ru-66647 and Haemophilus-Infections

Haemophilus influenzae is one of the main aetiological agents of community-acquired respiratory tract infections. The primary aim of this study was to evaluate the antibacterial activity of telithromycin against H. influenzae clinical isolates showing different pattern of resistance in comparison with azithromycin and clarithromycin at 1/4 x, 1/2 x, 1 x, 2 x, 4 x minimum inhibitory concentration (MIC) and to peak concentrations in epithelial lining fluid (ELF). The secondary aim was to determine the influence of CO2 enriched atmosphere on bacterial susceptibility.. Telithromycin showed high activity against H. influenzae, including strains susceptible to beta-lactams (n = 200), beta-lactamase producer (n = 50) and beta-lactamase negative ampicillin resistant (BLNAR) (n = 10), with MIC from < or =0.03 to 4 mg/L, and MIC50/MIC90 of 1/2 mg/L with susceptibility rate of 100%, and minimum bactericidal concentrations (MBC) from 2 to 4-fold higher than the MIC. Azithromycin was the most active tested macrolide (range: 0.25 - 4 mg/L; MIC50/MIC90: 1/2 mg/L), comparable to telithromycin, while clarithromycin showed the highest MICs and MBCs (range: 0.25 - 8 mg/L; MIC50/MIC90: 2/8 mg/L). In time-kill studies, telithromycin showed a bactericidal activity at the higher concentrations (4 - 2 x MIC and ELF) against all the strains, being complete after 12 - 24 hours from drug exposition. At MIC concentrations, at ambient air, bactericidal activity of telithromycin and azithromycin was quite similar at 12 hours, and better than that of clarithromycin. Besides, telithromycin and clarithromycin at ELF concentrations were bactericidal after 12 hours of incubation for most strains, while 24 hours were needed to azithromycin to be bactericidal. Incubation in CO2 significantly influenced the MICs and MBCs, and only slightly the in vitro killing curves.. Telithromycin showed an in-vitro potency against H. influenzae comparable to azithromycin, with an in-vitro killing rate more rapid and superior to clarithromycin at 2X-MIC against beta-lactamase producers and BLNAR strains, and to azithromycin at ELF concentrations against beta-lactamase negative strains. Against all strains, MICs and MBCs were lower in the absence of CO2 for the tested antibiotics, showing an adverse effect of incubation in a CO2 environment. The in-vitro potency together with the tissue concentrations of the antimicrobial, should be considered in predicting efficacy.

Topics: Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Carbon Dioxide; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Time Factors

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Humans; International Cooperation; Ketolides

This study investigated the presence of telithromycin and azithromycin efflux in 58 clinical strains of Haemophilus influenzae with various susceptibilities to macrolides, azalides, and ketolides. Efflux pumps were studied by measuring accumulation of radioactive [3H]telithromycin and [N-methyl-3H]azithromycin in the presence and absence of carbonyl m-chlorophenylhydrazone (CCCP), a protonophore. In 17 strains for which the telithromycin MICs were 0.06 to 0.5 microg/ml (azithromycin MICs, < or = 0.06 to 0.125 microg/ml; clarithromycin MICs, < or = 0.06 to 2 microg/ml), telithromycin and azithromycin accumulations were high without CCCP and not affected by its addition, which indicates absence of efflux. In 22 strains for which the telithromycin MICs were 0.25 to 4 microg/ml (azithromycin MICs, 0.25 to 1 microg/ml; clarithromycin MICs, 1 to 8 microg/ml), initially low levels of telithromycin accumulation became higher after addition of CCCP, indicating a functioning efflux pump. Nineteen strains for which the telithromycin MICs were > or = 2 microg/ml had efflux as well as various mutations in ribosomal proteins L4, L22, and/or 23S rRNA (domains II and V). Of these 19 strains, the telithromycin MICs (> or = 8 microg/ml) for 17 of them were significantly raised (azithromycin, MICs 4 to >32 microg/ml; clarithromycin MICs, 8 to >32 microg/ml). From these results we conclude that telithromycin efflux with or without additional ribosomal alterations is present in all H. influenzae strains, except for those for which the telithromycin MICs were very low.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Ketolides; Macrolides; Microbial Sensitivity Tests; Time Factors

Topics: Anti-Bacterial Agents; Bacterial Infections; Bronchitis; Chronic Disease; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Treatment Outcome

The National Committee for Clinical Laboratory Standards standard broth microdilution method for testing the susceptibility of Haemophilus influenzae to ampicillin, azithromycin, clarithromycin, and telithromycin was evaluated by altering one variable at a time. Variables that were tested included age of colony for inoculum preparation, inoculum density, test medium, incubation atmosphere, and incubation time. For the macrolide, azalide, and ketolide agents, incubation in 5 to 7% CO(2) most significantly affected the MICs, producing nearly twofold increases for clarithromycin and telithromycin and a greater than threefold increase for azithromycin. For ampicillin, a 10-fold increase in inoculum density increased the geometric mean MICs for beta-lactamase-negative strains from 1. 50 to 2.45 microg/ml. In addition, 206 H. influenzae strains were tested for their susceptibilities to the same drugs by the broth microdilution tests in two media, as well as by agar dilution tests, disk diffusion tests, and Etests, on six different agar media. The three standard methods with Haemophilus test medium (HTM) compared favorably with each other except for a high minor discrepancy rate (27%) by the disk diffusion test with ampicillin and clarithromycin. Agar dilution test MICs on the five comparative media were generally higher than those on HTM agar but were only rarely more than one twofold concentration higher. Etest MICs of azithromycin and telithromycin were more than twofold higher than agar dilution and broth microdilution MICs on HTM; ampicillin Etest MICs were nearly twofold lower. The use of media other than HTM agar appears to have a minimal effect on susceptibility test results for the ketolide, azalide, or macrolide drugs that we tested against H. influenzae.

Topics: Ampicillin; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Culture Media; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Quality Control

The in vivo activity of telithromycin against erythromycin A- and penicillin G-resistant Streptococcus pneumoniae was superior to that of azithromycin, clarithromycin, cefdinir, and levofloxacin. In respiratory tract infections caused by erythromycin A-susceptible S. pneumoniae or Haemophilus influenzae in mice, telithromycin was more effective than clarithromycin and comparable to azithromycin.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Half-Life; Ketolides; Macrolides; Male; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Pneumococcal Infections; Respiratory Tract Infections; Streptococcus pneumoniae

KETOLIDES: The principal advantage of this series of original compounds elaborated from macrolides is their activity against pneumococci and against macrolide-resistant streptococci while preserving the remainder of the macrolide spectrum of activity, particularly for intracellular germs. TELITHROMYCIN: To date, the main indications have been assessed in adults: pneumonia, super-infection of chronic bronchitis, sinusitis and pharyngitis. The recommended dose is 800 mg once a day. The safety of this dose has been validated for patients treated for 7 to 10 days for community-acquired pneumonia. CONTRIBUTION TO CURRENT STRATEGIES: Should telithromycin be proposed as first line treatment for community-acquired respiratory tract infections or should it be used as an alternative treatment for situations where no other antibiotic can be used?

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Respiratory Tract Infections

The MICs of HMR 3004 and HMR 3647 at which 90% of beta-lactamase-producing Haemophilus influenzae isolates were inhibited were 4 and 2 micrograms/ml, respectively. Both HMR 3004 and HMR 3647 were active against beta-lactamase-producing H. influenzae in a murine model of experimental pneumonia. As assessed by pulmonary clearance of H. influenzae, HMR 3004 was more effective (P < 0.05) than was azithromycin, ciprofloxacin, clarithromycin, erythromycin A, pristinamycin, or HMR 3647 in this model.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Colony Count, Microbial; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Mice; Mice, Inbred C57BL; Pneumonia, Bacterial

The in vitro activities of HMR 3647, erythromycin A, clarithromycin, azithromycin, roxithromycin, penicillin G, ampicillin, cefuroxime, trimethoprim/sulfamethoxazole, tetracycline, ciprofloxacin, and levofloxacin were determined for 1179 Streptococcus pneumoniae, 1438 Haemophilus influenzae, and 428 Moraxella catarrhalis isolated from respiratory tract specimens by 18 medical centers across Canada during 1997-1998. On a per weight basis, HMR 3647 was the most active agent tested against S. pneumoniae with MIC90s of < or = 0.12 microgram/mL for both penicillin susceptible and penicillin intermediate isolates and 0.25 microgram/mL for penicillin-resistant isolates. HMR 3647 was also highly active against M. catarrhalis (MIC90, < or = 0.12 microgram/mL), but less active against H. influenzae (MIC90, 4 micrograms/mL).

Topics: Administration, Oral; Anti-Bacterial Agents; Canada; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Neisseriaceae Infections; Respiratory Tract Infections; Streptococcal Infections; Streptococcus pneumoniae