What is the recommended first‑line antibiotic regimen for uncomplicated acute cystitis in an otherwise healthy adult woman, including alternatives based on renal function and local resistance?

Acute Uncomplicated Cystitis Management

First-Line Antibiotic Recommendation

Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days is the preferred first-line treatment for acute uncomplicated cystitis in otherwise healthy adult women. 1, 2, 3

This regimen achieves clinical cure rates of 88-93% and bacteriological cure rates of 81-92%, with minimal resistance patterns and limited collateral damage to normal flora. 1, 2

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Treatment Selection Algorithm

Step 1: Confirm Uncomplicated Cystitis

Verify the patient has:

• Dysuria, urinary frequency, urgency, or suprapubic pain 1
• No fever, flank pain, costovertebral angle tenderness, nausea, or vomiting (these indicate pyelonephritis) 1, 2
• No pregnancy, structural urinary abnormalities, or recent instrumentation 2

Step 2: Assess Renal Function

• If eGFR ≥30 mL/min → proceed with nitrofurantoin 1, 2, 3
• If eGFR <30 mL/min → nitrofurantoin is contraindicated due to inadequate urinary concentrations and increased risk of peripheral neuropathy; use fosfomycin instead 1, 2, 3

Step 3: Check for Contraindications to Nitrofurantoin

Nitrofurantoin should not be used if:

• Any suspicion of pyelonephritis (even mild flank pain or low-grade fever) exists, as it does not achieve adequate renal tissue concentrations 1, 3
• Creatinine clearance is <30 mL/min 2, 3

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Alternative First-Line Options

When nitrofurantoin cannot be used, select from these alternatives:

Fosfomycin Trometamol

• Dose: 3 g single oral dose 1, 2
• Efficacy: Clinical cure 90-91%, microbiological cure 78-80% 1
• Best for: Patients with reduced renal function (eGFR <30 mL/min) or adherence concerns 1
• Avoid if: Early pyelonephritis is suspected 1, 2

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• Dose: 160/800 mg (one double-strength tablet) twice daily for 3 days 1, 2
• Use ONLY if:
  • Local E. coli resistance is documented <20% 1, 2
  • Patient has not received TMP-SMX in the preceding 3 months 1
• Efficacy: 84-88% for susceptible strains, but drops to 41-54% for resistant strains 1
• Critical pitfall: Do not prescribe empirically without knowing local resistance rates 1, 2

Pivmecillinam

• Dose: 400 mg twice daily for 3-7 days 1
• Availability: Europe only (not available in North America) 1, 2
• Avoid if: Pyelonephritis is suspected 1

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Second-Line (Reserve) Agents

Use these only when first-line options are contraindicated:

Fluoroquinolones

• Options: Ciprofloxacin 250 mg twice daily for 3 days OR levofloxacin 1, 2
• Efficacy: Clinical cure ~95% 1
• Reserve for: Pyelonephritis or when all first-line agents are unsuitable 1, 2
• Rationale for restriction: High propensity for collateral damage, promotes resistance, and FDA warnings regarding tendon rupture, peripheral neuropathy, and aortic dissection 1, 3

Oral β-Lactams

• Options: Amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoxime-proxetil, cephalexin 1, 2
• Duration: 3-7 days 1
• Use only when: No first-line agents are available 1, 2
• Limitation: Generally inferior efficacy and more adverse effects compared to nitrofurantoin or TMP-SMX 1, 2

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Agents to Avoid

Never use amoxicillin or ampicillin alone empirically due to poor efficacy and worldwide resistance rates exceeding 30%. 1, 2

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Special Considerations Based on Renal Function

eGFR (mL/min)	Recommended Agent	Avoid
≥60	Nitrofurantoin 100 mg BID × 5 days [1,2]	—
30-59	Nitrofurantoin 100 mg BID × 5 days (acceptable per 2015 Beers revision) [3]	—
<30	Fosfomycin 3 g single dose [1,2]	Nitrofurantoin [2,3]

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Local Resistance Considerations

When TMP-SMX Resistance is <20%

• TMP-SMX 160/800 mg twice daily for 3 days is acceptable as an alternative first-line option 1, 2

When TMP-SMX Resistance is ≥20%

• Do not use TMP-SMX empirically 1, 2
• Default to nitrofurantoin or fosfomycin 1, 2

When Fluoroquinolone Resistance is >10%

• Consider pivmecillinam (if available) or β-lactams as alternatives 4

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Common Pitfalls and How to Avoid Them

1. Using nitrofurantoin for "borderline" upper-tract symptoms

   • Any flank pain, fever >38°C, or systemic symptoms mandates a fluoroquinolone or cephalosporin, not nitrofurantoin 1, 3

2. Prescribing TMP-SMX without local resistance data

   • Treatment failure rates are unacceptably high when resistance exceeds 20% 1, 2

3. Shortening nitrofurantoin to <5 days

   • The full 5-day course is required for optimal efficacy 1, 2, 3

4. Using fluoroquinolones as first-line therapy

   • Despite 95% efficacy, reserve these for pyelonephritis to preserve their utility and minimize resistance 1, 2

5. Prescribing nitrofurantoin in elderly patients with CrCl <30 mL/min

   • Absolute contraindication due to peripheral neuropathy risk and inadequate urinary concentrations 2, 3

6. Using fosfomycin when pyelonephritis is suspected

   • Fosfomycin has lower microbiological cure rates and should be avoided if upper-tract infection is possible 1

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Follow-Up Guidance

• Routine post-treatment urine cultures are unnecessary for asymptomatic patients 1, 2
• Obtain urine culture with susceptibility testing if:
  • Symptoms persist at end of treatment 1, 2
  • Symptoms recur within 2-4 weeks 1, 2, 5
  • Atypical presentation or suspected pyelonephritis 1, 5
• If treatment fails: Retreat with a 7-day regimen using a different appropriate agent based on culture results 1, 2