What is the recommended nitrofurantoin dosing regimen, contraindications, adverse effects, and alternative treatments for uncomplicated acute cystitis in an adult with normal estimated glomerular filtration rate (≥60 mL/min)?

Nitrofurantoin for Uncomplicated Acute Cystitis

Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days is the recommended first-line treatment for uncomplicated acute cystitis in adults with normal renal function (eGFR ≥60 mL/min), achieving 84-90% clinical cure rates with minimal resistance and excellent safety. 1

Recommended Dosing Regimen

• Standard dose: Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days 1, 2
• Alternative duration: A 7-day course (100 mg twice daily) is acceptable and achieves 89-93% clinical cure rates, though the 5-day regimen is preferred to minimize antibiotic exposure 2
• Avoid 3-day regimens: The 100 mg four times daily for 3 days regimen shows inferior efficacy (88% clinical cure, 74% bacterial cure) and should not be used 2

Expected Clinical Outcomes

• Clinical cure rates: 84-90% at 30-day follow-up 1, 2
• Bacterial eradication: 81-92% at early follow-up (5-9 days post-treatment) 1, 2
• Equivalence to alternatives: The 5-day nitrofurantoin regimen is equivalent to trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days when organisms are susceptible 1, 3

Absolute Contraindications

• Suspected pyelonephritis: Never use nitrofurantoin if the patient has fever >38°C, flank pain, costovertebral angle tenderness, nausea, or vomiting—the drug does not achieve adequate renal tissue concentrations for upper tract infections 1, 2
• Severe renal impairment (CrCl <30 mL/min): Contraindicated due to reduced efficacy and increased risk of peripheral neuropathy 1, 2
• Last trimester of pregnancy: Avoid due to potential fetal risks 4

Renal Function Considerations (CrCl 30-60 mL/min)

• Current guidelines recommend avoiding nitrofurantoin when CrCl <60 mL/min 2
• However, one retrospective study found nitrofurantoin was effective in 69% of hospitalized patients with CrCl 30-60 mL/min, with only 2 of 26 failures attributable to renal insufficiency itself 5
• Clinical decision: Strictly adhere to the CrCl ≥60 mL/min threshold for outpatient uncomplicated cystitis; the evidence for use between 30-60 mL/min is insufficient to override guideline recommendations 1, 2

Common Adverse Effects

• Most frequent: Nausea and headache, occurring in 5.6-34% of patients 1, 2
• Serious but rare: Pulmonary toxicity (0.001%) and hepatotoxicity (0.0003%) are extremely uncommon with short-course therapy 1
• Long-term use risks: Peripheral neuropathy and chronic pulmonary reactions occur mainly with prolonged prophylactic use, not with 5-7 day treatment courses 6

Alternative First-Line Treatments

When nitrofurantoin cannot be used, consider these alternatives in order of preference:

1. Trimethoprim-Sulfamethoxazole (TMP-SMX)

• Dose: 160/800 mg (one double-strength tablet) twice daily for 3 days 4, 7
• Use only if: Local E. coli resistance is <20% AND the patient has not used TMP-SMX in the preceding 3 months 1, 4
• Efficacy when susceptible: 90-100% clinical cure 4
• Efficacy when resistant: Only 41-54% clinical cure—treatment failure is expected 4
• Critical caveat: Hospital antibiograms overestimate community resistance; obtain local outpatient surveillance data 4

2. Fosfomycin Trometamol

• Dose: 3 g as a single oral dose 1, 7
• Efficacy: Slightly lower than nitrofurantoin (approximately 90% vs 95% clinical cure) but offers single-dose convenience 2
• Advantage: Minimal resistance rates (<10%) across all regions 4

3. Fluoroquinolones (Reserve for Complicated Infections)

• Ciprofloxacin: 250 mg twice daily for 3 days achieves 93-97% bacteriologic eradication 4
• Should be avoided for simple cystitis: FDA warnings include tendon rupture, peripheral neuropathy, CNS toxicity, and aortic dissection 1
• Reserve for: Pyelonephritis or complicated UTIs where benefits outweigh risks 1, 7
• Resistance concern: Community resistance now approximately 24%, limiting empiric use 1

Agents to Avoid for Uncomplicated Cystitis

• Amoxicillin or ampicillin alone: Globally high resistance rates make these unsuitable for empiric therapy 1, 4
• Beta-lactams (amoxicillin-clavulanate, cephalosporins): Inferior efficacy compared to nitrofurantoin and higher adverse event rates 1, 7
• Aminoglycosides (gentamicin): Require parenteral administration and carry nephrotoxicity/ototoxicity risks; reserved for severe infections 1

Clinical Decision Algorithm

Step 1: Confirm uncomplicated lower UTI

• Symptoms limited to dysuria, urgency, frequency, or suprapubic discomfort 1
• No fever >38°C, flank pain, costovertebral angle tenderness, nausea, or vomiting 1
• Patient is non-pregnant, pre-menopausal, and has no urological abnormalities 1

Step 2: Verify renal function

• Confirm eGFR or CrCl ≥60 mL/min 1, 2
• If CrCl <60 mL/min, choose TMP-SMX or fosfomycin instead 2

Step 3: Prescribe nitrofurantoin

• Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days 1, 2
• Counsel patient to ensure adequate hydration during treatment 1

Step 4: Follow-up strategy

• Do not obtain routine post-treatment urine cultures in asymptomatic patients 1
• If symptoms persist at end of treatment or recur within 2 weeks, obtain urine culture with susceptibility testing 1
• Retreat with a 7-day course of an alternative agent if symptoms persist 1

Common Pitfalls to Avoid

• Using nitrofurantoin for "borderline" upper tract symptoms: Any flank pain or low-grade fever indicates pyelonephritis; nitrofurantoin will fail because it does not reach therapeutic renal tissue concentrations 1
• Prescribing TMP-SMX without knowing local resistance rates: When resistance exceeds 20%, treatment failure rates are unacceptably high (41-54% cure) 4
• Extending therapy beyond 7 days: Each additional day increases adverse event risk by 5% without improving efficacy 4
• Treating asymptomatic bacteriuria: Antibiotics should not be prescribed for asymptomatic bacteriuria in non-pregnant patients 1
• Using fluoroquinolones as first-line therapy: Reserve ciprofloxacin for pyelonephritis to preserve efficacy and minimize serious adverse effects 1, 7

Special Populations

Men with Uncomplicated Cystitis

• Nitrofurantoin 100 mg twice daily for 7 days (not 5 days) is required for adequate cure in men 4
• Do not use if prostatitis is suspected—nitrofurantoin does not penetrate prostatic tissue adequately 1

Women with Diabetes

• Treat identically to women without diabetes if no voiding abnormalities are present 7
• Use standard 5-day nitrofurantoin regimen 1, 7

Recurrent UTIs

• Nitrofurantoin 50-100 mg once daily at bedtime can be used for prophylaxis due to lower resistance development 1, 2
• Obtain urine culture before treatment to guide antibiotic selection 1