Antibiotics use leads to more resistance

Date: 18 November 2016

Introduction: Antibiotic use is widely associated with antibiotic resistance. Demonstrating causality is challenging, but that's exactly what UAntwerp researchers have done.

European research has shown that amoxicillin use is a crucial driver of resistance to amoxicillin, a penicillin-like antibiotic. Whereas use of macrolide antibiotics leads to a major increase in macrolide-resistant streptococci that persists for at least 6 months after therapy, changes effected by amoxicillin in the oro-pharyngeal flora  on the other hand are rather short-lived. Specifically, the majority of the streptococci exhibiting high-level resistance to amoxicillin that had emerged immediately after amoxicillin therapy had disappeared within a month.

Antibiotic use is widely associated with antibiotic resistance, but demonstrating causality is challenging. Previously the effects in volunteers administered two macrolides, azithromycin or clarithromycin were studied, showing wide variation not only in the proportions of macrolide-resistant streptococci but also in the resistance-conferring genes and mechanisms selected by these antibiotics. In addition to antibiotic use, the magnitude of the ‘fitness cost’ associated with a resistance mechanism impacts the survival and dissemination of the bacterium in the absence of antibiotic selective pressure. It was also found that maintaining macrolide use below a critical threshold was associated with a low prevalence of macrolide-resistant Streptococcus pyogenes in Belgium and an increased proportion of a ‘low-cost’, macrolide-resistance conferring gene in S. pyogenes.

Amoxicillin, a penicillin-like antibiotic, however is recommended as first-line therapy by the European Respiratory Society for treatment of community-acquired lower respiratory tract infections (CA-LRTI), the commonest reason for patient consultations in the community. Amoxicillin is therefore also the most commonly prescribed antibiotic in European primary care, accounting for an average 40% of the total outpatient antibiotic use in European countries. Despite this, its potential for selection of resistance in Streptococcus pneumoniae, the most common bacterial pathogen causing CA-LRTI, and its persistence in vivo is not yet known. As with other penicillins, amoxicillin affects bacterial cell wall synthesis. Resistance to β-lactams in streptococci, including S. pneumoniae, occurs by chromosomal alterations in cell wall synthesizing enzymes, the so-called penicillin-binding proteins (PBPs). Such alterations in PBPs are due to a continuous mutation process that causes various degrees of resistance, from reduced susceptibility through low-level resistance—conventionally termed intermediate or non-susceptibility—to full clinical resistance.

It is demonstrated that oropharyngeal streptococci are ideal model organisms to study resistance selection in S. pneumoniae in vivo. Here European researchers carried out a randomized, placebo-controlled trial (RCT) to quantify the impact of exposure to amoxicillin treatment on resistance in the oropharyngeal flora of patients with confirmed CA-LRTI. Furthermore, they also studied the molecular mechanisms of resistance and associated fitness costs in streptococci that emerged under amoxicillin therapy and correlated these to the resistance trajectory (

This RCT has clearly defined the impact of amoxicillin use on resistance selection and has shown that persistence of resistance selection is significantly shorter following amoxicillin use compared with the newer macrolides, azithromycin and clarithromycin. These findings provide a strong evidence base supporting: (i) European clinical guidelines that recommend prescribing amoxicillin when an antibiotic is indicated for CA-LRTI;9 (ii) clinical prescribing of an antibiotic with a lower ecological impact such as amoxicillin when an antibiotic needs to be prescribed; and (iii) future antibiotic policy making for respiratory tract infections.