What are the next steps for an adult or adolescent patient with a chronic cough that persists after treatment with zithromycin (azithromycin)?

Management of Chronic Cough Persisting After Azithromycin Treatment

Stop the azithromycin immediately—it provides no benefit for chronic cough and should not be continued or repeated. 1, 2, 3

Immediate First Steps

Discontinue ACE Inhibitors If Present

• If the patient is taking an ACE inhibitor for hypertension or other conditions, stop it immediately and replace with an alternative medication. 1, 4, 5 ACE inhibitor-induced cough can persist for up to 26 days (median) after discontinuation. 2

Obtain Chest Radiography

• Order a chest X-ray now if not already done to exclude pneumonia, lung cancer, heart failure, or other structural abnormalities. 2, 4, 5 This is particularly important given the chronic nature of symptoms.

Smoking Cessation Counseling

• If the patient smokes, provide immediate counseling and assistance with cessation—cough can resolve within 4 weeks of quitting. 1, 4, 3

Systematic Treatment Algorithm for Chronic Cough

The American College of Chest Physicians (ACCP) recommends treating the three most common causes sequentially and additively, as more than one cause is often present. 1

Step 1: Treat Upper Airway Cough Syndrome (UACS) First

• Start with a first-generation antihistamine/decongestant combination (e.g., chlorpheniramine-pseudoephedrine) as empiric first-line therapy. 1, 2, 4 This addresses post-nasal drip, which is the most common cause of chronic cough.
• Expect response within 1-2 weeks, though complete resolution may take several weeks. 2, 4

Step 2: Add Asthma Treatment If Cough Persists

• After treating UACS, if cough persists, initiate treatment with inhaled corticosteroids (ICS) combined with long-acting β-agonists (LABA) such as fluticasone/salmeterol. 1, 4 The medical history is unreliable for ruling asthma in or out. 1
• Ideally, perform bronchoprovocation challenge (BPC) if spirometry doesn't show reversible airflow obstruction, but if unavailable, proceed with empiric therapy. 1, 4
• Continue the antihistamine/decongestant from Step 1 while adding asthma treatment. 1
• Allow 2-4 weeks to assess response. 4

Step 3: Add GERD Treatment If Still No Resolution

• If cough persists despite treating UACS and asthma, add empiric proton pump inhibitor therapy for gastroesophageal reflux disease. 1, 4 Continue all previous treatments as cough is often multifactorial. 4
• Note: The 2016 CHEST guideline states that in patients with unexplained chronic cough and a negative workup for acid reflux, proton pump inhibitors should not be prescribed. 1 However, for initial empiric treatment without extensive testing, a trial is reasonable per the 2006 ACCP guidelines. 1

Step 4: Consider Non-Asthmatic Eosinophilic Bronchitis (NAEB)

• If diagnoses of UACS and asthma have been eliminated or treated without resolution, consider NAEB with induced sputum testing for eosinophils. 1, 4
• If induced sputum testing cannot be performed, an empiric trial of corticosteroids should be the next step. 1

When to Refer or Pursue Advanced Evaluation

Refer to Pulmonology If:

• Cough persists beyond 8 weeks despite systematic empiric treatment. 2
• Chest X-ray shows masses, infiltrates, lymphadenopathy, or interstitial changes—this requires immediate pulmonology referral. 2
• The cause remains unexplained after sequential treatment trials. 1, 4

Advanced Diagnostic Testing

• For unexplained chronic cough, the 2016 CHEST guideline recommends objective testing for bronchial hyperresponsiveness and eosinophilic bronchitis, or a therapeutic corticosteroid trial. 1
• High-resolution computed tomography may be indicated if the cause is not identified. 5

Critical Pitfalls to Avoid

• Never continue or repeat antibiotics (including azithromycin) for chronic cough—this is explicitly contraindicated and contributes to antibiotic resistance. 2, 3 The research shows azithromycin is ineffective for chronic cough in most populations. 6
• Don't use cough suppressants if the cough is productive and helping clear secretions. 2
• Don't assume colored sputum indicates bacterial infection requiring antibiotics. 3
• Don't treat each cause in isolation—use sequential and additive steps because multiple causes frequently coexist. 1
• Don't skip the systematic approach and jump to advanced testing—empiric treatment based on the most common causes is the recommended first approach. 1, 5

Treatment for Unexplained Chronic Cough (If All Above Fails)

If cough remains unexplained after 8 weeks and systematic treatment of UACS, asthma, NAEB, and GERD:

• Consider a trial of gabapentin after discussing potential side effects and risk-benefit profile with the patient. 1 Dosing based on the Ryan trial: start low and titrate up. 1
• Reassess the risk-benefit profile at 6 months. 1
• Consider multimodality speech pathology therapy-based intervention, which has shown positive benefit on cough severity. 1