What is the first‑line antibiotic regimen for uncomplicated cystitis in an otherwise healthy adult woman?

First-Line Antibiotic for Uncomplicated Cystitis in Healthy Adult Women

Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days is the preferred first-line treatment for uncomplicated cystitis in otherwise healthy adult women. 1, 2

Primary First-Line Options

The IDSA/European Society for Microbiology and Infectious Diseases guidelines recommend the following as first-line agents 1:

• Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days – This is the most consistently recommended first-line agent across current guidelines 1, 2, 3, 4

• Trimethoprim-sulfamethoxazole 160/800 mg (one double-strength tablet) twice daily for 3 days – Use ONLY if local E. coli resistance rates are documented to be below 20% AND the patient has not used this antibiotic for UTI in the previous 3 months 1, 2

• Fosfomycin trometamol 3 g single oral dose – Convenient single-dose option, though it has slightly lower efficacy compared to nitrofurantoin and trimethoprim-sulfamethoxazole 1, 2, 5

Why Nitrofurantoin is Preferred

Nitrofurantoin has emerged as the optimal first-line choice because 2, 6:

• It maintains excellent activity against E. coli with resistance rates typically remaining below 10% 2
• It produces minimal "collateral damage" to normal flora, preserving broader-spectrum antibiotics 2
• It has lower treatment failure rates compared to trimethoprim-sulfamethoxazole in the current resistance environment 2
• The WHO specifically recommends it as first-choice treatment for lower UTIs 2

Critical Contraindications and Warnings

Do not use nitrofurantoin if 1, 2:

• Creatinine clearance is <60 mL/min (inadequate urinary concentrations) 2
• Pyelonephritis is suspected (fever, flank pain, systemic symptoms) – nitrofurantoin does not achieve adequate tissue concentrations 1, 2
• Patient is in the third trimester of pregnancy or has infants under 4 months (risk of hemolytic anemia) 2

When to Choose Trimethoprim-Sulfamethoxazole Instead

Use trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days only when 1, 2:

• Local E. coli resistance rates are documented to be <20% 1, 2
• The patient has NOT used this antibiotic for UTI in the previous 3 months 1
• Nitrofurantoin is contraindicated (renal insufficiency) 2

Important caveat: Rising resistance rates to trimethoprim-sulfamethoxazole have necessitated downgrading this from universal first-line status, with studies showing clinical cure rates drop from 84% with susceptible organisms to only 41% with resistant organisms 1

When to Choose Fosfomycin

Fosfomycin trometamol 3 g single dose is appropriate when 1, 5:

• Patient compliance is a concern (single-dose convenience) 5
• Other first-line agents cannot be used due to allergy or contraindications 1
• The infection is caused by E. coli or Enterococcus faecalis 5

Key limitation: Fosfomycin has slightly inferior efficacy compared to 5-day nitrofurantoin or 3-day trimethoprim-sulfamethoxazole regimens 1, 2

Second-Line Alternatives (When First-Line Agents Cannot Be Used)

Fluoroquinolones should be RESERVED as alternative agents, not first-line 1, 2:

• Ciprofloxacin 250 mg twice daily for 3 days OR
• Levofloxacin 250 mg once daily for 3 days 1
• Use only when first-line agents cannot be used due to allergy, intolerance, or documented resistance 2
• The FDA has issued serious safety warnings regarding tendon, muscle, joint, nerve, and CNS effects 2, 6
• Local resistance rates now exceed 10% in many regions, making empiric use problematic 2

β-lactam agents (use with caution, inferior efficacy) 1:

• Amoxicillin-clavulanate, cefdinir, cefaclor, or cefpodoxime-proxetil for 3-7 days 1
• These have generally inferior efficacy and more adverse effects compared to first-line agents 1

Never use amoxicillin or ampicillin alone – very high worldwide resistance rates and poor efficacy 1

Clinical Decision Algorithm

Step 1: Confirm uncomplicated cystitis 1:

• Absence of fever, flank pain, or systemic symptoms (rules out pyelonephritis)
• Patient can take oral medication
• No pregnancy, anatomic abnormalities, or recent instrumentation

Step 2: Check for nitrofurantoin contraindications 2:

• Creatinine clearance ≥60 mL/min? (If <60, skip to Step 3)
• No suspicion of early pyelonephritis? (If suspected, use fluoroquinolone instead)
• If both criteria met: Prescribe nitrofurantoin 100 mg twice daily for 5 days 1, 2

Step 3: If nitrofurantoin contraindicated, assess local resistance 1, 2:

• Is local E. coli resistance to trimethoprim-sulfamethoxazole <20%?
• Has patient NOT used trimethoprim-sulfamethoxazole in past 3 months?
• If yes to both: Prescribe trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days 1

Step 4: If Steps 2 and 3 fail 1, 5:

• Consider fosfomycin 3 g single dose (if compliance is concern or other options unavailable) 5
• Consider fluoroquinolone (ciprofloxacin 250 mg twice daily for 3 days) only if no other options 1, 2

Common Pitfalls to Avoid

• Do not prescribe fluoroquinolones as first-line – reserve for pyelonephritis or when first-line agents fail 1, 2
• Do not use nitrofurantoin for suspected pyelonephritis – it does not achieve adequate tissue concentrations 1, 2
• Do not use trimethoprim-sulfamethoxazole empirically in high-resistance areas (>20% resistance) – clinical failure rates are unacceptably high 1
• Do not treat for longer than necessary – 5 days for nitrofurantoin, 3 days for trimethoprim-sulfamethoxazole is sufficient 1, 2
• Do not obtain urine culture before treatment in straightforward uncomplicated cystitis – empiric therapy is appropriate 2, 4

When to Obtain Urine Culture

Culture is NOT necessary for routine uncomplicated cystitis 2, 4. However, obtain culture if 2:

• Symptoms persist or recur within 2-4 weeks after treatment
• Patient has recurrent UTIs (≥3 episodes in 12 months)
• Atypical presentation or concern for resistant organism
• Pregnancy or other complicating factors