Published: May 2002

Publications

Pulmonary Reactions with Nitrofurantoin

Information on this subject has been updated. Read the most recent information.

Prescriber Update 23(2): 24-25
May 2002

Dr Michael Tatley, Medical Assessor,
Centre for Adverse Reactions Monitoring, Dunedin

A recent New Zealand case report of fatal interstitial lung disease resulting from long-term nitrofurantoin therapy highlights the need to be vigilant for pulmonary toxicity.  Nitrofurantoin is known to cause both acute and chronic pulmonary reactions.  Interstitial lung disease and pulmonary fibrosis may develop with long-term use.  Patients on prolonged nitrofurantoin therapy should be monitored for lung function changes and nitrofurantoin discontinued at the first signs of damage.  Symptom improvement is usually rapid but radiographic findings may remain unresolved.

NZ fatality following nitrofurantoin-induced interstitial lung disease

The Centre for Adverse Reactions Monitoring (CARM) has received a report of interstitial pneumonitis following long-term use of nitrofurantoin.  A 67-year-old female with a history of severe rheumatoid arthritis developed a chronic cough after 20 months of nitrofurantoin therapy taken for severe recurrent urinary tract infections.  She continued to receive nitrofurantoin for a further six months before it was discontinued after interstitial lung disease was diagnosed.  She died three months later of severe hypoxia.

In the CARM database, 34% of the nitrofurantoin adverse reaction reports involve the respiratory system.  Half of these reflect lung tissue damage including nine reports of pulmonary fibrosis.  Twenty-six reports for respiratory reactions were as a consequence of chronic nitrofurantoin therapy.

Acute and chronic forms of pulmonary reactions can occur

First described in 1957,¹  pulmonary toxicity with nitrofurantoin is rare with an estimated incidence of 1 in 5,000 first administrations for acute severe disease.²  Chronic pulmonary reactions are 10-20 times less frequent than acute reactions.²  However, pulmonary adverse reactions are among those most frequently reported for nitrofurantoin and cover a spectrum ranging from acute to chronic forms.^2-4  Acute pulmonary reactions typically have hypersensitivity-type features,^1,5 and usually affect women aged 40-50 years.²  They occur 1-2 weeks after initiation of nitrofurantoin, and can recur within minutes to hours of subsequent use.^2,5  Chronic pulmonary reactions mainly involve older persons,² are often insidious in onset and associated with therapy of six months or longer.^3,4  Interstitial lung disease and pulmonary fibrosis may develop.⁶  The insidious onset can result in an erroneous diagnosis of cardiac failure.¹

Possible immune or toxicity mechanism

The two forms of pulmonary reaction are considered to be different disease entities and the acute type does not necessarily lead to chronic reactions.^2,5  The acute pulmonary reaction is likely to be caused by an immune reaction of the hypersensitivity type.⁵  In the chronic form, the causative role of nitrofurantoin is less clear,² but could be via a toxicity mechanism.⁵  The majority of pulmonary reactions are not severe, but persisting damage is common with chronic reactions.³  Mortality has been estimated to occur in 10% of patients affected by either form.⁶  There have also been isolated reports of pulmonary haemorrhage⁷ and bronchiolitis obliterans organising pneumonia (BOOP) with nitrofurantoin.⁸

Cautious use and monitoring can reduce morbidity

Nitrofurantoin is contraindicated in patients with impaired renal function as there may be an increase in plasma concentration with subsequent toxicity.^9,10  Care should be exercised in the elderly, or those with impaired renal function who may also be at increased risk of toxicity.⁵  Long-term use of nitrofurantoin should not exceed six months unless the benefits clearly outweigh the risks.  The pulmonary condition of patients undergoing prolonged nitrofurantoin therapy should be monitored.^9,10  This should include careful vigilance for early features of emerging pulmonary toxicity, which may be evidenced by cough or shortness of breath,¹¹ indicating the need for further investigation.  Nitrofurantoin-induced pulmonary injury can present with a diverse range of clinical manifestations,¹¹ posing a diagnostic challenge.  Where there is a high index of suspicion, investigation should include chest x-ray and spirometry.¹²

Nitrofurantoin must be withdrawn at the first signs of pulmonary damage.^9,10  Evidence indicates that in general there is rapid improvement of clinical symptoms on withdrawal of nitrofurantoin, although x-ray findings resolve slowly and clearing may remain incomplete in 50% of patients.²  Patients who have experienced pulmonary toxicity with nitrofurantoin should not be re-exposed to this medicine.⁵

Pulmonary reactions occur with other medicines too

A number of other medicines have also been implicated in causing significant pulmonary injury.  These include methotrexate and amiodarone.¹³  The cases reported to CARM are a reminder about the role of nitrofurantoin in the pathogenesis of pulmonary toxicity, and the need for vigilance in patients taking these medicines.

Competing interests (author): none declared

Correspondence to Dr Michael Tatley, CARM, PO Box 913, Dunedin. E-mail: michael.tatley@stonebow.otago.ac.nz

References

1. Willcox PA, Maze SS, Sandler M, et al. Pulmonary fibrosis following long-term nitrofurantoin therapy. S Afr Med J 1982;61:714-717.
2. Krause M, Ruef C. Miscellaneous antibacterial drugs. In Dukes MNG, Aronson JK (Eds). Meyler's Side Effects of Drugs 14th Edn. 2000: Elsevier BV, Amsterdam, p884-885.
3. Keaney NP. Respiratory disorders. In Davies DM, Ferner, RE, de Glanville H. Textbook of Adverse Drug Reactions 5th Edn. 1998: Chapman & Hall Medical, London, p220-221.
4. Magee F, Wright JL, Chan N, et al. Two unusual pathological reactions to nitrofurantoin: case reports. Histopathology 1986;10:701-706.
5. Holmberg L, Boman G, Bottiger LE, et al. Adverse reactions to nitrofurantoin - Analysis of 921 reports. Am J Med 1980;69:733-738.
6. Schattner A, Von der Walde J, Kozak N, et al. Nitrofurantoin-induced immune-mediated lung and liver disease. Am J Med Sci 1999;317(5):336-340.
7. Meyer MM, Meyer RJ. Nitrofurantoin-induced pulmonary hemorrhage in a renal transplant recipient receiving immunosuppressive therapy: case report and review of the literature. J Urol 1994;152:938-940.
8. Cameron RJ, Kolbe J, Wilsher ML, et al. Bronchiolitis obliterans organising pneumonia associated with the use of nitrofurantoin. Thorax 2000;55:249-251.
9. Pharmacia. Furadantin data sheet 13 November 2000.
10. WM Bamford and Company Limited. Nifuran data sheet 29 March 2000. www.medsafe.govt.nz/Profs/Datasheet/n/Nifurantab.htm
11. Schattner A, Von der Walde J, Kozac N, et al. Nitrofurantoin-induced immune-mediated lung and liver disease. Am J Med Sci 1999;317:336-340.
12. Renolds HY. Interstitial lung diseases. In Fauci AS, Martin JB, Braunwald E et al (Eds) Harrison's Principles of Internal Medicine. 14^th Edn. 1998: McGraw-Hill Inc, United States of America, p1460-1463.
13. Foucher P, Biour M, Blayac JP, et al. Drugs that may injure the respiratory system. Eur Respir J 1997;10:265-279.