What should I prescribe for a patient whose urinary tract infection persists despite a 2‑week course of nitrofurantoin (Macrobid)?

Management of Persistent UTI After 2 Weeks of Nitrofurantoin

Obtain a urine culture with susceptibility testing immediately and switch to a different antibiotic class for a 7-day course—do not repeat nitrofurantoin. 1

Immediate Diagnostic Steps

• Send urine culture and susceptibility testing now, before prescribing any new antibiotic, because persistent symptoms after completing therapy mandate culture-guided treatment rather than empiric therapy. 1
• The presumptive cause of treatment failure is either resistance to nitrofurantoin (though rare, occurring in <5% of E. coli) or an unrecognized upper-tract infection (pyelonephritis) that nitrofurantoin cannot treat. 1

Critical Assessment: Was This Actually Lower-Tract Cystitis?

Before prescribing the next antibiotic, verify the patient has NO upper-tract signs:

• Fever >38°C (100.4°F), flank pain, costovertebral-angle tenderness, nausea, or vomiting all indicate pyelonephritis, which nitrofurantoin cannot treat because it does not achieve adequate renal tissue concentrations. 1
• If any of these signs are present now or were present 2 weeks ago, the initial nitrofurantoin prescription was inappropriate and the infection was never adequately treated. 1

Empiric Treatment While Awaiting Culture Results

Prescribe a fluoroquinolone for 7 days as empiric therapy pending culture results:

• Ciprofloxacin 500 mg orally twice daily for 7 days is the recommended empiric choice for suspected pyelonephritis or treatment-failure cystitis, achieving 93–97% bacteriologic eradication when organisms are susceptible. 1, 2
• Levofloxacin 750 mg orally once daily for 5 days is an alternative fluoroquinolone regimen for complicated UTI or pyelonephritis. 3

Why Fluoroquinolones Are Appropriate Here (Despite Being "Reserved" Agents)

• Fluoroquinolones should be reserved for pyelonephritis and complicated infections rather than simple cystitis—this patient now has a complicated infection by definition (treatment failure). 1, 2
• The FDA warnings about tendon rupture, peripheral neuropathy, and aortic dissection are real, but the benefit outweighs the risk when treating a persistent infection that has already failed first-line therapy. 1

Alternative If Fluoroquinolones Are Contraindicated

If the patient cannot take fluoroquinolones (e.g., history of tendon rupture, aortic aneurysm, myasthenia gravis, or severe adverse reaction):

• Trimethoprim-sulfamethoxazole 160/800 mg (one double-strength tablet) orally twice daily for 7 days is the next choice, but only if local E. coli resistance is <20% or if the culture confirms susceptibility. 1, 2, 4
• If local resistance data are unavailable or exceed 20%, TMP-SMX will fail in 46–59% of cases and should not be used empirically. 2

What NOT to Prescribe

• Do not repeat nitrofurantoin for any duration—repeating a failed antibiotic selects for resistance and delays effective treatment. 1
• Do not prescribe amoxicillin, ampicillin, or amoxicillin-clavulanate empirically; E. coli resistance to these agents exceeds 55–67% worldwide, and they demonstrate inferior efficacy to other UTI antimicrobials. 1, 2
• Do not prescribe cephalosporins (cephalexin, cefpodoxime, ceftriaxone) for uncomplicated cystitis; they have inferior efficacy compared with nitrofurantoin and fluoroquinolones and are not guideline-recommended for this indication. 1

Adjust Therapy Based on Culture Results (3–5 Days Later)

• If the organism is susceptible to the empiric fluoroquinolone, complete the full 7-day course. 1
• If the organism is resistant to the empiric agent, switch immediately to an antibiotic to which the organism is susceptible and complete a full 7-day course from the time of the switch. 1
• If the culture grows a resistant organism and the patient has upper-tract signs, consider hospitalization for IV antibiotics (ceftriaxone 1–2 g IV daily or gentamicin 5–7 mg/kg IV daily). 5

Common Pitfalls to Avoid

• Do not assume this is "recurrent cystitis" requiring only another short course—symptoms persisting or recurring within 2 weeks of treatment indicate treatment failure, not a new infection. 1
• Do not prescribe a 3-day or 5-day regimen—treatment failures require a full 7-day course to ensure adequate eradication. 1
• Do not obtain a post-treatment urine culture if symptoms resolve—routine post-treatment cultures are not indicated for asymptomatic patients. 1

Special Considerations

If the Patient Is Male

• Men require 7-day courses for uncomplicated cystitis (not 3 days), and persistent symptoms raise concern for prostatitis, which requires ciprofloxacin 500 mg twice daily for 28 days or levofloxacin 500 mg once daily for 28 days. 1, 3
• Nitrofurantoin does not penetrate prostatic tissue adequately and should never be used for prostatitis. 1

If the Patient Has Reduced Renal Function

• Verify creatinine clearance before prescribing—nitrofurantoin is contraindicated at CrCl <30 mL/min, and fluoroquinolones require dose adjustment at CrCl <50 mL/min. 1, 3

If the Patient Is Pregnant

• Avoid fluoroquinolones entirely (teratogenic); use IV ceftriaxone 1–2 g daily or IV gentamicin 5–7 mg/kg daily for pyelonephritis or treatment-failure cystitis. 5
• Nitrofurantoin should be avoided in late pregnancy (after 36 weeks) due to risk of hemolytic anemia in the newborn. 5