What is the first‑line oral treatment for uncomplicated acute cystitis in a non‑pregnant adult woman without urinary tract abnormalities, recent antibiotic use, or drug allergies?

Treatment of Acute Uncomplicated Cystitis

Nitrofurantoin monohydrate/macrocrystals 100 mg orally twice daily for 5 days is the preferred first-line treatment for acute uncomplicated cystitis in non-pregnant adult women without renal impairment or suspected upper tract involvement. 1

First-Line Treatment Options

Nitrofurantoin (Preferred Agent)

• Nitrofurantoin 100 mg twice daily for 5 days achieves clinical cure rates of 88–93% and bacteriological eradication rates of 81–92%, with worldwide resistance rates below 1%. 1
• This agent causes minimal disruption to intestinal flora compared with fluoroquinolones and broad-spectrum cephalosporins, thereby reducing the risk of Clostridioides difficile infection and preserving the microbiome. 1, 2
• Contraindications: Do not use when estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² because therapeutic urinary concentrations cannot be achieved. 1, 3
• Do not use for suspected pyelonephritis (fever >38°C, flank pain, costovertebral angle tenderness) because nitrofurantoin does not reach adequate renal tissue concentrations. 1, 3

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• TMP-SMX 160/800 mg twice daily for 3 days provides 93% clinical cure and 94% microbiological eradication when the pathogen is susceptible. 1, 4
• Use only when BOTH criteria are met:
  • Local E. coli resistance to TMP-SMX is <20% (verify with local antibiogram data)
  • Patient has not received TMP-SMX in the preceding 3 months 1, 5
• Many regions now report TMP-SMX resistance >20%, making this agent unsuitable for empiric therapy in those areas. 1
• When resistance exceeds 20%, clinical cure rates drop to 41–54% versus 84–88% for susceptible strains. 1

Fosfomycin (Single-Dose Alternative)

• Fosfomycin trometamol 3 g as a single oral dose achieves approximately 90–91% clinical cure and maintains therapeutic urinary concentrations for 24–48 hours. 1, 2, 6
• Microbiological eradication rates are modestly lower (78–80%) compared with nitrofurantoin (86%), but overall clinical efficacy is comparable. 1
• Contraindications: Do not use for suspected pyelonephritis or upper tract infections due to insufficient tissue penetration. 1, 2, 6
• Particularly useful when adherence to multi-day regimens is doubtful or when nitrofurantoin is contraindicated (e.g., eGFR <30 mL/min). 1

Reserve (Second-Line) Agents – Use Only When First-Line Options Fail

Fluoroquinolones

• Ciprofloxacin 250 mg twice daily for 3 days or levofloxacin 250 mg once daily for 3 days achieve approximately 95% clinical cure rates. 1, 4
• Reserve exclusively for:
  • Culture-proven resistant pathogens
  • Documented failure of first-line agents
  • Suspected or confirmed pyelonephritis 1, 3
• Do not use empirically for uncomplicated cystitis because of serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity, aortic dissection) and rising global resistance rates (>10% in many regions). 1, 4
• Fluoroquinolones cause significant collateral damage to intestinal flora and promote resistance to these critically important agents. 1

Beta-Lactam Agents

• Amoxicillin-clavulanate, cefdinir, cefaclor, or cefpodoxime-proxetil for 3–7 days achieve only 89% clinical cure and 82% microbiological eradication, which is significantly inferior to first-line agents. 1, 4
• Use only when first-line agents are contraindicated (e.g., documented allergy, intolerance, or resistance). 1
• Never use amoxicillin or ampicillin alone because worldwide E. coli resistance exceeds 55–67%. 1

Diagnostic Recommendations

When Urine Culture Is NOT Required

• Routine urine culture is unnecessary for otherwise healthy women presenting with typical lower urinary tract symptoms (dysuria, frequency, urgency, suprapubic discomfort) without vaginal discharge. 1, 5

When Urine Culture IS Mandatory

• Obtain urine culture and susceptibility testing when any of the following occur:
  • Persistent symptoms after completing the prescribed regimen
  • Recurrence of symptoms within 2–4 weeks
  • Fever >38°C, flank pain, or costovertebral angle tenderness (suggesting pyelonephritis)
  • Atypical presentation or presence of vaginal discharge
  • Pregnancy with urinary symptoms
  • History of recurrent infections or prior isolation of resistant organisms 1, 5

Management of Treatment Failure

• If symptoms persist at the end of therapy or recur within 2 weeks, obtain urine culture and susceptibility testing immediately. 1
• Switch to a different antibiotic class for a full 7-day course (not the original short regimen), assuming the original pathogen is resistant. 1
• Reserve fluoroquinolones only for culture-proven resistance. 1

Clinical Decision Algorithm

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

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

• If <20% and patient has not used TMP-SMX recently → prescribe TMP-SMX 160/800 mg twice daily for 3 days. 1, 5
• If ≥20% or local 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. 1
• Switch to a different antibiotic class for a 7-day course. 1
• Reserve fluoroquinolones only for culture-proven resistance. 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 for uncomplicated cystitis despite high efficacy; serious adverse effects outweigh benefits. 1, 4
• 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, 3
• Do not use oral fosfomycin for suspected upper tract infection or pyelonephritis. 1, 6
• Do not extend nitrofurantoin therapy beyond 5–7 days; this provides no additional efficacy and increases adverse event risk. 1, 3