Cephalexin for Staphylococcus aureus Infections
Cephalexin is highly effective for treating methicillin-susceptible Staphylococcus aureus (MSSA) infections, particularly skin and soft tissue infections, but is completely ineffective against methicillin-resistant S. aureus (MRSA) and should never be used when MRSA is suspected or confirmed. 1, 2
FDA-Approved Indications
Cephalexin is FDA-approved specifically for skin and skin structure infections caused by Staphylococcus aureus, as well as bone infections caused by S. aureus. 3 The drug demonstrates consistent activity against MSSA with cure rates of 90% or higher in clinical practice. 4
Clinical Efficacy for MSSA
For uncomplicated skin infections caused by MSSA, cephalexin 500 mg four times daily orally for 7 days is the recommended regimen per IDSA guidelines. 1, 2
Pediatric dosing is 25-50 mg/kg/day divided into 3-4 doses for children with MSSA skin infections. 2
Cephalexin achieves clinical cure rates of 84-90% for MSSA skin and soft tissue infections, demonstrating comparable efficacy to other anti-staphylococcal agents like dicloxacillin and clindamycin. 4, 5
For bone and joint infections, cephalexin has demonstrated effectiveness with MIC50 values of 2 μg/mL and MIC90 values of 4 μg/mL against MSSA isolates from pediatric musculoskeletal infections. 6
Critical Limitation: Complete Ineffectiveness Against MRSA
Cephalexin has zero activity against MRSA and must never be used empirically when MRSA is suspected or as definitive therapy when MRSA is confirmed. 2, 7
In populations with high MRSA prevalence, a randomized controlled trial showed that cephalexin provided no benefit over placebo after incision and drainage of abscesses, with 87.8% of S. aureus isolates being MRSA. 5
When MRSA is suspected, switch immediately to clindamycin, doxycycline, or trimethoprim-sulfamethoxazole instead of cephalexin. 1, 2, 8
Clinical Decision Algorithm
Step 1: Determine methicillin susceptibility
- Obtain cultures before initiating therapy when feasible. 1, 3
- Consider local MRSA prevalence rates in your community and institution. 1
Step 2: Assess risk factors for MRSA
- Penetrating trauma, injection drug use, known MRSA colonization, prior MRSA infection, or purulent cellulitis all indicate high MRSA risk—do not use cephalexin empirically. 1
- For non-purulent cellulitis without MRSA risk factors, cephalexin is appropriate empiric therapy. 1, 2
Step 3: Select appropriate therapy
- If MSSA confirmed: Cephalexin 500 mg four times daily for 7 days (adults) or 25-50 mg/kg/day divided into 3-4 doses (children). 1, 2
- If MRSA confirmed or suspected: Use clindamycin 300-450 mg three times daily, doxycycline 100 mg twice daily, or trimethoprim-sulfamethoxazole. 1, 8
Comparative Positioning
Cephalexin is comparable in efficacy to dicloxacillin and other first-generation cephalosporins for MSSA infections. 2, 7, 4
For serious MSSA infections requiring parenteral therapy, penicillinase-resistant penicillins (nafcillin, oxacillin) or cefazolin remain preferred over oral cephalexin. 1, 7
Cephalexin can serve as effective oral suppressive therapy for MSSA ventricular assist device infections, with success in 8/8 patients without bacteremia and 3/6 with bacteremia. 9
Common Pitfalls to Avoid
Never assume S. aureus is methicillin-susceptible in purulent infections or in patients with MRSA risk factors—empiric cephalexin will fail in these scenarios. 1, 5
Do not use cephalexin in patients with immediate-type penicillin hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis) as cross-reactivity exists. 7
For simple abscesses after adequate incision and drainage, antibiotics including cephalexin may provide no additional benefit, with cure rates of 90.5% with drainage alone versus 84.1% with drainage plus cephalexin. 5
Extend therapy beyond 5-7 days only if clinical improvement is inadequate at the initial treatment endpoint. 1