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Nitrofurantoin is a synthetic derivative of imidazolinedione, used to treat uncomplicated urinary tract infections. It acts by inhibiting bacterial DNA, RNA and cell wall protein synthesis. It is used prophylactically as a urinary anti-infective agent against most gram-positive organism and for long-term suppression of infections. Nitrofurantoin-associated pulmonary injuries occur in 1% of patients, presenting with dyspnoea and dry cough, and it can mimic interstitial lung disease. We present a case of an 81-year-old woman with shortness of breath and cough 3 days after initiation of nitrofurantoin. CT of the chest revealed bilateral pleural effusion and extensive pulmonary interstitial prominence, suggesting pulmonary fibrosis. According to the Naranjo Adverse Drug Reaction Probability Scale score of 6, it was determined that nitrofurantoin was the probable cause, and immediate cessation of the medication showed a marked clinical improvement and resolution after 10 days.
In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.
Nitrofurantoin is an antimicrobial drug recommended as the first-line treatment for uncomplicated cystitis, urinary tract infection (UTI) and prophylaxis for recurrent UTI.1–3 It is the treatment of choice for patients with known allergy to trimethoprim–sulfamethoxazole. The most common side effects are gastrointestinal such as nausea, vomiting and diarrhoea, and very rarely can present with pulmonary toxicity.3 Pulmonary toxicity may range from acute, subacute or chronic.4 Both acute and subacute reactions are thought to be secondary to a hypersensitivity reaction and are dose independent. In contrast, chronic pulmonary reactions, which include diffuse interstitial pneumonitis and pulmonary fibrosis, are related to the total lifetime dosage.2 5 In addition, nitrofurantoin-induced interstitial lung disease is more frequent in elderly female patient.6
This case presents an 81-year-old woman with a medical history of hypertension, hyperlipidaemia, hypothyroidism and mild dementia. She quit smoking a decade ago, with no known drug allergies, pets at home or occupational exposure. She presented to the emergency room (ER) complaining of right-sided flank pain, dysuria, nausea and vomiting. She was diagnosed with right-sided acute pyelonephritis and hydronephrosis by CT of the abdomen/pelvis with contrast. ER physician prescribed outpatient treatment empirically with nitrofurantoin 100 mg every 12 hours for 7 days. After 4 days of treatment, she presented to the ER again, as she developed shortness of breath associated with cough and generalised fatigue. She denied other symptoms such as fever, chills, wheezing or chest pain.
On examination, she was normotensive with a blood pressure of 104/46 mm Hg, heart rate of 60 beats/min, respiratory rate of 18 respirations/min and oxygen saturation of 90% on 3 L of oxygen via nasal cannula. Chest auscultation revealed decreased breath sounds and crackles on both lung bases, no wheezing and normal cardiovascular findings, with no ugular vein distention (JVD) or peripheral oedema noted. Rest of physical examination was within normal limits.
Laboratory results (table 1) showing in the complete blood count (CBC) elevated eosinophils in comparison to previous ER visit 4 days before. The complete metabolic panel was within normal limits, and biochemistry showed a positive ANA.
The ECG showed normal sinus rhythm. On admission, CT of the thorax with contrast (figure 1) revealed moderate bilateral pleural effusion and pronounced pulmonary interstitial prominence, reflecting more acute process with differential diagnosis, including drug toxicity, pulmonary oedema or other aetiology. These findings were not found on the previous CT done 4 days ago (figure 2) when she was diagnosed with pyelonephritis. She was admitted with the diagnosis of interstitial pneumonitis with bilateral pleural effusion, with oxygen provided by nasal cannula. Patient refused to have bronchoscopy/biopsy to evaluate bronchoalveolar lavage fluid and cytopathology of the tissue.
On medication reconciliation, she was currently on: clonazepam 1 mg nightly, gemfibrozil 600 mg every 12 hours, memantine–donepezil 28–10 mg daily, multivitamin 1 tab daily, protonix 40 mg daily and nitrofurantoin 100 mg every 12 hours. According to the Naranjo Adverse Drug Reaction (ADR) Probability Scale, her score was 6 (table 2), indicating that findings were probably related to the use of Nitrofurantoin, reason for which the medication was immediately stopped.
Ceftriaxone 1 g intravenous daily was started for the treatment of pyelonephritis. The patient’s symptoms rapidly improved, and after 3 days, she was discharged home with cephalexin 500 mg every 6 hours for 7 more days. The patient posteriorly followed-up with her primary care physician and continue to improve with the complete resolution of symptoms.
Four days before admission, when the patient was diagnosed with acute pyelonephritis, a CT of the abdomen/pelvis showed clear lung bases (figure 2). The patient was prescribed nitrofurantoin 100 mg every 12 hours for 7 days at that time.
On the day of admission, CT of the thorax showed moderate bilateral pleural effusion and pronounced pulmonary interstitial prominence, reflecting more acute process with differential consideration, including drug toxicity, pulmonary oedema or other aetiology, imaging ruled out pulmonary embolism (figure 1).
On the day of admission, chest X-rays (CXRs) showed small bilateral pleural effusions with increased interstitial opacities bilaterally (figure 3).
Ten days after hospital discharge, CXR demonstrated pleural effusion and basilar interstitial infiltrates that had resolved almost entirely (figure 4).
During the COVID-19 pandemic, any patient with respiratory symptoms and similar radiographic changes should be suspicious for COVID-19 infection, and we should test for it. The first case of COVID-19 worldwide occurred many months after our patient presented to our ER, reason why it is not included in our differential and she was not tested for it.
Bilateral pleural effusion and crackles on physical examination should raise concern for acute congestive heart failure and pulmonary oedema. Nonetheless, our patient did not have a history of heart problems or other signs of heart failure.
The history was not compatible with pulmonary embolism (no hypercoagulable state, lengthy travel or immobility). Physical examination did not show any signs or symptoms of deep vein thrombosis, and ultimately, CT of the thorax ruled out pulmonary embolism.
Another differential diagnosis to consider is hypersensitivity pneumonitis. The patient did not report exposure to common inhaled antigens, like animals or pets in her household. CXR did not show a reticulonodular pattern on the upper lung zones more consistent with the mentioned diagnosis.
Finally, no fever, purulent sputum, leucocytosis or consolidation was observed on the CXR, which ruled out community-acquired pneumonia.
The patient’s clinical condition improved considerably over the 3-day hospitalisation period, after complete cessation of the medication and supportive care. Follow-up CXR showed improvement of pleural effusion and basilar interstitial infiltrates. The addition of nitrofurantoin to the patient’s allergy list was performed, and she was instructed to avoid the use of this medication in the future.
Outcome and follow-up
Ten days after discharge, she followed-up with her primary care physician. Physical examination was normal, with oxygen saturation of 96% on room air. CXR was repeated, showing nearly resolved bibasilar interstitial infiltrates and bilateral pleural effusions.
Nitrofurantoin is a common antibiotic used for the treatment of uncomplicated UTIs. The risk of an adverse reaction to nitrofurantoin increases with the patient’s age and is higher in women than in men.5 7 8 The first case of acute pulmonary toxicity due to nitrofurantoin was reported by Israel and Diamond in 1962, demonstrating a clear cause-and-effect relationship by intentional rechallenge with the drug.5
Acute reactions occur in approximately 1 in 5000 patients after first exposure and are categorised as rare but are the most common clinical presentation (83%). The acute reaction is characterised by fever, shortness of breath, cough and peripheral eosinophilia, manifesting in the first 8–9 days in 8% of cases, and all will occur within 1 month of starting nitrofurantoin therapy.7 8 The subacute presentation has a more insidious onset of symptoms, with most cases reported within the first 6 months. Chronic presentations and pulmonary fibrosis are mostly seen in patients who have been on long-term therapy from 6 months to 6 years, and usually present as progressive dyspnoea and dry cough.4 5 8 The exact mechanism is unknown, and several mechanisms have been proposed. The most probable cause for acute cases is hypersensitivity to nitrofurantoin itself and is believed not to be dose related. Lymphocytes are likely activated by nitrofurantoin and produce mediators that promote release of cytokines, resulting in lymphocytic alveolitis. Nitrofurantoin-induced production of oxidants and immune complex-mediated reactions are other hypothesised mechanisms.8 Our patient presented with signs and symptoms after only 4 days of starting nitrofurantoin, which is considered an acute response.
On physical examination, patients will usually appear acutely ill along with some degree of respiratory distress, often with cyanosis, and some patients may present with hypotension. On chest auscultation, bibasilar rales are the most common finding.9 CXR may be normal, but in 90% of the cases, diffuse parenchymal changes or mixed interstitial alveolar shadowing in the lower zones may be observed, as well as pleural effusions, as it was seen in our patient. CT findings will report bilateral ground-glass opacities in the more acute phase and a mixed picture of ground glass, as our patient showed, and chronic presentations will report consolidation and fibrosis.2 5 8 10 On laboratory testing, white blood cell counts can be normal or high, and peripheral eosinophilia is typically seen, but usually absent in the initial phase; erythrocyte sedimentation rate can also be high.5 7 Comparably, our patient’s laboratory data had mild eosinophilia, and all other investigations were negative, with no evidence of viral or bacterial infection.
Early diagnosis is vital but often difficult to attain, as most patients are initially treated for pneumonia, myocardial infarction, pulmonary embolism, heart failure, acute exacerbation of chronic diseases, among others. Delaying the correct diagnosis and initiating unrelated, empiric treatments will increase morbidity and mortality.2 8 9
The Naranjo ADR Probability Scale, in conjunction with the physician’s clinical judgement, aids in diagnosing when a drug-induced adverse reaction is suspected to be the cause of the symptoms. Naranjo scores of 9–10 indicate that an event was ‘definitely’ an ADR; scores of 5–8 rate the likelihood as ‘probable’ (as in our patient); scores of 1–4 are ‘possible’ and scores of <1 are ‘doubtful’.4 8
Treatment of acute pulmonary toxicity is the immediate discontinuation of the culprit, nitrofurantoin in our case, with marked clinical improvement in the next 24 hours.5 8 Additional therapies may be granted, such as respiratory support with positive-airway pressure devices and bronchodilators. The use of steroids is somewhat still controversial.7 11 12 Prognosis is excellent, with a 0.5% mortality.5
Nitrofurantoin is a commonly used medication. Physicians need awareness of this adverse drug reaction and the importance of monitoring for the occurrence of pulmonary toxicity. A high index of suspicion should proceed when patients present with symptoms such as cough, shortness of breath and fever, in combination with radiological findings of diffuse parenchymal changes or bilateral ground-glass opacities. Additionally, physicians should examine elderly patients closer, who possess a higher risk for drug interactions and adverse reactions due to reduced renal clearance and polypharmacy that increase plasma concentrations of drugs with subsequent toxicity.4 8 11 13 Patients who suffered from an ADR to nitrofurantoin should carry written warnings to avoid re-exposure, and the medication should not be used again.
Nitrofurantoin is a common drug used to treat urinary tract infections and can have fatal pulmonary adverse reactions in 1% of the cases.
The Naranjo Adverse Drug Reaction Probability Scale is a useful tool that, in conjunction with the clinician’s judgement, can help determine the possibility of a medication adverse reaction.
If nitrofurantoin-induced lung injury is suspected, immediate cessation of the drug is necessary and clinical improvement will be seen in a short period of time.
Patient consent for publication
Contributors Summary and treatment: VKK. Background, investigations, outcome and follow-up: AB-B. Case presentation: EM. Differential diagnosis: GO. Discussion and learning points/take-home messages: EM and GO.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.