Impact of extensive antibiotic treatment on faecal carriage of antibiotic-resistant enterobacteria in children in a low resistance prevalence setting.

Per Kristian Knudsen,Fredrik Müller,Karianne Wiger Gammelsrud,Martin Steinbakk,Tore G Abrahamsen,Petter Brandtzaeg,Ørjan Samuelsen,E Arne Høiby,Jon Bohlin,Nades Palaniyar

doi:10.1371/journal.pone.0187618

Abstract

We prospectively studied the consequences of extensive antibiotic treatment on faecal carriage of antibiotic-resistant enterobacteria in a cohort of children with cystic fibrosis (CF) and a cohort of children with cancer compared to healthy children with no or low antibiotic exposure. The study was conducted in Norway in a low resistance prevalence setting. Sixty longitudinally collected faecal samples from children with CF (n = 32), 88 samples from children with cancer (n = 45) and 127 samples from healthy children (n = 70) were examined. A direct MIC-gradient strip method was used to detect resistant Enterobacteriaceae by applying Etest strips directly onto agar-plates swabbed with faecal samples. Whole genome sequencing (WGS) data were analysed to identify resistance mechanisms in 28 multidrug-resistant Escherichia coli isolates. The prevalence of resistance to third-generation cephalosporins, gentamicin and ciprofloxacin was low in all the study groups. At inclusion the prevalence of ampicillin-resistant E. coli and trimethoprim-sulfamethoxazole-resistant E. coli in the CF group compared to healthy controls was 58.6% vs. 28.4% (p = 0.005) and 48.3% vs. 14.9% (p = 0.001), respectively, with a similar prevalence at the end of the study. The prevalence of resistant enterobacteria was not significantly different in the children with cancer compared to the healthy children, not even at the end of the study when the children with cancer had been treated with repeated courses of broad-spectrum antibiotics. Children with cancer were mainly treated with intravenous antibiotics, while the CF group mainly received peroral treatment. Our observations indicate that the mode of administration of antibiotics and the general level of antimicrobial resistance in the community may have an impact on emergence of resistance in intestinal enterobacteria during antibiotic treatment. The WGS analyses detected acquired resistance genes and/or chromosomal mutations that explained the observed phenotypic resistance in all 28 multidrug-resistant E. coli isolates examined.

Highlights

The worldwide increasing prevalence of antimicrobial resistance with decreased access to effective antimicrobials has become one of the biggest health care challenges of our time [1, 2]
Given the fact that systematic, longitudinal studies of the consequences of long-time extensive antibiotic exposure in infants and children are lacking, we have investigated the faecal flora in children with cystic fibrosis (CF) and cancer, two patient groups known to receive much antibiotic treatment
From some of the samples there was no growth of Gram-negative enterobacteria despite several attempts to inoculate the faecal specimens on different agars, possibly due to recent or on-going antibiotic exposure

Summary

Introduction

The worldwide increasing prevalence of antimicrobial resistance with decreased access to effective antimicrobials has become one of the biggest health care challenges of our time [1, 2]. Several studies have documented an association between antibiotic use in humans and the development of resistance both at a population level and in individuals [5,6,7]. During antibiotic treatment both pathogens and commensals are exposed to antibiotics. Resistant endogenous enterobacteria may cause infections that are difficult to treat, and the gut microbiota may serve as a reservoir for antibiotic resistance genes [12, 13]. These resistance genes may spread between bacterial strains and species within the microbiome [14,15,16], between individuals, and to the environment [17, 18]

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