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.

Keywords:

• biofilms
• combined treatment
• cystic fibrosis
• epidemic strains
• hypermutation
• infection control
• multidrug resistance
• PK/PD parameters
• Pseudomonas aeruginosa
• sequential treatment

Financial & competing interests disclosure

A Oliver is supported by the Ministerio de Economía y Competitividad of Spain and the Instituto de Salud Carlos III, through the Spanish Network for the Research in Infectious Diseases (RD06/0008 and RD12/0015), and by the Direcció General d´Universitats, Recerca i Transferència del Coneixement del Govern de les Illes Balears. A Oliver has received research grants from Jannsen Cilag, Cubist Pharmaceuticals and Gilead Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The isolation of multidrug resistant (MDR) pathogens from the cystic fibrosis (CF) respiratory tract is increasing, mainly due to the extensive use of antibiotics.

• Biofilm growth is an efficient adaptive strategy for survival and persistence of bacteria in the CF lungs due to its inherent tolerance to the immune system and antibiotics.

• Mutators are highly prevalent in CF chronic respiratory infection and play a major role in resistance development.

• Epidemic and transmissible Burkholderia cepacia, Pseudomonas aeruginosa and Staphylococcus aureus strains have been identified infecting CF patients and frequently show MDR profiles.

• The CF airway hosts a complex microbiome in which genetic exchange can occur contributing to development of resistance.

• Treatments should be based on pharmacokinetic/pharmacodynamic parameters and on the pathogen resistance mechanisms; combined and sequential inhaled antibiotic treatments seem to be a promising alternative.

• Targeting the biofilms and the antimutator strategies arise as innovative approaches to overcome the current lack of effective antimicrobial treatments.

• Strict infection control measures are required to prevent the inter-patient transmission of MDR and epidemic strains.

Notes