Cephalexin for UTI
Cephalexin is an effective and FDA-approved treatment for urinary tract infections caused by susceptible organisms, particularly when first-line agents cannot be used or based on local resistance patterns, though current guidelines generally position it as an alternative rather than first-line therapy for uncomplicated cystitis. 1
FDA-Approved Indications
Cephalexin is specifically FDA-approved for genitourinary tract infections caused by Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae 1. The drug achieves excellent urinary concentrations, with peak levels of approximately 1000,2200, and 5000 mcg/mL following 250 mg, 500 mg, and 1 g doses respectively, with over 90% excreted unchanged in urine within 8 hours 1.
Guideline Positioning
Uncomplicated Cystitis
- First-line agents according to the 2024 European Association of Urology guidelines are fosfomycin trometamol, nitrofurantoin, and pivmecillinam 2
- Cephalosporins (including cephalexin) are listed as alternatives when other recommended agents cannot be used, with the caveat that β-lactams generally have inferior efficacy and more adverse effects compared to other UTI antimicrobials 2
- The 2011 IDSA guidelines note that β-lactams should be used with caution for uncomplicated cystitis and are less well studied than preferred agents 2
Uncomplicated Pyelonephritis
- Oral cephalosporins (cefpodoxime 200 mg twice daily for 10 days or ceftibuten 400 mg daily for 10 days) are recommended options for empiric treatment 2
- An initial intravenous dose of a long-acting parenteral antimicrobial (e.g., ceftriaxone) should be administered when oral cephalosporins are used empirically 2
- Note that oral cephalosporins achieve significantly lower blood and urinary concentrations than the intravenous route 2
Complicated UTIs
- Second-generation cephalosporins plus an aminoglycoside are recommended for complicated UTIs with systemic symptoms 2
- Treatment duration is generally 7-14 days (14 days for men when prostatitis cannot be excluded) 2
Optimal Dosing Strategy
For uncomplicated UTIs, cephalexin 500 mg twice daily for 5-7 days is as effective as four-times-daily dosing and should be preferred to improve adherence. 3, 4, 5
- A 2023 multicenter study of 261 patients found no difference in treatment failure between twice-daily (12.7%) versus four-times-daily dosing (17%, P=0.343) 4
- A 2023 single-center study of 264 patients treated with twice-daily cephalexin showed 81.1% clinical success rates 3
- A 2025 study of 214 ED patients found treatment failure rates of 18.7% with twice-daily versus 15.0% with four-times-daily dosing (P=0.465) 5
Clinical Considerations in the Modern Era
When to Consider Cephalexin
- Local resistance patterns favor cephalexin over traditional first-line agents 3
- Fluoroquinolone-sparing strategy is desired 6
- Patient has contraindications to nitrofurantoin, fosfomycin, or trimethoprim-sulfamethoxazole 2
- Cefazolin susceptibility testing is available (CLSI and USCAST recommend cefazolin as a surrogate for cephalexin) 6
Susceptibility and Coverage
- Cephalexin is active against most strains of E. coli, Klebsiella pneumoniae, and Proteus mirabilis 1
- Not active against: Pseudomonas spp., Enterococcus spp., methicillin-resistant staphylococci, most Enterobacter spp., or ESBL-producing organisms 1, 6
- Local resistance rates should be <20% for empiric use in uncomplicated cystitis 2
Common Pitfalls to Avoid
- Do not use cephalexin for pyelonephritis without an initial parenteral dose of a long-acting agent like ceftriaxone, as oral cephalosporins achieve inadequate blood levels 2
- Do not assume cephalexin covers Enterococcus or Pseudomonas—these require alternative agents 1
- Avoid empiric use in patients with recent fluoroquinolone exposure or healthcare-associated infections where ESBL prevalence is high 6
- Do not prescribe four-times-daily dosing when twice-daily achieves equivalent outcomes with better adherence 4, 5