Leif Tueffers1, Camilo Barbosa1, Ingrid Bobis2, Sabine Schubert3, Marc Höppner4, Malte Rühlemann4, Andre Franke4, Philip Rosenstiel4, Anette Friedrichs2, Annegret Krenz-Weinreich5, Helmut Fickenscher3, Burkhard Bewig2, Stefan Schreiber2,4, Hinrich Schulenburg1. 1. Evolutionary Ecology and Genetics, Zoological Institute, Christian-Albrechts-Universität zu Kiel, Am Botanischen Garten 1-9, Kiel, Germany. 2. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel Campus, Arnold-Heller-Straße 3, Kiel, Germany. 3. Institute of Infection Medicine, Christian-Albrechts-Universität zu Kiel and University Medical Center Schleswig-Holstein, Brunswiker Straße 4, Kiel, Germany. 4. Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Rosalind-Franklin-Straße 12, Kiel, Germany. 5. LADR laboratories Plön, Krögen 6, Plön, Germany.
Abstract
BACKGROUND: Chronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only. OBJECTIVES: To investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome. METHODS: We investigated a cohort of adult CF patients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies. RESULTS: In two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance. CONCLUSIONS: We show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs.
BACKGROUND:Chronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only. OBJECTIVES: To investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome. METHODS: We investigated a cohort of adult CFpatients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies. RESULTS: In two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance. CONCLUSIONS: We show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs.
Authors: Richard A Stanton; Davina Campbell; Gillian A McAllister; Erin Breaker; Michelle Adamczyk; Jonathan B Daniels; Joseph D Lutgring; Maria Karlsson; Kyle Schutz; Jesse T Jacob; Lucy E Wilson; Elisabeth Vaeth; Linda Li; Ruth Lynfield; Paula M Snippes Vagnone; Erin C Phipps; Emily B Hancock; Ghinwa Dumyati; Rebecca Tsay; P Maureen Cassidy; Jacquelyn Mounsey; Julian E Grass; Sandra N Bulens; Maroya Spalding Walters; Alison Laufer Halpin Journal: Antimicrob Agents Chemother Date: 2022-09-06 Impact factor: 5.938
Authors: Matthias Merker; Leif Tueffers; Marie Vallier; Espen E Groth; Lindsay Sonnenkalb; Daniel Unterweger; John F Baines; Stefan Niemann; Hinrich Schulenburg Journal: Front Immunol Date: 2020-08-27 Impact factor: 7.561