What is the first‑line oral regimen for uncomplicated acute cystitis in a healthy adult and the recommended alternatives for patients with renal impairment, pregnancy, men, or suspected acute pyelonephritis?

Treatment of Urinary Tract Infections in Adults

First‑Line Oral Regimen for Uncomplicated Acute Cystitis in Healthy Adults

Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days is the preferred first‑line oral regimen for uncomplicated acute cystitis in otherwise healthy, non‑pregnant adults. 1

• This regimen achieves clinical cure rates of 88–93 % and bacteriologic cure rates of 81–92 %, while maintaining minimal resistance and limited collateral damage to normal flora. 1, 2
• The 5‑day duration is required for optimal efficacy; shorter courses are inadequate. 1, 2

Alternative First‑Line Options (when nitrofurantoin cannot be used)

• Fosfomycin trometamol 3 g as a single oral dose provides clinical cure rates of 90–91 % and microbiologic cure rates of 78–80 %, offering a convenient single‑dose option when multi‑day adherence is problematic. 1
• Trimethoprim‑sulfamethoxazole (TMP‑SMX) 160/800 mg twice daily for 3 days is appropriate only if local E. coli resistance is < 20 % and the patient has not received TMP‑SMX in the preceding 3 months. 1, 3
• Pivmecillinam 400 mg twice daily for 3–5 days is available only in Europe and has slightly lower efficacy than nitrofurantoin or TMP‑SMX. 1

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Recommended Alternatives for Special Populations

Patients with Renal Impairment

• Avoid nitrofurantoin when estimated glomerular filtration rate (eGFR) is < 30 mL/min due to reduced efficacy and increased risk of peripheral neuropathy. 1, 2
• Use fosfomycin trometamol 3 g single dose as the preferred alternative in patients with eGFR < 30 mL/min. 1
• TMP‑SMX 160/800 mg twice daily for 3 days may be used if local resistance is < 20 % and renal function permits dose adjustment. 3

Pregnant Patients

• Nitrofurantoin 100 mg twice daily for 5 days remains appropriate throughout pregnancy. 1
• Fosfomycin trometamol 3 g single dose is safe throughout pregnancy. 1
• Avoid TMP‑SMX in the last trimester due to fetal risk (kernicterus). 1, 3
• Avoid TMP‑SMX in the first trimester due to potential teratogenic effects. 3

Men with Uncomplicated Cystitis

• TMP‑SMX 160/800 mg twice daily for 7 days is the recommended regimen for men with uncomplicated cystitis; the 3‑day course effective in women is insufficient for men. 1, 3
• Nitrofurantoin 100 mg twice daily for 7 days is an alternative when TMP‑SMX cannot be used. 1
• The longer duration (7 days versus 3 days) is required because short‑course therapy that is effective in women fails in men. 3

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Suspected Acute Pyelonephritis (Upper Tract Infection)

Nitrofurantoin and fosfomycin should never be used for suspected or confirmed pyelonephritis because they do not achieve adequate renal tissue concentrations. 1, 2

First‑Line Regimens for Mild‑to‑Moderate Pyelonephritis

• Ciprofloxacin 500 mg twice daily for 7 days is the preferred oral regimen for mild‑to‑moderate pyelonephritis when local susceptibility data support its use. 1, 3
• Levofloxacin 750 mg once daily for 5 days is an alternative fluoroquinolone regimen. 1
• TMP‑SMX 160/800 mg twice daily for 14 days may be used only if susceptibility is confirmed. 3, 4

Diagnostic Criteria for Pyelonephritis

• Suspect pyelonephritis when any of the following are present: fever > 38 °C, flank pain, costovertebral‑angle tenderness, nausea, vomiting, or systemic symptoms. 1, 2
• Obtain a urine culture with susceptibility testing before initiating therapy for suspected pyelonephritis. 1

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Reserve (Second‑Line) Agents for Uncomplicated Cystitis

• Fluoroquinolones (ciprofloxacin 250 mg twice daily for 3 days or levofloxacin) achieve bacteriologic eradication rates of 93–97 % but should be reserved for situations where first‑line agents are unsuitable, to preserve their utility for serious infections and minimize collateral damage. 1, 3
• Oral β‑lactams (cefdinir, cefaclor, cefpodoxime‑proxetil, cephalexin, amoxicillin‑clavulanate) for 3–7 days demonstrate inferior efficacy and higher adverse‑event rates compared with nitrofurantoin or TMP‑SMX; use only when first‑line agents cannot be used. 1

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Agents to Avoid Empirically

• Amoxicillin or ampicillin alone should never be used empirically for uncomplicated cystitis because worldwide resistance exceeds 30 %, resulting in poor therapeutic outcomes. 1, 3
• Fluoroquinolones should not be employed as first‑line therapy for uncomplicated cystitis despite high efficacy, to preserve their utility for pyelonephritis and complicated infections. 1, 3

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Resistance‑Based Decision Points

• Do not use TMP‑SMX empirically when local E. coli resistance rates exceed 20 %. 1, 3
• When organisms are susceptible to TMP‑SMX, clinical cure rates are 90–100 %; when resistant, cure rates plummet to 41–54 %, making treatment failure the expected outcome. 1, 3
• Recent TMP‑SMX exposure (within 3–6 months) or recent international travel (within 3–6 months) independently predict resistant infections and contraindicate empiric TMP‑SMX use. 3

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Diagnostic Considerations

• Urine culture is not routinely required for typical uncomplicated cystitis in otherwise healthy women; reserve it for atypical presentations, treatment failures, or recurrence within 2–4 weeks. 1
• Clinical diagnosis can be made based on dysuria, urinary frequency, urgency, or suprapubic pain without fever, flank pain, or other signs of pyelonephritis. 1

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Follow‑Up and Management of Therapeutic Failure

• Routine follow‑up or repeat urine culture is unnecessary in asymptomatic patients after completing therapy. 1
• If symptoms persist at the end of treatment or recur within 2 weeks, obtain a urine culture with susceptibility testing and retreat with a 7‑day regimen using a different appropriate agent. 1

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Common Pitfalls to Avoid

• Using nitrofurantoin for "borderline" upper‑tract symptoms (e.g., mild flank pain or low‑grade fever) is ineffective because the drug does not reach therapeutic concentrations in renal tissue. 1, 2
• Prescribing TMP‑SMX without local resistance data leads to unacceptably high treatment failure rates when resistance exceeds 20 %. 1, 3
• Shortening nitrofurantoin therapy to < 5 days reduces efficacy; always prescribe the full 5‑day course. 1, 2
• Using fosfomycin when pyelonephritis is suspected is inappropriate; avoid fosfomycin in the presence of fever, flank pain, or other signs of upper‑tract infection. 1
• Relying on hospital antibiograms for community‑acquired cystitis overestimates resistance because they reflect complicated infections; outpatient surveillance data are preferred. 3