Background: According to the 2019 CDC Antibiotic Resistance Threats Report, more than 2.8 million antibiotic-resistant infections occur in the United States each year, leading to more than 35,000 deaths. Among the most urgent threats identified by the CDC are carbapenem-resistant Enterobacterales (CRE). Despite efforts to control the spread of these organisms, the number of estimated cases between 2012 and 2017 remained stable. In 2017, an estimated 13,100 hospitalized cases of CRE led to approximately 1,100 deaths and $130 million attributable healthcare costs. This dissertation seeks to address this issue from both a pharmacokinetic/pharmacodynamic and epidemiological perspective.
Methods: We evaluated the susceptibility of 140 CRE clinical isolates against novel agents eravacycline and plazomicin using techniques standardized by the Clinical and Laboratory Standards Institute. We performed in-vitro static time-kill assays in 8 Verona Integron-encoded metallo-beta-lactamase (VIM)-producing CRE using single and combination exposures of cefepime, meropenem, piperacillin/tazobactam, amikacin, and plazomicin along with aztreonam and aztreonam/avibactam. Additionally, we performed a 10-year, inverse probability of treatment weighting adjusted retrospective cohort study comparing the risk in observing a composite outcome of all-cause mortality or discharge to hospice in patients having CRE vs. carbapenem-susceptible Enterobacterales (CSE) infections after 14 and 30 days. In this cohort, we also reported on the prevalence of CRE across the decade. Additionally, we compared the organism composition and susceptibilities of isolates cultured in both the CRE and CSE groups.
Results: Plazomicin showed higher susceptibility than eravacycline against our CRE isolates. In time kill studies, plazomicin was bactericidal against 5/8 isolates as monotherapy. Meropenem/amikacin or meropenem/plazomicin were bactericidal in all experiments, except for one isolate which regrew against meropenem/plazomicin. Aztreonam/avibactam was bactericidal in all experiments tested. Neither cefepime nor piperacillin/tazobactam improved the activity of plazomicin against our isolates. Cefepime with amikacin showed inconsistent activity. In the retrospective cohort study, the overall incidence of CRE infections was 1.8%. CRE isolates exhibited higher resistance across all routinely tested antimicrobials classes compared to CSE. The CRE population appeared to be largely non-carbapenemase-producing given the high susceptibility of meropenem and the high prevalence of E. cloacae, a known AmpC-producer. Overall, the risk of composite outcome only appeared to be increased among patients with a bloodstream infection on the index date and could only be assessed when utilizing an exposure of carbapenem-non-susceptible Enterobacterales (CNSE) due to insufficient sample size. However, the results were inconclusive as they were not statistically significant.
Conclusions: Novel antimicrobial agents plazomicin and aztreonam/avibactam were highly active against a collection of CRE including both Klebsiella pneumoniae carbapenemase (KPC) and VIM. Aztreonam/avibactam, meropenem/amikacin, and meropenem/plazomicin all exhibited comparably bactericidal activity. Furthermore, at an academic medical center in a non-endemic region for CRE, it appears that CRE infection may have increased the risk of experiencing the composite outcome after both 14 and 30 days, but definitive conclusions may not be drawn given the lack of statistical significance and imprecision in the estimation of the effect. The difficulties in drawing definitive conclusions from this study owing to limited sample size in the CRE or CNSE group stresses the importance of developing novel strategies and performing larger, multicenter studies when investigating highly resistant infections with low prevalence
