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

Malhotra-Kumar, Surbhi ; Van Heirstraeten, Liesbet ; Coenen, Samuel ; Lammens, Christine ; Adriaenssens, Niels ; Kowalczyk, Anna ; Godycki-Cwirko, Maciek ; Bielicka, Zuzana ; Hupkova, Helena and Lannering, Christina LU , et al. (2016) In Journal of Antimicrobial Chemotherapy 71(11). p.3258-3267
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... (More)

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.

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published
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in
Journal of Antimicrobial Chemotherapy
volume
71
issue
11
article number
dkw234
pages
10 pages
publisher
Oxford University Press
external identifiers
  • scopus:84994517934
  • pmid:27353466
  • wos:000388005100033
ISSN
0305-7453
DOI
10.1093/jac/dkw234
language
English
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yes
id
1b2a5732-8960-4c65-a386-1cfe2ea691be
date added to LUP
2016-12-08 12:16:52
date last changed
2024-04-19 14:42:20
@article{1b2a5732-8960-4c65-a386-1cfe2ea691be,
  abstract     = {{<p>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 &lt; 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 &gt; 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 &lt; 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.</p>}},
  author       = {{Malhotra-Kumar, Surbhi and Van Heirstraeten, Liesbet and Coenen, Samuel and Lammens, Christine and Adriaenssens, Niels and Kowalczyk, Anna and Godycki-Cwirko, Maciek and Bielicka, Zuzana and Hupkova, Helena and Lannering, Christina and Mölstad, Sigvard and Fernandez-Vandellos, Patricia and Torres, Antoni and Parizel, Maxim and Ieven, Margareta and Butler, Chris C. and Verheij, Theo and Little, Paul and Goossens, Hermanon}},
  issn         = {{0305-7453}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{3258--3267}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of Antimicrobial Chemotherapy}},
  title        = {{Impact of amoxicillin therapy on resistance selection in patients with community-acquired lower respiratory tract infections : A randomized, placebo-controlled study}},
  url          = {{http://dx.doi.org/10.1093/jac/dkw234}},
  doi          = {{10.1093/jac/dkw234}},
  volume       = {{71}},
  year         = {{2016}},
}