Surbhi Malhotra-Kumar1, Liesbet Van Heirstraeten2, Samuel Coenen2,3, Christine Lammens2, Niels Adriaenssens2,3, Anna Kowalczyk4, Maciek Godycki-Cwirko4, Zuzana Bielicka5, Helena Hupkova6, Christina Lannering7, Sigvard Mölstad8, Patricia Fernandez-Vandellos9, Antoni Torres9, Maxim Parizel2, Margareta Ieven2, Chris C Butler10,11, Theo Verheij12, Paul Little13, Herman Goossens2. 1. Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium surbhi.malhotra@uantwerpen.be. 2. Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium. 3. Centre for General Practice, Department of Primary and Interdisciplinary care (ELIZA), University of Antwerp, Antwerp, Belgium. 4. Department of Family and Community Medicine, Medical University of Lodz, Lodz, Poland. 5. Clinical Research Associates and Consultants, Bratislava, Slovakia. 6. Institute of Microbiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia. 7. Unit of R&D, Jönköping, Sweden. 8. Department of Clinical Sciences, Lund University, Lund, Sweden. 9. Hospital Clinic of Barcelona, Barcelona, Spain. 10. Cardiff University, Cardiff, UK. 11. Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK. 12. University Medical Center Utrecht, Utrecht, The Netherlands. 13. University of Southampton, Southampton, UK.
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 receivingamoxicillin 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.
RCT Entities:
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.
Authors: Jilei Zhang; Jiawei Wang; Li Chen; Afrah Kamal Yassin; Patrick Kelly; Patrick Butaye; Jing Li; Jiansen Gong; Russell Cattley; Kezong Qi; Chengming Wang Journal: Appl Environ Microbiol Date: 2017-12-15 Impact factor: 4.792
Authors: Leon D'Hulster; Steven Abrams; Robin Bruyndonckx; Sibyl Anthierens; Niels Adriaenssens; Chris C Butler; Theo Verheij; Herman Goossens; Paul Little; Samuel Coenen Journal: JAC Antimicrob Resist Date: 2022-06-29
Authors: Rune Aabenhus; Malene Plejdrup Hansen; Laura Trolle Saust; Lars Bjerrum Journal: NPJ Prim Care Respir Med Date: 2017-05-19 Impact factor: 2.871
Authors: Titus H Divala; Elizabeth L Corbett; Helen R Stagg; Marriott Nliwasa; Derek J Sloan; Neil French; Katherine L Fielding Journal: Syst Rev Date: 2018-12-23
Authors: M Ieven; S Coenen; K Loens; C Lammens; F Coenjaerts; A Vanderstraeten; B Henriques-Normark; D Crook; K Huygen; C C Butler; T J M Verheij; P Little; K Zlateva; A van Loon; E C J Claas; H Goossens Journal: Clin Microbiol Infect Date: 2018-02-12 Impact factor: 8.067
Authors: Calvin Sindato; Leonard E G Mboera; Bugwesa Z Katale; Gasto Frumence; Sharadhuli Kimera; Taane G Clark; Helena Legido-Quigley; Stephen E Mshana; Mark M Rweyemamu; Mecky Matee Journal: Antimicrob Resist Infect Control Date: 2020-12-07 Impact factor: 4.887
Authors: Andrew Smith; Rania Al-Mahdi; William Malcolm; Nikolaus Palmer; Gunnar Dahlen; Mohammed Al-Haroni Journal: BMC Oral Health Date: 2020-06-16 Impact factor: 2.757
Authors: Mina Bakhit; Tammy Hoffmann; Anna Mae Scott; Elaine Beller; John Rathbone; Chris Del Mar Journal: BMC Med Date: 2018-08-07 Impact factor: 8.775
Authors: R Bruyndonckx; B Stuart; P Little; N Hens; M Ieven; C C Butler; T Verheij; H Goossens; S Coenen Journal: Clin Microbiol Infect Date: 2017-11-03 Impact factor: 8.067
Authors: Paul Little; Nick A Francis; Beth Stuart; Gilly O'Reilly; Natalie Thompson; Taeko Becque; Alastair D Hay; Kay Wang; Michael Sharland; Anthony Harnden; Guiqing Yao; James Raftery; Shihua Zhu; Joseph Little; Charlotte Hookham; Kate Rowley; Joanne Euden; Kim Harman; Samuel Coenen; Robert C Read; Catherine Woods; Christopher C Butler; Saul N Faust; Geraldine Leydon; Mandy Wan; Kerenza Hood; Jane Whitehurst; Samantha Richards-Hall; Peter Smith; Michael Thomas; Michael Moore; Theo Verheij Journal: Lancet Date: 2021-09-22 Impact factor: 79.321