Doripenem monohydrate, a broad-spectrum carbapenem antibiotic

Abstract

Background: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic, has been approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs).

Objective: This article reviews available information on doripenem in the management of patients with complicated bacterial infections, including its chemistry, spectrum of activity, resistance mechanisms, pharmacokinetics, pharmacodynamics, drug interactions, therapeutic efficacy, tolerability, and dosing and administration. Also discussed are pharmacoeconomic considerations associated with doripenem.

Methods: Pertinent English-language literature was identified from searches of MEDLINE (1996-October 2008) and BIOSIS (1993-October 2008). Search terms included, but were not limited to, doripenem, S-4661, spectrum of activity, resistance, pharmacology, pharmacokinetics, pharmacodynamics, adverse events, and therapeutic use. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (2003-2007).

Results: Doripenem is a parenteral carbapenem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms. It is stable against a wide variety of beta-lactamases, including extended-spectrum and AmpC beta-lactamases; it is, however, inactivated by organisms that produce class A enzymes, KPC enzymes, class B metallo-beta-lactamases, and class D enzymes. Doripenem is eliminated primarily in the urine (68%-80% unchanged). It should be used cautiously in patients receiving valproic acid, as combined use may lead to a precipitous decline in serum concentrations of valproic acid. A large Phase III study in the treatment of cIAIs found doripenem noninferior to meropenem (clinical cure rates, 83.9% and 85.9%, respectively; difference, -2.1; 95% CI, -9.8 to 5.6). A Phase III study in the treatment of cIAIs, including pyelonephritis, found doripenem non-inferior to levofloxacin (clinical cure rates, 95.1% and 90.2%, respectively; 95% CI, 0.2 to 9.6). With respect to the treatment of nosocomial pneumonia, one Phase III study found doripenem noninferior to imipenem (clinical cure rates, 68.3% and 64.8%, respectively; difference, 3.5%; 95% CI, -9.1 to 16.1), and another found it noninferior to piperacillin/tazobactam (clinical cure rates, 81.3% and 79.8%, respectively; difference, 1.5%; 95% CI, -9.1 to 12.1). Adverse events with doripenem were similar to those of other antibiotics with which it has been compared. Adverse events in clinical trials of doripenem have included anaphylaxis and rash (l%-5%), gastrointestinal effects (25%-32%, including nausea [1.1%-12.0%], diarrhea [1.9%-11.0%], and vomiting [1.5%-6.6%]), and central nervous system effects (headache [2.1%-16.0%], insomnia [3.7%], anxiety [2.9%], and, rarely, seizures).

Conclusions: In Phase III studies, doripenem was noninferior to meropenem in the treatment of cIAIs; noninferior to levofloxacin in the treatment of cUTIs; and noninferior to imipenem and piperacillin/tazobactam in the treatment of nosocomial pneumonia. As with all new antibiotics, because of the risk of selecting for resistant organisms, use of doripenem should be reserved for infections in which a multidrug-resistant gram-negative organism, polymicrobial infection, or Pseudomonas aeruginosa is suspected.