What is the first‑line empiric therapy for an uncomplicated lower urinary tract infection in a healthy adult woman?

First-Line Empiric Therapy for Uncomplicated Lower Urinary Tract Infection in Healthy Adult Women

Nitrofurantoin 100 mg orally twice daily for 5 days is the preferred first-line agent for uncomplicated cystitis in healthy adult women, achieving approximately 93% clinical cure and 88% microbiological eradication with worldwide resistance rates below 1%. 1, 2

Primary First-Line Options

Three agents are recommended as first-line therapy, selected based on local resistance patterns, patient factors, and convenience:

• Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days provides excellent activity against E. coli (the causative pathogen in 75–95% of uncomplicated cystitis cases) with minimal disruption to intestinal flora and the lowest risk of promoting antimicrobial resistance. 1, 2, 3

• Trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg orally twice daily for 3 days achieves 93% clinical cure and 94% microbiological eradication but should only be used when local E. coli resistance is documented to be <20% AND the patient has not received TMP-SMX in the preceding 3 months. 1, 2, 4, 3

• Fosfomycin tromethamine 3 g as a single oral dose provides approximately 91% clinical cure with therapeutic urinary concentrations maintained for 24–48 hours, offering the convenience of single-dose administration with resistance rates around 2.6% in initial infections. 1, 5, 6, 3

Decision Algorithm for Selecting Among First-Line Agents

Step 1: Verify local TMP-SMX resistance patterns

• If local E. coli resistance to TMP-SMX is <20% and the patient has not used TMP-SMX in the prior 3 months → TMP-SMX 160/800 mg twice daily for 3 days is appropriate. 1, 2
• If resistance is ≥20%, data are unavailable, or recent TMP-SMX exposure occurred → proceed to Step 2. 1

Step 2: Choose between nitrofurantoin and fosfomycin

• Nitrofurantoin is preferred when adherence to a 5-day twice-daily regimen is feasible and estimated glomerular filtration rate (eGFR) is ≥30 mL/min/1.73 m². 1, 2
• Fosfomycin is preferred when single-dose convenience is paramount or when the patient has difficulty with multi-day regimens. 1, 5, 6

Critical Contraindications and Limitations

• Nitrofurantoin must be avoided when eGFR <30 mL/min/1.73 m² because therapeutic urinary concentrations cannot be achieved. 1, 2

• Fosfomycin is not recommended for suspected pyelonephritis or upper urinary tract infections due to insufficient tissue penetration and lack of efficacy data for complicated disease. 1, 5, 6

• TMP-SMX should not be used empirically in many regions because resistance now exceeds 20% in multiple communities worldwide, with some areas reporting rates up to 78.3% in persistent infections. 1, 2

Reserve (Second-Line) Agents—Use Only When First-Line Options Are Unsuitable

• 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 because serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity, C. difficile infection) outweigh benefits in uncomplicated cystitis. 1, 2, 7

• Beta-lactam agents (amoxicillin-clavulanate, cefdinir, cefpodoxime for 3–7 days) achieve only 89% clinical cure and 82% microbiological eradication—significantly inferior to first-line agents—and should be used only when first-line options are contraindicated. 1

• Amoxicillin or ampicillin alone should never be used because worldwide resistance rates exceed 55–67%. 1

When to Obtain Urine Culture and Susceptibility Testing

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, 3

Obtain urine culture and susceptibility testing when any of the following occur:

• Persistent symptoms after completing the prescribed regimen 1, 3
• Recurrence of symptoms within 2–4 weeks 1, 3
• 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 isolation of resistant organisms 1
• Pregnancy with urinary symptoms 1

Management of Treatment Failure

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

• Obtain urine culture and susceptibility testing immediately 1, 3
• Switch to a different antibiotic class for a full 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

If fever persists beyond 72 hours, perform renal ultrasound or CT imaging to exclude obstruction, abscess, or other complications requiring non-antibiotic intervention. 1

Common Pitfalls to Avoid

• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized women—this promotes resistance without clinical benefit. 1, 2

• Do not use empiric fluoroquinolones as first-line therapy for uncomplicated cystitis due to serious adverse effects and rising global resistance (now exceeding 10% in many regions). 1, 7

• Do not prescribe TMP-SMX without confirming local resistance is <20%—failure rates increase sharply above this threshold, and clinical/mathematical modeling studies consistently identify 20% as the cutoff for empiric use. 1

• Do not use nitrofurantoin for suspected pyelonephritis or when upper-tract involvement cannot be excluded—tissue penetration is inadequate. 1, 2

• Do not use oral fosfomycin for suspected upper urinary tract infection—switch to parenteral cephalosporin or fluoroquinolone if pyelonephritis is suspected. 1, 5, 6

Rationale for Prioritizing Nitrofurantoin

Nitrofurantoin is preferred over other first-line agents because it:

• Preserves intestinal microbiota better than fluoroquinolones and cephalosporins, thereby lowering the risk of C. difficile infection and other collateral antimicrobial damage 1, 2
• Maintains worldwide resistance rates below 1%, compared with TMP-SMX resistance exceeding 20% in many communities 1, 2
• Does not share cross-resistance with more commonly prescribed antimicrobials, supporting antimicrobial stewardship from a public health perspective 8, 7