Pharmacology Update

Doripenem Injection (Doribax™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved a new antimicrobial agent from the carbapenem class. Carbapenems are broad spectrum, beta lactam, antimicrobial agents. The class currently includes imipenem, meropenem, and ertapenem. The newest member, doripenem is manufactured by Shionogi & Co. Ltd in Japan and marketed by Ortho-McNeil Pharmaceuticals as Doribax.

Indications

Doripenem is indicated 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 Peptostreptocococccus micron. It is also indicated for complicated urinary tract infections, including pyelonephritis, caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.1

Dosage

The recommended adult dose is 500 mg every 8 hours given by intravenous infusion over one hour. The duration of treatment is 5-14 days for intra-abdominal infections. Appropriate oral therapy (eg, amoxicillin/clavulanate) should be considered after at least 3 days of parenteral therapy. The duration of therapy for complicated urinary tract infections is 10 days but can be extended to 14 days with concurrent bacterial infection. Dosage adjustment is required in patients with moderate or severe renal dysfunction. The recommended doses are 250 mg every 8 hours for patients with estimated creatinine clearance of 30 to 50 ml/min and 250 mg every 12 hours for >10 up to 30 ml/min.1

Doripenem is supplied as single-dose 500 mg vials.

Potential Advantages

Doripenem has improved in vitro activity against Pseudomonas aeruginosa compared to imipenem and meropenem.2,3

Potential Disadvantages

The most frequent adverse events are headache, nausea, diarrhea, rash, and phlebitis. Carbapenems in general may reduce serum concentrations of valproic acid and increase the risk of seizures. Levels of valproic acid should be monitored and alternative antibacterial or anticonvulsant therapy should be considered. Probenecid increases bioavailability of doripenem by interfering with active renal tubular excretion.1

Commentary

Doripenem is the newest member of the carbapenem beta lactam antimicrobials to be approved. Its in vitro activity against aerobic bacteria is similar to meropenem against gram-negative bacteria and to imipenem against gram-positive bacteria.4 Against anaerobic bacteria, doripenem is comparable or slightly less active than imipenem and meropenem.5 Doripenem was approved based on multinational, multicenter, double-blind, non-inferior trials compared to meropenem in complicated intra-abdominal infections and levofloxacin in complicated urinary tract infections.1 In two studies of adults with intra-abdominal infections (n = 946), doripenem (500 mg every 8 hour) and meropenem (1 g every 8 hour) for 5-14 days), with the option of oral therapy after three days, showed comparable microbiological eradication. Patients were categorized as either microbiologically evaluable (ME) or microbiologically modified intent-to-treat (mMITT). ME was defined as those with susceptible pathogens at baseline with no protocol deviations and microbiological eradication assessed 25-45 days after completion of therapy. Those with baseline pathogens regardless of susceptibility were included in the mMITT analysis. Eradication rates for ME were 81.0% and 82.8% for doripenem and 82.1% and 85.9% for meropenem. For mMITT, rates were 71.9% and 73.7% and 74.2% and 78.0% for doripenem and meropenem respectively. Similarly, doripenem was found to be non-inferior to levofloxacin (250 mg every 24 hours) in complicated urinary tract infections (n = 1171). Adverse events appear to be similar to the comparator drugs. In a study presented in poster form, doripenem (500 mg every 8 hours) was similar to imipenem (500 mg every 6 hours or 1 g every 8 hours) in terms of overall cure rate in patients with ventilator-associated pneumonia (68.3% vs 64.8%).6 Cure rate was higher for doripenem against P. aeruginosa infections (65% vs 36%). The daily cost for doripenem (500 mg every 8 hours) is $230 compared to $177 for meropenem (1 g every 8 hours).

Clinical implications

Doripenem is a new carbapenem that has not demonstrated any clinical advantage over existing therapy for complicated intra-abdominal and complicated urinary tract infections. It should be used judiciously and only for infections caused by pathogens with known or strongly suspected susceptibility to the drug.

References

1. Doribax Product Information. Ortho-McNeil Pharmaceutical, Inc. October 2007.

2. Jones RN, et al. J Antimicrob Chemother. 2004;54(1):144-154.

3. Zhanel GG, et al. Drug. 200767(7):1027-1052.

4. Ge Y, et al. Antimicrob Agents Chemother. 2004;48(4):1284-96.

5. Wexler HM, et al. Antimicrob Agents Chemother. 2005;49:4413-4417.

6. Chastre J, et al. ICAAC Conference, September 17-20, 2007. Chicago, IL (poster 1220).