Efficacy of BB-83698, a novel peptide deformylase inhibitor, in a mouse model of pneumococcal pneumonia.
The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 10(5) CFU (virulent strains) into immunocompetent mice or 10(7) CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 micro g/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 micro g/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 micro g. h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.
Azoulay-Dupuis
E
E
INSERM, EMI-9933, Faculté de Médecine Xavier Bichat, Paris, France. eazoulay@bichat.inserm.fr
Mohler
J
J
Bédos
J P
JP
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007958:Leukocyte Count; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D010406:Penicillins / Q000494:pharmacology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects; D016019:Survival Analysis
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; C481664:BB-83698; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D006877:Hydroxamic Acids; D018942:Macrolides; D010406:Penicillins; D000658:Amoxicillin; D000581:Amidohydrolases; C084507:peptide deformylase