generally associated with decreased accumulation in E. coli and P. aeruginosa (except in the case of pefloxacin) but was associated with increased accumulation in S. aureus (except in the case of difloxacin). Ciprofloxacin had the highest accumulation in E. coli and P. aeruginosa, while pefloxacin had the highest accumulation in S. aureus.
Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice
Authors: Kuhlencord A , Maniera T , Eibl H , Unger C
Published: June 2012

Hexadecylphosphocholine (He-PC), a novel phospholipid derivative, was tested against Leishmania donovani and Leishmania infantum, the causative agents of visceral leishmaniasis. In vitro, promastigotes were highly susceptible to He-PC; the 50% inhibitory concentrations were between 0.89 and 2.25 micrograms/ml for the different leishmanial strains. In vivo, a marked antileishmanial activity in infected BALB/c mice could be demonstrated after oral administration of He-PC. Whereas parasite suppression and killing in the liver were comparable after 5 days of treatment with He-PC (10 or 20 mg/kg of body weight per day administered orally) and sodium stibogluconate (120 mg of pentavalent antimonal agent per kg/day administered subcutaneously), a superior reduction in the parasite load in the spleen and bone marrow was observed after oral treatment with He-PC. After a 4-week treatment period, parasite suppression in the spleen was better than that observed with standard sodium stibogluconate therapy by a factor of more than 600.
In vitro antibacterial activity of Q-35, a new fluoroquinolone
Authors: Ito T , Otsuki M , Nishino T
Published: June 2012

The in vitro activity of Q-35, an 8-methoxy fluoroquinolone, was compared with those of ofloxacin, ciprofloxacin, tosufloxacin, lomefloxacin, and sparfloxacin. The MICs of Q-35 for 90% of strains tested (MIC90s) of Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes were 0.2, 6.25, 0.2, 0.39, and 0.39 micrograms/ml, respectively. The activity of Q-35 was 4- to 16-fold greater than those of ofloxacin, ciprofloxacin and lomefloxacin but equal to those of tosufloxacin and sparfloxacin against these organisms. For 82 ciprofloxacin-resistant staphylococci (MIC90 = 100 micrograms/ml), Q-35 was the most active of the new quinolones tested (MIC90 = 6.25 micrograms/ml). The MIC90s of Q-35 against Escherichia coli, Enterobacter aerogenes, and Pseudomonas aeruginosa were 0.2, 0.78, and 12.5 micrograms/ml, respectively, and Q-35 was 2- to 16-fold less active than the other quinolones tested. Q-35 showed potent bactericidal activity and inhibited the supercoiling activity of DNA gyrase of S. aureus, E. coli, and P. aeruginosa.
Antifungal susceptibility testing of Candida spp. by relative growth measurement at single concentrations of antifungal agents
Authors: Odds F C
Published: June 2012

The relative growth (percentage of growth relative to control growth) of 496 isolates representing six Candida species was assessed as a means of determining in vitro susceptibilities of the isolates in microdilution plate wells containing single concentrations of each of seven antifungal agents. The relative growth data were highly reproducible. With flucytosine and amorolfine they correlated well with MICs, but for an azole antifungal agent, terconazole, they did not correlate with MICs. Distributions of relative growth percentages for different Candida spp. showed significant differences in species susceptibility to individual agents. For example, C. albicans was less susceptible than the other species to amorolfine; C. parapsilosis isolates were particularly susceptible to terbinafine; and C. glabrata, C. guilliermondii, and C. krusei isolates were less susceptible than C. albicans to fluconazole and ketoconazole but equally susceptible as or more susceptible than C. albicans to itraconazole. Differential patterns of susceptibility to individual azole antifungal agents were noted for some individual strains as well as for Candida spp.
Temperature-dependent in vitro antimicrobial activity of four 4-quinolones and oxytetracycline against bacteria pathogenic to fish
Authors: Martinsen B , Oppegaard H , Wichstrøm R , Myhr E
Published: June 2012

The in vitro antimicrobial activities of oxolinic acid, flumequine, sarafloxacin, enrofloxacin, and oxytetracycline against strains of bacteria pathogenic to fish (Aeromonas salmonicida subsp. salmonicida, atypical A. salmonicida, Vibrio salmonicida, Vibrio anguillarum, and Yersinia ruckeri) were determined at two different incubation temperatures, 4 and 15 degrees C, by a drug microdilution method. The main objective of the study was to examine the effect of incubation temperature on the in vitro activities of 4-quinolones and oxytetracycline against these bacteria. When tested against A. salmonicida subsp. salmonicida, all of the quinolones examined had MICs two- to threefold higher at 4 degrees C than at 15 degrees C. Similarly, 1.5- to 2-fold higher MICs were recorded for all of the quinolones except sarafloxacin at 4 degrees C than at 15 degrees C when the drugs were tested against V. salmonicida. In contrast to those of the quinolones, the MICs of oxytetracycline were two- to eightfold lower at 4 degrees C than at 15 degrees C against all of the bacterial species tested. Of the antimicrobial agents tested against the bacterial species included in the study, enrofloxacin was the most active and oxytetracycline was the least active. Sarafloxacin was slightly more active than flumequine and oxolinic acid, especially against oxolinic acid-resistant A. salmonicida subsp. salmonicida strains.
Inhibition of rabies virus transcription in rat cortical neurons with the dissociative anesthetic ketamine
Authors: Lockhart B P , Tordo N , Tsiang H
Published: June 2012

In a previous study (B. P. Lockhart, H. Tsiang, P. E. Ceccaldi, and S. Guillemer, Antiviral Chem. Chemother. 2:9-15, 1991), we demonstrated an antiviral effect of the general anesthetic ketamine for rabies virus in neuronal cultures and in rat brain. This report describes an attempt to determine at what level ketamine acts on the rabies virus cycle in rat cortical neuron cultures. Immunofluorescence and [35S]methionine labelling of infected neurons showed that ketamine (1 to 1.5 mM) inhibited viral nucleoprotein and glycoprotein syntheses. Northern (RNA) blots of total RNA from drug-treated neurons, hybridized with 32P-labelled oligonucleotide probes for rabies virus nucleoprotein, matrix protein, and glycoprotein genes, showed a marked reduction (5- to 11-fold) in the levels of rabies virus mRNAs, relative to those in untreated neurons. No significant change in the levels of cellular beta-actin mRNA were detected in ketamine-treated cells. A similar antiviral effect was observed with MK-801; however, no inhibition of rabies virus synthesis was observed with the general anesthetic chloral hydrate. The antiviral effect was not complete; a time-dependent recovery of viral transcription and rabies virus protein synthesis was observed, but no infectious virus was released into the culture supernatant. The lack of any modification of cellular protein or mRNA synthesis by ketamine suggests an antiviral mechanism acting at the level of rabies virus genome transcription.
Antibacterial activity of RU44790, a new N-tetrazolyl monocyclic beta-lactam
Authors: Chantot J F , Klich M , Teutsch G , Bryskier A , Collette P , Markus A , Seibert G
Published: June 2012

RU44790 belongs to a new class of synthetic monocyclic beta-lactam antibiotics which feature a bioisosteric tetrazole moiety instead of the more classical acidic functions at the N-1 position of the beta-lactam ring. Its antibacterial activity was evaluated against some 900 strains and was compared with those of other recent beta-lactam derivatives, especially aztreonam. RU44790 is endowed with potent activity against gram-negative bacteria. At less than or equal to 0.6 micrograms/ml, RU44790 inhibited 90% of all strains of the family Enterobacteriaceae with the exception of Citrobacter spp. (MIC for 90% of strains tested, 1.2 micrograms/ml). The activity was similar to that of aztreonam against strains that are normally susceptible to expanded-spectrum cephalosporins. On the other hand, the new compound was 10 to 100 times more potent than aztreonam and most of the other antibiotics tested against enterobacteria that produce chromosome-encoded or plasmid-mediated extended-spectrum beta-lactamases. Pseudomonas aeruginosa isolates were equally susceptible to both monobactams. RU44790 was inactive against staphylococci and had only marginal activity against streptococci (MIC for 50% of strains tested, 2.5 micrograms/ml). RU44790 was highly resistant to hydrolysis by various beta-lactamases, particularly cephalosporinases such as P99. The latter enzyme was also inhibited by the compound. RU44790 showed a high affinity for penicillin-binding protein 3 of Escherichia coli. The results suggest that RU44790 has good potential in the treatment of infections caused by gram-negative microorganisms.
In vitro activities of streptomycin and 11 oral antimicrobial agents against clinical isolates of Klebsiella rhinoscleromatis
Authors: Perkins B A , Hamill R J , Musher D M , O'Hara C
Published: June 2012

We tested in vitro the activities of streptomycin and tetracycline--antibiotics that have long been used to treat rhinoscleroma--as well as several newer oral agents by using 23 isolates of the causative organism Klebsiella rhinoscleromatis. All isolates were inhibited by clinically achievable concentrations of trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, chloramphenicol, ciprofloxacin, cephalexin, cefuroxime, and cefpodoxime.
Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant
Authors: Mentec H , Vallois J M , Bure A , Saleh-Mghir A , Jehl F , Carbon C
Published: June 2012

The efficacy of tazobactam, a beta-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extended-spectrum beta-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 micrograms/ml, MBC = 8 micrograms/ml with 10(7)-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 micrograms/ml). Tazobactam (1 microgram/ml) restored the activity of piperacillin against KpR (MIC = 2 micrograms/ml, MBC = 4 micrograms/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 micrograms/ml for KpS and KpR, respectively). The piperacillin-tazobactam-gentamicin combination was synergistic in vitro. The piperacillin/tazobactam ratio in plasma and in vegetations was always lower than the 4/1 injected dose ratio. In vivo, piperacillin (300 mg/kg of body weight four times a day [QID]) was active against KpS but not against KpR. Tazobactam (75 mg/kg QID) was able to restore the in vivo effect of piperacillin (300 mg/kg QID) against KpR (-3.0 log10 CFU/g of vegetation versus that of controls). Gentamicin (4 mg/kg twice a day [BID]) was active against both strains. Compared with controls, the combination of gentamicin plus piperacillin against KpS (-5.6 log10 CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against KpR (-4.4 log10 CFU/g of vegetation) achieved the greatest decrease in bacterial counts in vegetations and were the only regimens that significantly increased the proportion of sterile vegetations. It is concluded that (i) tazobactam was able to restore the effect of piperacillin against a TEM-3 extended-spectrum Beta-lactamase-producing strain of K. pneumoniae, both in vitro and in a severe experimental infection with high inoculum, when used in a 4/1 piperacillin/tazobactam dose ratio; (ii) gentamicin alone was effective because of the high peak/MBC ratio in plasma; (iii) piperacillin-tazobactam-gentamicin, probably because of the effect of gentamicin in reducing bacterial inoculum in vivo, as stressed by the results obtained by piperacillin-gentamicin against KpS, may be the most effective regimen against KpR.
In vitro activity of L-627, a new carbapenem
Authors: Catchpole C R , Wise R , Thornber D , Andrews J M
Published: June 2012

The in vitro activity of L-627, a new parenterally administered carbapenem, was compared with those of imipenem, meropenem, FCE 22101 (a penem), ceftazidime, and ceftriaxone. L-627 was active against members of the family Enterobacteriaceae (MIC for 90% of strains tested [MIC90] ranging from 0.03 to 4 micrograms/ml). L-627 displayed activity equal to that of meropenem against Pseudomonas aeruginosa (MIC90, 2 micrograms/ml), although, as with other carbapenems, the antipseudomonal activity was reduced against D2-deficient strains. Staphylococci and streptococci were susceptible (MIC90 of 1.0 micrograms/ml for Staphylococcus aureus and 0.015 micrograms/ml for group A streptococci). L-627 also had activity against anaerobic bacteria (MIC90, 2.0 micrograms/ml for Bacteroides fragilis). Neisseria gonorrhoeae and Neisseria meningitidis were highly susceptible (MIC90, 0.06 micrograms/ml), and against the common respiratory pathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis), the MIC90s were less than or equal to 2.0 micrograms/ml. The protein binding of L-627 ranged from 13.8 to 22%, depending on the concentration. The presence of human serum had little effect on the MIC or MBC of L-627. These results suggest that L-627 merits further study in the treatment of infections caused by a wide range of pathogens.
In vitro antibacterial activities of tosufloxacin against and uptake of tosufloxacin by outer membrane mutants of Escherichia coli, Proteus mirabilis, and Salmonella typhimurium
Authors: Mitsuyama J , Itoh Y , Takahata M , Okamoto S , Yasuda T
Published: June 2012

The antibacterial activities of tosufloxacin and other quinolones against and apparent uptakes of tosufloxacin and other quinolones by outer membrane mutants of Escherichia coli, Proteus mirabilis, and Salmonella typhimurium were studied. The hydrophobicity of tosufloxacin was nearly equal to that of ofloxacin or lower than those of sparfloxacin and nalidixic acid. OmpF- and OmpC-deficient E. coli and 40-kDa porin-deficient P. mirabilis mutants were twofold more susceptible to tosufloxacin and sparfloxacin but two- to fourfold less susceptible to other quinolones than their parent strains. In S. typhimurium lipopolysaccharide-deficient (rough) mutants, the differences in susceptibility to tosufloxacin were similar to those to sparfloxacin and nalidixic acid. The apparent uptake of tosufloxacin by intact cells was increased in porin-deficient mutants compared with that by their parent strain. These results suggest that the permeation route of tosufloxacin across the outer membrane is different from that of other fluoroquinolones and that tosufloxacin may permeate mainly through the nonporin pathway, presumably phospholipid bilayers. However, this characteristic is independent of the hydrophobicity of the molecule.
Inhibition of intrahepatic hepatitis B virus replication by antiviral drugs in a novel transgenic mouse model
Authors: Nagahata T , Araki K , Yamamura K , Matsubara K
Published: June 2012

Transgenic mice which carry the integrated human hepatitis B virus (HBV) genome and produce HBV particles in the liver were treated with antiviral compounds, and the amount of viral DNA in the liver and serum was monitored by Southern analyses. Mouse alpha interferon (200,000 U per injection, twice daily for 3 days) and a novel nucleoside, oxetanocin G (15 mg/kg of body weight per injection, twice daily for 7 days), inhibited viral DNA synthesis in the liver almost completely. This animal model should prove useful in evaluating anti-HBV agents.
Susceptibilities of members of the Bacteroides fragilis group to 11 antimicrobial agents
Authors: Horn R , Lavallée J , Robson H G
Published: June 2012

The susceptibilities of 200 clinical isolates of the Bacteroides fragilis group to 11 antimicrobial agents were determined by the broth microdilution method of the National Committee for Clinical Laboratory Standards. All isolates were susceptible to imipenem and ticarcillin-clavulanic acid. The rates of resistance to cefoxitin and clindamycin were low (4 and 6%, respectively), while those to ceftizoxime and cefotetan were higher (10.5 and 24%, respectively).
Effect of biliary obstruction on the hepatic excretion of imipenem-cilastatin
Authors: Leung J W , Chan C Y , Lai C W , Ko T C , Cheng A F , French G L
Published: June 2012

The biliary excretion of imipenem-cilastatin studied by endoscopic cannulation of the common bile duct in patients with complete obstruction and in a group without obstruction showed that despite a 24-h prophylaxis, the bile obtained from patients with obstruction immediately after cannulation contained neither imipenem nor cilastatin, while there were 2 and 5% of peak concentrations in serum for imipenem and cilastatin, respectively, in the bile from patients without obstruction. Biliary excretion of both compounds increased rapidly after decompression, reaching a maximum of 15% of peak levels in serum within 2 h. Twenty-four hours after drainage, the biliary excretion of the drugs further improved. We conclude that since biliary obstruction impairs excretion of antibiotics, drainage is necessary for the control of sepsis in obstructed cholangitis.
Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease
Authors: Kort J J , Bilello J A , Bauer G , Drusano G L
Published: June 2012

A synthetic, symmetry-based inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, A77003, was evaluated for antiviral activity and cytotoxicity in vitro in human peripheral blood lymphocytes or cell lines H9, CEM, and U937. Toxicity and antiviral activity of the HIV-1 protease inhibitor were compared with those of the reverse transcriptase inhibitors zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine and human recombinant alpha and beta interferons. Production of infectious virus particles, cell-free p24 antigen, and cell-associated viral proteins was reduced 50% by the HIV-1 protease inhibitor at concentrations of 0.12 to 0.26 microM (50% effective concentration [EC50]) in acute infection and 0.2 to 1.7 microM (EC50) in persistent infection. Fluorescence-activated cell sorter analysis of U937 cells persistently infected with HIVIIIB using a monoclonal antibody to HIV also showed a reduction of cell-associated viral protein in A77003-treated cells. Furthermore, toxicity of A77003 assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was not observed at greater than 100 times the EC50. A77003 was more effective in persistent HIV-1 infection than alpha and beta interferons (1,000 U/ml), while zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine were not active.