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Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems

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Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems A 2-Part Series on Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems Date of Release: August 2007 Expiration Date: August 31, 2008 FACULTY Lena M. Napolitano, MD, PROGRAM OVERVIEW Rising rates of nosocomially acquired multidrug-resistant (MDR) Gram- negative pathogens have drastically narrowed the spectrum of available therapeutic options. FACS, FCCP, FCCM Resistance to antimicrobials is a mounting health concern, both in the United States and world- Professor of Surgery wide. Infections caused by resistant Gram-negative pathogens, such as Pseudomonas aeruginosa Division Chief, Acute Care Surgery and Acinetobacter baumannii, result in higher morbidity, mortality, prolonged hospitalization, and Trauma, Burn, Critical Care, increased costs compared with sensitive strains. Carbapenems possess high potency against a Emergency Surgery broad spectrum of organisms and are regarded as the agents of choice for serious infections with Associate Chair of Surgery for extended-spectrum β-lactamase–producing organisms. However, increased prevalence of pan- Critical Care resistant P. aeruginosa and A. baumannii strains worldwide has limited the utility even of the car- Department of Surgery bapenems. To reduce the likelihood of emergence of resistance, clinical practice guidelines have Director, Surgical Critical Care been developed to direct antimicrobial treatment of nosocomial infections. Initial empiric therapy University of Michigan Health System should offer broad-spectrum coverage of Gram-negative pathogens, and therapy should be tai- Ann Arbor, Michigan lored and de-escalated after positive culture results are obtained. Although the polymyxins have been reintroduced, particularly as a last-line treatment of MDR Gram-negative pathogens, hetero- Robert C. Owens, Jr, PharmD resistance to these agents has already been documented, highlighting the need for more appro- Co-Director, Antimicrobial priate use of antimicrobials to minimize suboptimal outcomes. Stewardship Program Doripenem, a novel, broad-spectrum carbapenem, offers impressive in vitro activity and clinical Clinical Pharmacy Specialist, efficacy against P. aeruginosa and A. baumannii (including many MDR strains). Doripenem is Infectious Diseases well tolerated and its effects on the central nervous system are negligible. This special report pro- Department of Pharmacy Services files the properties of the carbapenem class, emphasizes key principles of clinical practice guide- and Division of Infectious Diseases lines for antimicrobial treatment selection and use, and reviews doripenem, the pending addition Maine Medical Center to the carbapenem class. Portland, Maine Clinical Assistant Professor LEARNING OBJECTIVES After reviewing this supplement, participants should be able to: Department of Medicine 1 Discuss the impact of resistant Gram-negative organisms on outcomes and management University of Vermont‚ College strategies in critically ill patients with pneumonia and intra-abdominal infections. of Medicine 2 Choose appropriate guideline-based treatments for infections caused by resistant Gram- Burlington‚ Vermont negative pathogens in critically ill patients. John P. Quinn, MD, FACP 3 Review features of available carbapenem agents. Professor of Medicine 4 Evaluate the utility of new agents to combat infections resulting from P. aeruginosa and Rush University A. baumannii. Stroger Hospital of Cook County 5 Weigh the benefits and risks of each carbapenem-based treatment in managing infections in Scientific Director the intensive care unit. Chicago Infectious Disease Research Institute TARGET AUDIENCE This activity has been developed for critical care physicians and surgical Chicago, Illinois critical care physicians. Andrew F. Shorr, MD, MPH ACCREDITATION University of Kentucky College of Medicine Associate Director, Pulmonary and This activity has been planned and implemented in accordance with the Essential Areas and poli- Critical Care Medicine cies of the Accreditation Council for Continuing Medical Education through the joint sponsorship Associate Professor of Medicine of the University of Kentucky College of Medicine and Rxperience. The University of Kentucky Washington Hospital Center College of Medicine is accredited by the ACCME to provide continuing medical education for Washington, DC physicians. The University of Kentucky College of Medicine designates this educational activity for a maxi- mum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the presentation is provided solely by presenters who have been selected for presentations because of recognized expertise in their field. Supported by an educational grant Jointly sponsored by the Distribution via: from Ortho-McNeil, Inc. University of Kentucky College of Medicine and Rxperience. INFECTIOUS DISEASE SPECIAL EDITION FACULTY AND SPONSOR DISCLOSURE All faculty members participating in continuing medical education programs sponsored by the University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office are expected to disclose any real or perceived conflict of interest related to the content of their presentations. Significant relationships exist with the following companies/organizations whose products or services may be discussed: Lena M. Napolitano, MD, FACS, FCCP, FCCM, has disclosed that she is a member of the speakers’ bureaus of and has accepted consultant fees from Merck & Co, Inc, Ortho-McNeil, Inc, Pfizer Inc, and Schering-Plough Corporation. Robert C. Owens, Jr, PharmD, has disclosed that he has accepted consultant fees from Elan Corporation, plc, Ortho-McNeil, Inc, and Schering-Plough Corporation. John P. Quinn, MD, FACP, has disclosed that he has accepted research grants and consultant fees from Roche and that he has accepted research grants and consultant fees from, and is a member of the speakers’ bureaus of, Cubist Pharmaceuticals, Johnson & Johnson, and Merck & Co, Inc. Andrew F. Shorr, MD, MPH, has disclosed that he has accepted research grants and consultant fees from, and is a member of the speakers’ bureaus of, Astellas Pharma US, Inc, AstraZeneca, GlaxoSmithKline, Ortho-McNeil, Inc, Pfizer Inc, and sanofi-aventis. Additionally, he is a member of the speakers’ bureaus of Boehringer International and Merck & Co, Inc. The University of Kentucky is an equal opportunity university. The content for this activity was provided by Rxperience. Introduction to Carbapenem Agents class include doripenem, ertapenem, faropenem, imipenem, meropenem, and panipenem/betamipron.10 The molecular Gram-negative pathogens belonging to the Pseudomonas structures of doripenem, ertapenem, imipenem, and meropen- and Acinetobacter species are prevalent and important caus- em are depicted in Figure 1. es of nosocomial infections among critically ill patients. The first carbapenem that was developed, imipenem, is Acquired mechanisms of resistance that exhibit multiple, active against a broad spectrum of pathogens. Imipenem is diverse actions have caused some strains of these pathogens coadministered with cilastatin—an inhibitor of human renal to be much more difficult to treat.1,2 The continuing increase in dehydropeptidase I—because imipenem is hydrolyzed by this antimicrobial resistance across US hospitals remains a major enzyme.10 Imipenem is indicated for hospitalized patients with concern for patients, clinicians, and public health officials.3 intra-abdominal infections (IAIs), lower respiratory tract infec- Outbreaks of nosocomial infection caused by Gram-nega- tions, gynecologic and genitourinary tract infections, skin and tive pathogens are not isolated, regional occurrences but soft tissue infections (SSTIs), sepsis, and endocarditis. Imipen- rather worldwide events and have most recently reached pro- em is considered an appropriate empirical treatment when portions of a global health issue.4 Based on in vitro and clinical there is a high likelihood of infection with resistant pathogens data, carbapenems have been and continue to be the agents or multiple organisms, including aerobes and anaerobes. The of choice for serious infections with extended-spectrum β-lacta- plasma half-life of imipenem is approximately 1 hour, and it is mase (ESBL)–producing organisms.5 However, resistance to β- 10% to 20% protein bound. The most common adverse effects lactam antimicrobials, including carbapenems, is increasing of imipenem include phlebitis, thrombophlebitis, nausea, diar- among strains of Pseudomonas aeruginosa and Acinetobac- rhea, and vomiting. This agent is not indicated for central ner- ter baumannii, leaving clinicians with a dearth of viable thera- vous system (CNS) infections because of its proconvulsive peutic options to treat nosocomially acquired Gram-negative activity.13 infections. Interestingly, the polymyxins have been resurrected Meropenem is a carbapenem that has activity against Gram- as last-resort treatments for patients infected with multidrug- negative, Gram-positive, and anaerobic microorganisms. As is resistant (MDR) pathogens.1 However, increased use of imipenem, meropenem is highly resistant to hydrolysis by most polymyxins will likely lead to emergence of resistance, thus of the
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