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Laboratory Capacity to Detect Antimicrobial Resistance, 1998

Emerging mechanisms of antimicrobial resistance have clinical, microbiologic, and infection-control implications for health-care providers. Antimicrobial resistant organisms include Staphylococcus aureus with reduced susceptibility to vancomycin (minimum inhibitory concentration [MIC] greater than or equal to 4 µg/mL), including vancomycin intermediate S. aureus (VISA; vancomycin MIC=8-16 µg/mL) (1-4) and Enterobacteriaceae that produce extended spectrum ß-lactamases (ESBLS), which result in resistance to a broad range of ß-lactam antibiotics (5). Detecting VISA and ESBLs-producing gram-negative pathogens can be difficult for clinical microbiology laboratories. Although CDC (1-3,6) and the National Committee for Clinical Laboratory Standards (NCCLS) (7-9) have published screening and confirmatory methods for these pathogens (Tables 1 and 2), the extent of use of these methods is unknown. This report summarizes results from a survey of microbiology laboratories that participate in the Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program (EIP) Network to assess the capacity of clinical microbiology laboratories to detect VISA and ESBL-producing pathogens; findings indicate that despite adequate capacity for proper testing, many laboratories do not have appropriate methodology to detect these resistant pathogens.

A survey of laboratory practices was sent to the primary contact for participating ABCs/EIP Network laboratories during August-September 1998. Follow-up was conducted by site coordinators.

As of June 1999, 416 (93%) of 447 ABCs/EIP Network laboratorians from eight states (California, Connecticut, Georgia, Maryland, Minnesota, New York, Oregon, and Tennessee) had responded to the survey. Of the 416 respondents, 369 (89%) performed clinical microbiologic services (i.e.,"study laboratorians"). Of the 369 study laboratorians, 44 (12%) were from referral laboratories. The other 325 (88%) served health-care facilities that had a median of 121 (range:5-2506) licensed beds. Seventy-six (36%) of the laboratorians served health-care facilities that were part of a health-maintenance organization.

In reviewing the susceptibility testing methods for S. aureus, 278 (84%) of 329 laboratorians used methods that allowed them to detect an isolate with reduced susceptibility to vancomycin. Fifty-two (16%) laboratorians used methods that would not identify these isolates, such as disk diffusion with no additional method (n=13), Microscan ® Walkaway Rapid* panels (which provides less than 24 hours incubation) (n=four), and Vitek systems (bioMérieux, Hazelwood, Missouri) with a vancomycin MIC of greater than or equal to 8 µg/mL as the indicator for additional testing (Vitek software typically did not report isolates of S. aureus with an MIC greater than 4 µg/mL) (n=25). Of 369 study laboratorians, 216 (59%) reported performing confirmatory testing of suspected isolates that were possibly VISA (candidate strains). Of the 204 study laboratorians who reported criteria for selecting strains of S. aureus as candidates for confirmatory susceptibility testing to vancomycin, 173 (85%) used recommended criteria. Of the 201 study laboratorians who reported methodology for confirming S. aureus with reduced susceptibility to vancomycin, 135 (67%) used an acceptable methodology.

Of the 369 study laboratorians, 117 (32%) reported performing tests to identify ESBL-producing organisms. Of the 112 laboratorians who described their methods, 93 (83%) used adequate methods for ESBL screening, and 19 (17%) reported performing definitive confirmatory tests for ESBL production (i.e., E-Test, MIC susceptibility testing of ceftazidime, alone and in combination with clavulanic acid). One hundred eight laboratorians commented on interpretation and clinical reporting of extended-spectrum cephalosporin and other susceptibility to ß-lactam agents: 76 (70%) reported isolates identified as ESBL-producers as resistant to all extended-spectrum cephalosporins; 57 (53%) reported that these isolates also were resistant to aztreonam.

Variability in practices occurred based on demographics and characteristics of laboratories. Within the ABCs/EIP Network, the percentage of study laboratories confirming S. aureus with reduced susceptibility to vancomycin or testing for ESBL-producing organisms varied from 39% to 100% and 18% to 84%, respectively. Laboratories performing services for hospitals with greater than 200 beds were significantly more likely to confirm S. aureus with reduced susceptibility to vancomycin (odds ratio [OR]=8.2; p=0.0001) or test for ESBL-producing organisms (OR=2.1; p=0.002) than were other laboratories surveyed. Managed-care-based laboratories were significantly less likely to confirm S. aureus with reduced susceptibility to vancomycin than were laboratories that were not part of a managed-care organization (OR=0.3; 95% confidence interval=0.2-0.6).

Reported by: W Baughman, M Farley, K Toomey, P Daily, G Rothrock, L Gelling, N Mokerjee, N Barrett, M Pass, K White, J Rainbow, B Damaske, K Stefonek, B Barnes, S Zansky, C Morin, Q Phan, P Moshar, J Hadler, Active Bacterial Core Surveillance/Emerging Infections Program Network. Respiratory Diseases Br, Div of Bacterial and Mycotic Diseases; Hospital Infections Program, National Center for Infectious Diseases; and an EIS Officer, CDC.

Editorial Note:

The findings in this report indicate that most ABCs/EIP Network laboratories were using routine methods that would allow detection of VISA or ESBL-producing pathogens; however, approximately 40% of the laboratories were not performing confirmatory testing of S. aureus for reduced susceptibility to vancomycin and even fewer laboratories tested Enterobacteriaceae for ESBL production. Smaller hospital-based laboratories, managed-care-based laboratories, and laboratories from specific ABCs/EIP state locations did not report testing for these resistant pathogens.

Recent reports of S. aureus with reduced susceptibility to vancomycin underscore the importance of increasing awareness of clinical microbiology laboratory personnel on proper testing methods (1-4). The testing of isolates of S. aureus for reduced susceptibility to vancomycin requires that laboratorians know the appropriate susceptibility testing methods and strategies for selecting candidate strains. Despite the national recommendations for testing, many laboratorians may not be aware of the need to perform confirmatory testing on candidate VISA strains. Manufacturers should be aware of the difficulties in resistance identification. For example, Vitek systems software typically did not report MICs greater than 4 µg/mL for S. aureus isolates. Therefore, a laboratory that used this system and the criteria for additional testing of 8 µg/mL may not have reliably detected isolates. In November 1999, Vitek upgraded its software to improve detection and reporting of S. aureus isolates with reduced susceptibility to vancomycin.

The recommendations and guidelines for testing for ESBL-producers have evolved over several years, and this may explain the variations in practices among ABCs/EIP laboratories. In January 1999, NCCLS attempted to clarify this topic by publishing new recommendations (10), including methods to confirm ESBL production (Table 2).

The findings in this report are subject to at least two limitations. First, the data were self reported. The degree of correlation between actual practice and such reports is unknown. Second, the sample was not random and results may not be representative of other facilities. Despite these limitations, the survey indicates a need to increase awareness among clinical microbiology laboratory and related personnel about evolving practices of susceptibility testing for antimicrobial resistant bacteria.

Additional information about survey results or resistance testing is available from CDC's Hospital Infections Program, telephone (404) 639-6413. In addition, information about testing for these resistant organisms is available on CDC's National Center for Infectious Diseases, Hospital Infections Program World-Wide Web site, http://www.cdc.gov/ncidod/hip.htm, click on "Laboratory."

References

CDC. Reduced susceptibility of Staphylococcus aureus to vancomycin--Japan, 1996. MMWR 1997;46:624-6.
CDC. Staphylococcus aureus with reduced susceptibility to vancomycin--United States, 1997. MMWR 1997;46:765-6.
CDC. Update: Staphylococcus aureus with reduced susceptibility to vancomycin--United States, 1997. MMWR 1997;46:813-5.
Smith T, Pearson M, Wilcox K, et al. Emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med 1999;440:493-501.
National Nosocomial Infection Surveillance (NNIS) System. Report, data summary from January 1990-May 1999. Am J Infect Control 1999;27:520-32.
CDC. Interim guidelines for prevention and control of staphylococcal infection associated with reduced susceptibility to vancomycin. MMWR 1997;46:626-8,635-6.
National Committee for Clinical Laboratory Standards. Approved standard M7-A4: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 4th ed. Villanova, Pennsylvannia: National Committee for Clinical Laboratory Standards, 1997.
National Committee for Clinical Laboratory Standards. Approved standard M100-S8: performance standards for antimicrobial susceptibility testing. Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards, 1998.
National Committee for Clinical Laboratory Standards. Approved standard M100-S9: performance standards for antimicrobial susceptibility testing. Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards, 1999.
Tenover FC, Lancaster MV, Hill BC, et al. Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. J Clin Microbiol 1998;36:2167.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.

Table 1

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TABLE 1. Recommendations for testing for Staphylococcus aureus with reduced susceptibility to vancomycin

Strategies for selection of strains for additional testing:

Select isolates with vancomycin minimum inhibitory concentrations (MICs) of >=4 µg/mL. This is based on the apparent heterogeneity of strains because organisms with MICs of >=4 µg/mL have subpopulations with higher MICs (6).Clinical treatment failures have occurred with vancomycin in infections with these isolates (6).
Select isolates with vancomycin MICs of >=8 µg/mL (based on National Committee for Clinical Laboratory Standards [NCCLS] breakpoints*) (7).
Select all methicillin-resistant S. aureus (MRSA). All identified isolates of S. aureus with reduced susceptibility to vancomycin have been MRSA (10).
Select all S. aureus isolates. Because little is known about the extent of this resistance, any S. aureus potentially could have reduced susceptibility to vancomycin.

Testing and confirmation:

Primary testing of S. aureus against vancomycin requires 24 hours of incubation time (7).
Disk diffusion is not an acceptable method for vancomycin susceptibility testing of S. aureus. None of the known strains of S. aureus with reduced susceptiblity to vancomycin have been detected by this method (10).
An MIC susceptibility testing method should be used to confirm vancomycin test results (6).

* NCCLS MIC breakpoints for vancomycin are: susceptible, <=4 µg/mL ; intermediate, 8-16 µg/mL; and resistant, >=32 µg/mL.

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Table 2

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TABLE 2. National Committee for Clinical Laboratory Standards 1999 guidelines for susceptibility testing for Enterobacteriaceae with potential extended-spectrum ß-lactamases (ESBLs) production

Testing:

Expanded screening to include special breakpoints for the three previously includedantimicrobials, two cephalosporins (ceftazidime, cefpodoxime), and aztreonam, but alsocefotaxime and ceftriaxone.
Confirmatory testing methods for potential ESBLs-producing isolates of Klebsiellapneumoniae, K. oxytoca, and Escherichia coli by testing both cefotaxime and ceftazidime, alone and in combination with clavulanic acid. Testing can be performed by the broth microdilution method or by disk diffusion.

Reporting and interpretation:

Confirmed ESBL producers should be reported as resistant to all penicillins, cephalosporins (not including cephamycins such as cefoxitin and cefotetan), and aztreonam.

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