Impact of amoxicillin therapy on resistance selection in patients with community-acquired lower respiratory tract infections: A randomized, placebo-controlled study

Surbhi Malhotra-Kumar, Liesbet Van Heirstraeten, Samuel Coenen, Christine Lammens, Niels Adriaenssens, Anna Kowalczyk, Maciek Godycki-Cwirko, Zuzana Bielicka, Helena Hupkova, Christina Lannering, Sigvard Mölstad, Patricia Fernandez-Vandellos, Antoni Torres, Maxim Parizel, Margareta Ieven, Chris C. Butler, Theo Verheij, Paul Little, Hermanon Goossens, Niels Frimodt-MøllerPascale Bruno, Iris Hering, Marieke Lemiengre, Katherine Loens, Bo Eric Malmvall, Magdalena Muras, Nuria Sanchez Romano, Matteu Serra Prat, Igor Svab, Jackie Swain, Paolo Tarsia, Frank Leus, Robert Veen, Tricia Worby

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: To determine the effect of amoxicillin treatment on resistance selection in patients with community-acquired lower respiratory tract infections in a randomized, placebo-controlled trial. Methods: Patients were prescribed amoxicillin 1 g, three times daily (n = 52) or placebo (n = 50) for 7 days. Oropharyngeal swabs obtained before, within 48 h post-treatment and at 28-35 days were assessed for proportions of amoxicillin-resistant (ARS; amoxicillin MIC ≥2 mg/L) and -non-susceptible (ANS; MIC ≥0.5 mg/L) streptococci. Alterations in amoxicillin MICs and in penicillin-binding-proteins were also investigated. ITT and PP analyses were conducted. Results: ARS and ANS proportions increased 11- and 2.5-fold, respectively, within 48 h post-amoxicillin treatment compared with placebo [ARS mean increase (MI) 9.46, 95% CI 5.57-13.35; ANS MI 39.87, 95% CI 30.96-48.78; P < 0.0001 for both]. However, these differences were no longer significant at days 28-35 (ARS MI -3.06, 95% CI -7.34 to 1.21; ANS MI 4.91, 95% CI -4.79 to 14.62; P > 0.1588). ARS/ANS were grouped by pbp mutations. Group 1 strains exhibited significantly lower amoxicillin resistance (mean MIC 2.8 mg/L, 95% CI 2.6-3.1) than group 2 (mean MIC 9.3 mg/L, 95% CI 8.1-10.5; P < 0.0001). Group 2 strains predominated immediately post-treatment (61.07%) and although decreased by days 28-35 (30.71%), proportions remained higher than baseline (18.70%; P = 0.0004). Conclusions: By utilizing oropharyngeal streptococci as model organisms this study provides the first prospective, experimental evidence that resistance selection in patients receiving amoxicillin is modest and short-lived, probably due to 'fitness costs' engendered by high-level resistance-conferring mutations. This evidence further supports European guidelines that recommend amoxicillin when an antibiotic is indicated for community-acquired lower respiratory tract infections.

Original languageEnglish
Article numberdkw234
Pages (from-to)3258-3267
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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