What is the recommended dose and frequency of Keflex (cephalexin) monohydrate for an adult patient with an uncomplicated urinary tract infection (UTI)?

Cephalexin Dosing for Uncomplicated UTI

For uncomplicated cystitis in adults, cephalexin 500 mg twice daily for 7-14 days is the recommended regimen, though it should be noted that cephalexin is not a first-line agent and should only be used when preferred antibiotics cannot be administered. 1

Dosing Regimen

Standard Adult Dosing

• Dose: 500 mg orally twice daily (every 12 hours) 1
• Duration: 7-14 days for uncomplicated cystitis 1
• The FDA-approved labeling specifically states that 500 mg every 12 hours is appropriate for uncomplicated cystitis in patients over 15 years of age 1

Alternative Dosing

• The traditional regimen of 250 mg four times daily (every 6 hours) is also FDA-approved, but less practical for adherence 1
• For more severe infections, larger doses may be needed, though if daily doses exceed 4 grams, parenteral cephalosporins should be considered 1

Evidence Supporting Twice-Daily Dosing

Recent research strongly supports that twice-daily dosing is as effective as four-times-daily dosing for uncomplicated UTIs, with the added benefit of improved patient adherence. 2

• A 2023 multicenter retrospective study found no difference in treatment failure between cephalexin 500 mg twice daily (12.7% failure) versus 500 mg four times daily (17% failure, P=0.343) 2
• Another 2023 study of 264 patients treated with twice-daily cephalexin showed 81.1% clinical success at 30 days 3
• Historical data from 1976 demonstrated that 1 gram twice daily had equivalent efficacy to traditional four-times-daily dosing 4

Important Clinical Context

Position in Treatment Algorithm

Cephalexin is classified as an alternative, not first-line agent for uncomplicated cystitis. 5

The 2024 European Association of Urology guidelines list first-line agents as:

• Fosfomycin trometamol 3g single dose 5
• Nitrofurantoin 100 mg twice daily for 5 days 5
• Pivmecillinam 400 mg three times daily for 3-5 days 5

Cephalosporins (including cephalexin/cefadroxil) are listed as alternatives at 500 mg twice daily for 3 days, but only if local E. coli resistance is <20% 5

Key Caveats

• β-lactams generally have inferior efficacy and more adverse effects compared to other UTI antimicrobials 5
• The 2011 IDSA guidelines note that β-lactams should be used with caution for uncomplicated cystitis due to lower efficacy 5
• However, increasing resistance to first-line agents has made cephalexin a more attractive option in settings with favorable local susceptibility patterns 3

Pharmacologic Rationale

Cephalexin achieves urinary concentrations of 500-1000 mcg/mL following 250-500 mg oral doses, which far exceeds the minimum inhibitory concentration for typical urinary pathogens. 6

• The drug is completely absorbed in the upper intestine and 70-100% is excreted unchanged in urine within 6-8 hours 6
• It does not penetrate host tissue cells, which likely accounts for its low incidence of side effects 6
• Dose adjustment is required when creatinine clearance falls below 30 mL/min 6

Practical Recommendations

For patients in whom cephalexin is appropriate:

• Prescribe 500 mg orally twice daily for 7-14 days 1
• Verify local E. coli susceptibility patterns support cephalosporin use 5
• Consider obtaining urine culture if symptoms don't resolve or recur within 4 weeks 5
• Twice-daily dosing improves adherence without compromising efficacy 2, 3