What are the first‑line oral antibiotics and dosing for an uncomplicated urinary tract infection in an adult with no known drug allergies, and when is cephalexin appropriate?

First-Line Oral Antibiotics for Uncomplicated UTI in Adults

For uncomplicated urinary tract infection in adults with no drug allergies, prescribe nitrofurantoin 100 mg twice daily for 5 days, trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days (only if local E. coli resistance is <20%), or fosfomycin 3 g as a single dose. 1

Primary First-Line Options

• Nitrofurantoin 100 mg orally twice daily for 5 days achieves approximately 93% clinical cure and 88% microbiological eradication, with worldwide resistance rates <1% and minimal disruption to intestinal flora. 2

• Trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg twice daily for 3 days provides 93% clinical cure and 94% microbiological eradication when the organism is susceptible, but should only be used when local E. coli resistance is <20% and the patient has not received TMP-SMX in the prior 3 months. 1, 2

• Fosfomycin 3 g as a single oral dose delivers approximately 91% clinical cure with therapeutic urinary concentrations maintained for 24-48 hours, offering single-dose convenience with minimal collateral damage to gut flora. 1, 2

When Cephalexin Is Appropriate

Cephalexin is NOT a first-line agent for uncomplicated UTI and should only be used when first-line options are contraindicated or unavailable. 1, 2

• Cephalexin 500 mg every 12 hours for 7-14 days is FDA-approved for uncomplicated cystitis in patients over 15 years of age, but demonstrates inferior efficacy compared to first-line agents. 3

• Oral β-lactams including cephalexin achieve only approximately 89% clinical cure and 82% microbiological eradication—significantly lower than nitrofurantoin, TMP-SMX, or fosfomycin. 2

• A recent study showed cephalexin 500 mg twice daily is as effective as four-times-daily dosing for uncomplicated UTI, with treatment failure rates of 12.7% vs 17% respectively (not statistically different), but these failure rates remain higher than first-line agents. 4

Critical Decision Algorithm

Step 1: Verify local E. coli TMP-SMX resistance rates. If <20% and no TMP-SMX use in past 3 months → prescribe TMP-SMX 160/800 mg twice daily for 3 days. 2

Step 2: If TMP-SMX is unsuitable (resistance ≥20%, recent use, or sulfa allergy) → choose nitrofurantoin 100 mg twice daily for 5 days OR fosfomycin 3 g single dose based on patient preference for adherence. 1, 2

Step 3: Reserve cephalexin 500 mg twice daily for 7 days only when all first-line agents are contraindicated (e.g., nitrofurantoin contraindicated if eGFR <30 mL/min, TMP-SMX contraindicated by allergy or resistance, fosfomycin unavailable). 2, 3, 4

Agents to Avoid

• Fluoroquinolones (ciprofloxacin, levofloxacin) should be reserved for pyelonephritis or culture-proven resistant organisms due to serious adverse effects including tendon rupture and C. difficile infection, despite their high efficacy. 1, 2

• Amoxicillin or ampicillin alone should never be used empirically because worldwide E. coli resistance exceeds 55-67%. 2

Common Pitfalls

• Do not use cephalexin as first-line therapy when nitrofurantoin, TMP-SMX, or fosfomycin are available—this represents suboptimal care with higher failure rates. 1, 2

• Do not prescribe TMP-SMX without confirming local resistance is <20%—treatment failure rates rise sharply when this threshold is exceeded. 2

• Do not obtain routine urine culture for straightforward uncomplicated cystitis in otherwise healthy women; reserve cultures for treatment failure, recurrence within 2 weeks, or atypical presentation. 2, 5

• Avoid nitrofurantoin when eGFR <30 mL/min/1.73 m² because urinary drug concentrations become insufficient for bacterial eradication. 2