Reply to Pogue and Heil, “The Clinical Impact of a Negative Molecular β-Lactamase Gene Test for Enterobacteriaceae : Let's Not Let Perfect Be the Enemy of Really Good”

Abstract

Gram-negative bacteria in the United States and agree that these tests can provide tremendous value to antimicrobial stewardship. We further agree with the authors that the use of these tests for de-escalation purposes is optimal when the practitioner has a good understanding of their local resistance patterns. Not all hospitals are equipped with advanced stewardship programs with the expertise and resources to evaluate local epidemiology and interpret molecular resistance genotype tests. The limitation of this was demonstrated by Rivard and colleagues in their evaluation of a test that detected CTX-M from positive blood cultures at seven Cleveland Clinic Health System sites (1). The investigators found that when this test was combined with antimicrobial stewardship, the time to antimicrobial de-escalation was reduced a median of 15 h at the academic medical center site (P Ͻ 0.001) but was largely unchanged at the six regional hospitals evaluated. At these sites, the authors found that the test was being used primarily as a tool to identify resistant pathogens for therapy escalation purposes, rather than as a tool for de-escalation (1). A second study similarly demonstrated that clinicians are more confident initiating or escalating therapy based on the results of genotypic tests, as opposed to de-escalating therapy. Among 382 physicians surveyed, 86% indicated that they would escalate therapy based on a report of Enterococcus with vanA detected, but only 53% indicated that they would de-escalate therapy based on the results of S. aureus that was negative for mecA (2). Routine evaluation of local epidemiology is typically limited to construction of an annual institutional antibiogram that summarizes data for all patients. However, select patient populations, for example, those with prior exposure to health care facilities or antimicrobial therapy within the past month, are well documented to have much higher prevalences of antimicrobial-resistant infections (3). As the prevalence of resistance increases, the negative predictive value (NPV) of a genetic resistance marker test decreases. The definition of what constitutes an acceptable NPV for major therapeutic decisions (like antimicrobial de-escalation) differs by clinician, but a recent survey of 238 internal medicine physicians found that they require a threshold of 90% (interquartile range, 80 to 95%) for patients with severe sepsis (4). Dependent on the local epidemiology and individual patient risk factors, the NPV for genotypic tests can be below this threshold. To highlight this point, we compared data from the Johns Hopkins Medical Center (JHMC) to those reported by Drs. Pogue and Heil for the University of Maryland Medical Center (UMMC). Both hospitals are large academic medical centers in Baltimore, MD, and both studies evaluated bacterial isolates collected during roughly the same time period (2014 to 2015 at JHMC and 2015 to 2016 at UMMC). At JHMC, the prevalence of ceftriaxone nonsusceptibility was 25% (5). A test for CTX-M would have an NPV of 89.9%...

Management of Gram-Negative Bloodstream Infections in the Era of Rapid Diagnostic Testing: Impact With and Without Antibiotic Stewardship

“…Potential reasons for the scarcity of data to support use of RDTs in GN BSI include the increased diversity of pathogenic organisms, the complexity and multifactorial nature of antibiotic resistance, and the potential downstream clinical consequences of missed organism identification and/or phenotypic resistance [ 43 , 44 ]. Overall, in vitro studies have demonstrated high sensitivity and specificity for organisms and resistance determinants; however, these studies typically occur in monomicrobial blood samples with on-panel targets without mention of phenotypic resistance [ 13 , 14 , 45 ].…”

Multicenter Evaluation of the BIOFIRE Blood Culture Identification 2 Panel for Detection of Bacteria, Yeasts, and Antimicrobial Resistance Genes in Positive Blood Culture Samples

“…Similar to the findings of a study by Spafford and colleagues, genetic resistance markers like CTX-M and KPC are able to identify many Enterobacterales isolates that lack susceptibility to relevant beta-lactams, but a substantial minority of Enterobacterales isolates that are not susceptible to third- or fourth-generation cephalosporins do not have CTX-M ( 10 ). When the presence or absence of a single gene marker (e.g., CTX-M) is used to guide empirical antimicrobial therapy, it is important to consider not only the sensitivity of an assay but also its negative predictive value, which is dependent upon local prevalence of overall resistance and also resistance mechanisms ( 11 ). In the future, characterization and analysis of full genomic data rather than single gene markers could be used to more accurately predict phenotypic susceptibility and resistance ( 12 ).…”

Using Molecular Diagnostics to Develop Therapeutic Strategies for Carbapenem-Resistant Gram-Negative Infections

“…The problems are illustrated in an exchange between Spafford et al. ( Spafford et al., 2019 ; Humphries et al., 2020 ) and Pogue and Heil (2020) , regarding the use of genotypic tests for bla CTX-M , bla KPC , and bla NDM in blood culture panels to predict phenotypic resistance or susceptibility to extended-spectrum cephalosporins and carbapenems in gram-negative organisms. The high very major error rates (which indicate false susceptibility to an antimicrobial agent) and variable negative predictive values of the molecular tests by geographic region and hospital type, led Spafford et al.…”

“…Detection of a CRG has a high positive predictive value as an indicator of phenotypic resistance in most bacterial species; however, the absence of a resistance gene does not always indicate that the organism detected will be phenotypically susceptible to an antibiotic. The problems are illustrated in an exchange between Spafford et al (Spafford et al, 2019;Humphries et al, 2020) and Pogue and Heil (2020), regarding the use of genotypic tests for bla CTX-M , bla KPC , and bla NDM in blood culture panels to predict phenotypic resistance or susceptibility to extended-spectrum cephalosporins and carbapenems in gram-negative organisms. The high very major error rates (which indicate false susceptibility to an antimicrobial agent) and variable negative predictive values of the molecular tests by geographic region and hospital type, led Spafford et al to raise flags of caution regarding the interpretation of genotypic results.…”