Health care-associated infections are the leading cause of mortality in acute care hospitals, with over 50% of them due to infections caused by multidrug-resistant (MDR) bacteria. These resistant pathogens result in a number of disturbing sequelae including increased morbidity, increased mortality, prolonged hospitalizations, and increased medical cost. Common nosocomial gram-negative organisms (e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter species) are adept at acquiring genes that confer resistance to a variety of classes of antimicrobial agents. Moreover, there has been a dramatic decline in the discovery and development of antimicrobial agents active against gram-negative microorganisms in the past two decades. We are now in the presence of gram-negative bacilli (GNB) that are resistant not only to first-line antimicrobials (amikacin, tobramycin, cefepime, ceftazidime, imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, moxifloxacin, and levofloxacin) but also to second-line agents such as tigecycline and polymyxins.^1,2

The Infectious Diseases Society of America has identified six top-priority perilous pathogens for which there are few effective drugs surfacing in the near future. These pathogens are termed ESKAPE (extended-spectrum beta-lactamase [ESBL]-producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and vancomycin-resistant Enterococcus faecium), four of which are GNB.

The principle cause of antimicrobial resistance is inappropriate antimicrobial use, though other factors play a part as well, including population demographics, patient compliance, comorbidities, poor infection control, increased travel, and alcohol and drug abuse. Doctors prescribe over 133 million courses of antibiotics in an outpatient setting and over 190 million courses in a hospital setting.3 Risk factors for developing MDR GNB include age over 65 years, hospitalization in the preceding 90 days, recent antibiotic use, residence in a nursing home or long-term treatment facility, fecal incontinence, chronic indwelling catheter or feeding tube, mechanic ventilation, and/or long-term hemodialysis.⁴

Table 38-1 demonstrates the four major types of MDR GNB resistance mechanisms: (1) production of enzymes that destroy the integrity of the antibiotic (e.g., ESBL-producing and carbapenemase-producing Enterobacteriaceae), (2) mutations in the
antimicrobial binding site (e.g., DNA gyrase and topoisomerase mutations causing resistance to fluoroquinolones), (3) down-regulation of outer membrane proteins (e.g., imipenem-resistant P. aeruginosa), and (4) efflux pumps that efficiently remove an antibiotic from the cell.

ESBL enzymes are perhaps the most common clinically significant mechanism of resistance demonstrated by all gram-negative bacteria. ESBLs are beta-lactamases that are able to hydrolyze the penicillins, cephalosporins, and monobactams but not the cephamycins or carbapenems. The plasmids carrying the ESBLs frequently also carry resistant genes for other antimicrobial agents, so that resistance to fluroquinolones and aminoglycosides frequently coexist with resistance to penicillins and cephalosporins. Suspicion for ESBLs should be high in elderly patients with comorbid conditions, recent hospitalization(s), invasive devices, and/or recent use of broad-spectrum antibiotics (quinolones, cephalosporins).⁵ Carbapenemases are the beta-lactamases with the broadest gamut of activity. The plasmid-borne Klebsiella pneumoniae carbapenemases (KPCs) are among the most widely recognized and prevalent. The recommended method for detecting carbapenemases is the modified Hodge test, which is labor intensive and requires an additional day to perform, making the detection of carbapenemases rather difficult. The Clinical and Laboratory Standards Institute (CLSI) has recently lowered the breakpoints that define susceptibility of Enterobacteriaceae in an effort to improve the screening process for detection of carbapenemases. The recent discovery of the New Dehli metallo-beta-lactamase (NDM-1) in Enterobacteriaceae is concerning as this class of beta-lactamase confers resistance to all beta-lactam drugs, including carbapenems. NDM-1 is transmitted on plasmids that frequently cotransmit resistance genes to fluoroquinolones and aminoglycosides. Other metallo-beta-lactamases are prevalent in P. aeruginosa, A. baumannii, and Stenotrophomonas maltophilia (Table 38-1).