Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations

Abstract

Objectives: To investigate the potency of doripenem, a broad-spectrum carbapenem characterized by a wider spectrum of activity combining antimicrobial and bactericidal features of imipenem and meropenem. Methods: This parenteral compound was studied against recent clinical isolates (2001–2002) from a worldwide organism collection. A total of 902 strains were susceptibility tested by reference methods against doripenem and six to 28 comparators including ertapenem, imipenem and meropenem. The organisms tested included: Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci (39), enterococci (84), streptococci (163), various anaerobes (98), and other Gram-positive species such as Corynebacterium and Bacillus spp. (17). Results: Against Enterobacteriaceae, the average doripenem MIC₉₀ was 0.03 mg/L (range, ≤0.015–0.25 mg/L). Doripenem was two- to 16-fold more potent than imipenem and comparable to ertapenem and meropenem; all doripenem MIC values with enteric bacilli were ≤4 mg/L. Doripenem was active against Aeromonas (MIC₅₀, 0.03 mg/L), Bacillus spp. (MIC₅₀, 0.03 mg/L) and all tested anaerobic species (MIC range, ≤0.015–4 mg/L), but was less active against S. maltophilia (MIC₉₀, >32 mg/L) and Enterococcus faecium (MIC₉₀, >32 mg/L) among the enterococcal species. Time-dependent bactericidal action was observed for doripenem and broth MIC results were slightly greater when compared to agar MIC results. In pilot testing, the optimal doripenem disc concentration was 10 μg, identical to standardized reagents for other clinically available carbapenems. Conclusions: Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other β-lactams appears to be warranted.