The problems of antibiotic resistance in cystic fibrosis and solutions

Abstract

Chronic respiratory infection is the main cause of morbidity and mortality in cystic fibrosis (CF) patients. One of the hallmarks of these infections, led by the opportunistic pathogen Pseudomonas aeruginosa, is their long-term (lifelong) persistence despite intensive antimicrobial therapy. Antimicrobial resistance in CF is indeed a multifactorial problem, which includes physiological changes, represented by the transition from the planktonic to the biofilm mode of growth and the acquisition of multiple (antibiotic resistance) adaptive mutations catalyzed by frequent mutator phenotypes. Emerging multidrug-resistant CF pathogens, transmissible epidemic strains and transferable genetic elements (such as those encoding class B carbapenemases) also significantly contribute to this concerning scenario. Strategies directed to combat biofilm growth, prevent the emergence of mutational resistance, promote the development of novel antimicrobial agents against multidrug-resistant strains and implement strict infection control measures are thus needed.

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

“…First, they belong to the 136 most frequently mutated genes in an ongoing whole-genome sequencing project with serial isolates from people with CF seen at the CF clinic Hannover. Second, they are known from the literature to be associated with susceptibility and/or resistance to antimicrobial drugs (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…These loci are known from the literature to be associated with the emergence of drug resistance in P. aeruginosa (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Hence, we became interested to know if and to what extent the global P. aeruginosa population in lungs of patients (CF lungs) carries mutations in these genes.…”

“…The high antimicrobial pressure exerted on the microorganism, which can persist and diversify in the patient's airways for decades, drives the emergence of drug resistance phenotypes (9,10). Typical targets are elements of replication, transcription, and translation, the cell wall, and transport and its regulation (9)(10)(11).…”

Deciphering the Resistome of the Widespread Pseudomonas aeruginosa Sequence Type 175 International High-Risk Clone through Whole-Genome Sequencing

“…Indeed, P. aeruginosa is the number one pathogen causing ventilator-associated pneumonia (VAP) and burn wound infections, both associated with very high (Ͼ30%) mortality rates (3). Likewise, P. aeruginosa is the most frequent and severe driver of chronic respiratory infections in patients suffering from cystic fibrosis (CF) or other chronic underlying diseases, such as bronchiectasis and chronic obstructive pulmonary disease (COPD) (4).…”

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“…By far the most common of these mutations, H274Y, restricts the inhibition of oseltamivir by displacing the pentyloxy group out of a hydrophobic pocket close to the active site [16][17][18][19] Other mutations, particularly E119V, E119G, and R292K can affect binding of both oseltamivir and zanamivir but arise much less frequently 20,21 Drug resistance and environmental influences helped this adaptive mutation of the strains to promote its efficacy multiple times than normal 22 . Thus, neuraminidase is a promising drug target for the treatment of various influenza viruses.…”