Study finds increased risk of death in sepsis patients treated with broad-spectrum antibiotic

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A new study indicates that one of the most frequently prescribed broad-spectrum empiric antibiotics for patients with suspected sepsis is associated with increased mortality, US researchers reported yesterday in JAMA Internal Medicine.

The study, led by researchers with 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 1 additional death for every 20 patients with suspected sepsis. 

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.

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 that began 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 study, 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 a one-of-a-kind opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes," study co-author Robert Dickson, MD, of the University of Michigan Medical School's division of pulmonary & critical care medicine, said in a university press release.

Increased 90-day mortality, worse outcomes

Using electronic health records, the researchers analyzed adults with suspected sepsis who were treated with either regimen in the emergency department of the University of Michigan from July 2014 through December 2018. 

Patients with indications for antianaerobic 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 years) 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.

We saw this Zosyn shortage as a one-of-a-kind opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes.

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 antianaerobic 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 hospitalized 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 generalizable 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."