Antibiotic Found to Increase Deaths in Sepsis Patients

Hospital records show Zosyn is more likely to lead to death than other treatments for sepsis.

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Researchers at the Veterans Affairs Ann Arbor Healthcare System and the University of Michigan Medical School, Ann Arbor found a widely used antibiotic for the treatment of sepsis was more likely to be associated with mortality than another treatment.

A period of shortage of the antibiotic Zosyn—trade name piperacillin-tazobactam—was used by researchers to help determine the death rate associated with it. Bacterial sepsis patients who received Zosyn were 5 percent more likely to die within 90 days than those treated with cefepime, an antibiotic in a different class. Zosyn is commonly used to treat stomach infections, skin and uterine infections, and pneumonia.

Anti-Aerobic Antibiotics and Sepsis

The study was published in JAMA Internal Medicine last month. Researchers studied the outcomes of 7,569 patients with sepsis, median age of 63. There were 4,523 patients treated with piperacillin-tazobactam and 3,046 treated with cefepime. Both groups also received vancomycin, an antibiotic that kills bacteria in the intestines. An increase in the number of days of organ failure and use of ventilators in the piperacillin-tazobactam group was also noted.

The researchers concluded that the use of anti-aerobic antibiotics to treat sepsis may be harmful. Cefepime, which acts similarly against sepsis-causing bacteria, has little effect on anaerobic bacteria found in the stomach and intestines. Cefepime is used to treat bacteria causing pneumonia, and skin and urinary tract infections.

Anaerobic infections can result from trauma or surgery. Zosyn kills most anaerobic bacteria in the gut, which also have beneficial effects on immunity, metabolism, and infection prevention. Vancomycin is an antibiotic that fights against intestinal bacteria.

The study examined hospital records of admissions from July 1, 2014, to Dec. 31, 2018, including the Zosyn shortage period of 15 months, beginning June 12, 2015. At the treatment mark of 90 days, Zosyn “was associated with an absolute mortality increase of 5.0%,” the study report says.

The study report shows that one additional septic patient out of 20 may die if treated with Zosyn instead of Cefepime.

“Our results demonstrate that antibiotics really can’t be considered a single entity, as they have widely different impacts on the microbiome and on our patients,” said Dr. Robert Dickson, associate professor of internal medicine, University of Michigan Medical School, in a press release. “Patients who received anti-anaerobic antibiotics did far worse than patients who didn’t. We think that which antibiotic is given probably matters more than how quickly they are administered.”

Critically ill patients may suffer when given antibiotics that cleanse anaerobic bacteria from the stomach and intestines, a team including some of the same researchers concluded in a 2022 study. They found that anti-aerobic antibiotics are commonly administered, although those treated with them “did far worse” than patients who did not receive those drugs. The bacteria that were being destroyed play a role in health, including protection against death, organ failure, and pneumonia.

“In observational studies, there is always a risk that a mortality difference is due to confounding; maybe the patients who received anti-anaerobic antibiotics were just sicker,” said Dr. Rishi Chanderraj, a clinical instructor at the University of Michigan Infectious Disease Clinic and co-author of the study, in a press release. “But the fact that we were able to recapitulate these findings in two different animal models gives us confidence these findings are real.”

Dr. Michael Sjoding, a pulmonary and critical care physician at University of Michigan Medical Center, said the prior research suggested Zosyn might be causing harm, but that observational study was limited.

“That’s why the drug shortage was such an amazing opportunity,” said Dr. Sjoding, the most recent study’s senior author, in a press release. “It created an almost perfect natural experiment that let us test the difference between these two drugs on patient outcomes in a very rigorous manner.”

The Shadow of Sepsis

Sepsis is a major contributor to patient deaths in hospitals. A 2014 study found that among two hospital cohorts, one out of every two or three deaths had a contributing factor of sepsis—a body’s extreme response to an infection. The body’s response to an infection can cause vital organs to shut down, often starting with the kidneys.

In some cases, sepsis can result from poor sanitary hospital conditions or failure to diagnose and treat infections.

Piperacillin and Tazobactam for injection won approval in 1993 from the U.S. Food and Drug Association, according to the drug’s package insert. The insert warns that the combined drug may cause kidney failure in critically ill patients and is associated with delayed recovery of kidney function. “Combined use of Piperacillin and Tazobactam and Vancomycin may be associated with an increased incidence of acute kidney injury,” the insert says.

A study of 3,032 critically ill patients, published in 2023, reported in the research team’s conclusion that “early treatment with anti-anaerobic antibiotics is associated with increased mortality.” The research team, led by Dr.  Chanderraj, that because of the “consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.”