What is nitrofurantoin?

What is Nitrofurantoin?

Nitrofurantoin is a broad-spectrum antibiotic specifically used for treating urinary tract infections, functioning as a prodrug that requires activation by bacterial nitroreductases to inhibit multiple bacterial processes including DNA, RNA, cell wall, and protein synthesis. 1, 2

Mechanism and Pharmacology

• Nitrofurantoin is a nitrofuran derivative that has been in clinical use for over 60 years (since 1953) for antibacterial therapy of UTIs 1, 3
• It acts as a prodrug requiring activation by bacterial nitroreductases, after which it inhibits bacterial DNA, RNA, cell wall, and protein synthesis 2
• The drug achieves urinary concentrations approximately 100-fold higher than plasma concentrations, making it highly effective for urinary tract infections 4
• Its antimicrobial activity is driven by the AUC/MIC (area under the curve over minimum inhibitory concentration) ratio 4

Clinical Indications and Guidelines

First-Line Agent for Lower UTI

• The WHO, Infectious Diseases Society of America, and European Association of Urology all recommend nitrofurantoin as a first-line treatment option for uncomplicated lower urinary tract infections (cystitis) 5, 6
• The WHO categorizes nitrofurantoin as an "Access" antibiotic, emphasizing its role as a preferred first-choice option 5, 6
• It maintains sustained susceptibility rates of 95-99% against E. coli, the most common uropathogen 6
• Despite decades of use, nitrofurantoin has retained good activity against E. coli and other UTI pathogens including Staphylococcus saprophyticus and Enterococcus species, with minimal development of resistance 1, 3

Dosing Recommendations

• Standard dosing is 50-100 mg four times daily for 5 days, or 100 mg twice daily for 5 days for uncomplicated cystitis 5, 6
• Treatment duration should be 5 days (not single-dose regimens) 5, 6

Critical Contraindications and Limitations

Nitrofurantoin should NOT be used for:

• Pyelonephritis or upper urinary tract infections due to inadequate tissue penetration 5, 6
• Patients with creatinine clearance <30 mL/min (some sources cite <60 mL/min) due to inadequate urinary concentrations 7, 3
• The last three months of pregnancy 3
• Severe renal impairment of any degree 3

Serious Adverse Effects

Pulmonary Reactions (Most Important)

• Chronic, subacute, or acute pulmonary hypersensitivity reactions may occur and can be severe 7
• Chronic pulmonary reactions typically occur in patients receiving continuous treatment for 6 months or longer, manifesting as malaise, dyspnea on exertion, cough, and altered pulmonary function 7
• Radiologic and histologic findings may show diffuse interstitial pneumonitis or fibrosis 7
• Pulmonary function may be permanently impaired even after cessation of therapy, particularly if chronic pulmonary reactions are not recognized early 7
• Acute pulmonary reactions usually occur within the first week of treatment and are reversible with cessation of therapy 7

Neurologic Reactions

• Peripheral neuropathy may occur and can become severe or irreversible; fatalities have been reported 7
• Risk factors include renal impairment (creatinine clearance <60 mL/min), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating diseases 7
• Other neurologic effects include asthenia, vertigo, nystagmus, dizziness, headache, and drowsiness 7

Hepatic Reactions

• Hepatic reactions including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis occur rarely but are serious 7

Other Adverse Effects

• Gastrointestinal: nausea, emesis, anorexia (most common and dose-related), abdominal pain, diarrhea 7
• Hematologic: hemolytic anemia, agranulocytosis, leukopenia, thrombocytopenia, megaloblastic anemia 7
• Dermatologic: exfoliative dermatitis, erythema multiforme (including Stevens-Johnson syndrome), transient alopecia 7
• Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide postmarketing experience 7

Clinical Context and Resistance Patterns

• Nitrofurantoin has been repositioned as first-line therapy due to alarming resistance rates of E. coli to cotrimoxazole and fluoroquinolones in many countries 1, 3
• Unlike many other antibiotics, nitrofurantoin has not been associated with R-factor resistance development 8
• The WHO Expert Committee specifically chose nitrofurantoin over fosfomycin based on randomized controlled trials showing significantly greater likelihood of clinical and microbiologic resolution at 28 days, plus lower cost 5