Nitrofurantoin-Induced Lung Disease

Nitrofurantoin induced lung disease is an adverse reaction to nitrofurantoin, an antibiotic used for urinary infection and long term prophylaxis. It has an acute form and a chronic form, with distinct features.

The acute reaction is much commoner, and appears within hours to 2 weeks of starting, usually in the first month. The chronic form appears after 6 months or more of continuous use, more often in women and older adults, and it may be fatal if the drug is continued.

Pathophysiology. The acute form is a hypersensitivity reaction. The chronic form is thought to result from oxidant injury and an immune reaction, causing interstitial inflammation and fibrosis, with nonspecific interstitial pneumonia and organising pneumonia patterns.

Acute: fever, cough, dyspnoea, chest pain, rash and eosinophilia, with a rapid onset, bilateral crackles and sometimes a pleural effusion. Chronic: insidious cough and exertional dyspnoea over months, fatigue and weight loss, with crackles and sometimes clubbing, often without fever or eosinophilia.

Severe dyspnoea, hypoxaemia or respiratory failure after starting the drug needs urgent care and immediate withdrawal.

• Clinical diagnosis based on the exposure, the time course and improvement after stopping, after excluding other causes.
• Acute: chest radiograph with diffuse or bibasal infiltrates and effusion. Eosinophilia in about a third to a half. CT shows ground glass and consolidation.
• Chronic: high resolution CT with basal ground glass, reticulation and traction bronchiectasis (nonspecific interstitial pneumonia), or patchy consolidation (organising pneumonia). Spirometry shows restriction with low DLCO.
• Bronchoalveolar lavage (lymphocytosis or eosinophils) and exclusion of infection, heart failure and pulmonary embolism.
• Liver function tests, since hepatic reactions can occur together, and a review of other drugs.
• Serology for connective tissue disease in chronic cases.

Differential diagnosis.

• Pneumonia and aspiration
• Heart failure
• Pulmonary embolism
• Other drug induced lung disease
• Idiopathic interstitial pneumonia and connective tissue disease associated disease
• Hypersensitivity pneumonitis

• Stop nitrofurantoin immediately and record it as an allergy.
• Acute reaction: improves within 24 to 72 hours after stopping in most. Give oxygen and supportive care. Prednisolone 0.5 to 1 mg/kg daily (30 to 40 mg) for 1 to 2 weeks for severe cases.
• Chronic reaction: prednisolone 0.5 to 1 mg/kg daily (30 to 40 mg) for 4 to 8 weeks, then tapered over 3 to 6 months, with response judged by symptoms, spirometry and CT. Fibrosis may persist.
• Alternatives for urinary infection and prophylaxis, by sensitivity and renal function: trimethoprim 200 mg twice daily for 3 days (100 mg at night for prophylaxis), cefalexin 500 mg twice daily for 3 days (125 to 250 mg at night for prophylaxis), fosfomycin 3 g single dose, pivmecillinam 400 mg three times daily for 3 days, or methenamine hippurate 1 g twice daily for prophylaxis. Non-antibiotic measures such as hydration, vaginal oestrogen in postmenopausal women, and behavioural advice.
• Prevention: avoid long term nitrofurantoin where alternatives exist, avoid in eGFR under 45 (reduced efficacy and higher toxicity), and educate patients to report new cough or breathlessness.
• Prophylaxis against Pneumocystis when prednisolone is 20 mg or more daily for over 4 weeks: co-trimoxazole 960 mg three times weekly.

Complications and prognosis. Acute disease resolves fully in most. Chronic disease improves in most when stopped early, but fibrosis and death can occur in those with delayed diagnosis.

Monitoring. Review at 2 weeks and 3 months with symptoms, oxygen saturation and spirometry with DLCO, and CT if abnormal. Annual review in those with residual fibrosis.

Referral and escalation. Refer to a respiratory physician for chronic disease, severe reaction or persistent abnormalities.