Cystic Fibrosis (CF)

Cystic fibrosis (CF) is an inherited disease caused by pathogenic mutations in the CF transmembrane conductance regulator (CFTR) gene.¹ These mutations affect the levels or functioning of the CFTR protein, which subsequently leads to dehydration of the mucus in several organs. Both gastrointestinal and pancreatic ducts, as well as the lungs, are preferential sites for mucus build-up. This mucus has a thicker consistency and is therefore more difficult to remove by the cilia of the cells.² Patients with CF commonly experience blockage of the airways due to this abnormal mucus. Additionally, since the mucus is less able to eliminate pathogens due to changes in its biophysical and biochemical properties, bacterial infections are common in CF.^2,3 Over the course of the disease, the airways become chronically colonized with bacterial pathogens, and this colonization correlates with declines in overall health.  Both morbidity and mortality in CF are greatly impacted by lung disease resulting from chronic respiratory infections.⁴ Antibiotics are either used to fight these infections or prevent them, and they can be administered via inhalation as regular treatment, orally, or intravenously.⁵

Bacterial Pathogens in Cystic Fibrosis

Several bacterial species have been identified as respiratory pathogens in CF. These include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia complex. S aureus is typically isolated in pediatric patients, while adult patients are commonly colonized by P aeruginosa from early adulthood. P aeruginosa is the bacterial pathogen most commonly associated with an increased risk of hospitalization, severe reductions in pulmonary function measures, and end-stage lung disease in CF.⁴ Decreases in lung function and mortality are also affected by persistent infections with methicillin-resistant S aureus (MRSA).⁶

Guidelines for Antibiotic Use in Advanced Lung Disease

The goal of using antibiotics in CF is to preserve or improve lung function.⁶ Patients with CF and chronic airway infections are recommended to use intermittent (28 days on/off) inhaled antibiotics. Patients with severe disease may also benefit from continuously alternating between 2 different inhaled antibiotics.⁷ There is, however, scarce data on the long-term efficacy of this method.⁶ The choice of which antibiotic to use depends on which microorganisms are present in respiratory cultures. Selected patients who are candidates for a lung transplant may also receive continuous intravenous therapy.⁷

Antibiotics in Cystic Fibrosis

There are several antibiotics available for treating respiratory infections in CF. Common classes of these antibiotics include penicillins such as amoxicillin, oxacillin, and piperacillin (orally and intravenously administered), aminoglycosides such as tobramycin and gentamicin (inhaled and intravenously administered), cephalosporins such as cephalexin and cefazolin (orally and intravenously administered), and tetracyclines such as doxycycline and minocycline (orally and intravenously administered). Patients must complete the full course of antibiotics to decrease the risk of developing resistant strains, which limit treatment options.⁵

Chronic infections with P aeruginosa are commonly managed with inhaled antibiotics. This approach is supported by previous studies reporting a reduction in the pathogen’s density in the sputum with a simultaneous improvement in respiratory symptoms. Inhaled antibiotics are delivered directly into the airways in high levels with reduced systemic toxicity, offering advantages to other routes of administration. The most commonly used inhaled antibiotics for P aeruginosa infections in CF include colistin, tobramycin, aztreonam lysine, and levofloxacin. A combination of antibiotics are often used to achieve synergistic activity and decrease drug resistance in P aeruginosa infections. Colistin is typically used in Europe, while tobramycin is prescribed in the United States. Tobramycin offers superior activity against P aeruginosa compared to other aminoglycosides.⁶ The effective use of aztreonam has been proven in different clinical trials. The efficacy and tolerability of levofloxacin have also been reported in a phase III clinical trial in CF patients with chronic P aeruginosa infections.^8,9 

Treating infections caused by S aureus relies on the use of oral or intravenous antibiotics such as penicillins, cephalosporins, carbapenems, tetracyclines, and vancomycin. Cystic fibrosis patients with MRSA infections may be prescribed sulfamethoxazole/trimethoprim, vancomycin, doxycycline, and quinolones such as ciprofloxacin.⁵

References

1.  Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3

2. Morrison CB, Markovetz MR, Ehre C. Mucus, mucins, and cystic fibrosis. Pediatr Pulmonol. 2019;54(Suppl 3):S84-S96. doi:10.1002/ppul.24530

3. Research into mucus. Cystic Fibrosis Foundation. Accessed January 18, 2022.

4. Kiedrowski MR, Bomberger JM. Viral-bacterial co-infections in the cystic fibrosis respiratory tract. Front Immunol. 2018;9:3067. doi:10.3389/fimmu.2018.03067

5. Antibiotics. Cystic Fibrosis Foundation. Accessed January 18, 2022.

6. Taccetti G, Francalanci M, Pizzamiglio G, et al. Cystic fibrosis: recent insights into inhaled antibiotic treatment and future perspectives. Antibiotics (Basel). 2021;10(3):338. doi:10.3390/antibiotics10030338

7. Kapnadak SG, Dimango E, Hadjiliadis D, et al. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. J Cyst Fibros. 2020;19(3):344-354. doi:10.1016/j.jcf.2020.02.015

8. Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ; Mpex 204 Study Group. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-1516. doi:10.1164/rccm.201008-1293OC

9. Stuart Elborn J, Geller DE, Conrad D, et al. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J Cyst Fibros. 2015;14(4):507-514. doi:10.1016/j.jcf.2014.12.013

Reviewed by Kyle Habet, MD, on 1/31/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.