Dataset Information

Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic.

ABSTRACT: We report the emergence of non-susceptibility to cefiderocol from a subpopulation of Pseudomonas aeruginosa recovered from a patient without history of cefiderocol exposure. Whole genome sequencing identified mutations in major iron transport pathways previously associated with cefiderocol uptake. Susceptibility testing should be performed before therapy with siderophore cephalosporins.

SUBMITTER: Streling AP

PROVIDER: S-EPMC8825772 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic.

Streling Ana Paula AP Al Obaidi Mohanad M MM Lainhart William D WD Zangeneh Tirdad T Khan Ayesha A Dinh An Q AQ Hanson Blake B Arias Cesar A CA Miller William R WR

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20211201 11

We report the emergence of non-susceptibility to cefiderocol from a subpopulation of Pseudomonas aeruginosa recovered from a patient without history of cefiderocol exposure. Whole genome sequencing identified mutations in major iron transport pathways previously associated with cefiderocol uptake. Susceptibility testing should be performed before therapy with siderophore cephalosporins. ...[more]

PMID: 33411899

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Project description:Pseudomonas aeruginosa is an opportunistic human pathogen that usually causes difficult-to-treat infections due to its low intrinsic antibiotic susceptibility and outstanding capacity for becoming resistant to antibiotics. In addition, it has a remarkable metabolic versatility, being able to grow in different habitats, from natural niches to different and changing inpatient environments. Study of the environmental conditions that shape genetic and phenotypic changes of P. aeruginosa toward antibiotic resistance supposes a novelty, since experimental evolution assays are usually performed with well-defined antibiotics in regular laboratory growth media. Therefore, in this work we address the extent to which the nutrients' availability may constrain the evolution of antibiotic resistance. We determined that P. aeruginosa genetic trajectories toward resistance to tobramycin, ceftazidime, and ceftazidime-avibactam are different when evolving in laboratory rich medium, urine, or synthetic sputum. Furthermore, our study, linking genotype with phenotype, showed a clear impact of each analyzed environment on both the fitness and resistance level associated with particular resistance mutations. This indicates that the phenotype associated with specific resistance mutations is variable and dependent on the bacterial metabolic state in each particular habitat. Our results support that the design of evolution-based strategies to tackle P. aeruginosa infections should be based on robust patterns of evolution identified within each particular infection and body location. IMPORTANCE Predicting evolution toward antibiotic resistance (AR) and its associated trade-offs, such as collateral sensitivity, is important to design evolution-based strategies to tackle AR. However, the effect of nutrients' availability on such evolution, particularly those that can be found under in vivo infection conditions, has been barely addressed. We analyzed the evolutionary patterns of P. aeruginosa in the presence of antibiotics in different media, including urine and synthetic sputum, whose compositions are similar to the ones in infections, finding that AR evolution differs, depending on growth conditions. Furthermore, the representative mutants isolated under each condition tested render different AR levels and fitness costs, depending on nutrients' availability, supporting the idea that environmental constraints shape the phenotypes associated with specific AR mutations. Consequently, the selection of AR mutations that render similar phenotypes is environment dependent. The analysis of evolution patterns toward AR requires studying growth conditions mimicking those that bacteria face during in vivo evolution.

Project description:The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed the inpatient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro, and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.IMPORTANCE Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen Pseudomonas aeruginosa upon recurrent exposures to antibiotics. Our studies show that tolerance protects P. aeruginosa against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance.

Dataset Information

Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic.

Publications

Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic.

Similar Datasets

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