What is the appropriate next step in managing an otherwise healthy adult woman with acute cystitis that has not improved after initial empiric therapy?

Management of Unresolved Acute Cystitis

When acute cystitis fails to improve after initial empiric therapy, immediately obtain a urine culture with susceptibility testing and switch to a different antibiotic class for a full 7-day course—not a repeat of the original short regimen. 1, 2

Immediate Diagnostic Steps

• Obtain urine culture and susceptibility testing immediately when symptoms persist after completing therapy or recur within 2–4 weeks. 1, 2, 3
• Assess for upper tract involvement: Check for fever >38°C, flank pain, or costovertebral angle tenderness that would indicate pyelonephritis requiring different management. 1, 2
• Consider imaging (ultrasound or CT) if fever persists beyond 72 hours to exclude obstruction, abscess, or anatomic abnormality. 2

Antibiotic Selection for Treatment Failure

If Initial Therapy Was Nitrofurantoin or Fosfomycin

• Switch to trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg orally twice daily for 7 days if local E. coli resistance is <20% and the patient has not received TMP-SMX in the prior 3 months. 1, 2
• If TMP-SMX is unsuitable, use a fluoroquinolone (ciprofloxacin 250–500 mg twice daily or levofloxacin 250–750 mg once daily) for 7 days, but only after culture confirmation of resistance to first-line agents. 1, 2

If Initial Therapy Was TMP-SMX

• Switch to nitrofurantoin 100 mg orally twice daily for 7 days (provided eGFR ≥30 mL/min/1.73 m²) or fosfomycin 3 g as a single dose. 1, 2
• Nitrofurantoin achieves 93% clinical cure and 88% microbiological eradication with worldwide resistance rates <1%, making it highly effective for TMP-SMX failures. 2

Reserve Agents (Culture-Directed Only)

• Fluoroquinolones should be reserved exclusively for culture-proven resistant organisms because serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity, C. difficile infection) outweigh benefits in uncomplicated cystitis. 1, 2
• Beta-lactams (amoxicillin-clavulanate, cefdinir, cefpodoxime) for 7 days achieve only 89% clinical cure and 82% microbiological eradication—significantly inferior to first-line agents—and should be used only when all other options are contraindicated. 1, 2, 4
• Never use amoxicillin or ampicillin alone because worldwide E. coli resistance exceeds 55–67%. 1, 2, 4

Critical Decision Points

When to Suspect Pyelonephritis

• Any fever >38°C, flank pain, or CVA tenderness mandates treatment for pyelonephritis, not cystitis: use ciprofloxacin 500 mg twice daily for 7 days (or levofloxacin 750 mg once daily for 5 days) with or without an initial IV dose of ceftriaxone 1 g if fluoroquinolone resistance exceeds 10% locally. 1
• Do not use oral fosfomycin or nitrofurantoin for suspected pyelonephritis because tissue penetration is insufficient. 1, 2

When to Extend Treatment Duration

• Extend therapy to 7–14 days (not the original 3–5 day regimen) when treating failure of initial therapy, as the pathogen is presumed resistant to the first agent. 1, 2
• A 7-day course is mandatory for complicated cystitis (e.g., diabetes, immunosuppression, anatomic abnormality, catheter use). 2, 4

Common Pitfalls to Avoid

• Do not repeat the same antibiotic or class that failed initially; assume the organism is resistant and switch to a different mechanism of action. 1, 2
• Do not prescribe TMP-SMX empirically without confirming local E. coli resistance is <20%; failure rates increase sharply above this threshold. 1, 2, 5
• Do not use nitrofurantoin when eGFR <30 mL/min/1.73 m² because therapeutic urinary concentrations cannot be achieved. 2
• Do not treat asymptomatic bacteriuria in non-pregnant, non-catheterized patients, as this promotes resistance without clinical benefit. 1, 2
• Do not rely solely on a hospital antibiogram, which often overrepresents inpatient or complicated isolates and may underestimate susceptibility in community-acquired uncomplicated cystitis. 2

Algorithmic Approach to Unresolved Cystitis

1. Obtain urine culture and susceptibility testing immediately. 1, 2, 3
2. Assess for pyelonephritis (fever, flank pain, CVA tenderness); if present, treat as upper tract infection with fluoroquinolone or parenteral cephalosporin for 7–14 days. 1
3. If lower tract symptoms only, switch to a different antibiotic class for 7 days based on culture results:
   • If resistant to initial agent but susceptible to TMP-SMX → use TMP-SMX 160/800 mg twice daily for 7 days. 1, 2
   • If resistant to TMP-SMX → use nitrofurantoin 100 mg twice daily for 7 days (if eGFR ≥30). 2
   • If resistant to both → use culture-directed fluoroquinolone for 7 days. 1, 2
4. If fever persists >72 hours despite appropriate antibiotics, obtain imaging to exclude obstruction or abscess. 2
5. Repeat urine culture 7 days after completing therapy if symptoms persist or recur, and consider referral to urology for anatomic evaluation. 2

Resistance Considerations

• Prior culture within 2 years has excellent predictive value (≥0.90) for detecting future susceptibility to fluoroquinolones, cephalosporins, and aminoglycosides, and good predictive value (0.78–0.85) for TMP-SMX and nitrofurantoin. 5
• Fosfomycin resistance remains low (2.6% in initial infections, 5.7% at 9 months), making it an excellent choice for multidrug-resistant organisms including ESBL-producing E. coli. 2, 6
• Approximately 30% of E. coli isolates in recurrent cystitis populations are resistant to TMP-SMX, and 38% in some cohorts, underscoring the importance of culture-directed therapy in treatment failures. 2, 5