Importance of beta-lactam pharmacokinetics and pharmacodynamics on the recovery of microbial diversity in the airway of persons with cystic fibrosis

Abstract

Cystic fibrosis (CF) is a chronic lung disease characterized by acute pulmonary exacerbations (PExs) that are frequently treated with antibiotics. The impact of antibiotics on airway microbial diversity remains a critical knowledge gap. We sought to define the association between beta-lactam pharmacokinetic (PK) and pharmacodynamic target attainment on richness and alpha diversity. Twenty-seven children <18 years of age with CF participated in the prospective study. Airway samples were collected at hospital admission for PEx, end of antibiotic treatment (Tr), and >1 month in follow-up (FU). Metagenomic sequencing was performed to determine richness, alpha diversity, and the presence of antibiotic resistance genes. Free plasma beta-lactam levels were measured, and PK modeling was performed to determine time above the minimum inhibitory concentration (fT>MIC). 52% of study subjects had sufficient fT>MIC for optimal bacterial killing. There were no significant differences in demographics or PEx characteristics, except for F508del homozygosity. No significant differences were noted in richness or alpha diversity at individual time points, and both groups experienced a decrease in richness and alpha diversity at Tr compared with PEx. However, alpha diversity remained decreased at FU compared with PEx in those with sufficient fT>MIC but increased in those with insufficient fT>MIC (Shannon -0.222 vs +0.452, p=0.031, and inverse Simpson -1.376 vs +1.388, p=0.032). Fluoroquinolone resistance was also more frequently detected in those with insufficient fT>MIC (log2 fold change (log2FC) 2.29, p=0.025). These findings suggest sufficient beta-lactam fT>MIC is associated with suppressed recovery of alpha diversity following the antibiotic exposure period.

Keywords: anti-bacterial agents; lung diseases; microbiota.

Figure 1

Relative bacterial taxonomic abundance. The 19 bacterial species that contributed to at least 20% of the total relative abundance of one or more samples compared to the other 176 bacterial species are shown. E, exacerbation sample; F, follow-up sample; PtID, participant ID; T, treatment sample.

Figure 2

Box and whiskers plot of richness and alpha diversity. Observed indicates observed bacterial taxa; Shannon indicates Shannon diversity; ‘no’ indicates fT>MIC not sufficient; ‘yes’ indicates fT>MIC sufficient; ‘x’ corresponds to mean values. The center horizontal line corresponds to the median. Colored boxes represent the IQRs. Small circles represent individual values. E, exacerbation sample; F, follow-up sample; fT>MIC, time above the minimum inhibitory concentration; T, treatment sample.

Figure 3

Box and whiskers plot of changes in richness, alpha diversity, and beta diversity across time points. (A) Changes in observed taxa. (B) Changes in Shannon Diversity. (C) Changes in Inverse Simpson Index. (D) Intraperson Morista-Horn Index. ‘No’ indicates fT>MIC not sufficient; ‘yes’ indicates fT>MIC sufficient; ‘x’ corresponds to mean values. The center horizontal line corresponds to the median. Colored boxes represent the IQRs. Small circles represent individual values. *P<0.05. Ex, exacerbation; Tr, end of antibiotic treatment; fT>MIC, time above the minimum inhibitory concentration; FU, follow-up.

Figure 4

Relative abundance of antimicrobial resistance genes. E, exacerbation sample; F, follow-up sample; MLS, macrolides, lincosamides, and streptrogramin A and B drugs; PtID, participant ID; T, treatment sample.