Carbapenem-Resistant Pseudomonas aeruginosa in Chronic Lung Infection: Current Resistance Profile and Hypermutability in Patients with Cystic Fibrosis

Almeida, Mila M.; Freitas, Meyvianne T.; Folescu, Tânia Wrobel; Firmida, M C; Carvalho-Assef, Ana Paula D’A.; Marques, Elizabeth Andrade; Leão, Robson Souza

doi:10.1007/s00284-020-02337-0

Cited by 6 publications

(5 citation statements)

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“…A caveat to these calculations is that they are based only on NCBI genome sequences without functional verification, and we cannot rule out sequencing errors and assembly artifacts, though the prevalence would have to be extraordinarily high to explain these findings. Another caveat is that isolates from cystic fibrosis respiratory specimens, where hypermutators are common, may be overrepresented in the genomic databases [4,[12][13][14][15][16][17][18]. However, even if hypermutators and MexAB-OprM efflux deficient isolates are somewhat less common than our estimates of �2.3% and �3.9%, this would still suggest that the co-occurrence of hypermutation and preexisting MexAB-OprM functional deficiencies may be substantially more common than appreciated.…”

Section: P Aeruginosa Hypermutators and Mexab-oprm-deficient Assembli...mentioning

confidence: 56%

“…Hypermutation due to deficiencies in the mismatch repair (MMR) system in particular has been shown to accelerate the emergence of antimicrobial resistance (AMR) both in vitro and in vivo and is thus of considerable clinical concern [9][10][11]. Hypermutator P. aeruginosa isolates have been found in up to 50% of cystic fibrosis respiratory specimens, and hypermutation has been linked to development of MDR phenotypes over periods of years to decades in this context [4,[12][13][14][15][16][17][18]. Recent work has also demonstrated that hypermutation can lead to the evolution of antibiotic resistance over the time course of days in the context of acute systemic infection [19].…”

Section: Introductionmentioning

confidence: 99%

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Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors

Chiang¹,

Patil²,

Beka³

et al. 2022

PLoS Biol

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Hypermutation due to DNA mismatch repair (MMR) deficiencies can accelerate the development of antibiotic resistance in Pseudomonas aeruginosa. Whether hypermutators generate resistance through predominantly similar molecular mechanisms to wild-type (WT) strains is not fully understood. Here, we show that MMR-deficient P. aeruginosa can evolve resistance to important broad-spectrum cephalosporin/beta-lactamase inhibitor combination antibiotics through novel mechanisms not commonly observed in WT lineages. Using whole-genome sequencing (WGS) and transcriptional profiling of isolates that underwent in vitro adaptation to ceftazidime/avibactam (CZA), we characterized the detailed sequence of mutational and transcriptional changes underlying the development of resistance. Surprisingly, MMR-deficient lineages rapidly developed high-level resistance (>256 μg/mL) largely without corresponding fixed mutations or transcriptional changes in well-established resistance genes. Further investigation revealed that these isolates had paradoxically generated an early inactivating mutation in the mexB gene of the MexAB-OprM efflux pump, a primary mediator of CZA resistance in P. aeruginosa, potentially driving an evolutionary search for alternative resistance mechanisms. In addition to alterations in a number of genes not known to be associated with resistance, 2 mutations were observed in the operon encoding the RND efflux pump MexVW. These mutations resulted in a 4- to 6-fold increase in resistance to ceftazidime, CZA, cefepime, and ceftolozane-tazobactam when engineered into a WT strain, demonstrating a potentially important and previously unappreciated mechanism of resistance to these antibiotics in P. aeruginosa. Our results suggest that MMR-deficient isolates may rapidly evolve novel resistance mechanisms, sometimes with complex dynamics that reflect gene inactivation that occurs with hypermutation. The apparent ease with which hypermutators may switch to alternative resistance mechanisms for which antibiotics have not been developed may carry important clinical implications.

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Section: P Aeruginosa Hypermutators and Mexab-oprm-deficient Assembli...mentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors

Chiang¹,

Patil²,

Beka³

et al. 2022

PLoS Biol

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“…[52] The frequency of these variants tends to be higher in individuals with CF than in immunocompromised, burned or ulcerated patients, [53] and in different nations, variants resistant to carbapenems (CR) have recently been reported. [54,55] The frequency of MDR strains in these patients has increased from 15.7 % of MDR strains registered in the 2013 report of the CF Foundation (CFF) [56] to 42.4 % by 2022, coupled with 12.7 % of XDR variants. [57] Additionally, the lung environment of individuals with CF is crucial in the emergence and dispersal of P. aeruginosa variants with high transmission and propagation capacities, which have been defined as "epidemic strains" that have managed to infect and cause disease in individuals without CF and in their companion animals.…”

Section: P Aeruginosa and People With Cfmentioning

confidence: 99%

“…CF patients are subjected to early and prolonged antibiotic therapy even before being infected with P. aeruginosa ; [50,51] this favours the emergence of AMR variants [52] . The frequency of these variants tends to be higher in individuals with CF than in immunocompromised, burned or ulcerated patients, [53] and in different nations, variants resistant to carbapenems (CR) have recently been reported [54,55] . The frequency of MDR strains in these patients has increased from 15.7 % of MDR strains registered in the 2013 report of the CF Foundation (CFF) [56] to 42.4 % by 2022, coupled with 12.7 % of XDR variants [57] …”

Section: Pseudomonas Aeruginosamentioning

confidence: 99%

Diagnosis and Therapeutic Strategies Based on Nucleic Acid Aptamers Selected against Pseudomonas aeruginosa: The Challenge of Cystic Fibrosis

Gutiérrez‐Santana,

Coria‐Jiménez

2023

ChemMedChem

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Antimicrobial resistance (AMR) is a rapidly spreading global health problem, and approximately five million deaths associated with AMR pathogens were identified prior to the COVID‐19 pandemic. Pseudomonas aeruginosa has developed increasing AMR, and in patients with cystic fibrosis (CF) colonized by this bacterium, rare phenotypes have emerged that complicate the diagnosis and treatment of the hosts, in addition to multiple associated “epidemic strains” with high morbidities and mortalities. The conjugation of aptamers with fluorochromes or nanostructures has allowed the design of new identification strategies for Pseudomonas aeruginosa with detection limits of up to 1 cell ⋅ mL−1, and the synergy of aptamers with antibiotics, antimicrobial peptides and nanostructures has exhibited promising therapeutic qualities. Some selected aptamers against this bacterium have shown intrinsic antimicrobial activity. However, these aptamers have been poorly evaluated in clinical isolates and have shown decreased interactions for CF isolates, demonstrating, in these cases, uncommon phenotypes resulting from the selective qualities of this disease as well as the great adaptive capacity of the pathogen. Therefore, finding an aptamer or set of aptamers that have the ability to recognize strange phenotypes of this bacillus is crucial in the battle against AMR.

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“…98 106 In a recent study of 179 respiratory isolates from eight CF patients with chronic PA infections, levels of AMR included CPR 44.1%, MDR (39.6%), and XDR (4.4%). 191 Among 120 patients with CF in three European countries, high rates of CPR (37–52%) were cited from 2006 to 2012. 174 Some epidemic strains have adapted to allow persistence in the host without increasing the degree of AMR.…”

Section: Pseudomonal Pulmonary Infections In Cf and Non-cf Bronchiectasismentioning

confidence: 99%

Pseudomonas aeruginosa Pneumonia: Evolution of Antimicrobial Resistance and Implications for Therapy

Lynch

Zhanel

2022

Semin Respir Crit Care Med

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Pseudomonas aeruginosa (PA), a non–lactose-fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of urinary tract, intra-abdominal, wounds, skin/soft tissue, and bloodstream. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance (AMR) among PA has escalated globally, via dissemination of several international multidrug resistant “epidemic” clones. We discuss the importance of PA as a cause of pneumonia including health care–associated pneumonia, hospital-acquired pneumonia, VAP, the emergence of AMR to this pathogen, and approaches to therapy (both empirical and definitive).

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Carbapenem-Resistant Pseudomonas aeruginosa in Chronic Lung Infection: Current Resistance Profile and Hypermutability in Patients with Cystic Fibrosis

Cited by 6 publications

References 50 publications

Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors

Hypermutator strains of Pseudomonas aeruginosa reveal novel pathways of resistance to combinations of cephalosporin antibiotics and beta-lactamase inhibitors

Diagnosis and Therapeutic Strategies Based on Nucleic Acid Aptamers Selected against Pseudomonas aeruginosa: The Challenge of Cystic Fibrosis

Pseudomonas aeruginosa Pneumonia: Evolution of Antimicrobial Resistance and Implications for Therapy

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