The Current State of Multidrug-Resistant Gram-Negative Bacilli in North America

Anthony M. Nicasio, PharmD.; Joseph L. Kuti, PharmD.; David P. Nicolau, PharmD., FCCP


Pharmacotherapy. 2008;28(2):235-249. 

In This Article

Abstract and Introduction


Although much of today's media focuses on multidrug-resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, resistance within gram-negative bacilli continues to rise, occasionally creating situations in which few or no antibiotics that retain activity are available. Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella sp are emerging threats nationally. Although carbapenems are considered the antibiotic class of choice to treat ESBL-producing Enterobacteriaceae, the ability of these organisms to produce carbapenemases has now become apparent in some regions throughout the United States. Although still rare, Klebsiella sp that produce KPC-2 retain susceptibility only to tigecycline, polymyxins, and occasionally aminoglycosides. Multidrug resistance among Pseudomonas aeruginosa and Acinetobacter sp has always been apparent across many hospitals in the United States. Recent surveillance indicates increasing resistance to all currently available antibiotics, including carbapenems, cephalosporins, penicillins, fluoroquinolones, and aminoglycosides. Against many strains, only polymyxins retain activity; however, resistance has also been reported to these agents. Fortunately, resistance mechanisms such as metallo-β-lactamases are still rare in the United States. As no new antibiotics with novel mechanisms against many of these gram-negative bacilli are expected to be developed in the foreseeable future, careful and conservative use of agents combined with good infection control practices is required.


Bacterial resistance is an ever-evolving survival tactic that has enabled bacteria to outlast available antibiotics. Even in the early days of antibiotics, resistance within Staphylococcus aureus was documented soon after the introduction of penicillin (i.e., penicillinase-producing S. aureus) and methicillin (i.e., methicillin-resistant S. aureus [MRSA]).[1,2] Although multidrug resistance among gram-positive organisms, such as MRSA and vancomycin-resistant Enterococcus, has stolen much of the media attention and caused the pharmaceutical industry to focus efforts on developing novel antibiotics to combat these organisms, perhaps a more concerning event has been developing simultaneously—that is, multidrug resistance among gram-negative bacilli. Gram-negative organisms still account for most of the nosocomial infections, including pneumonia, skin infections, intraabdominal sepsis, and urosepsis, and are reemerging as a significant cause of bloodstream infections.[3,4]

Resistance among gram-negative bacilli is not necessarily a new phenomenon. The first report of enzymes in Escherichia coli that were able to inactivate penicillin was presented early after the introduction of the drug in the 1940s.[5] Organisms such as Pseudomonas aeruginosa have always had a unique ability to evade new antimicrobial therapies and develop resistance; however, where resistance did develop, usually at least a few other therapeutic options were available for treatment. More recently, panresistant gram-negative bacilli have been documented at hospitals globally, and although still infrequent, such strains are beginning to emerge in the United States. Besides the glycylcyclines, there is notable concern with the limited amount of new antimicrobial classes developed in the last 20 years.[6] As noted by the Infectious Diseases Society of America's "Bad Bugs, No Drugs" campaign, during the next decade, no new antimicrobial classes are expected to be developed to target some of these multidrug-resistant gram-negative bacilli.[7]

In addition to this unfortunate situation, concern revolves around the types of gram-negative bacilli that have obtained or developed this resistance. For instance, nonfermenting gram-negative bacteria such as P. aeruginosa and Acinetobacterbaumannii are now multidrug resistant, which is defined as resistant to three or more of the following antibiotic classes: β-lactams, including penicillins, cephalosporins, and monobactams; carbapenems; fluoroquinolones; and aminoglycosides. Even more concerning, these bacteria can be panresistant, defined as resistant to all available antibiotic options.[8] Meanwhile, once easily treatable organisms such as E. coli and Klebsiella sp now harbor resistance mechanisms, which make them nearly panresistant. Increased patient mortality, prolonged length of hospitalization, and greater hospital costs have resulted.[9,10] In the United States, health care costs associated with multidrug resistance in general have been estimated at several billion dollars.[6]


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