Recent research by American scientists suggests that a commonly prescribed antibiotic for patients with suspected sepsis may be linked to increased mortality.
The study, led by researchers from the University of Michigan Medical School and the Veteran Affairs (VA) Anne Arbor Healthcare System, found that in patients with suspected sepsis and no clear indication for anti-anaerobic antibiotics, the combination of piperacillin-tazobactam and vancomycin was associated with a 5% absolute mortality increase at 90 days compared with cefepime and vancomycin.
The researchers estimate that the regimen may contribute to one additional death for every 20 patients with suspected sepsis, they wrote in JAMA Internal Medicine.
Taking advantage of Zosyn shortage
Piperacillin-tazobactam, which combines a penicillin antibiotic with a beta-lactamase inhibitor and is marketed under the name Zosyn, is a broad-spectrum intravenous antibiotic known to have potent activity against anaerobic gut bacteria.
Clinicians choose the combination of piperacillin-tazobactam and vancomycin for empiric treatment of sepsis patients when they want to cover as many potential pathogens as possible, reports CIDRAP.
But several observational and experimental studies have suggested empiric use of piperacillin-tazobactam is associated with adverse outcomes in critically ill patients, including increased death rates.
One hypothesis is that the activity against anaerobic gut bacteria, some of which can have a protective effect, might be to blame.
Over a 15-month period starting in 2015, there was a nationwide shortage of piperacillin-tazobactam that forced clinicians to use the other common empiric regimen for suspected sepsis, vancomycin and cefipeme, which doesn’t have activity against anaerobic bacteria.
The authors of the paper, who had conducted a previous study that found early treatment with antianaerobic antibiotics may harm patients, used this shortage to test the hypothesis that empiric use of piperacillin-tazobactam is linked to increased mortality compared with cefepime.
“We saw this Zosyn shortage as an opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in patient outcomes,” said study co-author Robert Dickson, MD, of the University of Michigan Medical School’s division of pulmonary and critical care medicine.
Increased 90-day mortality, worse outcomes
Using electronic health records, the researchers analysed adults with suspected sepsis who were treated with either regimen in the emergency department of the University of Michigan from July 2014 until December 2018.
Patients with indications for anti-anaerobic antibiotic therapy within 24 hours of presentation were excluded. The primary outcome was 90-day mortality. Secondary outcomes included organ failure-free, ventilator-free and vasopresser-free days.
Among the 7 569 patients (55% men; median age 63) with sepsis who met study eligibility, 4 523 were treated with vancomycin and piperacillin-tazobactam, and 3 046 received vancomycin and cefepime.
Of the piperacillin-tazobactam–treated patients, 97% were admitted outside the shortage period and 3% within. There were no significant differences between the treatment groups in terms of age, comorbidities, organ failure assessment scores, or time to antibiotic administration.
In an instrumental variable analysis that controlled for unobserved differences in patient characteristics, 90-day mortality in patients treated with piperacillin-tazobactam was 22.5%, compared with 17.5% in those treated with cefepime, for an absolute increase in 90-day mortality of 5% (95% confidence interval [CI], 1.9% to 8.1%).
Piperacillin-tazobactam was also associated with 2.1 fewer organ failure-free days (95% CI, 1.4 to 2,7), 1.1 fewer ventilator-free days (95% CI, 0.57 to 1.62), and 1.5 fewer vasopresser-free days (95% CI, 1.01 to 2.01).
Additional analysis found that metronidazole, another potent anti-anaerobic antibiotic that was used in sepsis patients during the piperacillin-tazobactam shortage, was also associated with increased 90-day mortality.
“These findings suggest that broad-spectrum antibiotics with anti-anaerobic activity, such as piperacillin-tazobactam, may cause harm in patients without a clear indication,” the study authors concluded.
Reasons for caution
While the results are aligned with previous observational studies, they contradict a recent clinical trial – the ACORN (Antibiotic Choice on Renal Outcomes) trial – that found among adults hospitalised with acute infections, acute kidney or death was not significantly different between those treated with piperacillin-tazobactam or cefepime.
But the authors note that the ACORN trial compared mortality at 14 days only.
“When we looked at two-week outcomes in our study, we didn’t find differences either,” said corresponding author Rajiv Chanderraj, MD. “But the differences at three months were dramatic.”
Chanderraj and his colleagues note that the results are vulnerable to unobserved confounding and may not be generalisable to other settings or patient populations. They also say more research is needed to determine why antibiotics that deplete anaerobic gut bacteria are associated with worse clinical outcomes.
Nonetheless, they believe the findings provide clinicians a reason to reconsider widespread use of anti-anaerobic antibiotics like piperacillin-tazobactam.
“We need to think about antibiotics like chemotherapy,” Chanderraj said. “In the right context, treatment can be lifesaving, but in the wrong context, it can be quite harmful.”
Study details
Mortality of patients with sepsis administered piperacillin-tazobactam vs cefepime
Rishi Chanderraj, Andrew Admon, et al
Published in JAMA Internal Medicine on 13 May 2024
Abstract
Importance
Experimental and observational studies have suggested that empirical treatment for bacterial sepsis with anti-anaerobic antibiotics (eg, piperacillin-tazobactam) is associated with adverse outcomes compared with anaerobe-sparing antibiotics (eg, cefepime). However, a recent pragmatic clinical trial of piperacillin-tazobactam and cefepime showed no difference in short-term outcomes at 14 days. Further studies are needed to help clarify the empirical use of these agents.
Objective
To examine the use of piperacillin-tazobactam compared with cefepime in 90-day mortality in patients treated empirically for sepsis, using instrumental variable analysis of a 15-month piperacillin-tazobactam shortage.
Design, Setting, and Participants
In a retrospective cohort study, hospital admissions at the University of Michigan from 1 July 2014 to 31 December 2018, including a piperacillin-tazobactam shortage period from 12 June 2015 to 18 September 2016, were examined. Adult patients with suspected sepsis treated with vancomycin and either piperacillin-tazobactam or cefepime for conditions with presumed equipoise between piperacillin-tazobactam and cefepime were included in the study. Data analysis was conducted from 17 December 2022 to 11 April 2023.
Main Outcomes and Measures
The primary outcome was 90-day mortality. Secondary outcomes included organ failure–free, ventilator-free, and vasopressor-free days. The 15-month piperacillin-tazobactam shortage period was used as an instrumental variable for unmeasured confounding in antibiotic selection.
Results
Among 7 569 patients (4 174 men [55%]; median age, 63 [IQR 52-73] years) with sepsis meeting study eligibility, 4 523 were treated with vancomycin and piperacillin-tazobactam and 3046 were treated with vancomycin and cefepime. Of patients who received piperacillin-tazobactam, only 152 (3%) received it during the shortage. Treatment groups did not differ significantly in age, Charlson Comorbidity Index score, Sequential Organ Failure Assessment score, or time to antibiotic administration. In an instrumental variable analysis, piperacillin-tazobactam was associated with an absolute mortality increase of 5.0% at 90 days (95% CI, 1.9%-8.1%) and 2.1 (95% CI, 1.4-2.7) fewer organ failure–free days, 1.1 (95% CI, 0.57-1.62) fewer ventilator-free days, and 1.5 (95% CI, 1.01-2.01) fewer vasopressor-free days.
Conclusions and Relevance
Among patients with suspected sepsis and no clear indication for anti-anaerobic coverage, administration of piperacillin-tazobactam was associated with higher mortality and increased duration of organ dysfunction compared with cefepime. These findings suggest that the widespread use of empirical anti-anaerobic antibiotics in sepsis may be harmful.
JAMA Internal Medicine article – Mortality of Patients with Sepsis Administered Piperacillin-Tazobactam vs Cefepime (Open access)
CIDRAP article – Proteins in blood could provide early cancer warning ‘by more than seven years’ (Open access)
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