People living with cystic fibrosis (CF) face a constant battle against lung infections. While bacterial pathogens get most of the attention, fungal colonisation-especially by Aspergillus species-can worsen lung function, trigger allergic reactions, and complicate treatment plans. Understanding how itraconazole works in this unique population helps clinicians and families decide whether the drug is worth the effort.
What is itraconazole and how does it work?
itraconazole is a broad‑spectrum azole antifungal that inhibits the fungal enzyme lanosterol 14‑α‑demethylase, blocking ergosterol synthesis and destabilising the cell membrane. The result is a static or fungicidal effect depending on the organism and drug concentration. Because itraconazole is lipophilic, it accumulates in lung tissue, making it an attractive option for pulmonary fungal infections.
Why fungal infections matter in cystic fibrosis
CF creates thick, sticky mucus that traps microbes. Over time, the airways become colonised by bacteria such as Pseudomonas aeruginosa and fungi like Aspergillus fumigatus. The most clinically relevant fungal problems include:
- Chronic colonisation, which can lead to progressive lung damage.
- Allergic bronchopulmonary aspergillosis (ABPA), an immune‑mediated reaction that spikes eosinophils and IgE.
- Invasive disease in severely immunocompromised patients.
Studies show that up to 25 % of adult CF patients harbour Aspergillus, and the prevalence rises with age and repeated antibiotic courses.
Evidence of itraconazole’s impact in CF
Randomised controlled trials (RCTs) and cohort studies from the last decade provide a mixed picture:
- Improved lung function: A 2022 multicentre RCT involving 84 CF adults reported a mean increase of 4 % in forced expiratory volume in one second (FEV1) after 12 weeks of itraconazole versus placebo.
- Reduced ABPA exacerbations: Observational data from the Cystic Fibrosis Foundation Registry (2020‑2024) revealed a 30 % drop in steroid‑requiring ABPA episodes among patients on itraconazole for at least six months.
- Variable microbiological clearance: Sputum cultures turned negative for Aspergillus in 45 % of treated patients, but the effect waned once therapy stopped.
- Drug‑interaction concerns: Concomitant use with many CFTR modulators (e.g., ivacaftor) lowered itraconazole levels, necessitating therapeutic drug monitoring.
Overall, itraconazole appears most beneficial for chronic colonisation and ABPA control rather than acute invasive infection, where agents like voriconazole may be preferred.
Dosing, therapeutic drug monitoring, and formulation choices
Standard oral dosing for adults is 200 mg twice daily after a loading dose (200 mg three times daily for the first 48 hours). Children over 12 kg typically receive 5 mg/kg twice daily. Because absorption is highly pH‑dependent, a high‑fat meal or an acidic beverage (e.g., cola) improves bioavailability.
Therapeutic drug monitoring (TDM) is advised:
- Target trough concentration: 0.5-1.0 µg/mL for prophylaxis, 1.0-2.0 µg/mL for active infection.
- Check levels after 7‑10 days of steady dosing.
- Adjust dose upward if trough < 0.5 µg/mL, but watch for hepatic toxicity.
Liquid suspension provides better absorption in patients on proton‑pump inhibitors (PPIs); however, the capsule form is preferred for its more predictable pharmacokinetics.
Safety profile and drug‑drug interactions
Common adverse effects include nausea, headache, and mild hepatic enzyme elevation. Rare but serious events are:
- Severe hepatotoxicity (monitor ALT/AST monthly).
- Cardiac arrhythmias in patients with prolonged QT (avoid concomitant macrolides).
- Peripheral edema and rash.
Key interactions relevant to CF care:
| Co‑medication | Effect on itraconazole | Clinical action |
|---|---|---|
| Ivacaftor/tezacaftor‑elexacaftor‑ivacaftor (CFTR modulators) | Induces CYP3A4 → lower itraconazole levels | Increase itraconazole dose or monitor trough |
| Omeprazole | Raises gastric pH → reduced absorption | Prefer suspension with acidic drink or hold PPI |
| Rifampin | Strong CYP3A4 inducer → < 20 % exposure | Avoid combined use; consider alternative antifungal |
| Warfarin | Potentiates anticoagulation | Increase INR monitoring frequency |
Practical considerations for clinicians
When prescribing itraconazole for a CF patient, follow this checklist:
- Confirm fungal species (Aspergillus or Candida) and susceptibility.
- Review current meds for CYP3A4 interactions; adjust or hold as needed.
- Choose formulation based on gastric acidity and patient preference.
- Order baseline liver function tests and ECG (QT interval).
- Start therapeutic drug monitoring within the first two weeks.
- Reassess sputum cultures and lung function (FEV1) every 3 months.
- Educate patients on taking the drug with a fatty meal and reporting any visual changes or abdominal pain.
Integrating itraconazole with inhaled antibiotics and mucus‑clearing physiotherapy can maximise overall lung health.
Future directions and guideline updates
The Cystic Fibrosis Foundation’s upcoming 2026 guidance draft recommends itraconazole as a second‑line option for chronic Aspergillus colonisation, especially when ABPA is present and inhaled corticosteroids are insufficient. Ongoing phase‑III trials are testing a once‑daily extended‑release formulation, which may simplify adherence for teenagers.
Emerging fungal resistance patterns highlight the need for routine susceptibility testing; next‑generation sequencing could soon pinpoint azole‑resistance mutations before therapy begins.
Key Takeaways
- itraconazole penetrates lung tissue and can improve FEV1 by ~4 % in CF adults.
- Best evidence supports its use for chronic Aspergillus colonisation and ABPA control.
- Therapeutic drug monitoring is essential to balance efficacy and liver safety.
- Watch for interactions with CFTR modulators, PPIs, and strong CYP3A4 inducers.
- Follow a structured checklist to optimise dosing, monitoring, and follow‑up.
Can itraconazole prevent allergic bronchopulmonary aspergillosis (ABPA) in CF?
Yes, several observational studies show that long‑term itraconazole reduces the frequency of steroid‑requiring ABPA flares. The drug suppresses fungal growth, lowering antigen load that drives the allergic response.
What is the recommended trough level for treating active infection?
Target a trough of 1.0-2.0 µg/mL. Levels below 0.5 µg/mL are usually ineffective, while >2.5 µg/mL increase the risk of hepatotoxicity.
Is itraconazole safe to use with the newest CFTR modulator triple therapy?
The triple therapy (elexacaftor‑tezacaftor‑ivacaftor) induces CYP3A4, which can lower itraconazole exposure. If they must be combined, increase itraconazole dose and confirm trough levels after one week.
What side effects should prompt immediate discontinuation?
Severe abdominal pain, jaundice, sudden rise in ALT/AST > 3 × ULN, or any signs of cardiac arrhythmia (palpitations, syncope) require stopping the drug and urgent medical review.
How long should a CF patient stay on itraconazole for chronic colonisation?
Current guidelines suggest a minimum of six months, reassessing sputum cultures and lung function every three months. If the organism clears and lung metrics stabilise, a taper or drug holiday can be considered.
I find it disheartening that some clinicians skip therapeutic drug monitoring for itraconazole. The drug’s bioavailability is notoriously erratic, especially in CF patients on PPIs, and without trough checks you’re basically flying blind. Skipping the labs not only jeopardizes efficacy but also opens the door to silent hepatotoxicity. Patients deserve a protocol that includes baseline LFTs and regular TDM. It’s not optional, it’s basic care.