Cystic fibrosis (CF), like many other genetic diseases, can result in a number of complications that plague patients for life. CF is usually the result of a mutation in the cystic fibrosis conductance regulator (CFTR) gene, and this single genetic defect creates pathology in nearly every organ in the body.

Major complications of CF include pulmonary exacerbations, which can occur with varying degrees of frequency in patients, even while on follow-up. 

“Pulmonary exacerbations are recognized as important events in the lives of people with cystic fibrosis, with prolonged and frequent exacerbations associated with declining lung function, reduced quality of life and decreased survival,” Stanford and colleagues wrote in a review article published in Chest.

How is pulmonary exacerbation defined? There is no universal consensus on the answer, but most agree it is an acute worsening of respiratory symptoms that requires urgent medical attention. The most commonly recognized major symptoms are: 

  • A reduction in pulmonary function by 10% or more
  • Radiographic changes
  • Low oxygen saturation
  • Hemoptysis. 

The most commonly recognized minor symptoms of pulmonary exacerbations are: 

  • Sputum changes
  • Increased coughing
  • Worsening dyspnea
  • Lower exercise tolerance
  • Loss of appetite
  • Weight loss. 

Some researchers propose that a diagnosis of pulmonary exacerbation should only be made if the patient presents with most of the symptoms listed above; others think that a few of those symptoms would suffice. 

In Current Opinion in Pulmonary Medicine, Ng and colleagues wrote, “A standardized definition is desirable as it could allow for better comparison of trials and could be used in the study of therapies intended to reduce exacerbation frequency.” Currently, clinical trials tend to accept a physician’s diagnosis for pragmatic purposes. 

Read more about cystic fibrosis etiology 

In addition to the lack of consensus on what should qualify as a pulmonary exacerbation of CF, “there is no unified consensus for the best treatment or prevention of [pulmonary exacerbations], and there is a lack of robust evidence to guide clinical practice,” Stanford et al wrote. 

In these circumstances, treatment is based on each physician’s discretion and experience. A number of management options have been studied and refined over the years. Let’s take a look at the role of antibiotics in treating pulmonary exacerbations in CF. 

Optimizing Treatment With Antibiotics

Antibiotic treatment is the main tool used to fight pulmonary exacerbations, given that bacterial infection is usually involved. Antibiotics can be administered orally, by inhalation, intramuscularly, or intravenously. Inhalation of antibiotics usually results in a higher local concentration of the antibiotics in the airways, which may eradicate bacteria while minimizing systemic exposure. 

“Antibiotics are used for treating pulmonary exacerbations based on acute infections, for eradicating pathogens in otherwise asymptomatic cystic fibrosis patients, and for reducing the bacterial burden in chronically infected patients, as some pathogens cannot be eradicated once a chronic infection has been established.” Akkerman-Nijland and colleagues wrote in Expert Opinion on Drug Metabolism & Toxicology.

The main bacterial strains associated with CF pulmonary exacerbations are Staphylococcus aureus in children and Pseudomonas aeruginosa in older patients. However, the prevalence of various bacterial strains vary significantly between countries and across time. For example, in Europe, the prevalence of Pseudomonas aeruginosa is decreasing, while the prevalence of Staphylococcus aureus is increasing. In the United States, the prevalence of methicillin-resistant Staphylococcus aureus rose rapidly from 2001 to 2014 before plateauing. 

So, what types of antibiotics should be used? Most initial isolates of Pseudomonas aeruginosa respond to commonly used antibiotics, but bacterial resistance does usually develop eventually. Traditionally, the best guide on which antibiotics to use is based on sputum culture, which should be collected when pulmonary exacerbation of CF is diagnosed. However, results from a sputum culture usually take days, so physicians often use previously available sputum culture data to choose the antibiotics to initially prescribe. 

Read more about cystic fibrosis treatment

Some pathogens, such as Staphylococcus aureus, are usually treated with a single antibiotic. However, others, such as Burkholderia cepacia and Pseudomonas aeruginosa, are most frequently treated with a combination of different antibiotics. This is to prevent resistance and to achieve synergy. The prescription of antibiotics has always been a medical gray area—the goal is always to resolve infection completely with as little antibiotics as possible. 

Another area of difficulty is determining the right dosage of antibiotics to prescribe, given the variability of lung penetration, altered pharmacokinetics in patients with CF, and the rise of antimicrobial resistance. Therefore, optimizing antibiotic treatment via therapeutic drug monitoring is important in treating these patients.

“Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ß-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF,” Akkerman-Nijland and colleagues wrote. 

Treatment Endpoints  

The goal of antibiotic treatment is to resolve bacterial infection in CF patients, but considering that cystic fibrosis is a chronic condition in which some measure of pulmonary pathology is always present, how do physicians decide on when to end antibiotic treatment? 

Studies suggest that 2 main endpoints are most often used: the improvement of forced expiratory volume in 1 second (FEV1) and the resolving of acute symptoms. However, the physician’s judgment of treatment success may not correlate with that of the patient. “This highlights the necessity to incorporate both objective measures and patient-reported outcome measures when evaluating treatment effects,” Stanford and colleagues wrote.

References

Ng C, Nadig T, Smyth AR, Flume P. Treatment of pulmonary exacerbations in cystic fibrosisCurr Opin Pulm Med. 2020;26(6):679-684. doi:10.1097/MCP.0000000000000730

Stanford GE, Dave K, Simmonds NJ. Pulmonary exacerbations in adults with cystic fibrosis: a grown-up issue in a changing cystic fibrosis landscapeChest. 2021;159(1):93-102. doi:10.1016/j.chest.2020.09.084

Akkerman-Nijland AM, Akkerman OW, Grasmeijer F, et al. The pharmacokinetics of antibiotics in cystic fibrosisExpert Opin Drug Metab Toxicol. 2021;17(1):53-68. doi:10.1080/17425255.2021.1836157