Doripenem: New molecular entity/carbapenem antibiotic approved by FDA for the treatment of complicated intra-abdominal and urinary tract infections, including pyelonephritis

FDA has approved doripenem, a carbapenem antibiotic, for the treatment of complicated intra-abdominal and urinary tract infections, including pyelonephritis

Key Points

Doripenem is a broad-spectrum antibiotic that is structurally related to the beta-lactam anti-biotics. This agent inhibits bacterial cell wall bio-synthesis, thus causing cell death. Doripenem was approved on October 12, 2007, as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus, and Peptostreptococcus micros and as a single agent for the treatment of complicated urinary tract infections (UTIs), including pyelo-nephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Efficacy. The efficacy of doripenem for the treatment of complicated intra-abdominal infections was evaluated in 2 identical multinational, multicenter, double-blind studies that enrolled a total of 946 adult patients. In both studies, patients were treated with doripenem 500 mg administered over 1 hour every 8 hours or with meropenem 1 g administered over 3 to 5 minutes every 8 hours. After ≥3 days of intravenous (IV) therapy, patients were permitted to switch to oral amoxicillin 875 mg/clavulanate 125 mg BID, for a total of 5 to 14 days of IV and oral treatment. In patients with susceptible pathogens isolated at baseline and with no major protocol deviations at test of cure visit (25–45 d after therapy completion) (microbiologically evaluable [ME] patients), doripenem was noninferior to meropenem when clinical cure rates were evaluated. Doripenem was also noninferior to meropenem in patients with baseline pathogens isolated regardless of susceptibility (microbiological modified intent-to-treat patients [mMITT]). The efficacy of doripenem for the treatment of complicated UTIs including pyelo-nephritis was evaluated in 2 multicenter, multinational studies that enrolled a total of 1,171 adult patients. In the first study, patients were treated with either doripenem 500 mg administered over 1 hour every 8 hours or with IV levofloxacin 250 mg every 24 hours; the second study was noncomparative but was otherwise of similar design. In both studies, patients were permitted to switch to oral levofloxacin 250 mg every 24 hours after ≥3 days of IV therapy, for a total of 10 days of IV and oral treatment. Doripenem was noninferior to levofloxacin in ME patients when microbiological eradication rates were evaluated at 5 to 11 days after therapy completion. Doripenem was also noninferior to levofloxacin in mMITT patients.

Safety. Serious, occasionally fatal hypersensitivity reactions have been reported in patients treated with beta-lactam antibiotics. Carbapenem anti-biotics may reduce serum valproic acid concentrations to subtherapeutic levels, which may lead to loss of seizure control. Nearly all antibacterial agents have been associated with occurrences of Clostridium difficile-associated diarrhea, ranging from mild diarrhea to fatal colitis. The most common adverse events reported in association with this agent include headache, nausea, diarrhea, rash, and phlebitis.