(546) Therapeutic Beta-lactam Dosages and Broad-spectrum Antibiotics are Associated with Short-term Reductions in Microbial Richness and Beta-diversity

Background: Persons with cystic fibrosis (PwCF) suffer from recurrent pulmonary exacerbations (PEx) associated with morbidity and mortality. Antibiotics are a mainstay of therapy, yet the beta-lactam doses administered are less than CF Foundation (CFF) dosing guidelines more than half the time [1]. Additionally, while higher microbial diversity is associated with higher lung function [2], there are conflicting data on the impact of short-term antibiotics (e.g., 10-14 days) on changes in microbial diversity. Our hypothesis was that sub-therapeutic and broad spectrum antibiotic exposure leads to decreasing microbial diversity over time by fostering an environment for select bacteria to dominate the microbiome.

Methods: This was a retrospective observational study of PwCF treated with IV antibiotics for PEx between 2016-2020 at Children’s National Hospital; respiratory samples (n=98 sputum/BAL, n=16 OP swab) and clinical information were collected at hospital admission for PEx (E), end of antibiotic treatment (T), and follow-up (F). Metagenomic sequencing was performed; PathoScope 2.0 was used for taxonomic assignment of sequences to bacteria. MW/Pharm was used for PK modeling to determine therapeutic time above the minimum inhibitory concentration (T >MIC). Comparison of categorical and continuous variables were performed in STATA/IC (v15.1); richness and alpha diversity between groups were compared using linear regression and controlling for repeat participant samples.

Results: Twenty-two PwCF experienced 43 PEx. The study cohort had a mean age of 14.6 yrs, 41% were female, 59% were white, 5% were Black, 36% were Hispanic, 45% were F508del homozygous, 23% were F508del heterozygous, and 32% had other genotypes. Pseudomonas aeruginosa was the most common bacterial species identified at the time of PEx (47%); all participants had a history of P. aeruginosa or other opportunistic gram-negative bacteria in culture. Only 12/43 beta-lactam courses had therapeutic PK and 18/43 were broad spectrum. In a multivariate model accounting for time between sample collection, a larger decrease in richness between E and T was seen in the therapeutic PK group (therapeutic -20.1 vs sub-therapeutic -1.59, p=0.025) and those receiving broad spectrum antibiotics (broad -14.5 vs narrow -2.8, p=0.030). Broad antibiotic spectrum was also significantly associated with a lower Morisita-Horn index between E and T (broad 0.221 vs narrow 0.477, p=0.036). Neither beta-lactam PK nor antibiotic spectrum had a significant impact on alpha or beta-diversity between E and F or percent predicted forced expiratory volume (ppFEV1) between E and T.

Conclusions: While both therapeutic beta-lactam PK and broad-spectrum antibiotics decreased richness between PEx and the end of treatment, we did not detect longstanding changes in alpha diversity or differences in pulmonary function recovery compared to sub-therapeutic dosing or narrow spectrum microbial coverage.

Acknowledgements: This work was supported by the Cystic Fibrosis Foundation [grant number HAHN18A0-Q].

References: [1] Zobell JT, Young DC, Waters CD, Ampofo K, Cash J, Marshall BC, Olson J, Chatfield BA. A survey of the utilization of anti-pseudomonal β-lactam therapy in cystic fibrosis patients. Pediatr Pulmonol. 2011;46(10):987-90.
[2] Zemanick ET, Harris JK, Wagner BD, Robertson CE, Sagel SD, Stevens MJ, Accurso FJ, Laguna TA. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. PLoS One. 2013; 8(4): e62917.