HMR 3647 human-like treatment of experimental pneumonia due to penicillin-resistant and erythromycin-resistant Streptococcus pneumoniae

Abstract

An experimental Streptococcus pneumoniae pneumonia model in rabbits was used to assess the efficacy of amoxycillin, erythromycin and a new ketolide, telithromycin (HMR 3647). The MICs of amoxycillin, erythromycin and HMR 3647 for the three clinical S. pneumoniae strains used were, respectively, (mg/L): 0.01, 16 and 0.02 (strain 195); 2, 0.25 and 0.02 (strain 16089); 8, >64 and 0.02 (strain 11724). Antibiotic therapy reproduced human serum pharmacokinetics (amoxycillin 1 g iv tds or erythromycin 500 mg qds or HMR 3647 800 mg bd). Forty-eight hours of therapy with HMR 3647 and amoxycillin resulted in significant bacterial clearance in the lungs and spleen of rabbits infected by S. pneumoniae strain 195 and strain 16089 (at least 3 log(10) cfu/g decrease, P < 0.001). Erythromycin was active against only the erythromycinsusceptible strain (3 log(10) cfu/g decrease at 48 h, P < 0.001). None of the antibiotics showed significant efficacy with strain 11724. All agents produced significant bacterial clearance when time above MBC was >33%, and microbiological failure when it was <25%, whereas MIC was not correlated with microbiological outcome with HMR 3647. Our findings suggest that pharmacodynamic data integrating MBC may be predictive of microbiological success or failure with greater accuracy than with MIC. HMR 3647 produced significant bacterial clearance in both penicillin- and erythromycin-resistant pneumonia, but was less effective against the highly erythromycin-resistant S. pneumoniae strain.

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model

“…The compound has also demonstrated a pharmacodynamic profile at both static concentrations and simulated human exposures that support its efficacy against S. pneumoniae with differing phenotypic profiles [12][13][14]. Additional data have demonstrated the in vivo potency of the TEL with a variety of pneumococcal phenotypes using several animal models including experimentally induced pneumonia [13,15,16]. Collectively, these in vitro and in vivo data suggest the potential clinical utility of TEL in the management of infection due to pneumococci with a broad range of phenotypic profiles.…”

Animal Models ofStreptococcus pneumoniaeDisease

“…The system mimics lethal pneumococcal pneumonia in patients and allows simulation in the rabbit of human antibiotic pharmacokinetics. As this model simulates "human-like treated pneumonia," it constitutes an extremely valuable tool for assessing drug efficacy and pharmacokinetics in humans (67,195,196), and it may also be useful for evaluating the selection of resistant pneumococcal strains in vivo (68). As aforementioned, the same research group also developed a novel infection model based on the induction of ventilatorassociated pneumococcal pneumonia in adult rabbits (57).…”

The impact of mechanical ventilation on the moxifloxacin treatment of experimental pneumonia caused by Streptococcus pneumoniae

“…The bacteria used in the present study was the strain 16089 (15,17,18). This strain was resistant to penicillin (minimal inhibitory concentration [MIC] ϭ 4 mg/L).…”