Published: 5 March 2020

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Spotlight on nitrofurantoin

Prescriber Update 41(1): 2-4
March 2020

This article on nitrofurantoin continues the spotlight series where Medsafe reviews the safety information on a specific medicine. The Centre for Adverse Reactions Monitoring continues to receive serious adverse reactions reported in association with nitrofurantoin use.

Please refer to the medicine data sheet for full prescribing information.

Indication

Nitrofurantoin is a bactericidal antibiotic with activity exclusively in the urine¹. It is indicated for the treatment and prophylaxis of urinary tract infections (UTIs) caused by susceptible bacteria².

Antimicrobial susceptibility data from New Zealand hospital and community laboratories indicate most urinary E. coli infections are susceptible to nitrofurantoin³. Nitrofurantoin is not effective against Pseudomonas, Proteus and Serratia species^2,4.

The recommended duration of treatment with nitrofurantoin for long-term prophylaxis against UTIs is up to 6 months. Only continue beyond 6 months when the benefits clearly outweigh the risks^2,5 and monitoring is in place to detect signs of nitrofurantoin toxicity (described below).

Mechanism of action

Bacterial flavoproteins reduce nitrofurantoin to reactive intermediates in the acidic urinary environment. The reactive intermediates interfere with bacterial ribosomal proteins and other macromolecules, inhibiting several biochemical and synthetic processes in the bacterial cell^1,2. This multi-modal mechanism of action is believed to contribute to the relatively low level of acquired bacterial resistance to nitrofurantoin^2,4.

Use of nitrofurantoin in renal impairment

Adequate glomerular filtration and renal tubular secretion is needed to achieve an effective therapeutic concentration in the urine¹. In patients with normal renal function, therapeutic doses of nitrofurantoin are rapidly excreted into the urine with no build-up in the plasma. In patients with impaired renal function, the plasma concentration increases and there is a higher risk of nitrofurantoin toxicity².

Significant renal impairment (eg, eGFR less than 60 mL/minute/1.73 m²) is a contraindication to nitrofurantoin². The Medicines Adverse Reactions Committee recently reviewed the evidence for safe use of nitrofurantoin in patients with a greater degree of renal impairment but considered that the available evidence did not support lowering the eGFR cut-off point^6,7.

Adverse effects

Monitoring requirements

Monitor patients on long-term prophylaxis for changes in clinical status that may increase the risk of nitrofurantoin toxicity^1,2. Discontinue nitrofurantoin at the first sign of toxicity.

Pulmonary reactions

Pulmonary reactions to nitrofurantoin may occur with short-term or long-term use. The reactions do not appear to be dose-related⁸.

Acute interstitial pneumonitis is a type of hypersensitivity reaction that may occur within 1–2 weeks of starting nitrofurantoin. Typically, it presents with fever, dry cough, chest pain and dyspnoea, with eosinophilia and radiological evidence of pulmonary infiltration. Acute reactions to nitrofurantoin are reversible on stopping the medicine^2,8.

Chronic pulmonary reactions may develop after several months (usually more than 6 months) of low-dose nitrofurantoin and are thought to be either a cell-mediated or toxic response⁸. Chronic interstitial lung disease may develop insidiously, typically presenting with dyspnoea, dry cough and fatigue. Monitor lung function in patients on long-term nitrofurantoin and advise patients to report new or worsening symptoms of cough or shortness of breath. Discontinue nitrofurantoin at the first sign of pulmonary toxicity. The risk of permanently impaired lung function increases with delayed diagnosis².

Hepatic reactions

Nitrofurantoin can cause an autoimmune-like hepatitis with prolonged use^9,10. Monitor liver function periodically in patients on long-term prophylaxis with nitrofurantoin and stop the medicine immediately if hepatitis develops^1,2. Hepatitis associated with short-term use of nitrofurantoin has been reported but is very rare¹⁰.

Peripheral neuropathy

Nitrofurantoin toxicity causes peripheral neuropathy (including optic neuritis), which may be severe and irreversible. Renal impairment increases the risk of peripheral neuropathy due to reduced clearance of nitrofurantoin from the blood. Other risk factors include anaemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency and debilitating disease. Monitor patients on long-term prophylaxis periodically for changes in renal function that may increase the risk of nitrofurantoin toxicity². Inform patients on prophylactic nitrofurantoin about symptoms of peripheral neuropathy and examine them periodically for signs of nerve damage.

Haemolytic anaemia

Nitrofurantoin may cause haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. If haemolysis occurs in these patients, discontinue treatment with nitrofurantoin.

There is also a risk of haemolytic anaemia in newborn infants with G6PD deficiency if exposed to nitrofurantoin in utero close to delivery or through breast milk. For this reason, nitrofurantoin should be avoided in late pregnancy and, if breastfeeding, for the first month after the birth².

Interactions

Antacids containing magnesium trisilicate (eg, Quick-Eze) reduce the absorption of nitrofurantoin, which may reduce its antibacterial effect in the urine².

New Zealand adverse reaction reports

During the 10-year period to the end of 2019, the Centre for Adverse Reactions Monitoring (CARM) received 150 adverse reaction reports in which nitrofurantoin was a suspect medicine. Most of the reported reactions occurred in female patients (133 reports), consistent with the higher use of nitrofurantoin for UTIs in women. Age at the time of the reaction ranged from 9 years to 94 years (median 67 years), consistent with higher use among older patients. Reports for interstitial lung disease, hepatic reactions and peripheral neuropathy are described below.

• Interstitial lung disease: 46 reports, of which 29 were serious, including two fatal reports.
• Hepatic reactions: 17 reports, including three reports of hepatic cirrhosis and one report in which the patient also had pneumonitis. Of these reports, 12 were assessed as serious, but none were fatal.
• Peripheral neuropathy: 3 reports.

References

1. New Zealand Formulary. 2020. New Zealand Formulary v91: Nitrofurantoin 1 January 2020. URL: nzf.org.nz/nzf_3293 (accessed 17 January 2020).
2. WM Bamford & Co. Ltd. 2017. Nifuran New Zealand Data Sheet 10 July 2017. URL: medsafe.govt.nz/profs/Datasheet/n/Nifurantab.pdf (accessed 17 January 2020).
3. Institute of Environmental Sciences and Research Ltd. 2017. Antimicrobial susceptibility data from hospital and community laboratories, 2017. URL: surv.esr.cri.nz/PDF_surveillance/Antimicrobial/AR/National_AR_2017.pdf (accessed 17 January 2020).
4. Gardiner BJ, Stewardson AJ, Abbott IJ, et al. 2019. Nitrofurantoin and fosfomycin for resistant urinary tract infections: Old drugs for emerging problems. Australian Prescriber 42: 14–19. DOI: 10.18773/austprescr.2019.002 (accessed 17 January 2020).
5. Medsafe. 2012. Nitrofurantoin – Do the benefits outweigh the risks long-term? Prescriber Update 33: 17–18. URL: medsafe.govt.nz/profs/PUArticles/NitrofurantoinBenefitsOutweighRisksJune2012.htm (accessed 17 January 2020).
6. Medsafe. 2019. Update on nitrofurantoin use in renal impairment. Presented at the 177^th Medicines Adverse Reaction Committee meeting, 14 March 2019. URL medsafe.govt.nz/committees/MARC/reports/177-3.2.4%20Update%20on%20nitrofurantoin%20use%20in%20renal%20impairment.pdf (accessed 17 January 2020).
7. Medsafe. 2019. Minutes of the 177th Medicines Adverse Reactions Committee meeting. URL: medsafe.govt.nz/profs/adverse/Minutes177.htm (accessed 17 January 2020).
8. de Zeeuw J, Gillissen AG. 2018. Nitrofurantoin-induced pulmonary injury. In: UpToDate 17 April 2018. URL: uptodate.com/contents/nitrofurantoin-induced-pulmonary-injury (accessed 17 January 2020).
9. Larson A. 2019. Drug-induced liver injury. In: UpToDate 10 May 2019. URL: uptodate.com/contents/drug-induced-liver-injury (accessed 17 January 2020).
10. LiverTox. 2014. Nitrofurantoin 7 February 2014. URL: ncbi.nlm.nih.gov/books/NBK548318/ (accessed 17 January 2020).