The commonly used antibiotic leads to more complications, death in the sickest patients

In emergency rooms and intensive care units across the country, doctors make split-second decisions about which antibiotics to give a patient when a life-threatening infection is suspected. A new UM study reveals that these decisions can have unintended consequences for patient outcomes. The study is published in the journal JAMA Internal Medicine.

Beginning in 2015, a 15-month national shortage of a commonly prescribed antibiotic, piperacillin/tazobactam, known under the brand name Zosyn, provided a unique opportunity to compare death rates in hospitalized patients with sepsis who were They administered two different types of antibiotics: one that spares the gut microbiome and one that profoundly alters it.

Piperacillin/tazobactam is a broad-spectrum antibiotic commonly given for sepsis, a life-threatening complication of infection. In its absence, doctors usually use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on anaerobic gut bacteria.

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

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

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

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

“These are powerful antibiotics that are given to patients every day in every hospital across the country,” Chanderraj said. “Doctors use them because they’re trying to treat all the possible pathogens that might be causing their patients’ disease. But our results suggest that their effects on the microbiome can also have important effects on patient outcomes.”

The study builds on previous work by the study team that suggested critically ill patients could get worse when given antibiotics that deplete the gut of anaerobes. Researchers have also seen similar effects when studying animal models.

“Our previous work suggested that there might be harm with piperacillin/tazobactam, but it was an observational study that had some limitations,” said Sjoding, the study’s lead author. “That’s why the drug shortage was such an amazing opportunity. It created an almost perfect natural experiment that allowed us to test the difference between these two drugs in patient outcomes in a very rigorous way.”

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

“When we looked at the two-week results in our study, we also found no differences,” Chanderraj said. “But the differences at three months were dramatic.”

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

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

Doctors should think more about whether anti-anaerobic antibiotics are warranted before prescribing them, Chanderraj added.

“We have to think of antibiotics like chemotherapy. In the right context, the treatment can save lives, but in the wrong context, it can be quite harmful.”