Impact of amoxicillin therapy on resistance selection in patients with community-acquired lower respiratory tract infections: A randomized, placebo-controlled study
Malhotra-Kumar S., Van Heirstraeten L., Coenen S., Lammens C., Adriaenssens N., Kowalczyk A., Godycki-Cwirko M., Bielicka Z., Hupkova H., Lannering C., Mölstad S., Fernandez-Vandellos P., Torres A., Parizel M., Ieven M., Butler CC., Verheij T., Little P., Goossens H., Frimodt-Møller N., Bruno P., Hering I., Lemiengre M., Loens K., Malmvall BE., Muras M., Romano NS., Prat MS., Svab I., Swain J., Tarsia P., Leus F., Veen R., Worby T.
© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. 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.