In Vitro Activity of Doripenem, a Carbapenem for the Treatment of Challenging Infections Caused by Gram-Negative Bacteria, against Recent Clinical Isolates from the United States

Abstract

Doripenem, a 1␤-methylcarbapenem, is a broad-spectrum antibiotic approved for the treatment of complicated urinary tract and complicated intra-abdominal infections. An indication for hospital-acquired pneumonia including ventilator-associated pneumonia is pending. The current study examined the activity of doripenem against recent clinical isolates for the purposes of its ongoing clinical development and future longitudinal analysis. Doripenem and comparators were tested against 12,581 U.S. clinical isolates collected between 2005 and 2006 including isolates of Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter spp. MICs (g/ml) were established by broth microdilution. By MIC 90 , doripenem was comparable to imipenem and meropenem in activity against S. aureus (methicillin susceptible, 0.06; resistant, 8) and S. pneumoniae (penicillin susceptible, <0.015; resistant, 1). Against ceftazidime-susceptible Enterobacteriaceae, the MIC 90 of doripenem (0.12) was comparable to that of meropenem (0.12) and superior to that of imipenem (2), though susceptibility of isolates exceeded 99% for all evaluated carbapenems. The activity of doripenem was not notably altered against ceftazidime-nonsusceptible or extended-spectrum ␤-lactamase screen-positive Enterobacteriaceae. Doripenem was the most potent carbapenem tested against P. aeruginosa (MIC 90 /% susceptibility [%S]: ceftazidime susceptible ‫؍‬ 2/92%S, nonsusceptible ‫؍‬ 16/61%S; imipenem susceptible ‫؍‬ 1/98.5%S, nonsusceptible ‫؍‬ 8/56%S). Against imipenem-susceptible Acinetobacter spp., doripenem (MIC 90 ‫؍‬ 2, 89.1%S) was twice as active by MIC 90 as were imipenem and meropenem. Overall, doripenem potency was comparable to those of meropenem and imipenem against gram-positive cocci and doripenem was equal or superior in activity to meropenem and imipenem against Enterobacteriaceae, including ␤-lactam-nonsusceptible isolates. Doripenem was the most active carbapenem tested against P. aeruginosa regardless of ␤-lactam resistance.Gram-negative bacilli play a significant role in the most prevalent types of nosocomial infections including hospitalacquired pneumonia, ventilator-associated pneumonia, urinary tract infections, and intra-abdominal infections (7,31,32). Although substantial attention has been given to the development of agents to combat drug-resistant gram-positive cocci, pursuit of antimicrobials for use in infections caused by gram-negative bacilli has not been as extensive (20). This trend combined with the continued emergence and spread of gram-negative bacilli resistant to ␤-lactam agents (9, 23, 28) has resulted in a growing need for new agents active against the resistant gram-negative pathogens encountered in hospitals.The stability of carbapenems to a wide variety of ␤-lactamases produced by gram-negative bacilli (4, 18), combined with their relatively low toxicity potential, makes this class of antibiotics good candidates for clinical development and use agai...

Open-Label Study To Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants Less than 12 Weeks in Chronological Age

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Population Pharmacokinetics of Doripenem Based on Data from Phase 1 Studies with Healthy Volunteers and Phase 2 and 3 Studies with Critically Ill Patients

“…Doripenem is a parenteral carbapenem with in vitro microbiological activity against a broad spectrum of clinically important Gram-positive and Gram-negative pathogens (9,14,23). It is approved for complicated intra-abdominal and complicated urinary tract infections (UTI) in the United States and in Europe, where it is also approved for nosocomial pneumonia (15).…”

Antibiotic Resistance in Urinary Tract Infections: Current Issues and Future Solutions

“…Analysis of 1,772 clinical www.intechopen.com E. coli isolates (many from complicated UTIs) found that 99.8% of them were susceptible to doripenem, including all 30 ESBL-producers (Pillar et al, 2008). Analysis of 6 Phase III clinical trials demonstrated that doripenem was as effective as levofloxacin, imipenem, meropenem and piperacillin-tazobactam in treatment of patients with complicated UTIs due to ciprofloxacin-resistant and ESBL-producing Enterobacteriaceae (largely UPEC) (Kaniga et al, 2010).…”