What is the recommended treatment approach for an uncomplicated urinary tract infection in a healthy non‑pregnant adult?

Approach to Uncomplicated UTI in Adults

For uncomplicated cystitis in women, prescribe nitrofurantoin 100 mg twice daily for 5 days as the preferred first-line agent, achieving 93% clinical cure with minimal resistance and low collateral damage to intestinal flora. 1

First-Line Treatment Options

Nitrofurantoin (Preferred)

• Nitrofurantoin 100 mg orally twice daily for 5 days provides 93% clinical cure and 88% microbiological eradication, with worldwide resistance rates below 1%. 1, 2
• This agent preserves intestinal microbiota better than fluoroquinolones and cephalosporins, thereby lowering the risk of Clostridioides difficile infection. 1
• Contraindication: Do not use when estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² because therapeutic urinary concentrations cannot be achieved. 1, 2
• Nitrofurantoin is not appropriate for pyelonephritis or upper urinary tract infections due to inadequate tissue penetration. 1, 2

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• TMP-SMX 160/800 mg orally twice daily for 3 days achieves 93% clinical cure and 94% microbiological eradication when the organism is susceptible. 1, 2
• Use only when local E. coli resistance is <20% and the patient has not received TMP-SMX in the preceding 3 months. 3, 1
• Many regions now report TMP-SMX resistance exceeding 20%, making verification of local antibiogram data mandatory before selection. 1

Fosfomycin

• Fosfomycin 3 g as a single oral dose provides approximately 91% clinical cure with therapeutic urinary concentrations maintained for 24–48 hours. 3, 1, 4
• Resistance rates remain low at only 2.6% in initial E. coli infections. 1, 4
• The single-dose regimen improves adherence compared to multi-day courses. 4
• Do not use for pyelonephritis or upper urinary tract infections due to insufficient tissue penetration and lack of efficacy data. 1, 4

When to Obtain Urine Culture

• Routine urine culture is NOT required for straightforward uncomplicated cystitis in otherwise healthy women with typical symptoms (dysuria, frequency, urgency) and no vaginal discharge. 1, 5
• Obtain urine culture and susceptibility testing when:
  • Symptoms persist after completing the prescribed course 1, 5
  • Symptoms recur within 2–4 weeks after treatment 1, 5
  • Fever >38°C, flank pain, or costovertebral angle tenderness suggesting pyelonephritis 1
  • Atypical presentation or presence of vaginal discharge 1, 5
  • History of recurrent infections or prior resistant organisms 1
  • Male patient (all UTIs in men warrant culture) 1

Reserve (Second-Line) Agents

Fluoroquinolones

• Ciprofloxacin 250–500 mg twice daily or levofloxacin 250–750 mg once daily for 3 days should be reserved for culture-proven resistant organisms or documented failure of first-line therapy. 3, 1
• The FDA has issued warnings about serious adverse effects including tendon rupture, peripheral neuropathy, and CNS toxicity that outweigh benefits for uncomplicated UTI. 3, 1
• Global fluoroquinolone resistance is rising, with some regions reporting >10% resistance among uropathogens. 1
• Do not use empirically as first-line therapy for uncomplicated cystitis. 3, 1

Beta-Lactams

• Amoxicillin-clavulanate, cefdinir, cefpodoxime for 3–7 days achieve only 89% clinical cure and 82% microbiological eradication, significantly inferior to first-line agents. 1
• Use only when first-line agents are contraindicated due to allergy or intolerance. 1
• Never use amoxicillin or ampicillin alone due to poor efficacy and worldwide resistance rates of 55–67%. 1

Treatment Algorithm

Step 1: Confirm uncomplicated UTI (no fever, flank pain, pregnancy, catheter, immunosuppression, or recent instrumentation). 1

Step 2: Check local E. coli TMP-SMX resistance:

• If <20% and no recent TMP-SMX exposure → prescribe TMP-SMX 160/800 mg twice daily for 3 days 3, 1
• If ≥20% or data unavailable → prescribe nitrofurantoin 100 mg twice daily for 5 days or fosfomycin 3 g single dose 1

Step 3: If symptoms persist after 2–3 days or recur within 2 weeks:

• Obtain urine culture and susceptibility testing immediately 1, 5
• 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

Management of Treatment Failure

• When symptoms do not resolve by the end of therapy, obtain urine culture before prescribing additional antibiotics. 1
• Retreatment requires a 7-day course with a different antimicrobial class because longer duration is specifically advised for treatment failures. 1
• If fever persists beyond 72 hours, consider imaging (ultrasound or CT) to exclude obstruction or abscess. 1

Critical Pitfalls to Avoid

• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized women, as this promotes resistance without clinical benefit and paradoxically increases recurrent UTI episodes. 1
• Do not prescribe TMP-SMX without confirming local resistance is <20%; failure rates increase sharply above this threshold. 1
• Do not use nitrofurantoin when eGFR <30 mL/min/1.73 m² or for suspected pyelonephritis. 1, 2
• Do not use oral fosfomycin for suspected upper-tract infection or pyelonephritis. 1, 4
• Do not perform routine post-treatment urinalysis or cultures in asymptomatic patients who have completed therapy successfully. 1

Special Populations

Men with Uncomplicated UTI

• All UTIs in men are considered complicated and warrant urine culture with susceptibility testing. 1, 5
• First-line antibiotics include trimethoprim, TMP-SMX, or nitrofurantoin for 7 days (longer than in women). 5
• Consider the possibility of urethritis or prostatitis in men with UTI symptoms. 5

Recurrent UTIs (≥3 per year or ≥2 in 6 months)

• Obtain urine culture with each symptomatic episode prior to treatment. 1
• Patient-initiated treatment (self-start) may be offered to select patients while awaiting cultures. 1
• For postmenopausal women, vaginal estrogen therapy reduces future UTI risk. 1
• Increased fluid intake, cranberry products, and methenamine hippurate can prevent recurrent infections. 5
• Daily antibiotic prophylaxis with nitrofurantoin for 6–12 months is effective but carries risk of adverse effects and resistance. 1, 5

Older Adults (≥65 years)

• Urine culture with susceptibility testing should be obtained to adjust antibiotic choice after initial empiric treatment. 5
• First-line antibiotics and treatment durations do not differ from those recommended for younger adults. 5