By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A multicenter observational study of patients with carbapenem-resistant Enterobacterales (CRE) bacteremia found that time to receipt of active antibiotic therapy and mortality were improved in those whose blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase gene (blaKPC). The mortality rate was 10% with ceftazidime-avibactam compared to 31% with polymyxin monotherapy (P = 0.08).
SOURCE: Satlin MJ, Chen L, Gomez-Simmonds A, et al. Impact of a rapid molecular test for Klebsiella pneumoniae carbapenemase and ceftazidime-avibactam use on outcomes after bacteremia caused by carbapenem-resistant Enterobacterales. Clin Infect Dis 2022;75:2066-2075.
Patients with bacteremia from carbapenem-resistant Enterobacterales (CRE) are at high risk for adverse outcomes, including death. Therefore, it is crucial that effective antibiotic therapy is started as soon as possible. Satlin et al evaluated a rapid diagnostic test for CRE bacteremia and assessed whether ceftazidime-avibactam was associated with better outcomes compared to polymyxin.
The study was an observational investigation conducted at eight academic medical centers in New York and New Jersey between January 2016 and June 2018. The cohort included patients with CRE bloodstream infections that underwent antibiotic susceptibility testing and whole-genome sequencing (WGS) by a central laboratory. Bacteremia onset was defined as the time of collection of the first blood culture from which CRE was recovered. Targeted therapy was defined as antibiotics administered within one day after the availability of antibiotic susceptibility data that was continued for two days or longer. Patients with CRE bacteremia whose blood cultures underwent blaKPC polymerase chain reaction (PCR) testing were compared to those whose blood cultures were not tested. A statistical method called Targeted Maximum Likelihood Estimation (TMLE) was employed to make sure differences in mortality between patients who had blaKPC PCR and those who did not were not due to differences in baseline characteristics.
The cohort included 137 patients. The median age was 64 years, 61% were male, 42% had cancer, and 34% had diabetes. The most common sources of infection included intra-abdominal (33%), vascular catheters (13%), respiratory tract (13%), and urinary tract (12%). Active therapy was administered to 107 (78%) patients. Of the 30 patients who never received active therapy, 14 died or became comfort care before the availability of antibiotic susceptibility results. Forty (29%) patients died within 14 days of bacteremia onset and 52 (38%) died within 30 days. Cancer, receipt of mechanical ventilation or renal replacement therapy, and increased Pitt bacteremia and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were associated with increased 30-day mortality.
CRE bacteremia most frequently was caused by Klebsiella pneumoniae (64%), followed by Escherichia coli (15%) and Enterobacter cloacae (11%). The blood cultures of 51 patients underwent blaKPC PCR testing (PCR patients), while 86 did not. The PCR patients had a median time of 22 hours (interquartile range [IQR], 15-72 hours) from collection of the blood culture until detection of CRE bacteremia, compared to 67 hours (IQR, 54-88 hours) in the non-PCR patients (P < 0.0001). Among the patients who received active therapy, the median time from collection of blood culture until initiation of active therapy was 24 hours (IQR, 4-50 hours) in PCR patients compared to 50 hours (IQR, 18-89 hours) in non-PCR patients (P = 0.009). Moreover, compared to non-PCR patients, the PCR patients had lower 14-day mortality (16% vs. 37%, respectively; P = 0.007) and 30-day mortality (24% vs. 47%, respectively; P = 0.007). PCR testing also was associated with decreased 30-day mortality using TMLE (adjusted odds ratio, 0.37; 95% confidence interval [CI], 0.16-0.84; P = 0.02).
Six (19%) of 32 patients who received ceftazidime-avibactam as targeted therapy died within 30 days compared to 22 (28%) of 80 patients who did not receive the drug (P = 0.33). Patients who received targeted therapy that included two or more agents had higher mortality than those who received one agent. The risk of acute kidney injury was similar between monotherapy and combination therapy.
COMMENTARY
Early initiation of active antibiotic therapy is well known to decrease mortality in patients with sepsis. Thus, the finding that rapidly identifying CRE bacteremia and treating it with ceftazidime-avibactam was associated with improved outcomes is in agreement with previous observations and makes sense from a mechanistic perspective. Rapid diagnostic testing also holds promise for reducing unnecessary broad-spectrum antibiotic use, a key goal of antibiotic stewardship. Indeed, rapid diagnostics eventually may lead to a shift in the current empiric antibiotic treatment paradigm to one of precision antibiotic prescribing.1
There are some limitations to the study worth mentioning. First, the observational design is susceptible to temporal trends and unmeasured confounding variables, thus it cannot establish causality. Second, because of the narrow geographic area in which the CRE isolates were obtained, the findings might not be generalizable to other sites and regions. Third, the study had limited power to detect differences in outcomes by treatment regimen. Finally, the study predated other effective therapies for CRE bacteremia, such as meropenem-vaborbactam and imipenem-relebactam, so these could not be compared to the antibiotics in the study.
The use of rapid PCR testing and ceftazidime-avibactam in CRE bacteremia appears to improve patient outcomes. Randomized clinical trials ideally should be performed to confirm these findings. It is hoped that ongoing advances in rapid diagnostic testing and their increased use will lead to additional reductions in patient morbidity and mortality.
REFERENCE
- Watkins RR. Antibiotic stewardship in the era of precision medicine. JAC Antimicrob Resist 2022;4:dlac066.
