The use of rapid diagnostic tests (RDTs) for blood cultures has become standard of care in the United States to inform early antimicrobial optimization. The relative ability of genotypic and phenotypic approaches to identify beta-lactam susceptibility in Escherichia coli, Klebsiella spp., and Proteus mirabilis was evaluated, using incidence rates of resistance mechanisms to third-generation cephalosporins, aztreonam, and piperacillin-tazobactam seen across U.S. census regions. Overall, the presence of CTX-M, KPC, and/or NDM genes was 81% (range, 57 to 87%) sensitive for the prediction of ceftriaxone, ceftazidime, and aztreonam resistance and 73% (range, 25 to 90%) sensitive for the detection of piperacillin-tazobactam resistance. The sensitivity of KPC or NDM to predict imipenem or meropenem resistance was 94.3% overall, and for meropenem ranged from 70 to 100% across U.S. census regions. Institutions that use genotypic RDTs to inform therapeutic de-escalation decisions should be aware of the incidence-base performance across U.S. geographies and in different patient populations, where resistance rates may vary.

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%...

BackgroundDefinitive therapy with piperacillin–tazobactam (TZP) for ceftriaxone (CRO)-resistant E. coli or K. pneumoniae bloodstream infections (BSI) has been shown to be inferior to carbapenem therapy in a randomized trial.MethodsThe Premier US database was queried for hospitalized patients with monomicrobial E. coli or Klebsiella spp BSI that were not susceptible (NS) to CRO between June 2015 and May 2018. Adults with index positive blood culture(s) drawn within the first 2 hospital days who were treated with active antibiotic therapy that continued for ≥3 consecutive days were included. We defined antibiotics administered on or prior to Day 3 as empirical therapy and all subsequent days as definitive therapy. Outcomes among patients who received definitive therapy with a carbapenem vs. TZP were evaluated.ResultsThere were 954 patients (mean age, 67.6 years; 52.4% women) who met selection criteria and received active empirical therapy. 729/954 received carbapenem definitive therapy and 38/954 received TZP definitive therapy. Median Charlson Comorbidity Index scores were similar between carbapenem and TZP definitive therapy groups (6 vs. 5, P = 0.78). Crude 14-day in-hospital mortality for CRO-NS BSI due to E. coli or Klebsiella spp. was 4.4%. Definitive therapy with TZP (6/38; 15.8%) was associated with an increased likelihood of 14-day mortality relative to that of a carbapenem (22/729; 3.0%; P < 0.0001). The increased 14-day mortality observation was consistent in a multivariate cox proportional hazards model (adjusted hazard ratio, 5.70; 95% CI, 2.09 to 13.23; P = 0.002). Of patients who received carbapenem definitive therapy, 14-day mortality was 2.7% (19/693) if a carbapenem was part of empirical therapy and 8.3% (3/36; P = 0.06) if empirical therapy did not include a carbapenem. Median post-blood culture length of stay (7 vs. 6 days, P = 0.65) and hospital costs ($13,886 vs. $13,559, P = 0.62) were similar between carbapenem and TZP definitive therapy groups<./p>ConclusionIn this large US database, definitive therapy with TZP was associated with an increased likelihood of 14-day mortality relative to that of definitive carbapenem therapy in patients with CRO-NS BSI due to E. coli or Klebsiella spp. These findings support recent clinical evidence in favor of definitive carbapenem therapy for CRO-NS BSI due to E. coli or Klebsiella spp.Disclosures All authors: No reported disclosures.