ArticleAntimicrobial agents and chemotherapy2011
Dynamics of mutator and antibiotic-resistant populations in a pharmacokinetic/pharmacodynamic model of Pseudomonas aeruginosa biofilm treatment.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Beyond Resistance Genes:Life (Basel, Switzerland) · 2026Review
- Collateral susceptibility-guided alternation of ceftolozane/tazobactam with imipenem prevents resistance development in XDRBiofilm · 2024Article
- Molecular basis of the phenotypic variants arising from aMicrobial genomics · 2023Article
- In Vitro Antimicrobial Susceptibility Testing of Biofilm-Growing Bacteria: Current and Emerging Methods.Advances in experimental medicine and biology · 2022Review
- Polygenic Adaptation and Clonal Interference Enable Sustained Diversity in Experimental Pseudomonas aeruginosa Populations.Molecular biology and evolution · 2021Article
- Tolerance and Persistence ofFrontiers in microbiology · 2020Review
- Pulse Dosing of Antibiotic Enhances Killing of aFrontiers in microbiology · 2020Article
- Effect ofInternational journal of molecular sciences · 2019Article
- Tolerance and Resistance ofFrontiers in microbiology · 2019Review
- Social Behavior of Antibiotic Resistant Mutants WithinFrontiers in microbiology · 2019Article
- Evolution of Antibiotic Resistance in Biofilm and Planktonic Pseudomonas aeruginosa Populations Exposed to Subinhibitory Levels of Ciprofloxacin.Antimicrobial agents and chemotherapy · 2018Article
- Review
- Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats.Antimicrobial agents and chemotherapy · 2017Article
- Real-Time Monitoring ofAntimicrobial agents and chemotherapy · 2017Article
- Spatial Organization Plasticity as an Adaptive Driver of Surface Microbial Communities.Frontiers in microbiology · 2017Review
- Sequential Treatment of Biofilms with Aztreonam and Tobramycin Is a Novel Strategy for Combating Pseudomonas aeruginosa Chronic Respiratory Infections.Antimicrobial agents and chemotherapy · 2016Article
- Antimicrobial Blue Light Inactivation of Gram-Negative Pathogens in Biofilms: In Vitro and In Vivo Studies.The Journal of infectious diseases · 2016Article
- Contribution of stress responses to antibiotic tolerance in Pseudomonas aeruginosa biofilms.Antimicrobial agents and chemotherapy · 2015Article
- Biofilm-specific antibiotic tolerance and resistance.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2015Review
- The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria.Clinical microbiology reviews · 2015Review
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4 authors.
Funding
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Abstract
Biofilm growth, antibiotic resistance, and mutator phenotypes are key components of chronic respiratory infections by Pseudomonas aeruginosa in cystic fibrosis patients. We examined the dynamics of mutator and antibiotic-resistant populations in P. aeruginosa flow-cell biofilms, using fluorescently tagged PAO1 and PAOMS (mutator [mutS] derivative) strains. Two-day-old biofilms were treated with ciprofloxacin (CIP) for 4 days (t4) at 2 μg/ml, which correlated with the mutant prevention concentration (MPC) and provided an AUC/MIC ratio of 384 that should predict therapeutic success. Biofilms were monitored by confocal laser scanning microscopy (CLSM), and the numbers of viable cells and resistant mutants (4- and 16-fold MICs) were determined. Despite optimized pharmacokinetic/pharmacodynamic (PK/PD) parameters, CIP treatment did not suppress resistance development in P. aeruginosa biofilms. One-step resistant mutants (MexCD-OprJ or MexEF-OprN overexpression) were selected for both strains, while two-step resistant mutants (additional GyrA or GyrB mutation) were readily selected only from the mutator strain. CLSM analysis of competition experiments revealed that PAOMS, even when inoculated at a 0.01 proportion, took over the whole biofilm after only 2 days of CIP treatment outnumbering PAO1 by 3 log at t4. Our results show that mutational mechanisms play a major role in biofilm antibiotic resistance and that theoretically optimized PK/PD parameters fail to suppress resistance development, suggesting that the increased antibiotic tolerance driven by the special biofilm physiology and architecture may raise the effective MPC, favoring gradual mutational resistance development, especially in mutator strains. Moreover, the amplification of mutator populations under antibiotic treatment by coselection with resistance mutations is for the first time demonstrated in situ for P. aeruginosa biofilms.
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