Science Spotlight

Antibiotics with anaerobic activity: an anti-hero against viruses

From the Boeckh Lab, Vaccine and Infectious Disease Division

The COVID-19 pandemic has given us an acute, first-hand experience of the risks and morbidities caused by respiratory virus infections. These risks are heightened for people who are immunocompromised, including recipients of hematopoietic cell transplantations. Very inconveniently, antibiotics can further heighten this risk. A previous study led by Dr. Chikara Ogimi, an affiliate investigator in the Boeckh lab in the Vaccine and Infectious Disease Division at the Fred Hutch, showed that cumulative antibiotic exposure immediately prior to the onset of respiratory viral infection is associated with respiratory disease progression in some transplant recipients. Two big questions arose from this study: whether exposure to specific classes of antibiotics increases the risk of respiratory viral disease progression, and whether the relationships between antibiotics and progression differs among different respiratory viruses. Dr. Ogimi, now the Division Chief of Pediatric Infectious Diseases at the National Center for Child Health and Development in Tokyo, Japan, and Elizabeth Krantz, a statistical research associate in the Antimicrobial Stewardship Program at the Fred Hutch, addressed these questions in a new study published in Bone Marrow Transplantation.

The researchers examined the relationship between antibiotic use immediately prior to a respiratory virus infection and progression to lower respiratory tract disease in 469 patients who received hematopoietic cell transplantations at Fred Hutch. They recorded the use of antibiotics up to 21 days before the onset of the respiratory virus infection, which included parainfluenza and the common cold (rhinovirus).

Previous studies suggested that antibiotic use alters the gut microbiota and reduces the production of short-chain fatty acids, including butyrate and propionate. This in turn may result in immunosuppression that makes an individual more vulnerable to respiratory disease progression. Given this hypothesis, the authors were particularly interested in antibiotics with activity against anaerobic bacteria, a class of antibiotics which significantly impairs the production of butyrate-producing bacteria in the gut. They further divided antibiotics with anaerobic activity into two classes: those with gram-positive anti-anaerobic activity (e.g. vancomycin), which primarily impact butyrate-producing bacteria, and those with broad anaerobic activity (e.g. metronidazole), which primarily impact propionate-producing bacteria. They then used Cox proportional hazards models to investigate the effect of these subtypes of antibiotics on the time to progression to lower respiratory tract disease.

In recipients of hematopoietic cell transplants, the use of antibiotics with anaerobic activity immediately prior to the onset of respiratory viral infection is associated with progression to lower respiratory tract disease.
In recipients of hematopoietic cell transplants, the use of antibiotics with anaerobic activity immediately prior to the onset of respiratory viral infection is associated with progression to lower respiratory tract disease. Image provided by Elizabeth Krantz.

The authors found that among the 469 patients sampled, 124 experienced progression to lower respiratory tract disease. “This study demonstrated that the risk of progression to lower respiratory tract disease was increased with recent exposure (immediately prior to onset of respiratory virus infection) to antibiotics with broad anaerobic activity, particularly when this type of antibiotic was given over a greater number of days. The association was significant for several respiratory virus species,” Dr. Ogimi explains. This result held up after adjusting for different factors including virus type, patient age, low blood-cell count, and steroid use.

The results from this study raised new questions for the team to pursue. Dr. Ogimi said, “This epidemiologic association raises the question of whether different antibiotic utilization strategies such as use of anaerobe-sparing antibiotics may impact respiratory viral disease progression. Furthermore, mechanistic studies exploring how the alteration of the microbiome affects viral progression to lower respiratory tract disease may be warranted.”

Dr. Ogimi also noted the importance of the Fred Hutchinson/University of Washington Cancer Consortium in carrying out this research. “We have maintained respiratory symptom-based surveillance strategies at the Hutch using a multiplex PCR respiratory virus testing platform the UW Virology lab developed and another multiplex platform at Seattle Children’s Hospital,” said Dr. Ogimi. “Large datasets maintained by Fred Hutch-based Clinical Research Data Systems and collaboration with various experts enabled our analysis.”

This work was supported by the National Institutes of Health, Fred Hutchinson Cancer Center Vaccine and Infectious Disease Division, and Seattle Children’s Research Institute Clinical Research Scholars Program Award.

The Fred Hutchinson/University of Washington Cancer Consortium members Drs. Catherine Liu,  Alpana Waghmare, Wendy Leisenring, Keith Jerome, Steven Pergam, David Fredricks, Janet Englund, and Michael Boeckh contributed to this work.

Ogimi C, Krantz EM, Golob JL, Liu C, Waghmare A, Akramoff A, Mallory A, Leisenring WM, Jerome KR, Chow VA, Pergam SA, Fredricks DN, Englund JA, and Boeckh M. 2022. Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant. Bone Marrow Transplantation. Epub ahead of print.