Is Keflex (cephalexin) effective for treating urinary tract infections (UTIs)?

Keflex (Cephalexin) for UTI

Cephalexin is an acceptable but not first-line option for uncomplicated UTIs, and should be reserved for situations where preferred agents (nitrofurantoin, fosfomycin, trimethoprim-sulfamethoxazole) cannot be used due to resistance patterns, allergies, or availability. 1

Guideline Recommendations

Position in Treatment Hierarchy

• β-lactam agents, including cephalexin, are classified as alternative rather than first-line therapy for acute uncomplicated cystitis 1
• The IDSA/ESMID guidelines explicitly state that β-lactams are "less well studied" and have "inferior efficacy and more adverse effects compared with other UTI antimicrobials" 1
• β-lactams other than pivmecillinam should be used with caution for uncomplicated cystitis 1

When Cephalexin Is Appropriate

• Cephalexin is appropriate when other recommended agents cannot be used 1
• In specific populations (Australian spinal cord injured athletes), cephalexin is listed alongside trimethoprim and amoxicillin-clavulanate as acceptable for uncomplicated UTIs 1
• The FDA label indicates cephalexin is approved for genitourinary tract infections caused by E. coli, Proteus mirabilis, and Klebsiella pneumoniae 2

Dosing Regimens

Evidence-Based Dosing

Recent high-quality research demonstrates that twice-daily dosing (500 mg BID) is as effective as four-times-daily dosing (500 mg QID) for uncomplicated UTIs:

• A 2023 multicenter retrospective study of 261 patients showed no difference in treatment failure between BID (12.7%) versus QID (17%) dosing (P = 0.343) 3
• A 2025 emergency department study of 214 patients found treatment failure rates of 18.7% for BID versus 15.0% for QID (P = 0.465) 4
• A 2023 single-center study of 264 patients demonstrated 81.1% clinical success with twice-daily dosing 5
• Historical data from 1976 confirmed that 1 g twice daily has equivalent efficacy to four-times-daily dosing 6

Recommended Dosing Strategy

• Cephalexin 500 mg twice daily for 5-7 days is the optimal regimen for uncomplicated UTIs 3, 5, 4
• This twice-daily approach improves patient adherence without compromising effectiveness 3
• Treatment duration should be 3-7 days according to IDSA guidelines 1

Clinical Efficacy Data

Success Rates

• Overall clinical success rates of 81.1% have been documented with short courses of twice-daily cephalexin 5
• Single-dose therapy (3 g) achieved 67% cure rates in unselected populations, with 87% success in patients under 25 years versus 46% in those over 40 years 7
• Age significantly impacts outcomes: younger patients (<25 years) respond better than older patients (>40 years) 7

Microbiological Considerations

• E. coli is the most commonly isolated pathogen (85.4%) in cephalexin-treated UTIs 3
• Cephalexin susceptibility testing should use cefazolin as the surrogate marker 2
• Infections with antibody-coated bacteria-negative tests show higher cure rates (71%) compared to positive tests (19%) 7

Important Limitations and Caveats

Resistance and Coverage Gaps

• Cephalexin has NO activity against Pseudomonas spp., Acinetobacter calcoaceticus, most Enterobacter spp., Morganella morganii, or Proteus vulgaris 2
• Methicillin-resistant staphylococci and most enterococci are resistant 2
• Penicillin-resistant Streptococcus pneumoniae is usually cross-resistant 2

When NOT to Use Cephalexin

• Do NOT use for pyelonephritis: Cephalexin is not listed in any guideline recommendations for uncomplicated or complicated pyelonephritis 1
• The 2024 EAU guidelines recommend oral cefpodoxime or ceftibuten (not cephalexin) for oral therapy of pyelonephritis 1
• Avoid in complicated UTIs unless culture-directed, as broader spectrum agents are typically needed 1

Patient-Specific Factors

• Inner-city patients had significantly lower cure rates (45%) compared to suburban patients (90%) in one study, likely reflecting different resistance patterns 7
• Local resistance patterns should guide empiric selection 1, 2
• Culture and susceptibility testing should be performed when indicated 2

Practical Algorithm for Use

Step 1: Confirm uncomplicated cystitis (not pyelonephritis, no fever, no flank pain)

Step 2: Assess if first-line agents are contraindicated:

• Nitrofurantoin contraindicated (renal dysfunction, G6PD deficiency)
• Fosfomycin unavailable or previously failed
• TMP-SMX resistance >20% locally or allergy

Step 3: If cephalexin is chosen:

• Prescribe 500 mg twice daily for 5-7 days 3, 5, 4
• Obtain urine culture before initiating therapy 2
• Adjust based on culture results if available

Step 4: Monitor for treatment failure:

• Return of symptoms within 30 days occurs in 10-19% of patients 3, 5, 4
• Consider alternative agent if symptoms persist beyond 2-3 days

Adverse Effects

• Reported adverse event rates are low (4.6-5.6%) with no difference between BID and QID dosing 3
• No increased risk of Clostridioides difficile infection within 30 days was observed 3