Microbial Activity as a Determinant of Health Status in Cystic Fibrosis

Project Leader

Alex H. Gifford, M.D.
Assistant Professor of Medicine
Geisel School of Medicine at Dartmouth

The practice of treating CF patients with specific antibiotics continues to be informed by reports of in vitro antibiotic susceptibility for pathogens recovered on selective media under aerobic conditions in the clinical microbiology laboratory. Cultures of respiratory tract specimens are laborious and costly to obtain, and clinicians are usually referencing data collected weeks or months before the encounter at which antibiotics need to be prescribed. Contradicting the utility of this paradigm are data from several studies employing 16S rRNA pyrosequencing to characterize the CF lung microbiome showing that bacterial richness and diversity change only modestly before pulmonary exacerbation and that microbial communities are resilient to the effects of systemic antibiotics used in this clinical context. These studies suggest that antibiotics have salubrious effects that are unrelated to their microbicidal action. Moreover, registry data demonstrate that most patients experience improvements in symptoms and pulmonary function after antibiotic courses. Add to these findings work demonstrating that clinical responses to antibiotics correlate poorly with standard, biofilm, and checkerboard synergy antibiotic susceptibility testing, we contend that clinical practices around this issue are highly empiric and need to be customized for optimal benefit. We have developed protocols to directly measure 16S rRNA from multiple pathogens in the same respiratory tract sample with multiplexed Nanostring® technology, thus interrogating microbial activity in vivo. We hypothesize that the Nanostring® platform will allow us to explore in sputum and a co-culture model of CF lung infection how health status relates to polymicrobial activities with the goal of rationalizing antibiotic use.