What is the first‑line therapy for an uncomplicated urinary‑tract infection (UTI) in a healthy, non‑pregnant adult without a sulfonamide allergy?

Primary Treatment for Uncomplicated UTI

For an otherwise healthy, non-pregnant adult without sulfonamide allergy, nitrofurantoin 100 mg orally twice daily for 5 days is the preferred first-line therapy for uncomplicated cystitis, achieving approximately 93% clinical cure with minimal resistance and collateral damage. 1

First-Line Treatment Options

Nitrofurantoin (Preferred)

• Nitrofurantoin 100 mg orally twice daily for 5 days achieves 93% clinical cure and 88% microbiological eradication with worldwide resistance rates below 1%. 1
• This agent preserves intestinal microbiota better than fluoroquinolones and cephalosporins, thereby reducing the risk of Clostridioides difficile infection and other collateral antimicrobial damage. 1
• Contraindication: Do not use when estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² because adequate urinary concentrations cannot be achieved. 1

Trimethoprim-Sulfamethoxazole (Conditional First-Line)

• TMP-SMX 160/800 mg orally twice daily for 3 days provides 93% clinical cure and 94% microbiological eradication when the pathogen is susceptible. 1, 2
• Use ONLY when both conditions are met: (1) local E. coli resistance is <20%, AND (2) the patient has not received TMP-SMX in the preceding 3 months. 1
• Many regions now report TMP-SMX resistance exceeding 20%, making verification of local antibiogram data mandatory before empiric use. 1

Fosfomycin (Alternative First-Line)

• Fosfomycin trometamol 3 g as a single oral dose yields approximately 91% clinical cure with therapeutic urinary concentrations maintained for 24–48 hours. 1
• Initial-infection resistance rates are only 2.6%, making this an excellent option when TMP-SMX is unsuitable. 1
• Critical limitation: Do not use for suspected pyelonephritis or upper urinary tract infections due to insufficient tissue penetration. 1

Treatment Selection Algorithm

Step 1: Assess Local Resistance

• Check your institution's antibiogram for E. coli TMP-SMX resistance rates. 1
• If resistance is <20% AND the patient has no TMP-SMX exposure in the past 3 months → TMP-SMX is acceptable. 1
• If resistance is ≥20% OR data are unavailable → proceed to Step 2. 1

Step 2: Choose Between Nitrofurantoin or Fosfomycin

• Nitrofurantoin is preferred for its superior efficacy (93% vs 91% clinical cure) and 5-day course ensuring sustained bacterial eradication. 1
• Fosfomycin offers single-dose convenience, improving adherence, but has slightly lower bacteriological eradication rates. 1
• Base the choice on patient preference, renal function (avoid nitrofurantoin if eGFR <30), and adherence concerns. 1

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 organisms. 1
• The FDA (July 2016) recommends against fluoroquinolone use for uncomplicated UTIs because serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity) outweigh benefits. 1
• Global fluoroquinolone resistance is rising, with some regions reporting >10% resistance among uropathogens. 1

Beta-Lactams

• Amoxicillin-clavulanate, cefdinir, or cefpodoxime for 3–7 days achieve only 89% clinical cure and 82% microbiological eradication—significantly inferior to first-line agents. 1
• Never use amoxicillin or ampicillin alone because worldwide E. coli resistance exceeds 55–67%. 1
• Reserve beta-lactams for cases where all first-line agents are contraindicated due to allergy or documented resistance. 1

When to Obtain Urine Culture

Routine urine culture is NOT required for otherwise healthy women with typical cystitis symptoms (dysuria, frequency, urgency). 1

Obtain culture and susceptibility testing when:

• Symptoms persist after completing the prescribed regimen. 1
• Symptoms recur within 2–4 weeks. 1
• Fever >38°C, flank pain, or costovertebral angle tenderness suggests 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 and susceptibility testing immediately. 1
• Switch to a different antibiotic class for a 7-day course (not the original short regimen). 1
• Reserve fluoroquinolones only for culture-proven resistance. 1

If fever persists beyond 72 hours:

• Perform renal ultrasound or CT imaging to exclude obstruction, abscess, or complicated infection. 1

Critical Pitfalls to Avoid

• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized women—this promotes resistance without clinical benefit. 1
• Do not use empiric fluoroquinolones as first-line therapy due to serious adverse effects and the need to preserve efficacy for life-threatening infections. 1
• Do not prescribe TMP-SMX without confirming local resistance is <20%; failure rates increase sharply above this threshold. 1
• Do not use nitrofurantoin for suspected pyelonephritis or when eGFR <30 mL/min/1.73 m². 1
• Do not use oral fosfomycin for suspected upper urinary tract infection. 1