What antibiotic should be used as first‑line treatment for an otherwise healthy, non‑pregnant adult woman with an uncomplicated urinary‑tract infection (cystitis)?

First-Line Antibiotic for Uncomplicated Cystitis in Non-Pregnant Women

Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days is the preferred first-line treatment for otherwise healthy, non-pregnant adult women with uncomplicated urinary tract infection (cystitis). 1, 2

Primary Recommendation

• Nitrofurantoin 100 mg twice daily for 5 days achieves clinical cure rates of 88–93% and bacteriologic cure rates of 81–92%, with minimal resistance rates (generally <10%) and limited collateral damage to normal flora. 1, 2, 3

• This regimen is endorsed by both the European Association of Urology (2024) and the Infectious Diseases Society of America as the optimal first-line agent because it preserves more systemically active antibiotics for serious infections while maintaining excellent efficacy. 1, 2

• Real-world evidence from over 1 million patients demonstrates that nitrofurantoin has a lower risk of treatment failure (0.3% pyelonephritis rate, 12.7% prescription switch rate) compared to trimethoprim-sulfamethoxazole. 3

Alternative First-Line Options (when nitrofurantoin cannot be used)

• Fosfomycin trometamol 3 g as a single oral dose provides clinical cure rates of 90–91% but lower microbiologic cure rates of 78–80%. 1, 2, 4

  • This single-dose regimen is particularly useful when adherence to multi-day therapy is a concern. 2
  • The FDA label specifies fosfomycin is indicated only for uncomplicated cystitis in women, not for pyelonephritis or perinephric abscess. 4

• Trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg twice daily for 3 days should be used only if local E. coli resistance is documented to be <20%. 1, 2

  • When organisms are susceptible, cure rates reach 90–100%; however, when resistant, cure rates plummet to 41–54%. 2, 5
  • Avoid TMP-SMX if the patient has used it within the preceding 3–6 months or has traveled internationally within that timeframe, as both factors independently predict resistance. 5

Reserve (Second-Line) Agents

• Fluoroquinolones (ciprofloxacin 250 mg twice daily for 3 days) achieve bacteriologic eradication rates of 93–97% but should be reserved for more serious infections such as pyelonephritis. 1, 2, 5

  • The 2024 European Association of Urology guidelines explicitly recommend against using fluoroquinolones as first-line therapy to prevent resistance development and avoid collateral damage, including increased MRSA rates. 1

• Oral β-lactams (cefdinir, cefaclor, cefpodoxime-proxetil, cephalexin) for 3–7 days demonstrate inferior efficacy and higher adverse-event rates compared to nitrofurantoin or TMP-SMX. 1, 2, 6

  • These should only be considered when all first-line agents are contraindicated. 2

Agents to Avoid

• Amoxicillin or ampicillin alone should never be used empirically due to worldwide resistance rates exceeding 30% and poor therapeutic outcomes. 2, 6, 7

• β-lactam monotherapy (without a β-lactamase inhibitor) is not recommended for empirical treatment of uncomplicated cystitis. 1

Diagnostic Considerations

• Diagnosis can be made clinically based on dysuria, frequency, urgency, and absence of vaginal discharge in women with typical symptoms. 1

• Urine culture is not routinely required for uncomplicated cystitis in otherwise healthy women; reserve it for atypical presentations, suspected pyelonephritis, treatment failures, or symptom recurrence within 2–4 weeks. 1, 2, 8

• Dipstick testing adds minimal diagnostic accuracy when symptoms are typical but may be helpful if the diagnosis is unclear. 1

Common Pitfalls to Avoid

• Do not prescribe TMP-SMX without knowing local resistance patterns. Hospital antibiograms often overestimate community resistance; outpatient surveillance data are more accurate. 5

• Do not use nitrofurantoin in patients with eGFR <30 mL/min due to reduced efficacy and increased toxicity risk. 9

• Do not extend nitrofurantoin beyond 7 days or use fluoroquinolones as first-line therapy despite their high efficacy, as this promotes resistance. 2, 9

• Do not assume 3-day regimens work in men—men require 7 days of therapy for uncomplicated cystitis. 2, 5

Treatment Algorithm

1. Confirm uncomplicated cystitis: dysuria, frequency, urgency, no fever, no flank pain, no comorbidities. 1, 6

2. Check renal function:

   • eGFR >30 mL/min → nitrofurantoin 100 mg twice daily for 5 days. 2, 9
   • eGFR <30 mL/min → fosfomycin 3 g single dose. 9

3. If nitrofurantoin and fosfomycin are contraindicated:

   • Verify local TMP-SMX resistance is <20% → TMP-SMX 160/800 mg twice daily for 3 days. 2, 5
   • If resistance ≥20% or recent TMP-SMX use → consider fluoroquinolone (ciprofloxacin 250 mg twice daily for 3 days) as last resort. 1, 2

4. Reassess at 2–3 days: lack of symptom improvement suggests resistance or alternative diagnosis; obtain urine culture with susceptibilities. 1, 2