What is the recommended therapy for an uncomplicated urinary tract infection in a non‑pregnant adult woman without structural urinary abnormalities, recent catheter use, diabetes, immunosuppression, or recent antibiotic exposure?

Uncomplicated UTI Treatment

First-Line Therapy

Nitrofurantoin 100 mg orally twice daily for 5 days is the preferred first-line agent for uncomplicated cystitis in non-pregnant adult women without structural urinary abnormalities, recent catheter use, diabetes, immunosuppression, or recent antibiotic exposure. 1, 2, 3

Why Nitrofurantoin is Preferred

• Nitrofurantoin achieves approximately 93% clinical cure and 88% microbiological eradication in uncomplicated UTIs 1, 3
• Worldwide resistance rates remain below 1% despite over 60 years of use 1, 2
• Causes minimal disruption to intestinal flora compared to fluoroquinolones and cephalosporins, reducing risk of Clostridioides difficile infection 1, 3
• Classified as an "Access" antibiotic by the WHO AWaRe framework, reflecting its favorable resistance profile 3

Alternative First-Line Options

• Fosfomycin 3 g as a single oral dose provides approximately 91% clinical cure, maintains therapeutic urinary concentrations for 24–48 hours, and has initial-infection resistance rates around 2.6% 1, 4
• Trimethoprim-sulfamethoxazole 160/800 mg orally twice daily for 3 days achieves 93% clinical cure and 94% microbiological eradication only when local E. coli resistance is <20% and the patient has not received TMP-SMX in the preceding 3 months 1, 2, 5

Critical Contraindications to Nitrofurantoin

• Do not use when estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² because adequate urinary concentrations cannot be achieved and risk of peripheral neuropathy increases 1, 3
• Do not use for suspected pyelonephritis (fever >38°C, flank pain, costovertebral angle tenderness, nausea/vomiting) because nitrofurantoin does not reach therapeutic concentrations in renal tissue 1, 3

When to Use TMP-SMX

• TMP-SMX should be prescribed only when local E. coli resistance is documented <20% and the patient has not used TMP-SMX in the prior 3 months 1, 2, 5
• Many regions now report TMP-SMX resistance >20% (some areas up to 78%), making it unsuitable for empiric therapy in those locations 1, 2
• Verify local antibiogram data before prescribing; if unavailable, default to nitrofurantoin or fosfomycin 1, 2

Reserve (Second-Line) Agents – Use Only When First-Line Fails

Fluoroquinolones

• Ciprofloxacin 250–500 mg twice daily or levofloxacin 250–750 mg once daily for 3 days should be reserved exclusively for culture-proven resistant pathogens or documented failure of first-line agents 1, 2
• The FDA issued a July 2016 advisory warning that fluoroquinolones should not be used for uncomplicated UTIs because serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity, aortic dissection) outweigh benefits 1, 2
• Global fluoroquinolone resistance exceeds 10% in many regions, with some areas reporting >83% resistance in persistent infections 1, 2

Beta-Lactams

• Amoxicillin-clavulanate, cefdinir, or cefpodoxime for 3–7 days achieve only 89% clinical cure and 82% microbiological eradication, which is significantly inferior to first-line agents 1, 2
• Beta-lactams are linked to more rapid UTI recurrence due to disturbance of protective peri-urethral and vaginal microbiota 1, 2
• Amoxicillin or ampicillin alone should never be used because worldwide E. coli resistance exceeds 55–67% 1, 2

Diagnostic Recommendations

• Routine urine culture is not required for otherwise healthy women presenting with typical lower-tract symptoms (dysuria, frequency, urgency) without vaginal discharge 1, 2, 6
• Obtain urine culture and susceptibility testing when any of the following occur:
  • Persistent symptoms after completing therapy 1, 2
  • Recurrence of symptoms within 2–4 weeks 1, 2
  • Fever >38°C, flank pain, or costovertebral angle tenderness suggesting pyelonephritis 1, 2
  • Atypical presentation or presence of vaginal discharge 1, 2
  • History of recurrent infections or prior isolation of resistant organisms 1, 2

Management of Treatment Failure

• If symptoms do not resolve by the end of therapy or recur within 2 weeks, obtain a urine culture and susceptibility test immediately 1, 2
• Switch to a different antibiotic class for a 7-day course (not the original short regimen) 1, 2
• Assume the original pathogen is resistant to the previously used agent 1, 2
• Reserve fluoroquinolones only for culture-proven resistance 1, 2

Critical Pitfalls to Avoid

• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized women; treatment provides no clinical benefit and promotes antimicrobial resistance 1, 2
• Do not use empiric fluoroquinolones as first-line therapy for uncomplicated cystitis because of serious adverse effects and rising resistance 1, 2
• Do not prescribe TMP-SMX without confirming that local E. coli resistance is <20%; failure rates increase sharply above this threshold 1, 2
• Do not use nitrofurantoin for suspected pyelonephritis or when eGFR <30 mL/min/1.73 m² 1, 3
• Do not use oral fosfomycin for suspected upper-tract infection or pyelonephritis due to insufficient tissue penetration 1, 4
• Routine post-treatment urinalysis or repeat cultures are unnecessary for asymptomatic patients who have completed therapy successfully 1, 2

Treatment Duration

• Nitrofurantoin: 5 days 1, 3
• Fosfomycin: Single 3 g dose 1, 4
• TMP-SMX: 3 days (when appropriate) 1, 2, 5
• Maximum duration for acute cystitis is 7 days; extending therapy beyond this provides no additional efficacy and increases adverse-event risk 1, 2