What is the recommended first‑line treatment for an otherwise healthy non‑pregnant adult with an uncomplicated urinary tract infection and an estimated glomerular filtration rate ≥30 mL/min/1.73 m²?

First-Line Treatment for Uncomplicated UTI with eGFR ≥30 mL/min/1.73 m²

Nitrofurantoin 100 mg orally twice daily for 5 days is the preferred first-line agent for otherwise healthy non-pregnant adults with uncomplicated urinary tract infection and normal renal function (eGFR ≥30 mL/min/1.73 m²). 1, 2

Rationale for Nitrofurantoin as First Choice

• Nitrofurantoin achieves 93% clinical cure and 88% microbiological eradication in uncomplicated cystitis, which is superior to other first-line options. 1, 2
• Worldwide resistance rates remain below 1% despite more than 60 years of use, making it the most reliable empiric choice. 1
• The drug causes minimal disruption to intestinal flora compared with fluoroquinolones and broad-spectrum agents, thereby reducing the risk of Clostridioides difficile infection and preserving the microbiome. 1, 2
• Multiple international guidelines—including the Infectious Diseases Society of America (IDSA), European Association of Urology (EAU), and American Urological Association (AUA)—all recommend nitrofurantoin as a first-line agent with strong evidence ratings. 1, 2

Alternative First-Line Options (When Nitrofurantoin Cannot Be Used)

• Fosfomycin 3 g as a single oral dose provides approximately 91% clinical cure with therapeutic urinary concentrations maintained for 24–48 hours and initial resistance rates of only 2.6%. 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 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, 3

Critical Decision Algorithm

1. Confirm uncomplicated lower UTI: Symptoms limited to dysuria, urgency, frequency, or suprapubic discomfort without fever >38°C, flank pain, nausea/vomiting, or costovertebral-angle tenderness. 1

2. Verify renal function: Nitrofurantoin requires eGFR ≥30 mL/min/1.73 m² for adequate urinary concentrations; below this threshold, the drug is contraindicated due to reduced efficacy and increased risk of peripheral neuropathy. 1, 2

3. Assess local TMP-SMX resistance:

   • If local E. coli resistance is <20% and the patient has not used TMP-SMX recently → TMP-SMX is acceptable. 1, 3
   • If resistance is ≥20% or data are unavailable → prescribe nitrofurantoin or fosfomycin. 1

4. Choose based on patient factors:

   • Nitrofurantoin for standard 5-day therapy with highest cure rates. 1, 2
   • Fosfomycin for single-dose convenience when adherence is a concern. 1
   • TMP-SMX only when resistance criteria are met and cost is a major consideration. 1, 3

Agents to Reserve or Avoid

• Fluoroquinolones (ciprofloxacin, levofloxacin) should be reserved exclusively for pyelonephritis or culture-proven resistant organisms because of FDA safety warnings (tendon rupture, peripheral neuropathy, aortic dissection) and rising community resistance rates approaching 24%. 1
• Beta-lactams (amoxicillin-clavulanate, cephalosporins) achieve only 89% clinical cure and 82% microbiological eradication, which is significantly inferior to nitrofurantoin; they should be used only when first-line agents are contraindicated. 1
• Amoxicillin or ampicillin alone are ineffective due to worldwide resistance rates of 55–67% and should never be used empirically. 1

When Urine Culture Is Mandatory

• Do not obtain routine urine culture for typical uncomplicated cystitis in otherwise healthy women. 1
• Obtain culture and susceptibility testing when any of the following occur:
  • Persistent symptoms after completing therapy. 1
  • Recurrence within 2–4 weeks. 1
  • Fever >38°C, flank pain, or costovertebral-angle tenderness suggesting pyelonephritis. 1
  • Atypical presentation or presence of vaginal discharge. 1
  • History of recurrent infections or prior resistant organisms. 1

Management of Treatment Failure

• If symptoms persist after 2–3 days or recur within 2 weeks, obtain urine culture immediately and switch to a different antibiotic class for a 7-day course (not the original short regimen). 1
• Assume the original pathogen is resistant to the previously used agent. 1
• Reserve fluoroquinolones only for culture-proven resistance. 1

Critical Pitfalls to Avoid

• Do not use nitrofurantoin for suspected pyelonephritis (any fever, flank pain, or systemic symptoms) because the drug does not achieve adequate renal tissue concentrations. 1, 2
• Do not prescribe TMP-SMX without confirming local resistance is <20%; treatment failure rates increase sharply above this threshold. 1
• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized patients; this promotes resistance without clinical benefit. 1
• Do not use oral fosfomycin for suspected upper-tract infection due to insufficient tissue penetration. 1