Nitrofurantoin
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute uncomplicated UTI (cystitis) — E. coli, S. saprophyticus (Macrobid) | Adults & children ≥12 years | Monotherapy | FDA Approved |
| Urinary tract infections — E. coli, enterococci, S. aureus, susceptible Klebsiella & Enterobacter spp. (Macrodantin) | Adults & children ≥1 month | Monotherapy | FDA Approved |
Nitrofurantoin is a urinary-specific antibacterial that achieves therapeutic concentrations exclusively in the urine while maintaining very low systemic levels. This pharmacokinetic profile makes it an ideal agent for lower urinary tract infections but renders it ineffective for infections outside the bladder. The IDSA 2010 guidelines recommend nitrofurantoin monohydrate/macrocrystals 100 mg BID for 5 days as a first-line option for uncomplicated cystitis, alongside TMP-SMX and fosfomycin, based on sustained low resistance rates and minimal ecological collateral damage.
Nitrofurantoin is not indicated for pyelonephritis, perinephric abscesses, or any systemic infection, as it does not achieve adequate tissue or serum concentrations outside the urinary tract.
UTI prophylaxis (recurrent cystitis) — 50–100 mg PO at bedtime for up to 6–12 months. AUA/CUA/SUFU 2019/2025 guideline-supported. Evidence quality: High.
UTI in patients with CrCl 30–59 mL/min (short courses only) — Retrospective data supports safety and efficacy for 5–7 day courses when CrCl is ≥30 mL/min. AGS Beers Criteria 2023 updated to allow short-term use when CrCl ≥30 mL/min. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute uncomplicated cystitis (Macrobid) | 100 mg PO q12h | 100 mg PO q12h | 200 mg/day | 5–7 days; take with food; IDSA recommends 5 days FDA PI (7 days); IDSA 2010 (5 days) |
| Acute uncomplicated cystitis (Macrodantin) | 50–100 mg PO q6h | 50–100 mg PO q6h | 400 mg/day | 7 days or for 3 days after sterile urine obtained; take with food FDA PI; higher GI side effects than Macrobid due to faster absorption |
| UTI prophylaxis — recurrent cystitis | 50–100 mg PO at bedtime | 50–100 mg PO at bedtime | 100 mg/day | 6–12 months; risk of pulmonary and hepatic toxicity increases with prolonged use (>6 months) AUA/CUA/SUFU 2019 guideline; monitor lung function and LFTs |
| Postcoital prophylaxis — recurrent cystitis | 50–100 mg PO single dose post-intercourse | — | 100 mg/dose | Single dose within 2 hours of intercourse; lower cumulative exposure than daily prophylaxis AUA/CUA/SUFU guideline |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute UTI (≥1 month, Macrodantin) | 5–7 mg/kg/day PO divided q6h | Same | 400 mg/day | 7 days; use suspension for children <25 kg Contraindicated in infants <1 month |
| UTI prophylaxis (≥1 month) | 1–2 mg/kg/day PO once daily at bedtime | Same | 100 mg/day | Duration based on clinical indication; monitor for pulmonary symptoms AAP; widely used for vesicoureteral reflux prophylaxis |
Macrobid (100 mg capsule) contains 25% macrocrystalline nitrofurantoin and 75% monohydrate that forms a gel matrix for slower release. This dual-release design allows BID dosing (vs QID for Macrodantin) and causes less GI upset due to more gradual dissolution. The urinary excretion profile is equivalent between the two formulations. For treatment of acute cystitis, Macrobid 100 mg BID is preferred for patient convenience and tolerability. Macrodantin capsules may be opened and mixed with food; Macrobid capsules should not be opened.
Pharmacology
Mechanism of Action
Nitrofurantoin is a prodrug activated by bacterial flavoproteins (nitroreductases) to generate reactive intermediates that simultaneously attack multiple bacterial targets. These intermediates inactivate or alter ribosomal proteins, disrupt aerobic energy metabolism, inhibit DNA and RNA synthesis, and impair cell wall formation. This broad-based, multi-target mechanism is unique among antibacterials and explains two clinically important features: bactericidal activity at urinary concentrations and a remarkably low rate of acquired resistance despite over 70 years of clinical use, since simultaneous mutations in multiple target macromolecules would be lethal to the organism.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed; bioavailability increased ~40% with food; Macrobid has slower, more sustained release than Macrodantin; peak plasma levels usually <1 mcg/mL (therapeutically insignificant) | Must always be taken with food to maximize urinary drug delivery; systemic levels too low to treat any infection outside the urinary tract |
| Distribution | Protein binding ~60%; crosses placenta; trace amounts in breast milk; achieves high concentrations in urine but very low tissue/serum levels; does not achieve adequate concentrations in renal parenchyma | Effective only for lower UTI (bladder); not appropriate for pyelonephritis, prostatitis, or any systemic infection; contraindicates use near term pregnancy (neonatal hemolysis) |
| Metabolism | Rapid tissue and hepatic reduction; most drug inactivated before renal excretion; active drug excreted in urine via glomerular filtration and tubular secretion | Hepatic metabolism is extensive; no active metabolites of clinical significance; liver disease does not require dose adjustment but prior nitrofurantoin hepatotoxicity is a contraindication |
| Elimination | 20–25% excreted unchanged in urine over 24 h (Macrobid); ~38% (Macrodantin 100 mg QID); plasma t½ ~20–60 min; urine may turn brown (harmless) | Adequate urinary concentration requires CrCl ≥60 mL/min per FDA label (though recent evidence supports short courses at CrCl ≥30); drug is dialyzable |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 8% | Most common adverse reaction; significantly reduced by taking with food; Macrobid better tolerated than Macrodantin |
| Headache | 6% | Usually mild and self-limiting |
| Flatulence | 1.5% | Related to the gel matrix formulation in Macrobid |
| Eosinophilia | 1–5% | Laboratory finding; may precede hypersensitivity reactions including pulmonary reactions |
| Increased AST/ALT | 1–5% | Usually mild and transient; distinguish from hepatotoxicity |
| Decreased hemoglobin | 1–5% | Monitor in patients at risk for hemolysis (G6PD deficiency) |
| Diarrhea | <1% | Evaluate for C. difficile if persistent |
| Dyspepsia / abdominal pain | <1% | Taking with food reduces GI symptoms |
| Dizziness / drowsiness | <1% | Counsel regarding driving |
| Brown discoloration of urine | Common (benign) | Harmless; counsel patient to expect this |
| Pruritus / urticaria | <1% | May represent early hypersensitivity; evaluate |
Note: No adverse effect reached ≥10% incidence in Macrobid clinical trials. The 1–5% laboratory values are reported without regard to drug relationship per FDA PI.
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Acute pulmonary hypersensitivity reaction (fever, chills, cough, dyspnea, eosinophilia, pleural effusion) | Uncommon | Within first week of therapy | Discontinue immediately; usually resolves rapidly after drug withdrawal; dramatic resolution is characteristic |
| Chronic pulmonary reaction (interstitial pneumonitis, pulmonary fibrosis) | Rare; generally with ≥6 months continuous use | Months of continuous therapy; insidious onset | Discontinue immediately; may be irreversible; fatalities reported; monitor pulmonary function on long-term therapy |
| Hepatotoxicity (hepatitis, cholestatic jaundice, chronic active hepatitis, hepatic necrosis) | Rare; fatalities reported | Days to months; chronic active hepatitis may be insidious | Discontinue immediately; monitor LFTs periodically during long-term use; prior nitrofurantoin hepatotoxicity is an absolute contraindication to rechallenge |
| Peripheral neuropathy | Rare; risk increased by renal impairment, anemia, diabetes, B-vitamin deficiency, debilitating disease | Variable; more common with prolonged use | Discontinue immediately; may become severe or irreversible; fatalities reported |
| Hemolytic anemia (G6PD-deficient patients) | Uncommon (linked to G6PD deficiency — 10% of Black Americans, some Mediterranean/Near-Eastern populations) | Days after initiation | Discontinue; hemolysis ceases upon withdrawal; consider G6PD testing in at-risk populations before prescribing |
| Stevens-Johnson syndrome / erythema multiforme | Very rare | Days to weeks | Discontinue immediately; dermatology referral; supportive care |
| Lupus-like syndrome | Very rare; typically associated with pulmonary reaction | Variable | Discontinue; usually resolves after drug withdrawal; may need corticosteroids |
| Optic neuritis | Very rare (postmarketing) | Variable | Discontinue; ophthalmology referral |
Nitrofurantoin causes two distinct forms of pulmonary toxicity. Acute pulmonary hypersensitivity typically occurs within the first week, presents with fever, cough, dyspnea, and eosinophilia, and resolves dramatically upon drug withdrawal. Chronic pulmonary reactions (interstitial pneumonitis, pulmonary fibrosis) develop insidiously in patients receiving therapy for 6 months or longer and may be irreversible — fatalities have been reported. Patients on long-term prophylaxis require periodic monitoring of pulmonary function, and the benefits of continued therapy must be weighed against this potentially fatal complication.
Drug Interactions
Nitrofurantoin has a relatively limited interaction profile, consistent with its minimal systemic absorption. The most clinically relevant interactions involve agents that reduce urinary drug concentrations (thereby reducing efficacy) or increase systemic drug levels (thereby increasing toxicity). It does not undergo significant hepatic CYP450 metabolism and is not known to inhibit or induce CYP enzymes at therapeutic concentrations.
Monitoring
- Renal FunctionBefore initiating therapy
RoutineCrCl must be ≥60 mL/min per FDA label. Recent evidence supports short-course use at CrCl ≥30 mL/min for uncomplicated cystitis. Contraindicated in anuria or oliguria. Periodic monitoring recommended for patients on long-term therapy. - Pulmonary FunctionPeriodically during long-term use (≥6 months)
RoutineAssess for cough, dyspnea on exertion, or malaise. Chronic pulmonary reactions (interstitial pneumonitis, fibrosis) develop insidiously and may be irreversible. Chest X-ray and pulmonary function tests if symptoms emerge. Stop drug at first sign of pulmonary reaction. - Hepatic FunctionPeriodically during long-term use; immediately if symptoms develop
RoutineMonitor LFTs for hepatitis, cholestatic jaundice, or chronic active hepatitis. Onset may be insidious. Fatalities have been reported. Elderly patients appear at higher risk. Discontinue immediately if hepatic injury detected. - CBCBaseline for patients at risk; during long-term therapy
Trigger-basedMonitor for hemolytic anemia (especially G6PD-deficient patients), leukopenia, thrombocytopenia, megaloblastic anemia. Aplastic anemia reported rarely. Eosinophilia may precede pulmonary hypersensitivity reactions. - Neurologic AssessmentEach visit for long-term therapy
Trigger-basedAssess for peripheral neuropathy symptoms (numbness, tingling). Risk increased with renal impairment, anemia, diabetes, B-vitamin deficiency. May become severe or irreversible. Discontinue immediately at first sign. - Urine CultureBefore and after treatment
RoutineConfirm susceptibility; repeat after therapy completion. Many patients experience bacteriuria persistence or reappearance due to nitrofurantoin’s lack of tissue distribution. If bacteriuria persists, switch to agent with broader tissue penetration.
Contraindications & Cautions
Absolute Contraindications
- Significant renal impairment (CrCl <60 mL/min or clinically significant elevated serum creatinine, per FDA label) — impaired drug excretion increases systemic toxicity and reduces urinary antibacterial concentrations
- Anuria or oliguria
- Neonates <1 month of age — immature erythrocyte enzyme systems (glutathione instability) create risk of hemolytic anemia
- Pregnancy at term (38–42 weeks), labor, and delivery — same hemolytic anemia risk to the neonate
- Previous cholestatic jaundice or hepatic dysfunction associated with prior nitrofurantoin use
- Known hypersensitivity to nitrofurantoin or other nitrofurans
Relative Contraindications (Specialist Input Recommended)
- G6PD deficiency — risk of hemolytic anemia; screen in at-risk populations
- CrCl 30–59 mL/min — FDA label contraindicates, but recent evidence (Beers Criteria 2023 update) supports short-course (5–7 day) use for uncomplicated cystitis when CrCl ≥30; avoid for prophylaxis
- Pre-existing pulmonary disease — may mask or exacerbate drug-induced pulmonary reactions
- Concurrent pyelonephritis suspected — nitrofurantoin lacks tissue penetration; requires alternative agent
Use with Caution
- Long-term use (>6 months) — increasing risk of chronic pulmonary reactions, hepatotoxicity, and peripheral neuropathy
- Elderly patients — higher proportion of severe pulmonary and hepatic reactions reported; more likely to have renal impairment
- Anemia, diabetes, electrolyte imbalance, vitamin B deficiency, debilitating disease — increased risk of peripheral neuropathy
- Early pregnancy — Pregnancy Category B; no confirmed teratogenicity, but use only if clearly needed
Acute, subacute, or chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. Fatalities have been reported. Chronic pulmonary reactions (diffuse interstitial pneumonitis, pulmonary fibrosis) can develop insidiously and generally occur in patients receiving therapy for six months or longer. Close monitoring of pulmonary condition is warranted for patients on long-term therapy. The benefits of therapy must be weighed against potential risks.
Patient Counselling
Purpose of Therapy
Nitrofurantoin is an antibiotic that works specifically in the urine to treat bladder infections (urinary tract infections). It is not effective for kidney infections or infections elsewhere in the body. It works by damaging multiple essential functions inside bacteria, which is why bacteria rarely become resistant to it.
How to Take
Always take nitrofurantoin with food (ideally breakfast and dinner for Macrobid) to increase drug absorption and reduce stomach upset. Swallow Macrobid capsules whole; do not open them. Macrodantin capsules may be opened and mixed with food if needed. Complete the full prescribed course even if symptoms improve within the first few days.
Sources
- Macrobid (nitrofurantoin monohydrate/macrocrystals) capsules. Full Prescribing Information. Almatica Pharma LLC. Rev. December 2020. FDA LabelPrimary regulatory reference for Macrobid: approved indication (acute uncomplicated cystitis), dosing, clinical trial adverse event rates, contraindications, and pulmonary/hepatic warnings.
- Macrodantin (nitrofurantoin macrocrystals) capsules. Full Prescribing Information. Almatica Pharma LLC. FDA LabelRegulatory label for the macrocrystalline formulation with broader approved organism coverage; includes PK data, adverse effects, and long-term use warnings.
- Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence. Ann Pharmacother. 2013;47(1):106–111. DOIEvidence review questioning the 2003 change from CrCl <40 to CrCl <60 mL/min contraindication; concluded limited evidence for the more restrictive threshold.
- Geerts AF, Eppenga WL, Heerdink R, et al. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care. Eur J Clin Pharmacol. 2013;69(9):1701–1707. DOILarge retrospective study supporting safety and efficacy of short-course nitrofurantoin in women with CrCl 30–50 mL/min.
- Bains A, Buna D, Hoag NA. A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment. Can Pharm J. 2009;142(5):248–252. DOIEarly retrospective study demonstrating similar clinical cure rates for nitrofurantoin in patients with CrCl >50 vs ≤50 mL/min.
- Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the IDSA and ESMID. Clin Infect Dis. 2011;52(5):e103–e120. DOILandmark IDSA guideline recommending nitrofurantoin monohydrate/macrocrystals 100 mg BID × 5 days as first-line for uncomplicated cystitis based on low resistance and minimal collateral damage.
- Anger J, Lee U, Ackerman AL, et al. Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline. J Urol. 2019;202(2):282–289. DOIAUA guideline supporting nitrofurantoin as an option for UTI prophylaxis (50–100 mg at bedtime) in women with recurrent uncomplicated cystitis.
- American Geriatrics Society 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2023;71(7):2052–2081. DOIUpdated Beers Criteria now allowing short-term nitrofurantoin use for uncomplicated cystitis when CrCl ≥30 mL/min; long-term use and use at CrCl <30 remain inappropriate.
- McOsker CC, Fitzpatrick PM. Nitrofurantoin: mechanism of action and implications for resistance development in common uropathogens. J Antimicrob Chemother. 1994;33(Suppl A):23–30. DOIDefinitive review of nitrofurantoin’s multi-target mechanism of action through bacterial flavoprotein reduction and the biological basis for sustained low resistance rates.
- Squadrito FJ, del Portal D. Nitrofurantoin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. StatPearlsContinuously updated clinical pharmacology overview covering indications, mechanism, dosing, adverse effects, and special population considerations.
- Conklin JD. The pharmacokinetics of nitrofurantoin and its related bioavailability. Antibiot Chemother (1971). 1978;25:233–252. DOIClassic PK reference for nitrofurantoin covering absorption differences between crystal forms, urinary excretion kinetics, and food effects on bioavailability.
- Muller AE, Verhaegh EM, Harbarth S, et al. Nitrofurantoin’s efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials. Clin Microbiol Infect. 2017;23(6):355–362. DOISystematic review confirming nitrofurantoin efficacy for UTI prophylaxis with quantified adverse event rates for long-term use.