Nitrofurantoin Pulmonary Toxicity

Nitrofurantoin Pulmonary Toxicity: A Rare but Serious Complication

Jennifer Twilla, PharmD, BCPS
John Winton, MD
Timothy H. Self, PharmD
Volume 50 - Issue 6 - June 2010

Nitrofurantoin has been widely used for the treatment and prevention of recurrent urinary tract infections since its introduction into clinical practice in 1953.1,2 Although it continues to be an effective antibiotic, nitrofurantoin is associated with several adverse effects, including pulmonary toxicity.

TYPES OF PULMONARY TOXICITY

Pulmonary complications occur in approximately 1 in 100,000 courses of nitrofurantoin therapy.1 Although these complications are rare, it is important to recognize them because they can be potentially serious and even fatal. Nitrofurantoin-induced pulmonary toxicity was first reported in 1962.3 From 1966 to 1976, 447 cases were reported in Sweden, and numerous cases have continued to be reported since then.4-13

Table 1 — Differential diagnoses of drug-induced lung disease
Acute conditions
• Acute respiratory distress syndrome
• Hypersensitivity pneumonitis
• Hypersensitivity reaction to a different agent
• Pulmonary edema
Chronic conditions
• Asbestosis
• Bronchiectasis
• Collagen vascular disease
• Idiopathic pulmonary fibrosis
• Lymphangioleiomyomatosis (rare)
• Psittacosis (rare)
• Pulmonary Langerhans cell histiocytosis (rare)
• Sarcoidosis
• Silicosis
• Tuberculosis or nontuberculous mycobacterial infection
Both acute and chronic conditions
• Allergic bronchopulmonary aspergillosis
• Bacterial pneumonia
• Cryptogenic organizing pneumonia
• Pneumocystis jiroveci pneumonia

Pulmonary reactions can manifest as pulmonary fibrosis, alveolar hemorrhage, cryptogenic organizing pneumonia (formerly bronchiolitis obliterans organizing pneumonia [BOOP]), collagen vascular disease, interstitial pneumonia, allergic reaction, and eosinophilic pneumonia.14,15 Thus, diagnosis of drug-induced lung disease can become an arduous task, especially in chronic cases. For that reason, clinical context and radiological features must be considered. Table 1 includes a list of differential diagnoses.

Nitrofurantoin pulmonary toxicity may present with 3 types of reactions: acute, subacute, and chronic. The most common manifestation is acute toxicity.5,14 Acute reactions may develop within 3 to 8 days of initiation of nitrofurantoin but may also appear a few hours to 4 weeks after the first dose. The only distinction between the subacute and chronic forms of nitrofurantoin pulmonary toxicity is that the former occurs after 1 month of drug therapy, whereas the latter occurs after 6 or more months.1,5,6,14 Table 2 lists the common presentations of both acute and chronic forms of nitrofurantoin pulmonary toxicity.

MECHANISM OF PULMONARY TOXICITY

Nitrofurantoin is thought to exert its toxic effects through a hypersensitivity reaction (acute form), or it can be directly related to oxidant-mediated tissue injury (chronic form).3,9,10 The exact mechanism of the acute hypersensitivity reaction still remains undetermined.6 Nitrofurantoin has been associated with pulmonary infiltrates coupled with eosinophilia, which is characteristic of Loeffler syndrome.7 Peripheral blood eosinophilia is found in 83% of acute cases, consistent with a hypersensitivity reaction.1 In contrast, the chronic form results from direct injury to lung parenchymal cells that is probably related to nitrofurantoin's ability to generate toxic oxygen radicals.9

RISK FACTORS

Nitrofurantoin should be avoided in patients with decreased renal function because the drug may not achieve adequate urine concentrations for bacterial killing and may increase the risk of neurological complications. This is a widely accepted practice; however, controversy remains about whether decreased renal function predisposes a patient to adverse pulmonary events.

Previous reports suggest that nitrofurantoin produces toxic metabolites in vitro in the presence of oxygen and lung microsomes.8 The toxic metabolites may cause lung injury that results in interstitial fibrosis. 8 Because renal excretion of nitrofurantoin directly correlates with creatinine clearance, the drug and its metabolites may accumulate in patients with decreased renal function. Consequently, the use of nitrofurantoin is contraindicated in patients with a creatinine clearance of less than 60 mL/min.10 Decreased renal function is common in elderly patients, and they should be evaluated before this medication is started.

MANAGEMENT

Diagnosis is by exclusion and by resolution of signs and symptoms after nitrofurantoin is discontinued. Initial treatment consists of drug withdrawal for both the acute and chronic forms of pulmonary toxicity.12 Corticosteroid therapy is of questionable efficacy. However, such therapy may be beneficial in some patients in whom corticosteroids are not contraindicated.

Recovery time is different for acute and chronic reactions. For acute reactions, symptoms may diminish or resolve within 24 hours.5 In contrast, the symptoms of chronic reactions may take up to a year to resolve. Even so, not all patients with chronic reactions respond to drug cessation. Therefore, corticosteroids may be used in these patients to lessen the inflammatory response.5 The typical regimen is prednisone, 20 to 40 mg/d, with slow tapering of the dosage over several months.13

KEY POINTS FOR YOUR PRACTICE

Pulmonary reactions are wellrecognized complications of nitrofurantoin therapy. Monitor patients who are receiving long-term therapy for these complications. In addition, teach patients to recognize the signs and symptoms of pulmonary toxicity and to report them promptly. Increased awareness of this complication may help prevent progression of this adverse event and possibly death.

 

Table 2 — Signs and symptoms of nitrofurantoin pulmonary toxicity
 AcuteCronic
Symptom occurrenceHours to days after initiation of drugWeeks to months of symptom progression during long-term administration of drug
SymptomsDyspnea++, tachypnea++, cough (usually nonproductive)++, fever+, hypoxia+, chest pain+/-, tachycardia+/-, rash (usually urticarial)+/-, arthralgia+/-Dyspnea++, tachypnea++, nonproductive cough++, hypoxia++, hemoptysis+/-, no fever
Laboratory findingsPeripheral blood eosinophilia (> 5% leukocytes)+, elevated ESR+/-, elevated ANA titer+/-Often normal CBC count
Chest x-ray findingsReticulo-alveolar infiltrates in bilateral lung basesInterstitial infiltrates in bilateral lung bases
HRCT findingsGround-glass opacitiesVariable (ground-glass opacities, patchy consolidation, fibrosis)
Pulmonary function testsRestrictive pattern+, decreased DLCO+Restrictive pattern++, decreased DLCO++
ResolutionCompleteVariable
++ High probability of occurring.
+ Good probability of occurring.
+/- May or may not occur.
ESR, erythrocyte sedimentation rate; ANA, antinuclear antibody; CBC, complete blood cell; HRCT, high-resolution computed tomography; DLCO, diffusing capacity of the lung for carbon monoxide.
References

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