Abstract
Determining the effects of antimicrobial therapies on airway microbiology at a population-level is essential. Such analysis allows, for example, surveillance of antibiotic-induced changes in pathogen prevalence, the emergence and spread of antibiotic resistance, and the transmission of multi-resistant organisms. However, current analytical strategies for understanding these processes are limited. Culture- and PCR-based assays for specific microbes require the a priori selection of targets, while antibiotic sensitivity testing typically provides no insight into either the molecular basis of resistance, or the carriage of resistance determinants by the wider commensal microbiota. Shotgun metagenomic sequencing provides an alternative approach that allows the microbial composition of clinical samples to be described in detail, including the prevalence of resistance genes and virulence traits. While highly informative, the application of metagenomics to large patient cohorts can be prohibitively expensive. Using sputum samples from a randomised placebo-controlled trial of erythromycin in adults with bronchiectasis, we describe a novel, cost-effective strategy for screening patient cohorts for changes in resistance gene prevalence. By combining metagenomic screening of pooled DNA extracts with validatory quantitative PCR-based analysis of candidate markers in individual samples, we identify population-level changes in the relative abundance of specific macrolide resistance genes. This approach has the potential to provide an important adjunct to current analytical strategies, particularly within the context of antimicrobial clinical trials.
Highlights
As in all clinical disciplines, the management of patients with chronic respiratory diseases is subject to a process of ongoing refinement, including through the development of novel antimicrobial drugs and treatment strategies
We describe a cost effective approach that can be used to guide the assessment of changes in antibiotic resistance gene carriage, which might represent a useful adjunct to conventional approaches that are based on a priori target selection
The BLESS randomised placebo-controlled trial that preceded this study included an assessment of whether erythromycin therapy resulted in an increased relative abundance of macrolide resistant oropharyngeal streptococci using culture-based proportional sensitivity testing [12]
Summary
As in all clinical disciplines, the management of patients with chronic respiratory diseases is subject to a process of ongoing refinement, including through the development of novel antimicrobial drugs and treatment strategies. The impact that evolving treatment strategies can have on airway microbiology can be seen, for example, in changes in the cystic fibrosis (CF) airway microbiota during recent decades. Within this context, the use of anti-Pseudomonal treatments, including parenteral therapies and fluoroquinolones, have been implicated in the Taylor et al Multidisciplinary Respiratory Medicine 2018, 13(Suppl 1): emergence of Stenotrophomonas maltophilia as an airway pathogen [1, 2]. The impact of antibiotic use is reflected in the increasing frequency of multi-drug resistant organisms in the airways of patients with chronic respiratory disease, with an estimated 25–45% of adult CF patients chronically infected with multi-drug resistant bacteria [5]. CF-derived methicillin-resistant Staphylococcus aureus (MRSA) isolates increasingly show resistance to newer therapies, including linezolid [6, 7], ceftaroline [8] and tigecycline [6], presumably as a result of frequent and prolonged exposures [9]
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