Antibiotics are often prescribed for patients experiencing a respiratory illness. But when tests reveal that a virus—such as influenza—is causing the illness, antibiotics should be stopped, Cedars-Sinai investigators say. That’s because antibiotics are not meant to treat a viral illness; they are only effective against bacterial infections.

Some flu patients continue taking antibiotics out of concern that they will also develop a bacterial pneumonia—a common “secondary” infection often seen in vulnerable patients with influenza and a leading cause of death in flu patients.

A team of investigators led by Cedars-Sinai found that when influenza patients take antibiotics, the drugs disturb the gut’s fungal microbiome. This results in an increase in immune cells called eosinophils in the lungs that hinder the function of alveolar macrophages—important immune cells that clear out pathogens from the lungs.

This chain of events actually makes it more likely that a flu patient taking antibiotics will develop a bacterial pneumonia rather than avoid one. The investigators also showed that increased levels of eosinophils are associated with poor clinical outcomes and more systemic inflammation. The results of the experimental study were published in The Journal of Clinical Investigation. 

“We need to be aware that antibiotics are not innocuous and can have harmful side effects,” said the study’s corresponding author, Peter Chen, MD, the Medallion Chair in Molecular Medicine and the interim chair of the Department of Medicine at Cedars-Sinai. “To be clear: When a flu patient has a confirmed bacterial infection, you definitely need to prescribe antibiotics. But when there is no direct evidence of such an infection, antibiotics should not be prescribed because they will not help, and could, in fact, be harmful.”

To conduct the study, investigators examined laboratory mice that had been infected with influenza followed by a bacterial infection caused by MRSA (methicillin-resistant Staphylococcus aureus), one of the most common causes of a secondary bacterial pneumonia. One group of mice received antibiotics prior to the onset of a bacterial infection; the control group did not receive any medication.

Compared with the control group, those treated with antibiotics experienced greater weight loss and showed evidence of greater lung damage after MRSA infection. The mice that were given antibiotics also had higher levels of MRSA bacteria in their lungs and higher levels of immune cells (macrophages and eosinophils). In other words, this data suggests that antibiotic treatment during an influenza infection actually impaired the body’s efforts to clear the MRSA bacteria rather than helping the body heal.

The investigators also evaluated a cohort of influenza patients at Cedars-Sinai and critically ill patients at Northwestern University and the University of Pittsburgh. They found that eosinophils increase with antibiotic use and are associated with a higher length of stay and systemic inflammation.

“Altogether, this research demonstrates that prescribing antibiotics during influenza infections may do more harm than good. This research also sheds light on the role that eosinophils play in regulating lung immunity,” said co-author David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease. “These results also support clinical trials using eosinophil-depleting strategies as a therapy to improve outcomes in patients admitted with influenza and other viral illnesses.”

Additional authors include Marilia Sanches Santos Rizzo Zuttion, Tanyalak Parimon, Stephanie A. Bora, Changfu Yao, Katherine Lagree, Catherine A. Gao, Richard G. Wunderink, Georgios D. Kitsios, Alison Morris, Yingze Zhang, Bryan J. McVerry, Matthew E. Modes, Alberto M. Marchevsky, Barry R. Stripp, Christopher M. Soto, Ying Wang, Kimberly Merene, Silvia Cho, Blandine L. Victor, Ivan Vujkovic-Cvijin, Suman Gupta, Suzanne L. Cassel, Fayyaz S. Sutterwala and Suzanne Devkota.

This work was supported by grants from the NIH (TP: K08HL1411590; CAG: F32HL162377; RGW: U19AI135964, U01TR003528,P01HL154998, R01HL14988, and R01LM013337; GDK: R03HL162655; AM: R01HL163646, R01HL164177; BJM: P01HL114453; PC: R01HL159953, R01HL155759). This research was also supported by NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.

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Liver fibrosis can be triggered by many factors, including viruses that cause hepatitis (infection and inflammation in the liver), long-term alcohol use or some metabolic disorders. Because it produces few or no symptoms at first, the condition typically progresses slowly for years, going undetected until it has caused serious organ damage. At that stage, liver transplantation may be the only effective treatment. The ability to undo the scarring would be a major breakthrough for patient care.

In their study, published in the peer-reviewed journal Nature Communications, Cedars-Sinai investigators examined three genes and the proteins that they made. One of them, FOXM1, is known to cause liver cancer, inflammation and fibrosis when it becomes overactive in hepatocytes, a type of liver cell. The two other genes, MAT2A and MAT2B, are required to activate another type of cell, hepatic stellate cells, which plays a key role in liver fibrosis. The study demonstrated that the proteins coded by these three genes interact and that all three are needed to produce liver fibrosis.

“We discovered that these proteins ‘talk’ with each other inside liver cells,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and corresponding author of the study. “They even influence nearby cells through extracellular vesicles—fat molecules filled with genetic fragments, proteins and other biological materials that act as messengers between cells. Working together, that is how these proteins stimulate each other, driving liver inflammation and fibrosis.”

These discoveries raised the possibility that inactivating just one of the three proteins might block liver fibrosis. To test that theory, the team induced liver inflammation and fibrosis in laboratory mice and treated them with a substance known as FDI-6 that blocks the FOXM1 protein. In a series of experiments, they showed that FDI-6 could prevent liver fibrosis from developing, halt further progression and even reverse the condition, resulting in the scarring disappearing.

Although both mice and humans have all three genes, and these genes also are more highly expressed in human liver fibrosis and cirrhosis, the study did not prove that a similar treatment would work in patients with liver fibrosis. Reaching that conclusion would require additional research and testing, Lu said. 

“What we achieved was to unveil the axis of FOXM1, MAT2A and MAT2B as a potential target for developing drugs to treat liver fibrosis,” Lu said. “Our findings suggest that blocking any of these proteins might be useful in treating this condition.”

Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, “This highly original study significantly advances our understanding of an insidious condition that too often leaves patients and doctors with few treatment options. It is emblematic of Cedars-Sinai’s innovative scientific work.”

Other Cedars-Sinai authors include Bing Yang, Liqing Lu, Ting Xiong, Wei Fan, Jiaohong Wang, Lucía Barbier-Torres, Jyoti Chhimwal, Sonal Sinha, Takashi Tsuchiya, Nirmala Mavila, Maria Lauda Tomasi, DuoYao Cao, Jing Zhang, Hui Peng, Komal Ramani, Jenny Han, Ekihiro Seki and Heping Yang. Additional authors include Jose M. Mato, Ting Liu, Xi Yang and Vladimir V. Kalinichenko.

Funding was provided by the National Institutes of Health grant P01CA233452 to S.C. Lu, H. Yang and E. Seki; Plan Nacional of I + D SAF2017-88041-R to J.M. Mato; and the National Natural Science Foundation of China 82070632 to Liu T.

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The drugs, known as glucagon-like peptide-1 receptor agonists (GLP-1RAs), are marketed under many brand names. They work by stimulating insulin secretion, slowing down food leaving the stomach, and causing a delay in gastric emptying. As a result, the drugs may help Type 2 diabetes patients manage their blood sugar and help patients with obesity to lose weight.

According to the study, published Oct. 1 in the journal JAMA Network Open, these medications may also lead to problems during upper endoscopies, which involve inserting an endoscope—a long, thin tube with a camera and a light on the end—into a patient’s esophagus, stomach and the beginning of the small intestine under sedation to diagnose diseases and conditions of the digestive system.

Researchers found that patients who regularly took GLP-1RAs were significantly more likely to retain food in their stomachs during the procedure than were patients who did not take the drugs. Food retention can raise the risk of aspiration, a rare but serious complication of surgeries in which stomach contents are introduced into the lungs while a patient is under sedation.  

The researchers found that even though patients in the study, as instructed, stopped taking the GLP-1RAs a week before their upper endoscopies, they were still more likely to retain food than those who did not take these drugs.

"The effects of the GLP-1RA drugs appeared to persist even when patients were asked to stop taking them a week before the procedure," said endocrinologist Ruchi Mathur, MD, professor of Medicine, director of Clinical Research and Clinical Operations for Medically Associated Science and Technology at Cedars-Sinai and the study's corresponding author. She added that although aspiration was not detected in any of the patients, food retention can make aspiration more likely.

A total of 70 individuals taking GLP-1RAs and 139 controls were included in the study.

Results showed that 17% of patients on the drugs who underwent upper endoscopy alone showed food retention, compared with none of the controls. They also observed that patients who underwent both a colonoscopy and an upper endoscopy on the same day, requiring a 24-hour clear liquid and bowel preparation protocol, showed no food retention in either the GLP-1RA group or the controls. "This protective effect against food retention may be due to the preparation typically required for colonoscopies, as opposed to upper endoscopies," Mathur said.

The researchers also found a clear association between GLP-1RA use, which can sometimes produce constipation as a side effect, and unsatisfactory bowel preparation for colonoscopies. Inadequate bowel preparation may contribute to missed lesions, patient dissatisfaction, and cancellation of the procedure.

"Overall, our results support the value of individualizing recommendations for patients and having risk-benefit discussions for patients on these drugs," Mathur said. "Any patients using a GLP-1RA drug should be sure to inform their physicians and anesthesiologists before undergoing gastrointestinal procedures."

Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, "The rigorous research performed by Dr. Mathur and her team represents an important contribution to our understanding of how these powerful obesity and diabetes medications may impact medical care."

Other Cedars-Sinai authors include Jason Nasser, MD; Ava Hosseini, MPH; Gillian Barlow, PhD; Roma Gianchandani, MD; Ali Rezaie, MD, MSc; and Mark Pimentel, MD.

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