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, Herman Goossens, GRACE study group ( Niels Frimodt-Møller, members)Niels Frimodt-Møller

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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.

OriginalsprogEngelsk
TidsskriftThe Journal of antimicrobial chemotherapy
Vol/bind71
Udgave nummer11
Sider (fra-til)3258-3267
Antal sider10
ISSN0305-7453
DOI
StatusUdgivet - nov. 2016

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