Extended-Spectrum-β-Lactamase, AmpC, and Carbapenemase Issues

Optimal use of microbiology laboratories is essential to combat the spread of multiply antibiotic-resistant pathogens. This is vital for patient care, as advocated by Jarvis in stressing the importance of active detection and isolation to control methicillin-resistant Staphylococcus aureus and other resistant hospital-acquired pathogens (17). It is also vital for hospital accreditation in the United States, where the Joint Commission has set requirements for the control of acquisition and transmission of multidrug-resistant organisms (http: //www.jointcommission.org/NR/rdonlyres/31666E86-E7F4-423E -9BE8-F05BD1CB0AA8/0/HAP_NPSG.pdf-NPSG.07.03.01). These requirements cannot be met without excellence in diagnostic microbiology. The absence of new, effective anti-gram-negative antibiotics makes infection control the most important countermeasure against multidrug-resistant gram-negative pathogens. Infection control can prevent additional infections and the spread of resistant pathogens and thereby reduce the need to use antibiotics. Infection control is most effective when directed by rapid, accurate laboratory results. In short, excellence in diagnostic microbiology is critical to quality initiatives in hospitals. Some resistant pathogens may not be recognized because they are falsely susceptible in routine tests. This can lead to patients receiving ineffective antibiotics and contribute to the spread of the pathogens. Because the detection of such “hidden” resistance is so critical, this Commentary focuses on its detection in gram-negative pathogens. Because susceptibility tests may be unreliable, special tests are required to detect the resistance mechanisms involved. The mechanisms include extended-spectrum -lactamases (ESBLs), AmpC -lactamases, and carbapenemases of molecular classes A and B. ESBLs ESBLs are typically inhibitor-susceptible -lactamases that hydrolyze penicillins, cephalosporins, and aztreonam and are encoded by mobile genes. The most frequently encountered ESBLs belong to the CTX-M, SHV, and TEM families. ESBL producers are usually multiply drug resistant (5, 30), but their cephalosporin and aztreonam resistance is not reliably detected by susceptibility tests (33). Many labs have adopted CLSI recommendations and only attempted to detect ESBLs in Escherichia coli, Klebsiella pneumoniae, K. oxytoca, and Proteus mirabilis (8). Since ESBL genes are transmissible, it is important that ESBLs be tested for in other organisms in hospital and long-term care facility patient populations where ESBLs are encountered. This may be unnecessary for community isolates, which at this time appear to be predominantly CTX-M-producing E. coli. The need for ESBL detection is under challenge on the supposition that it is possible to set breakpoints for injectable cephalosporins and aztreonam that accurately discriminate which ESBL-producing isolates can and cannot be reliably treated with these drugs. This approach is controversial (19) but has been adopted in slightly different forms by the European Committee on Antimicrobial Susceptibility Testing and the CLSI. It is based on limited therapeutic outcome data (3, 31), pharmacokinetic/pharmacodynamic data (3), and the concept that the lower the cephalosporin MIC the greater the