Cephalexin 500 mg for Uncomplicated Cystitis
Cephalexin 500 mg is an appropriate alternative agent for uncomplicated cystitis when first-line therapies (nitrofurantoin, fosfomycin, or trimethoprim-sulfamethoxazole) cannot be used, but it should not be prescribed empirically as a first-line agent due to inferior efficacy compared to recommended options. 1, 2
Position in Treatment Algorithm
First-line agents remain nitrofurantoin 100 mg twice daily for 5 days, fosfomycin 3 g single dose, or trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 days (only when local E. coli resistance < 20%), achieving clinical cure rates of 91–93% compared to cephalexin's 89% rate. 1, 2
Cephalexin is explicitly categorized as a second-line or alternative agent in international guidelines because β-lactam antibiotics demonstrate 15–30% higher failure rates than first-line options for uncomplicated UTI. 3, 1, 2
Reserve cephalexin for situations where first-line agents are contraindicated due to allergy (nitrofurantoin or sulfa allergy), renal impairment (eGFR < 30 mL/min contraindicates nitrofurantoin), or documented resistance to preferred agents. 3, 1
FDA-Approved Dosing for Uncomplicated Cystitis
The FDA label authorizes cephalexin 500 mg every 12 hours (twice daily) for uncomplicated cystitis in patients over 15 years of age, with therapy continued for 7–14 days. 4
Recent evidence demonstrates that cephalexin 500 mg twice daily is non-inferior to 500 mg four times daily for treatment of uncomplicated UTI, with no difference in treatment failure rates (12.7% vs 17%, P = 0.343) and improved adherence with the simpler regimen. 5, 6
Prescribe cephalexin 500 mg orally twice daily for 7 days as the evidence-based regimen that balances efficacy, convenience, and adherence while avoiding the outdated four-times-daily dosing. 4, 5, 6
Susceptibility Requirements and Limitations
Cephalexin should only be prescribed when urine culture demonstrates susceptibility to cefazolin, as cephalexin susceptibility is inferred from cefazolin testing per CLSI and USCAST guidelines; empiric use without culture risks failure with resistant strains. 3, 7, 8
Cephalexin is ineffective against ESBL-producing Klebsiella pneumoniae and Enterobacter species, which require alternative agents such as carbapenems or newer β-lactam/β-lactamase inhibitor combinations. 3, 7
First- and second-generation cephalosporins including cephalexin lack adequate activity against Enterobacter species, making culture-guided therapy essential rather than empiric use. 3
When to Obtain Urine Culture
Routine urine culture is not required for straightforward uncomplicated cystitis in otherwise healthy women with typical symptoms. 1
Obtain urine culture and susceptibility testing before prescribing cephalexin when any of the following occur: persistent symptoms after initial therapy, recurrence within 2–4 weeks, fever > 38°C or flank pain suggesting pyelonephritis, atypical presentation, history of recurrent infections, or prior isolation of resistant organisms. 1
Comparative Efficacy Data
In emergency department settings, cephalexin demonstrated 70% concordance with IDSA guidelines and 76.4% susceptibility match with isolated uropathogens, with E. coli showing 97% susceptibility to cefazolin (surrogate for cephalexin). 8
Among 107 E. coli isolates, cefazolin susceptibility was 97% compared to nitrofurantoin 96%, ciprofloxacin 87%, and trimethoprim-sulfamethoxazole 59%, supporting cephalexin as a reasonable alternative when first-line agents cannot be used. 8
Cephalexin achieves very good early bacteriological and clinical cures in uncomplicated UTI due to non-ESBL-producing Enterobacteriaceae, comparable to many traditionally first-line agents when the pathogen is susceptible. 7
Critical Pitfalls to Avoid
Do not use cephalexin for complicated UTIs, pyelonephritis, or upper-tract infections without prior parenteral therapy, as tissue penetration is insufficient and failure rates are higher. 3
Do not prescribe cephalexin empirically without confirming local E. coli susceptibility patterns, as resistance varies widely by geographic region and healthcare setting. 3, 7
Avoid cephalexin when ESBL-producing organisms are suspected or confirmed, as first- and second-generation cephalosporins are ineffective against these pathogens. 3, 7
Do not use amoxicillin or ampicillin alone for uncomplicated UTI, as worldwide E. coli resistance exceeds 55–67%, making these agents unacceptable for empiric therapy. 1
Fluoroquinolone-Sparing Strategy
Cephalexin 500 mg twice daily serves as a fluoroquinolone-sparing alternative when first-line agents cannot be used, helping preserve fluoroquinolones for complicated infections and reducing serious adverse effects (tendon rupture, peripheral neuropathy, CNS toxicity). 1, 7
Fluoroquinolones should be reserved exclusively for culture-proven resistant pathogens or documented failure of first-line therapy, as the FDA has warned that serious adverse effects outweigh benefits in uncomplicated UTI. 1