Scientists Uncover Unexpected Hidden Dangers of a Common Antibiotic

A University of Michigan study linked the use of the antibiotic piperacillin/tazobactam in the treatment of sepsis to a 5% increase in 90-day mortality, highlighting the importance of considering the effects of antibiotics on the gut microbiome when treating life-threatening infections.

In emergency rooms and intensive care units across the country, healthcare professionals must quickly decide on antibiotics for patients suspected of having serious infections. A recent study from the University of Michigan indicates that these quick decisions could have unexpected effects on patient outcomes.

Beginning in 2015, a 15-month national shortage of a commonly prescribed antibiotic, piperacillin/tazobactam, known by the brand name Zosyn, provided a unique opportunity to compare mortality rates among hospitalized patients with sepsis and having received two different types of antibiotics: one which spares the intestinal microbiome and one which profoundly modifies it.

Piperacillin/tazobactam is a broad-spectrum antibiotic commonly administered for sepsis, a life-threatening complication due to infection. In its absence, clinicians typically use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on intestinal anaerobic bacteria.

“We saw this shortage of Zosyn as a unique opportunity to ask whether this antibiotic, which we know depletes the gut of anaerobic bacteria, makes a difference in terms of patient outcomes,” said Robert Dickson, MD of the department. of the Division of Pulmonary and Critical Care Medicine and deputy director of the Weil Institute for Critical Care Research and Innovation.

In health, the intestinal microbiome is largely populated by anaerobic bacteria which rarely cause disease. Previous work by the study team found that even a single dose of piperacillin/tazobactam kills most of these anaerobic gut bacteria, which play an important role in metabolism, immunity and preventing infections of the gut. body.

Research findings and implications

Dickson, Rishi Chanderraj, MD of the Division of Infectious Diseases, Michael Sjoding, MD of the Division of Pulmonary and Critical Care Medicine and their multidisciplinary team from UM and VA Ann Arbor used patient chart data to examine the results of 7,569 patients. The team compared 4,523 patients treated with piperacillin/tazobactam to 3,046 patients who received cefepime.

They found marked differences: Piperacillin-tazobactam treatment was associated with a 5 percent increase in 90-day mortality, more days on a ventilator, and more time spent in organ failure.

“These are powerful antibiotics that are administered daily to patients in all hospitals across the country,” Chanderraj said. “Clinicians use them because they are trying to treat every possible pathogen that could be causing their patients’ illness. But our results suggest that their effects on the microbiome could also have important effects on patient outcomes.

The study builds on previous work by the study team that suggested that critically ill patients may fare worse when given antibiotics that deplete the gut of anaerobes. They also found similar effects when studying animal models.

“Our previous work suggested that the piperacillin/tazobactam combination might be harmful, but this was an observational study that had some limitations,” said Sjoding, the study’s lead author. “That’s why the drug shortage represented a tremendous opportunity. This created a near-perfect natural experiment that allowed us to very rigorously test the difference between these two drugs on patient outcomes.

A recent clinical trial pitted these two antibiotics against each other and compared side effects and mortality after two weeks. This trial found no short-term differences, a finding the UM team also observed in their analysis.

“When we looked at the two-week results in our study, we didn’t find any differences either,” Chanderraj said. “But the differences at three months were dramatic.”

Overall, the new results suggest that treatment with piperacillin/tazobactam instead of cefepime could contribute to one additional death for every 20 septic patients treated.

“A 5% difference in mortality has huge implications because sepsis is very common,” Dickson said. “Every day, thousands of clinicians decide which of these medications to use in septic patients. »

Doctors should think more about the suitability of anti-anerobic antibiotics before prescribing them, Chanderraj added. “We need to think of antibiotics like chemotherapy. In the right context, treatment can save lives, but in the wrong context, it can be very harmful.

Reference: “Mortality of patients with sepsis administered piperacillin-tazobactam vs cefepime” by Rishi Chanderraj, Andrew J. Admon, Ying He, Mark Nuppnau, Owen R. Albin, Hallie C. Prescott, Robert P. Dickson, and Michael W. Sjoding, May 13, 2024, JAMA Internal Medicine.
DOI: 10.1001/jamainternmed.2024.0581

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