PURPOSE: Doripenem is an investigational carbapenem with potent activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP). Two randomized, open-label, multicenter studies established the noninferiority of doripenem to comparators (piperacillin/tazobactam, imipenem).
METHODS: Of 979 adults diagnosed with NP and randomized, 489 received doripenem in 2 phase 3 randomized, open-label, multicenter trials. Overall, 260 treated with doripenem and 241 treated with comparators were considered clinically evaluable. Of these, 40% had non-VAP, 30% had early-onset VAP (<5 days mechanical ventilation) and 30% had late-onset VAP. Baseline lower respiratory tract isolates were tested for susceptibility. Resistance was defined as minimum inhibitory concentrations ≥16 μg/ml for doripenem and according to CLSI criteria for comparators.
RESULTS: Among Staphylococcus aureus, 23.7% were methicillin-resistant. Resistance of Pseudomonas aeruginosa (n=105) was 4% to doripenem, 14% to imipenem, and 18% to piperacillin/tazobactam. Resistance of Klebsiella pneumoniae (n=89) was 0% to doripenem and imipenem, and 24% to piperacillin/tazobactam. The doripenem clinical cure rate in microbiologically evaluable patients was 74.5% (149/200) vs. 70.5% (136/193) for comparators. Microbiological cure (eradication or presumed eradication) was 78.0% (156/200) vs. 73.1% (141/193) for comparators. Overall, doripenem clinically cured 84.8% (89/105) of the non-VAP, 62.3% (78/77) of the early-onset VAP, and 74.4% (58/78) of the late-onset VAP, with similar trends for comparators. The per-pathogen doripenem microbiological cure rates were 78.7% (37/47) S. aureus, 85.2% (23/27) Enterobacter cloacae, 82.5% (33/40) Haemophilus influenzae, 79.3% (23/29) K. pneumoniae, 74% (28/38) P. aeruginosa, and 76.2% (16/21) E. coli. In a trial of only VAP patients, resistant P. aeruginosa emerged during doripenem therapy in 14% (4/28) and during imipenem therapy in 40% (10/25; P=0.06).
CONCLUSION: Doripenem was clinically and microbiologically effective in NP and was non-inferior to comparators. Baseline susceptibility to doripenem was greater than to piperacillin/tazobactam for several important pathogens and emergence of resistance in P. aeruginosa was less frequent than with imipenem.
CLINICAL IMPLICATIONS: Doripenem is a promising investigational carbapenem for the empiric treatment of NP and VAP.
DISCLOSURE: Marin Kollef, Grant monies (from industry related sources) Merck, Pfizer, Elan, Johnson and Johnson; Consultant fee, speaker bureau, advisory committee, etc. Consultant fees: Bard, Elan, Johnson and Johnson. Speaker bureaus: Merck, Elan, Pfizer, Johnson and Johnson; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. doripenem