Elsevier

The Lancet

Volume 384, Issue 9944, 23–29 August 2014, Pages 703-713
The Lancet

Series
Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis

https://doi.org/10.1016/S0140-6736(14)61137-5Get rights and content

Summary

Cystic fibrosis is characterised by chronic polymicrobial infection and inflammation in the airways of patients. Antibiotic treatment regimens, targeting recognised pathogens, have substantially contributed to increased life expectancy of patients with this disease. Although the emergence of antimicrobial resistance and selection of highly antibiotic-resistant bacterial strains is of major concern, the clinical relevance in cystic fibrosis is yet to be defined. Resistance has been identified in recognised cystic fibrosis pathogens and in other bacteria (eg, Prevotella and Streptococcus spp) detected in the airway microbiota, but their role in the pathophysiology of infection and inflammation in chronic lung disease is unclear. Increased antibiotic resistance in cystic fibrosis might be attributed to a range of complex factors including horizontal gene transfer, hypoxia, and biofilm formation. Strategies to manage antimicrobial resistance consist of new antibiotics or localised delivery of antimicrobial agents, iron sequestration, inhibition of quorum-sensing, and resistome analysis. Determination of the contributions of every bacterial species to lung health or disease in cystic fibrosis might also have an important role in the management of antibiotic resistance.

Introduction

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene encodes an ion channel located on the apical membrane of epithelial cells and is expressed in many cells throughout the body. In the lungs, this ion channel helps to control the volume of airway surface liquid, which affects mucocilliary clearance. A defective CFTR in the cystic fibrosis airway surface results in thickened mucus secretions, which cannot be easily cleared. Trapped bacteria colonise the mucus and enables the development and persistence of pulmonary bacterial infection. Various mechanisms link defective CFTR gene to the poor clearance of bacteria deposited on the mucus surface, including a reduced volume of airway surface liquid and lower airway surface liquid pH in patients than controls.1, 2

A small number of bacteria, Staphylococcus aureus (including meticillin-resistant S aureus [MRSA]), Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia cepacia complex, are recognised as cystic fibrosis respiratory pathogens (figure 1). Additional important opportunistic pathogens, which infect the cystic fibrosis airways, have been described including Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and non-tuberculous mycobacterium (NTM). Isolation of these bacteria has been done on the basis of agar based culture methods in mostly aerobic conditions at 35–37°C.4 These pathogens have also been associated with pulmonary infection in other respiratory diseases (eg, non-cystic fibrosis bronchiectasis and chronic obstructive pulmonary disease).5, 6 Transient bacterial colonisation of the airways by cystic fibrosis pathogens might be followed by chronic infection, which is related to a progressive decrease in lung function.7 Patients with cystic fibrosis have intermittent episodes of pulmonary exacerbations, which are associated with an excessive immune response, irreversible tissue damage, and an accelerated decrease in lung function.8

Respiratory disease due to chronic bacterial infection is the cause of early morbidity and mortality in a large percentage (85%) of patients with cystic fibrosis.9 Therefore, the presence of recognised pathogens in cystic fibrosis respiratory secretions is examined by clinical laboratories and targeted by subsequent antibiotic treatment. Antibiotic treatment is initiated at a very young age to manage pulmonary infection and slow progression of lung deterioration. Various antimicrobial agents and complex regimens are used for prophylaxis, eradication, treatment of exacerbations, and chronic suppressive therapy.7, 10, 11, 12, 13 This Series paper focuses on the emergence of antimicrobial resistance and selection of highly antibiotic-resistant bacterial strains in cystic fibrosis respiratory microbiota, which results from such therapy. We consider why resistance develops and the issues that arise when the present definition of resistance is applied to chronic infection, in which bacteria grow as a biofilm. Although the clinical relevance of antibiotic resistance in cystic fibrosis airways infection remains to be clarified, this Series paper discusses some of the present and future strategies to minimise or overcome antimicrobial resistance.

Key messages

  • •

    Complex culture and molecular methods have shown that cystic fibrosis pulmonary infection is polymicrobial, and that the types and abundance of bacteria present in cystic fibrosis respiratory samples differ between individuals and over time

  • •

    Emergence of antimicrobial resistance and selection of highly antibiotic-resistant recognised cystic fibrosis pathogens is expected as patients are living longer and ultimately exposed to an increasing number and combination of antibiotics

  • •

    Antibiotic resistance has been reported in bacteria belonging to the cystic fibrosis airway microbiota, whose clinical significance is unknown

  • •

    The opportunity for horizontal gene transfer between bacteria might be enhanced as the cystic fibrosis pulmonary bacterial community is highly diverse

  • •

    Antimicrobial resistance is also affected by an acidic pH and hypoxia in the cystic fibrosis airways, by biofilm formation, and exposure of bacteria to subinhibitory antibiotic concentrations

  • •

    Potential future strategies to manage antimicrobial resistance might include the use of antibiotic adjuvants, resistome analysis, and identification of the role of anaerobic bacteria in cystic fibrosis airways infection and resistance

Section snippets

Cystic fibrosis microbiota

Research during the past 10 years has used complex culture and molecular methods to investigate the types and abundance of bacteria present in cystic fibrosis respiratory samples.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 These studies show that diverse polymicrobial communities exist within the airways of patients with cystic fibrosis with aerobic, facultative, and obligate anaerobes. As a result, the term cystic fibrosis microbiota now describes the intricate array of bacteria

Antibiotic regimens used to treat cystic fibrosis lung infections

The median predicted age of survival for patients with cystic fibrosis in the UK is now older than 40 years, whereas 50 years ago, death occurred in the first few years of life.30 One of the most important interventions that has contributed to increased life expectancy is antibiotic treatment directed against recognised pathogens of cystic fibrosis infecting the airways. Full details of antibiotic regimens used to treat cystic fibrosis lung infections are provided in consensus guidelines

Antimicrobial resistance in the cystic fibrosis microbiota

Bacteria are categorised as susceptible, intermediate resistant, or resistant to antibiotics through comparison of the minimum inhibitory concentration (MIC) to breakpoint concentrations of the antibiotic.38 Breakpoint concentrations are established after many factors are considered including clinical, pharmacological, and microbiological data and are based on antibiotic concentrations that are achievable via parenteral administration.38 A bacterium is described as resistant if the MIC of an

Other factors affecting antimicrobial resistance

Long-term persistence of bacteria in the presence of antibiotics might not only result from expression or acquisition of genetic mechanisms of resistance but also be affected by the microenvironment that exists and develops in cystic fibrosis airways.

Secretion of the bicarbonate ion (HCO3) might be defective in cystic fibrosis, resulting in more viscous mucus in affected organs.65 In an animal model of cystic fibrosis, airway surface liquid had a lower pH in the cystic fibrosis lung than

Detection of antimicrobial resistance

Conventional in-vitro susceptibility testing routinely done (eg, by use of broth microdilution, agar dilution, and Etest methods) by clinical laboratories use pure cultures of bacterial isolates that are grown planktonically. These methods are generally straightforward to complete but they do not accurately simulate the polymicrobial and chronically infected lung environment of cystic fibrosis where communities of bacteria might grow as a biofilm. Additionally, the same morphotype of a

Effects of long-term antibiotic use

Inhaled formulations of antimicrobial agents are important treatment strategies to manage cystic fibrosis lung infection because local administration of antibiotics to the lungs enables higher concentrations to reach the airways than does systemic administration.86

In a 5 year cohort study,87 long-term inhaled tobramycin use was reported as an independent risk factor for development of multidrug-resistant P aeruginosa.87 Furthermore, an ongoing clinical trial (NCT01375036) has been designed to

Antimicrobial adjuvants

New antibiotics need to be developed to treat multidrug-resistant pathogens of cystic fibrosis. Development of therapeutic agents able to prevent or disrupt biofilm formation in cystic fibrosis lungs might be an important strategy to treat chronic respiratory infection and could improve the action of antibiotic treatments.

Iron has a role in the formation and maintenance of P aeruginosa biofilm, with increased total iron and ferrous iron concentrations in cystic fibrosis sputum correlated with

Conclusions

Antibiotic treatment of recognised cystic fibrosis pathogens has undeniably resulted in increased life expectancy for patients with cystic fibrosis during the past 50 years. However, the subsequent emergence of antimicrobial resistance in recognised and potential pathogens in cystic fibrosis respiratory disease is of major concern. Although the clinical relevance of resistance in cystic fibrosis is not understood, research that aims to improve patient outcomes further while reducing antibiotic

Search strategy and selection criteria

We searched PubMed, Medline, and Scopus for literature published in English between Jan 1, 2004, and June 30, 2014. In PubMed and Medline we used the MeSH search terms “cystic fibrosis”, “bacterial infections”, “drug resistance”, “microbial” (two different MeSH terms combined for each search), and the free text terms “diversity”, “microbiota”, “resistance”, “molecular detection”, and all of the major cystic fibrosis pathogens stated in this Series paper sequentially in combination with “cystic

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