title: Impact of amoxicillin therapy on resistance selection in patients with community-acquired lower respiratory tract infections: a randomized, placebo-controlled study.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium surbhi.malhotra@uantwerpen.be.
authors.forename: Surbhi
authors.initials: S
authors.lastname: Malhotra-Kumar
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Liesbet
authors.initials: L
authors.lastname: Van Heirstraeten
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.|Centre for General Practice, Department of Primary and Interdisciplinary care (ELIZA), University of Antwerp, Antwerp, Belgium.
authors.forename: Samuel
authors.initials: S
authors.lastname: Coenen
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Lammens
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.|Centre for General Practice, Department of Primary and Interdisciplinary care (ELIZA), University of Antwerp, Antwerp, Belgium.
authors.forename: Niels
authors.initials: N
authors.lastname: Adriaenssens
authors.affiliation: Department of Family and Community Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Department of Family and Community Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Maciek
authors.initials: M
authors.lastname: Godycki-Cwirko
authors.affiliation: Clinical Research Associates and Consultants, Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Bielicka
authors.affiliation: Institute of Microbiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia.
authors.forename: Helena
authors.initials: H
authors.lastname: Hupkova
authors.affiliation: Unit of R&D, Jönköping, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Lannering
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Sigvard
authors.initials: S
authors.lastname: Mölstad
authors.affiliation: Hospital Clinic of Barcelona, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez-Vandellos
authors.affiliation: Hospital Clinic of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Torres
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Maxim
authors.initials: M
authors.lastname: Parizel
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Margareta
authors.initials: M
authors.lastname: Ieven
authors.affiliation: Cardiff University, Cardiff, UK.|Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Butler
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Verheij
authors.affiliation: University of Southampton, Southampton, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Little
authors.affiliation: Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D000658:Amoxicillin / Q000008:administration & dosage / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D018440:beta-Lactam Resistance; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D010919:Placebos / Q000008:administration & dosage; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology; D011446:Prospective Studies; D012641:Selection, Genetic; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013291:Streptococcus / Q000187:drug effects / Q000302:isolation & purification
chemical_list: D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D010919:Placebos