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Rapid genetic and phenotypic changes in Pseudomonas aeruginosa clinical strains during ventilator-associated pneumonia.

ABSTRACT: Treatment with antibiotics leads to the selection of isolates with increased resistance. We investigated if evolution towards resistance was associated with virulence changes, in the context of P. aeruginosa ventilator-associated pneumonia (VAP). Four patients were selected because they had multiple VAP episodes during short periods (12 days to 5 weeks), with emergence of resistance. We performed whole-genome sequencing of 12?P. aeruginosa from bronchoalveolar lavages or blood culture (3 isolates per patient). Production of quorum sensing-dependent virulence factors, serum resistance, cytotoxicity against A549 cells, biofilm production, and twitching motility were studied. Each patient was infected with a unique strain. For all patients, resistance development was explained by genetic events in ampD, mexR or oprD. Additional variations were detected in virulence- and/or fitness-associated genes (algB, gacA, groEL, lasR, mpl, pilE, pilM, rhlR) depending on the strain. We noticed a convergence towards quorum sensing deficiency, correlated with a decrease of pyocyanin and protease production, survival in serum, twitching motility and cytotoxicity. In one patient, changes in pilM and pilE were related to enhanced twitching. We show that the emergence of resistance in P. aeruginosa is associated with virulence modification, even in acute infections. The consequences of this short-term pathoadaptation need to be explored.

SUBMITTER: Persyn E

PROVIDER: S-EPMC6423012 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:BackgroundProbiotics could prevent Pseudomonas aeruginosa colonization in lower respiratory tract (LRT) and reduced P. aeruginosa ventilator-associated pneumonia (VAP) rate. Recent studies also suggested that probiotics could improve lung inflammation in mice infected with P. aeruginosa. It seems that microbiota regulation may be a potential therapy for P. aeruginosa VAP patients. However, we know less about the LRT microbial composition and its correlation with prognosis in P. aeruginosa VAP patients. This study aimed to characterize LRT microbiota in P. aeruginosa VAP patients and explore the relationship between microbiota and patient prognosis.MethodsDeep endotracheal secretions were sampled from subjects via intubation. Communities were identified by 16S ribosomal RNA gene sequencing. The relationship between microbiota and the prognosis of P. aeruginosa VAP patients were evaluated. Clinical pulmonary infection score and the survival of intensive care unit were both the indicators of patient prognosis.ResultsIn this study, the LRT microbial composition of P. aeruginosa VAP patients was significantly different from non-infected intubation patients, and showed significant individual differences, forming two clusters. According to the predominant phylum of each cluster, these two clusters were named Pro cluster and Fir-Bac cluster respectively. Patients from Pro cluster were dominated by Proteobacteria (adj.P < 0.001), while those from Fir-Bac cluster were dominated by Firmicutes, and Bacteroidetes (both adj.P < 0.001). These two varied clusters (Pro and Fir-Bac cluster) were associated with the patients' primary disease (χ2-test, P < 0.0001). The primary disease of the Pro cluster mainly included gastrointestinal disease (63%), and the Fir-Bac cluster was predominantly respiratory disease (89%). During the two-week dynamic observation period, despite the use of antibiotics, the dominant genera and Shannon diversity of the LRT microbiota did not change significantly in patients with P. aeruginosa VAP. In prognostic analysis, we found a significant negative correlation between Lactobacillus and clinical pulmonary infection score on the day of diagnosis (P = 0.014); but we found no significant difference of microbial composition between survivors and non-survivors.ConclusionsLRT microbial composition was diversified among P. aeruginosa VAP patients, forming two clusters which were associated with the primary diseases of the patients.

Project description:Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based strategies for treating bacterial infections. To date, most studies in the field have focused on the identification of CS patterns in model strains. However, one of the main requirements for the clinical application of this trade-off is that it must be robust and has to emerge in different genomic backgrounds, including preexisting drug-resistant isolates, since infections are frequently caused by pathogens already resistant to antibiotics. Here, we report the first analysis of CS robustness in clinical strains of Pseudomonas aeruginosa presenting different ab initio mutational resistomes. We identified a robust CS pattern associated with short-term evolution in the presence of ciprofloxacin of clinical P. aeruginosa isolates, including representatives of high-risk epidemic clones belonging to sequence type (ST) 111, ST175, and ST244. We observed the acquisition of different ciprofloxacin resistance mutations in strains presenting varied STs and different preexisting mutational resistomes. Importantly, despite these genetic differences, the use of ciprofloxacin led to a robust CS to aztreonam and tobramycin. In addition, we describe the possible application of this evolutionary trade-off to drive P. aeruginosa infections to extinction by using the combination of ciprofloxacin-tobramycin or ciprofloxacin-aztreonam. Our results support the notion that the identification of robust patterns of CS may establish the basis for developing evolution-informed treatment strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens. IMPORTANCE Collateral sensitivity (CS) is a trade-off of antibiotic resistance evolution that could be exploited to design strategies for treating bacterial infections. Clinical application of CS requires it to robustly emerge in different genomic backgrounds. In this study, we performed an analysis to identify robust patterns of CS associated with the use of ciprofloxacin in clinical isolates of P. aeruginosa presenting different mutational resistomes and including high-risk epidemic clones (ST111, ST175, and ST244). We demonstrate the robustness of CS to tobramycin and aztreonam and the potential application of this evolutionary observation to drive P. aeruginosa infections to extinction. Our results support the notion that the identification of robust CS patterns may establish the basis for developing evolutionary strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens.

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Rapid genetic and phenotypic changes in Pseudomonas aeruginosa clinical strains during ventilator-associated pneumonia.

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