Is Keflex (cephalexin) effective for treating an uncomplicated urinary tract infection (UTI)?

Cephalexin for Uncomplicated UTI: Not First-Line

Cephalexin should be reserved as a second-line or alternative agent for uncomplicated urinary tract infections, used only when first-line antibiotics (nitrofurantoin, trimethoprim-sulfamethoxazole, or fosfomycin) are contraindicated or unavailable. 1

Why Cephalexin Is Not Preferred

Beta-lactam antibiotics, including cephalexin, are explicitly not recommended as first-line therapy for uncomplicated UTIs due to inferior efficacy and significant collateral damage. 2, 1 The evidence against routine cephalexin use is compelling:

• Fluoroquinolones and cephalosporins are more likely than other antibiotic classes to alter fecal microbiota, cause Clostridioides difficile infection, and promote more rapid UTI recurrence due to loss of protective periurethral and vaginal microbiota. 2

• Beta-lactams are associated with higher rates of treatment failure and recurrence compared to nitrofurantoin, trimethoprim-sulfamethoxazole, and fosfomycin. 2, 1

• The European Urology Association specifically notes that cephalexin is associated with more adverse effects than other UTI antimicrobials. 1

First-Line Treatment Algorithm

For uncomplicated UTI in non-pregnant women, select from these evidence-based first-line options based on local resistance patterns: 1

• Nitrofurantoin 100 mg twice daily for 5 days (preferred when local resistance <20%) 1
• Trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days (only if local resistance <20%) 1
• Fosfomycin trometamol 3 g single dose 1

When Cephalexin May Be Considered

Cephalexin can be used as an alternative only when:

• Patient has documented contraindications or allergies to all first-line agents 1
• Urine culture demonstrates susceptibility to cephalexin/cefazolin 1
• Local resistance patterns support its use 1

Dosing When Cephalexin Is Used

If cephalexin must be used, prescribe 500 mg twice daily for 5-7 days. 3, 4 Recent evidence demonstrates:

• Twice-daily dosing (500 mg BID) is as effective as four-times-daily dosing (500 mg QID) with treatment success rates of 81-87% and no difference in treatment failure rates (12.7% vs 17%, p=0.343). 3, 4
• Twice-daily dosing improves patient adherence without compromising efficacy. 3
• Treatment duration of 3-7 days is recommended, with shorter courses preferred to reduce recurrence risk. 1

FDA-Approved Indications

The FDA label lists genitourinary tract infections caused by E. coli, Proteus mirabilis, and Klebsiella pneumoniae as approved indications for cephalexin. 5 However, this approval predates modern antibiotic stewardship principles and comparative effectiveness data showing superior outcomes with first-line agents.

Critical Caveats

Always obtain urine cultures before initiating therapy in cases of:

• Suspected treatment failure 1
• Recurrent UTIs (≥3 episodes in 12 months) 2, 1
• Atypical presentations 1

Cephalexin has no activity against:

• Methicillin-resistant Staphylococcus aureus 5
• Enterococci (Enterococcus faecalis) 5
• Pseudomonas species 5
• Most Enterobacter species, Morganella morganii, and Proteus vulgaris 5

Resistance considerations:

• Penicillin-resistant Streptococcus pneumoniae is usually cross-resistant to beta-lactams including cephalexin 5
• Extended-spectrum beta-lactamase (ESBL)-producing organisms render cephalexin ineffective 6

Antibiotic Stewardship Imperative

Antibiotic stewardship in UTI management requires treating all acute UTIs according to clinical practice guidelines using short-duration first-line therapy. 2 There is no evidence that longer courses or broader-spectrum antibiotics like cephalexin are needed for uncomplicated UTIs, and such approaches may paradoxically increase recurrence rates. 2