555 Review www.expert-reviews.com ISSN 1478-7210 © 2011 Expert Reviews Ltd 10.1586/ERI.11.28 Carbapenems (i.e., imipenem, meropenem, ertapenem and doripenem) are among the most potent commercially available b-lactam antibi- otics. As dipolar compounds, they rapidly enter Gram-negative bacteria through outer membrane proteins (OMPs or porins) and target bacterial penicillin-binding proteins (PBPs). By interfering with peptidoglycan synthesis (i.e., cross-linking) carbapenems are bactericidal. However, the emer- gence and dissemination of carbapenem-resistant Gram-negative pathogens is becoming a signifi- cant source of healthcare-associated morbidity and mortality [1–4] . In the past decade, numer- ous reports of serious infections with carbape- nem-resistant Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter bauman- nii and more recently Enterobacteriaceae, have appeared [5–8] . At this time, despite our best efforts in infection control and antibiotic steward- ship, carbapenem-resistant pathogens remain a formidable threat to patients, as few antimicrobial agents are effective against these bacteria. Will the limited antibiotics in development be released in time to combat this threat? In the clinical setting, reliance on carba- penems paralleled the global appearance of cephalosporin-resistant or extended-spectrum b -lactamase-producing (ESBL) Klebsiella pneumoniae and Escherichia coli (late 1980s to 1990s) [9] . Unfortunately, carbapenem resistance in Enterobacteriaceae followed. Nearly a decade ago, the carbapenem-resistant phenotype was very uncommon. In a short time period, how- ever, these highly resistant bacteria became entrenched in many institutions worldwide. Similar to the epidemiology of ESBLs, infections with these bacteria are uniformly associated with prolonged hospitalization, elevated costs and increased in-hospital mortality [2–4,10] . Generally speaking, resistance to carbapenems is mediated by b-lactamases. Briefly, b-lactamases are enzymes that are ubiquitous in the bacterial world and inactivate b-lactams using water (hence, b-lactamases are hydrolases). Despite many years of study, the details in which b-lactams are destroyed by b-lactamases is the subject of intense investigation [11] . These enzymes can be intrinsic (chromosomal) or acquired (plasmid-mediated). Currently, four different types (class A–D) and nearly 900 unique b-lactamases are found in bac- teria. Two systems classify these enzymes. TABLE 1 presents the two schemes that help us understand the diversity between b-lactamases. For simplic- ity, we will employ a classification that uses classes A–D [12,13] . Class A b-lactamases can be chromosomal or plasmid-encoded and predominantly inactivate penicillins. Single amino acid substitutions Gopi Patel 1 and Robert A Bonomo †2,3 1 Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 2 Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA 3 Department of Medicine, Case Western Reserve School of Medicine, Cleveland, OH, USA † Author for correspondence: Tel.: +1 216 791 3800 ext. 4399 Fax: +1 216 231 3482 robert.bonomo@med.va.gov Antimicrobial resistance in hospital and community-onset bacterial infections is a significant source of patient morbidity and mortality. In the past decade, we have witnessed the increasing recovery of carbapenem-resistant Gram-negative bacteria. For many isolates, carbapenem resistance is due to the production of carbapenemases, b-lactamases that can inactivate carbapenems and frequently other b-lactam antibiotics. Currently, these enzymes are mainly found in three different b-lactamase classes (class A, B and D). Regardless of the molecular classification, there are few antimicrobials available to treat infections with these organisms and data regarding agents in development are limited to in vitro studies. This article focuses on the epidemiology of carbapenemase-producing Gram-negative bacteria. We also review available agents and those in development with potential activity against this evolving threat. KEYWORDS:฀antibiotic฀resistance฀•฀carbapenemase฀•฀carbapenem฀resistant฀•฀Gram฀negative฀•฀KPC฀•฀MBL฀ •฀metallo-b-lactamases฀•฀NDM-1฀•฀oxacillinase Status report on carbapenemases: challenges and prospects Expert Rev. Anti Infect. Ther. 9(5), 555–570฀(2011) For reprint orders, please contact reprints@expert-reviews.com