Piperacillin-tazobactam was associated with an absolute 5% increase in mortality and fewer organ failure-free, ventilator-free, and vasopressor-free days.
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Piperacillin-tazobactam was associated with a higher rate of mortality and longer duration of organ dysfunction than cefepime for empiric treatment of sepsis among patients without indication of anaerobic infection, in a retrospective cohort study1 of patients’ 90 day course after treatment.
The investigators note that the two regimens were assumed to have equipoise as empiric choices for sepsis in absence of anaerobic infection; and that a recent pragmatic clinical trial (ACORN)2 did not distinguish between them for adverse outcomes. They point to several differences between the ACORN trial and their own, however, and particularly to the period of assessment after treatment.
“This (ACORN) study was limited by analyzing only short-term outcomes—14 days, frequent treatment crossover, and relatively low patient acuity,” observed Rishi Chanderraj, MD, MSc, Infectious Diseases Section, Ann Arbor Veterans Affairs Hospital, Ann Arbor MI, and colleagues.
The primary outcome of their own study, involving 7569 patients (55% men) treated between July 2014 through December 2018, was 90-day mortality; with secondary outcomes including organ failure-free, ventilator-free, and vasopressor-free days. Of them, 4523 were treated with vancomycin and piperacillin-tazobactam and 3046 with vancomycin and cefepime. The study was conducted during a period of shortage in the availability of piperacillin-tazobactam, which the investigators indicate was used as an instrumental variable for unmeasured confounding in antibiotic selection.
“The shortage period served as a natural experiment to study these two regimens,” Chanderraj explained to Contagion. “It was an external factor not tied to patient characteristics like severity of illness or burden of medical comorbidities that strongly influenced treatment decisions.It led to an increase in cefepime use at our hospital, and provided an opportunity to study a larger group of cefepime-treated patients.”
The study participants were patients meeting the Centers for Disease Control and Prevention (CDC) modified sepsis surveillance criteria, who had received empirical treatment with either regimen within the first 24 hours of presentation to the emergency medicine department (ED).To emulate conditions of a randomized trial, the investigators indicate, “we considered only data available to treatment prescribers within the first 24 hours of ED presentation to identify eligible patients.”
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The study found that patients treated with piperacillin-tazobactam had a higher 90-day mortality rate and longer duration of organ dysfunction compared to those treated with cefepime.
The investigators suggested that the differences in outcomes might be due to the broader anti-anaerobic activity of piperacillin-tazobactam.
The findings contrast with the ACORN trial, which found no significant difference in 14-day mortality between the two regimens.
The investigators found, in the instrumental variable analysis that controlled for unobserved differences in patient characteristics, piperacillin-tazobactam was associated with an absolute mortality increase of 5% at 90 days (95% CI, 1.9%-8.1%), 2.1 (1.4-2.7) fewer organ failure -free days, 1.1 (0.57-1.62) fewer ventilator-free days, and 1.5 (1.01-2.01) fewer vasopressor-free days than those treated with cefepime.
They reported that the differences in outcomes between regimens remained after controlling for temporal trends, source of infection, and other antibiotic treatments. In a sub-analysis, they also determined that the addition of another antianaerobic agent (such as metronidazole, more likely to be added to the cefepime regimen to broaden spectrum) was associated with worse outcomes.
Although both regimens are indicated as empiric treatment of sepsis presumed from non-anaerobic infection, the investigators suggest they pose different risk profiles.“…unlike cefepime, piperacillin-tazobactam has potent activity against anaerobic gut bactedria, which have a protective influence in numerous conditions,” Chanderraj and colleagues indicate.
“Patients with sepsis are at high risk for hospital readmission and death after hospital admission,” Chanderraj told Contagion. “Our study suggests that early treatment with anti-anaerobic antibiotics, when not clearly indicated, may increase this risk.This effect might be mediated by changes in the gut microbiome, and we hope that future work will look into potential mechanisms for the mortality difference we observed.”
As to the ACORN trial finding no difference in mortality at 14 days, and the implications for the duration of monitoring these patients, Chanderraj indicated that he expects that may also become clearer with further study.
“In the future, we plan to develop more specific recommendations for monitoring and supporting patients after hospital discharge. However, at this time, we are still attempting to unravel potential mechanisms of harm,” he commented.
