Overview of Seizure-Inducing Potential of Doripenem
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The seizure-inducing potential of carbapenems has been debated since the introduction of imipenem/cilastatin over 20 years ago. Doripenem is a new carbapenem, recently approved in the US for the treatment of adults with complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI), and additionally in the EU for nosocomial pneumonia, including ventilator-associated pneumonia. Here, the seizure-inducing potential of doripenem is evaluated, using data from in vitro and in vivo animal studies, doripenem clinical trials and doripenem postmarketing reports of seizures. Animal studies indicate that doripenem has low binding affinity for GABA receptors and does not induce seizures at doses greater than seizureinducing doses of imipenem or meropenem. In clinical studies of cUTI or cIAI, no seizures were reported in the 1332 patients treated with doripenem (500-mg infusion every 8 hours). In two studies, patients with nosocomial pneumonia were treated with doripenem 500 mg (1-or 4-hour infusion every 8 hours), and the incidence of seizures was lower for doripenem (1.2% [6/485]) than imipenem (3.8% [10/263]) or piperacillin/tazobactam (2.7% [6/221]). For patients with seizure-predisposing conditions, seizures occurred during treatment for 3/193 (1.5%) in doripenem, 1/66 (1.5%) in piperacillin/ tazobactam and 6/116 (5.2%) in the imipenem group. The review of data from both clinical trials and postmarketing surveillance supports the low seizureinducing potential of doripenem. The seizure potential of doripenem should be evaluated further in patients at increased risk for seizure.
KeywordsValproic Acid Imipenem Meropenem Bacterial Meningitis Carbapenems
Acknowledgements Johnson & Johnson Pharmaceutical Research & Development, LLC, provided funding for the design and conduct of the doripenem clinical studies discussed in the manuscript, including collection, management, and analysis of the data. Drs Ketter, Redman and Friedland are full-time employees of the company. Dr Zhanel has received grants from Abbott, Astellas Pharmaceuticals, Bayer, Merck, Ortho-McNeil, Wyeth, Targanta Therapeutics, Affinium Pharmaceuticals and Pfizer. Dr Rubinstein has no conflicts of interest that are directly relevant to the content of this manuscript. Diane Hedrich, MEd, and Bradford Challis, PhD, of Johnson & Johnson Pharmaceutical Research and Development, L.L.C., provided writing and editorial assistance during preparation of the manuscript. The doripenem clinical phase III studies are registered at http://www.ClinicalTrials.gov (DORI-05: NCT00229021; DORI-06: NCT00210990; DORI-07: NCT00210938; DORI-08: NCT00229060; DORI-09: NCT00211003; DORI 10: NCT00211016). Some of the data contained in this manuscript were presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 27–30 September 2006, San Francisco, CA; 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, 17–20 September 2007, Chicago, IL; and 48th Annual ICAAC/IDSA 46th Annual Meeting, 25–28 October 2008, Washington, DC.
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