Doripenem: An Early Look at a Carbapenem Not Yet Approved for Pediatrics

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Doripenem (Doribax, Ortho McNeil, Jansen Pharmaceuticals) is the most recent addition to the carbapenems, a group of synthetic antibiotics structurally related to β-lactam agents which include imipenem, meropenem, and ertapenem. The importance of these agents has been heightened by the increasing frequency of drug resistant Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter species, and extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae. Many of these organisms are now involved in hospital-acquired infections such as nosocomial pneumonias (including ventilator associated pneumonias) or in outbreaks in immune compromised patients, including premature infants, recipients of solid and hematologic transplants, children treated with immune suppressive therapies, and infections occurring in the pediatric intensive care unit.The in vitro activity of the carbapenems drugs have been well described and their comparative activity has been highlighted in several recent publications.1,2 However, with the exception of the older agents, imipenem and meropenem, the pharmacologic characteristics of these agents in children and neonates have received relatively meager attention Therefore, this review will focus on the in vitro and comparative activity of Doripenem with that of the other agents.PHARMACOLOGYPharmacologic and postlicensure studies of doripenem in children has been initiated. The package insert clearly states that the “safety and efficacy in pediatrics patients has not been studied.”3 Doripenem intended for use in adults is provided in single-use vial as 500 mg for intravenous use. The dosage recommendation for persons equal to, or greater than, 18 years of age is for 500 mg every 8 hours with infusion of the dose to be given in one hour. Significant dosage reductions are recommended for persons with reduced creatinine clearance to 250 mg every 8 hours and 250 mg every 12 hours for persons with creatinine clearance of ≥30 to 50 and >10 to <30 mL/min, respectively. Approximately 50% of the dose is removed during 4 hours of hemodialysis. Mean plasma concentration in adults following a 500 mg infusion is 23 mcg/mL. Doripenem has high penetration in peritoneal fluids and is primarily excreted by active glomerular filtration and tubular secretion. Approximately 70% of a dose is excreted unchanged in urine and 15% as the “ring-opened” metabolite; this metabolite forms as a result of urinary dehydropeptidase I, similar, but to a lesser degree than of imipenem.Reported adverse reactions include those similar to other related compounds,3,4 including hypersensitivity reactions, including anaphylaxis, and toxic epidermal necrolysis (Steven, Johnson syndrome), as well as mild to moderate phlebitis, headache, nausea, diarrhea, and rash. In addition, neutropenia and leucopenia have been reported. Other clinical and laboratory abnormalities noted during treatment course have included mild elevations in ALT and AST, mild thrombocytopenia, elevated eosinophil counts, and diarrhea. The package insert includes a precautions for the occurrence of mild to severe (including fatalities) Clostridium difficile associated colitis or diarrhea. Because of the occurrence of moderately severe pneumonitis with the aerosolized administration of doripenem, this route is listed as a contraindicated.The coadministration of doripenem with sodium valproate or valproic acid reduces the serum concentration of valproic acid. Reductions of the serum level of valproic acid below the therapeutic level (50–100 mcg/mL) occurs within 12 hours of initiating therapy.3 Case reports of a similar reduction in valproic acid has been noted with other carbapenems. Therefore, patients with seizure disorders controlled with valproic acid are at an increased risk of breakthrough seizures, during the administration of doripenem. However, in experimental animal studies conducted in the 1990s carbapenems induce seizure discharges caused by a lowering of a gamma-aminobutyric acid receptor antagonist.

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