Pharmacy & Therapeutics - March 2008 - (Page 134) DRUG FORECAST Doripenem (Doribax), a New Carbapenem Antibacterial Agent Olga Hilas, PharmD, BCPS, CGP; Danielle C. Ezzo, PharmD, BCPS; and Tomasz Z. Jodlowski, PharmD, BCPS INTRODUCTION Carbapenems represent a class of beta-lactam antibacterial agents with a broad spectrum of activity against grampositive, gram-negative, and anaerobic bacteria. This class is bactericidal in nature, but it does not cover species of Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), or Stenotrophomonas maltophilia. Collectively, the carbapenems have been used to treat a variety of infections. As with all antibiotics, resistance within the carbapenem class is a major concern. Although carbapenems remain the drugs of choice for extended-spectrum, beta-lactamase–producing organisms, resistance may emerge via other betalactamases, such as metallo–betalactamases, alteration of porin channels, or up-regulation of efflux pumps. Therefore, carbapenems should be used judiciously, and the appropriate use of these agents must be considered carefully.1,2 The Food and Drug Administration (FDA) has approved four carbapenems: • imipenem (a primary component of Primaxin IM, Merck) • meropenem (Merrem IV, Astra Zeneca) • ertapenem (Invanz, Merck) • doripenem (Doribax, Ortho-McNeil) Imipenem and meropenem are veteran agents of the carbapenem class and are used primarily to treat moderate-tosevere nosocomial and polymicrobial infections, including intra-abdominal infections, nosocomial pneumonia, septicemia, and febrile neutropenia. Imi penem possesses slightly more potent in vitro activity against gram-positive pathogens, whereas meropenem possesses slightly more potent in vitro activity against gram-negative pathogens, including Pseudomonas aeruginosa. Imipenem has a greater tendency to precipitate seizures; thus, caution must be taken, particularly among patients with impaired renal function. This carbapenem is also extremely susceptible to degradation via the enzyme dehydropeptidase-1 (DHP-1). In order to resolve this problem and ensure stability, the DHP-1 inhibitor cilastatin is used concomitantly with imipenem. The combination of imipenem/cilastatin is commonly known by its brand name, Primaxin IM.1,3,4 Compared with other carbapenems, ertapenem displays a decrease in activity against nosocomial infections associated with Enterococcus spp., Acinetobacter spp., and P. aeruginosa. Comparative trials have confirmed that ertapenem has comparable efficacy with piperacillin/ tazobactam (Zosyn, Wyeth) and ceftriaxone (Rocephin, Roche) for the treatment of complicated intra-abdominal infections, acute pelvic infections, complicated surgical-site infections, community-acquired pneumonia, complicated urinary tract infections (UTIs), and diabetic foot infections. Disclosure: The authors have no financial relationships to report in regard to this article. Ertapenem is used and clinically suitable primarily for the empirical coverage of severe infections when Acinetobacter spp. and P. aeruginosa are the unlikely causes of suspected infections. It is also preferred for outpatient use as a result of its favorable pharmacokinetic profile. However, ertapenem must be prescribed with caution because of its potential overuse, which may lead to an increase in resistance of this class of antimicrobials.1,4 In October 2007, the FDA approved the most recent addition to the carbapenem class, doripenem (Doribax). Doripenem seems to most closely resemble the profile of meropenem, except for its increased potency of in vitro activity against P. aeruginosa. It is indicated for patients with complicated intra-abdominal infections and UTIs, including pyelonephritis, when the infection is caused by susceptible bacteria.5–7 PHARMACOLOGY AND MECHANISM OF ACTION1,2,7,8 Carbapenems display bactericidal activity against gram-positive, gramnegative, and anaerobic bacteria, and they are stable to most beta-lactamases. Carbapenems cause bacterial cell death by inhibiting cell wall synthesis via inactivation of penicillin-binding proteins. Doripenem displays bactericidal action against susceptible species, stability to human renal DHP and beta-lactamases (including extended spectrum beta-lactamases [ESBLs], pharmacokinetic and pharmacodynamic profiles similar to meropenem (including minimal risk of seizure as an adverse reaction), postantibiotic effects in vitro against P. aeruginosa (about two hours), and low protein binding. Dr. Hilas is Assistant Clinical Professor of Clinical Pharmacy Practice at St. John’s University College of Pharmacy and Allied Health Professions in Queens, New York, and Clinical Coordinator of Internal Medicine/Geriatrics at New York-Presbyterian Hospital,Weill Cornell Medical Center, in New York. Dr. Ezzo is Assistant Clinical Professor of Clinical Pharmacy Practice at the same college and Clinical Coordinator of Ambulatory Care at Long Island Jewish Medical Center in New Hyde Park, NewYork. Dr. Jodlowski is Assistant Clinical Professor at the same college and Clinical Coordinator of Internal Medicine at Jacobi Medical Center in Bronx, New York. Drug Forecast is a regular department coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York. PHARMACOKINETICS AND PHARMACODYNAMICS6,7 In phase 1 trials, 125 to 1,000 mg of doripenem, when given by intravenous (IV) infusion, resulted in a mean maxi- 134 P&T® • March 2008 • Vol. 33 No. 3
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