Introduction
Nitrofurantoin is an antibacterial medication specifically indicated for the treatment and prevention of uncomplicated urinary tract infections (UTIs). First introduced in the 1950s, it remains a valuable therapeutic option due to its unique mechanism of action and favorable resistance profile against common uropathogens. This synthetic nitrofuran derivative is particularly effective against Escherichia coli and other susceptible organisms in the urinary tract.
Mechanism of Action
Nitrofurantoin exerts its antibacterial effects through multiple mechanisms. The drug is activated by bacterial nitroreductases to reactive intermediates that damage bacterial DNA, RNA, and proteins. These intermediates inhibit various bacterial enzyme systems, including acetylcoenzyme A, Krebs cycle enzymes, and protein synthesis. The multiple sites of action contribute to nitrofurantoin's bactericidal activity and make development of resistance less likely compared to single-target antibiotics.
Indications
- Treatment of acute uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli, Enterococcus, Staphylococcus aureus, and certain strains of Klebsiella and Enterobacter
- Prophylaxis against recurrent urinary tract infections
- Not indicated for the treatment of pyelonephritis or perinephric abscesses due to inadequate tissue penetration
Dosage and Administration
Macrocrystalline formulation (Macrobid):- Treatment: 100 mg orally twice daily for 5 days
- Prophylaxis: 50-100 mg orally once daily at bedtime
- Treatment: 50-100 mg orally four times daily for 7 days (or at least 3 days after sterility obtained)
- Prophylaxis: 50-100 mg orally once daily at bedtime
- Renal impairment: Contraindicated when CrCl <60 mL/min
- Hepatic impairment: Use with caution
- Geriatric: Consider renal function before prescribing
- Pediatrics: 5-7 mg/kg/day divided into 4 doses (treatment); 1-2 mg/kg/day as single dose (prophylaxis)
Pharmacokinetics
Absorption: Rapid but incomplete gastrointestinal absorption (bioavailability ~90% for macrocrystalline form). Food enhances absorption and reduces gastrointestinal upset. Distribution: Primarily concentrated in urine with minimal tissue penetration. Plasma protein binding approximately 60%. Metabolism: Partially metabolized in most body tissues, primarily via reduction. Elimination: Rapid renal excretion with half-life of 20-60 minutes. Urine concentrations are therapeutic; serum concentrations are low.Contraindications
- Hypersensitivity to nitrofurantoin or other nitrofuran derivatives
- Significant renal impairment (CrCl <60 mL/min)
- Pregnancy at term (38-42 weeks gestation)
- During labor and delivery
- In infants less than one month old
- Patients with history of cholestatic jaundice or hepatic dysfunction associated with nitrofurantoin
Warnings and Precautions
Pulmonary reactions: Acute, subacute, and chronic pulmonary reactions have been reported, including interstitial pneumonitis and pulmonary fibrosis Hepatic effects: Hepatic reactions, including hepatitis, cholestatic jaundice, and chronic active hepatitis Peripheral neuropathy: May occur, risk increased in patients with renal impairment, anemia, diabetes, electrolyte imbalance, vitamin B deficiency, or debilitating disease Hemolytic anemia: Associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency Clostridioides difficile-associated diarrhea: May range from mild diarrhea to fatal colitis Development of drug-resistant bacteria: Prescribing without proven or strongly suspected bacterial infection increases risk of developing drug-resistant bacteriaDrug Interactions
Antacids containing magnesium trisilicate: May reduce absorption and efficacy of nitrofurantoin Uricosuric drugs (probenecid): May antagonize nitrofurantoin efficacy by inhibiting renal tubular secretion Drugs that reduce renal function: May increase risk of toxicity due to decreased clearance Neurotoxic drugs: May increase risk of peripheral neuropathyAdverse Effects
Common (>10%):- Gastrointestinal: nausea, vomiting, anorexia, abdominal pain
- Discoloration of urine (brownish-yellow)
- Headache, dizziness
- Rash, pruritus
- Pulmonary reactions (cough, dyspnea)
- Pulmonary fibrosis
- Hepatotoxicity
- Peripheral neuropathy
- Hemolytic anemia
- Clostridioides difficile-associated diarrhea
- Stevens-Johnson syndrome
- Anaphylaxis
Monitoring Parameters
- Clinical response to therapy
- Signs of pulmonary toxicity (cough, dyspnea, abnormal breath sounds)
- Liver function tests (if prolonged therapy)
- Complete blood count (in patients with G6PD deficiency or anemia)
- Renal function (prior to and during prolonged therapy)
- Signs of peripheral neuropathy (numbness, tingling, pain)
- Signs of superinfection or C. difficile-associated diarrhea
Patient Education
- Complete the full course of therapy even if symptoms improve
- Take with food or milk to minimize stomach upset
- Report any breathing difficulties, cough, fever, or chest pain immediately
- Be aware that urine may turn dark yellow or brownish
- Report any numbness, tingling, or burning sensations in hands or feet
- Contact healthcare provider if diarrhea develops during or after treatment
- Do not use for respiratory infections or other non-urinary infections
- Inform all healthcare providers of nitrofurantoin use
- Store at room temperature away from moisture and heat
References
1. Pharmaceutical Press. Martindale: The Complete Drug Reference. 42nd ed. London: Pharmaceutical Press; 2020. 2. Macrodantin [package insert]. Philadelphia, PA: Almatica Pharma Inc; 2021. 3. Hooton TM, et al. Clinical Practice Guidelines for the Management of Asymptomatic Bacteriuria and Acute Uncomplicated Cystitis and Pyelonephritis in Women. Clin Infect Dis. 2011;52(5):e103-e120. 4. Gupta K, et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. 5. FDA Drug Safety Communication: Nitrofurantoin-containing products. U.S. Food and Drug Administration. Accessed January 2023. 6. Micromedex Solutions. Truven Health Analytics. Accessed January 2023. 7. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. Sperryville, VA: Antimicrobial Therapy Inc; 2022.