CFDB - Cystic Fibrosis DataBase

Antibiotics for prevention of respiratory exacerbations

Scheduled antibiotics every 3-4 months / symptom-based treatment

Background

The treatment of chronic infection in cystic fibrosis (CF) has the aim to maintain good lung function, to improve quality of life and to reduce mortality. There is no international consensus on the management of chronic infection in people with CF.

Two main strategies are widely practised. The elective regimen is to administer regular courses of intravenous (IV) antibiotics usually every three-months, regardless of the clinical status.

The alternative regimen is prompt treatment of acute exacerbations as determined by clinical or radiological findings or deterioration in lung function parameters (symptomatic regimen).

An alternative strategy could be the use of the oral route of administration of antibiotics.

The main attention about treatment of chronic infection is versus Pseudomonas aeruginosa (PA). Further microorganisms are relevant in the evaluation of chronic lung disease in CF (such as B. Cepacia, S. Maltophilia, MSSA and MRSA). Recent updates on the role of antimicrobial therapy in CF are available (Waters V. et al 2015)(Epps QJ, 2020).

An interesting point, strictly related to the intensive use of antibiotics in CF patients is the role of antibiotic adjuvant therapies, agents that may potentiate, refine or replace the action of antibiotics without exerting selective pressure for antibiotic resistance. They are a heterogeneous group of molecules that are similar in that they act by interfering with a mechanism the bacteria use to decrease their susceptibility to antibiotics; by reducing the microorganism’s virulence; or by rendering the germ more susceptible to the host immune system. Such agents include: quorum sensing inhibitors; agents that interfere with biofilm construction (the sugars fucose and galactose, and novel dendrimers acting on lectin blockade); efflux pump inhibitors that stop bacteria removing antibiotics from within the bacterial cell; glutamine as an amino acid supplement; and biological agents (such as bacteriophages) that infect bacteria causing their break-down and demise. In the case of bacteriophages that may cause the death of the organism, they act by 'infecting' the bacteria and therefore act differently to, but alongside, conventional antibiotics.

Issues

  1. To determine whether the use of elective (regular) IV antibiotics compared with symptomatic IV antibiotics is associated with an improvement in clinical status and survival rates in CF patients.
  2. To assess whether oral anti-pseudomonal antibiotics both as a treatment for pulmonary exacerbations and as a long-term treatment in chronic infection is associated with an improvement in clinical status and survival rates in people with CF.
  3. To recognize any adverse effects associated with the use of elective IV antibiotics.
  4. To detect whether the use of elective IV antibiotics leads to an increase in the development of resistant organisms.
  5. To determine if antibiotic adjuvant therapies improve clinical and microbiological outcome of pulmonary infection in people with CF.
  6. To evaluate the use of bronchoscopy-guided antimicrobial therapy in the management of lung infection in adults and children with cystic fibrosis.

What is known

4 CDSR evaluated these topics, one studying elective versus symptomatic IV antibiotic therapy, another evaluating the role of oral antibiotic therapy, the third determining if antibiotic adjuvant therapies improve clinical and microbiological outcome of pulmonary infection in people with CF and the last searching evidence to support the routine use of bronchoalveolar lavage for the diagnosis and management of pulmonary infection in subjects with CF.

No conclusive evidence is available that an elective regimen of IV antibiotics is more effective than a symptomatic regimen in maintaining respiratory function in CF (Breen L, 2012). Neither is there statistically significant evidence to suggest that an elective regimen was harmful encouraging the formation of antibiotic resistant micro-organisms and consequently increased mortality.

It should be noted that the total number of participants in well conducted RCT was small and that all studies were conducted in patients with chronic PA infection; more general conclusion on the treatment of chronic infection in CF are not possible.

A CDSR (Horsley A, 2016) assessed the effectiveness and safety of different antibiotic regimens in people with CF experiencing an exacerbation and chronically infected with organisms of the Burkholderia cepacia complex. No conclusions can be drawn from this review. Clinicians must continue to assess each person individually, taking into account in vitro antibiotic susceptibility data, previous clinical responses and their own experience.

Another CDSR (Remmington T, 2016) showed that no evidence is available from RCTs that oral anti-pseudomonal antibiotics, alone or in combination with another therapy, are any more or less effective in treating acute pulmonary infectious exacerbations or for long-term treatment of chronic infection in people with CF than other therapies.

There is no evidence that the use of adjuvant therapies may prove a beneficial alternative to conventional antibiotics alone in the treatment of pulmonary infection in CF people (Hurley MN, 2013).

In particular, neither beta-carotene or garlic showed a significant improvement in clinical state or the number of infections. One study of zinc supplementation showed fewer oral antibiotics were needed, but the same was not true for intravenous antibiotics (Abdulhamid I, 2008). A more recent  double-blind randomized placebo-controlled trial was conducted among children with CF to assess the effect of zinc supplementation (30 mg/day) on the need for antibiotics and pulmonary function tests (Sharma G, 2016). The study did not show any significant difference in the need forantibiotics, pulmonary function tests, hospitalization, colonization with Pseudomonas, or the need for antibiotics.

Finally, there is no clear evidence to support the routine use of bronchoalveolar lavage for the diagnosis and management of pulmonary infection in pre-school children with cystic fibrosis compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms. No evidence is available for adult and adolescent populations (Jain K, 2018).

Unresolved questions

There have been insufficient RCTs of elective versus symptomatic administration of intravenous antibiotics in people with CF to answer important questions about long-term outcomes.

Studies should be carried out to evaluate the effectiveness of routine elective IV antibiotics on long-term lung function, adverse effects and mortality in people with CF. The most widely used elective regimen is that of three-monthly administration and this should be compared with standard symptomatic IV treatment in a multicentre, adequately-powered and well-designed RCT to address these important issues.

Future trials should also be designed to adequately compare oral treatment with current standard therapies for both acute pulmonary exacerbations and long-term treatment of chronic infection.

No RCT is available about patients chronically infected with microorganisms different from PA. It could be of interest to evaluate the best choice for treatment of germs other than PA.

New strategies aiming to antibiotic adjuvant therapies should be founded on robust in vitro pre-clinical development work including models of bacterial infection considering both planktonic and biofilm modes of growth. Well-designed RCTs are required to determine the efficacy of any new strategy. Recent studies have found an association between vitamin D status and risk of PE in children and adults with CF. The ongoing “Vitamin D for enhancing the Immune System in Cystic fibrosis (DISC) study” is a multi-center, double-blind, randomized, placebo-controlled trial that will test the hypothesis of whether high dose vitamin D given as a single oral bolus of 250,000 IU to adults with CF during a PE followed by a maintenance dose of vitamin D will improve time to next PE and re-hospitalization, improve survival and lung function compared to placebo and reduce the rates of PE (for a description of the study see Tangpricha V, 2017).

Keywords: Bacterial Infections; Burkholderia cepacia; Colonization; Exacerbation; Haemophilus influenzae; Infection; Pneumonia; Pseudomonas aeruginosa; Respiratory Tract Infections; Staphylococcus aureus; Stenotrophomonas Maltophilia; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Cephalosporins; Macrolides; Monobactams; Others anti-bacterial agents; Penicillins; Quinolones; Tetracyclines;