General Information

Doribax is a synthetic, parenteral carbapenem antibiotic. It targets penicillin-binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall.

Doribax is specifically indicated for the treatment of the following infections caused by designated susceptible bacteria: complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Doribax is supplied as a solution designed for intravenous infusion. The initial recommended dose of the drug for complicated intra-abdominal infections is 500 mg administered every 8 hours, by intravenous infusion over one hour, in patients 18 years of age or older, for 5 to 14 days. The initial recommended dose of the drug for complicated urinary tract infections is 500 mg administered every 8 hours, by intravenous infusion over one hour, in patients 18 years of age or older, for 10 days. This may be extended to 14 days for patients with concurrent bacteremia.

Clinical Results

FDA Approval
FDA approval of Doribax was based on the results of four clinical trials.

Complicated intra-abdominal infections
Two identical, multinational, multi-center, randomized, double-blind studies enrolled a total of 946 adult subjects. The subjects received Doribax (500 mg administered over 1 hour every 8 hours) or meropenem (1 g administered over 3-5 minutes every eight hours). Subjects in both treatment arms were given the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg twice daily) after a minimum of 3 days of intravenous therapy for a total of 5-14 days of intravenous and oral treatment. Doribax was shown to be non-inferior to meropenem in clinical cure rates 25-45 days post-treatment. In the microbiologically evaluable population enrolled in Study 1, the Doribax clinical cure rate was 82.8% and in the meropenem arm the clinical cure rate was 85.9%, a -3.1 treatment difference. In the microbiologically evaluable population enrolled in the Study 2, the Doribex clinical cure rate was 81% and the meropenem clinical cure rate was 82.1%, a treatment difference of -1.1.

Complicated urinary tract infections
Two multi-center, multinational studies enrolled a total of 1,171 subjects. One study was double-blind and compared Doribax (500 mg administered over 1 hour every eight hours) to IV levofloxacin (250 mg administered every 24 hours). The second study had a similar design but was a non-comparative study. Subjects enrolled in both trials had the option of switching to oral levofloxacin (250 mg every q24h) after a minimum of 3 days of IV therapy for a total of 10 days of treatment. The subjects with confirmed concurrent bacteremia were allowed to receive 500 mg of IV levofloxacin (either IV or oral as appropriate) for a total of 10 to 14 days of treatment. Doribax was non-inferior to levofloxacin with regard to the microbiological eradication rates in microbiologically evaluable (ME) subjects 5-11 days post-treatment. In the microbiologically evaluable population, the eradication rate for the Doribax arm was 82.1% and in the Levofloxacin arm the eradication rate was 83.4%, a -1.3 treatment difference.

Mechanism of Action

Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

Literature References

Credito KL, Ednie LM, Appelbaum PC COMPARATIVE ANTI-ANAEROBIC ACTIVITY OF DORIPENEM BY MIC AND TIME-KILL ANALYSIS. Antimicrobial agents and chemotherapy 2007 Oct 15

Hori T, Nakano M, Kimura Y, Murakami K Pharmacokinetics and tissue penetration of a new carbapenem, doripenem, intravenously administered to laboratory animals. In vivo 2006 Jan-Feb;20(1):91-6

Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2005 Dec;11(12):974-84.

Bhavnani SM, Hammel JP, Cirincione BB, Wikler MA, Ambrose PG Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem. Antimicrobial agents and chemotherapy 2005 Sep;49(9):3944-7

Jones RN, Huynh HK, Biedenbach DJ Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrobial agents and chemotherapy 2004 Aug;48(8):3136-40

Nomura S, Nagayama A In vitro antibacterial activity of S-4661, a new parenteral carbapenem, against urological pathogens isolated from patients with complicated urinary tract infections. Journal of chemotherapy 2002 Apr;14(2):155-60