What is the recommended first‑line oral therapy for an otherwise healthy adult with an uncomplicated lower urinary tract infection?

First-Line Oral Therapy for Uncomplicated Lower Urinary Tract Infection in Healthy Adults

Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days is the preferred first-line treatment for otherwise healthy adults with uncomplicated cystitis. 1

Rationale for Nitrofurantoin as First-Line

• Nitrofurantoin achieves clinical cure rates of 88-93% and microbiological cure rates of 81-92% in uncomplicated cystitis, demonstrating superior efficacy compared to alternative agents. 1

• This agent maintains worldwide resistance rates below 1% among E. coli (the causative organism in 75-95% of cases), making it highly reliable for empiric therapy. 1, 2

• Nitrofurantoin causes minimal disruption to intestinal flora, substantially reducing the risk of Clostridioides difficile infection and other collateral damage compared to fluoroquinolones or broad-spectrum agents. 1, 2

• A head-to-head randomized trial demonstrated that 5-day nitrofurantoin resulted in 70% clinical resolution versus 58% with single-dose fosfomycin (12% absolute difference, P=0.004), establishing nitrofurantoin's superior efficacy. 3

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

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• TMP-SMX 160/800 mg (one double-strength tablet) twice daily for 3 days is appropriate only when local E. coli resistance is documented to be <20% and the patient has not received TMP-SMX within the preceding 3 months. 1, 4

• When susceptible organisms are present, TMP-SMX achieves clinical cure rates of 90-100%, but efficacy plummets to 41-54% against resistant strains. 1

• Many regions now report TMP-SMX resistance exceeding 20%, making verification of local antibiogram data mandatory before empiric use. 1, 2

Fosfomycin Trometamol

• Fosfomycin 3 g as a single oral dose provides clinical cure rates of 90-91% but lower microbiological cure rates of 78-80% compared to nitrofurantoin. 1, 2, 5

• This single-dose regimen is particularly useful when adherence to multi-day courses is doubtful or when eGFR is 30-44 mL/min (where nitrofurantoin is contraindicated). 1, 2

• Fosfomycin should be avoided if early pyelonephritis is suspected, as it lacks adequate tissue penetration for upper tract infections. 1, 2

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

Fluoroquinolones

• Ciprofloxacin 250 mg twice daily for 3 days or levofloxacin 250 mg once daily for 3 days achieve clinical cure rates of approximately 95% and microbiological eradication rates of 93-97%. 6, 1, 7

• Fluoroquinolones must be reserved for documented resistant pathogens or when all first-line agents are contraindicated due to their propensity for promoting resistance, serious adverse effects (tendon rupture, C. difficile infection), and the need to preserve them for life-threatening infections. 6, 1, 2

• The IDSA explicitly recommends that fluoroquinolones be used only as alternatives when other UTI agents cannot be employed. 6

Beta-Lactam Agents

• Oral beta-lactams (cefdinir, cefaclor, cefpodoxime-proxetil) for 3-7 days demonstrate inferior efficacy (approximately 89% clinical cure and 82% microbiological cure) and higher adverse-event rates compared to nitrofurantoin or TMP-SMX. 6, 1

• These agents should be used only when first-line options are absolutely unavailable. 6, 1

Agents to Avoid Completely

• Amoxicillin or ampicillin should never be used empirically for uncomplicated cystitis due to poor efficacy and worldwide resistance rates exceeding 30-55%. 6, 1, 2

Diagnostic Considerations

• Routine urine culture is not required for otherwise healthy women presenting with typical cystitis symptoms (dysuria, frequency, urgency, suprapubic pain) without vaginal discharge. 1, 4

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

  • Symptoms persist after completing therapy
  • Recurrence within 2-4 weeks
  • Atypical presentation or presence of vaginal discharge
  • History of resistant organisms or treatment failure
  • Pregnancy 1, 4

Renal Function Assessment

• If eGFR >30 mL/min/1.73 m² → prescribe nitrofurantoin 100 mg twice daily for 5 days. 1

• If eGFR <30 mL/min/1.73 m² → nitrofurantoin is contraindicated; use fosfomycin 3 g single dose as the alternative. 1, 2

Management of Treatment Failure

• If symptoms persist at the end of therapy or recur within 2 weeks, immediately obtain urine culture and susceptibility testing and 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 when selecting retreatment. 1

Critical Pitfalls to Avoid

• Do not use fluoroquinolones as first-line empiric therapy despite their high efficacy, as this promotes resistance to agents needed for serious infections like pyelonephritis. 6, 1, 2

• Do not prescribe TMP-SMX without verifying local resistance is <20%; if data are unavailable, default to nitrofurantoin or fosfomycin. 1, 2

• Do not treat asymptomatic bacteriuria in non-pregnant women, as treatment offers no benefit and promotes antimicrobial resistance. 1, 2

• Do not use oral fosfomycin for suspected pyelonephritis; switch to a fluoroquinolone or parenteral cephalosporin if upper-tract infection is suspected (fever, flank pain, costovertebral angle tenderness). 1, 2