Extended-Spectrum ß-Lactamases: Epidemiology, Detection, and Treatment

, and College of Pharmacy, University of Texas at Austin, Austin, Texas, and the Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Pharmacotherapy. 2001;21(8) 

In This Article

Problems Associated with ESBLs

Resistance

As previously described, ESBL enzymes are plasmid mediated, meaning that genes encoding these enzymes are located on plasmids and are easily transferable among different bacteria. Most of these plasmids not only contain DNA encoding ESBL enzymes but also carry genes conferring resistance to several non-ß-Lactam antibiotics.[3,4] Consequently, most ESBL isolates are resistant to many classes of antibiotics. The most frequent coresistances found in ESBL-producing organisms are aminoglycosides, fluoroquinolones, tetracyclines, chloram-phenicol, and sulfamethoxazole-trimethoprim.[2,3,4,31] Treatment of these multidrug-resistant organisms is a therapeutic challenge.

Detection

Identifying organisms that are ESBLs is a major challenge for the clinical microbiology laboratory. Due to the variable affinity of these enzymes for different substrates and the inoculum effect, some ESBL isolates may appear susceptible to a third-generation cephalosporin in vitro. However, treatment of infections due to an ESBL-producing organism with third-generation cephalosporins may result in clinical failure if the infection is outside the urinary tract.[32] For example, a K. pneumoniae strain that harbors the TEM 26 enzyme may appear resistant to ceftazidime (MIC > 256 µg/ml) but sensitive to cefotaxime (MIC 0.5 µg/ml) in vitro.[33] If cefotaxime is used to treat that infection, treatment failure is likely. This is due to the fact that TEM 26 is highly effective in inactivating ceftazidime, even at low colony counts. However, with the higher colony count frequently found at infection sites, the enzyme can inactivate cefotaxime and render the drug ineffective, resulting in a several-fold increase in MIC. Despite in vitro susceptibilities, reports of failures in both animal models and clinical settings are well documented when third-generation cephalosporins are used to treat ESBL infections, unless the infection is confined to the urinary tract.[8,17,34,35]

Using the susceptibility of an isolate against third-generation cephalosporins as an indicator for ESBL production is unreliable, due to the variable affinity of enzymes for different substrates. Cefpodoxime and ceftazidime have been proposed as indicators of ESBL production, since most ESBL enzymes found in North America have high affinity for these agents.[35] Cefotaxime or ceftriaxone alone are poor indicators for ESBL detection, since only a small number of ESBL-producing organisms will appear resistant to these agents in vitro.[36] Hence, an institution in which cefotaxime or ceftriaxone is the only third-generation cephalosporin used in the routine sensitivity testing panel may have difficulty in detecting ESBLs.

Current susceptibility testing methods are inefficient at detecting ESBLs.[37,38] Sensitivity breakpoints designated in the National Committee for Clinical Laboratory Standards (NCCLS) guidelines for Klebsiella sp and E. coli against cefotaxime, ceftriaxone, and ceftazidime are less than or equal to 8 µg/ml for susceptibility.[36] Some ESBL-producing organisms may have increased MICs against these agents compared with those of non-ESBLs isolates. However, the increased MICs are still lower than the cut-off value for susceptibility. The extent of this problem with regard to ceftazidime susceptibility remains unclear. However, it is conceivable that a significant portion of ESBL-producing organisms may have elevated MICs to ceftazidime that do not reach the NCCLS breakpoint for resistance (MIC > 8 µg/ml) and therefore may be incorrectly dismissed as non-ESBL-producing organisms. As a result, a clinician may be faced with a misleading sensitivity report, which in turn may lead to inappropriate selection of treatment.

The NCCLS has dedicated considerable effort in the past few years to standardizing methods for reliable recognition of ESBLs. Hence, the newest NCCLS guidelines recommend screening Klebsiella sp and E. coli isolates with a MIC greater than or equal to 2 µg/ml against cefpo-doxime, ceftazidime, aztreonam, cefotaxime, or ceftriaxone (order of preference for greatest sensitivity of detecting ESBL in North American strains) as potential ESBL producers.[36] The guidelines recommend using changes in MICs or changes in the sizes of the zone of inhibition of an isolate against cefpodoxime, ceftazidime, cefotaxime, or ceftriaxone in the absence and presence of ß-Lactamase inhibitor (clavulanic acid) as criteria to determine the presence of ESBLs. Two indicators of ESBLs are an 8-fold MIC reduction in the presence of clavulanic acid when using the broth dilution method, and the potentiation of the inhibition zone by clavulanic acid (> 5-mm increase in diameter of inhibition zone) when using the disk diffusion method.[35] For example, an isolate with an MIC of 16 µg/ml against ceftazidime but an MIC of 2 µg/ml when ceftazidime plus clavulanate is tested, indicates the presence of an ESBL enzyme. These methods are useful in detecting TEM and SHV ESBLs; however, they may not be useful in detecting ESBLs that are poorly inhibited by ß-Lactamase inhibitors, which are rare in the U.S. Once an isolate tests positive by confirmatory test (broth dilution or disk diffusion), the isolate should be reported as resistant to all penicillins, aztreonam, and the true cephalosporins.

Two recent studies evaluated the ability of clinical laboratories to detect and report the presence of ESBLs in either Klebsiella isolates or E. coli. A survey in Connecticut found that 21% of laboratories failed to detect ESBL-producing isolates.[37] A proficiency testing project for clinical laboratories participating in the National Nosocomial Infections Surveillance System indicated that as many as 58% of laboratories failed to detect and report ESBL isolates correctly.[38] These data suggest that improvements in the ability of clinical laboratories to detect ESBLs are needed. In addition, clinical pharmacists should be aware of the capability of the clinical laboratory in their hospital with regard to ESBL testing.

Testing for the presence of ESBLs using techniques recommended by the NCCLS guidelines is not easily performed in clinical practice. Fortunately, automated testing systems designed to detect ESBLs recently were approved by the Food and Drug Administration and are now commercially available (Vitek and Microscan). Another product that is effective in ESBL detection is ESBL Etest (AB Biodisk). All of these testing methods have been shown to have greater than 90% sensitivity in ESBL detection. A three-phase trial compared disk diffusion methods recommended by NCCLS guidelines with an automated growth-monitoring system (Vitek ESBL). Results indicate that the two testing methods were comparable in both sensitivity (98.6% for disk diffusion vs 99.7% for Vitek ESBL) and specificity (99.4% for disk diffusion and 100% for Vitek ESBL).[39] The efficacy of ESBL E-test also was compared with the disk diffusion method. Results demonstrated that E-test was more sensitive than the disk diffusion method (100% vs 87%), whereas both methods were comparable in specificity.[40] These advances are of great benefit to clinicians in overcoming the difficulties of ESBL detection.[39,40,41]

Outbreaks

A number of nosocomial outbreaks (unit to unit and hospital to hospital) caused by ESBL-producing organisms have been reported in the U.S.[6,7,8,34,42] Although most outbreaks were limited to high-risk patient-care areas (i.e., ICUs, oncology units), the first report of an outbreak in nursing homes recently appeared in the literature.[14] Therefore, the threat of these resistant organisms is not limited to institutions.

Morbidity and Mortality

There has been no prospective controlled trial of antimicrobial therapy in ESBL infections. However, several retrospective studies suggest that infections caused by ESBL isolates are associated with increased morbidity and mortality compared with infections caused by non-ESBL-producing organisms.[5,7,8,9,28,43] These data consistently indicate high clinical failure rates when third-generation cephalosporins were used to treat infections caused by ESBL-producing organisms. Exceptions are certain minor infections, such as those of the urinary tract. Therefore, appropriate therapy for ESBL infections is crucial.

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