What is the recommended treatment for soft tissue infections with Keflex (cephalexin)?

Cephalexin (Keflex) for Soft Tissue Infections

Cephalexin is a first-choice antibiotic for mild, uncomplicated skin and soft tissue infections caused by susceptible Staphylococcus aureus and Streptococcus pyogenes. 1

Primary Indication and Efficacy

The WHO Expert Committee elevated cephalexin from second-choice to first-choice status in 2021 for mild skin and soft tissue infections, placing it alongside amoxicillin-clavulanate and cloxacillin as preferred agents. 1 This recommendation is based on its appropriate Gram-positive coverage for the most common pathogens encountered in clinical practice. 1

• The FDA approves cephalexin specifically for skin and skin structure infections caused by Staphylococcus aureus and/or Streptococcus pyogenes. 2
• Clinical cure rates exceed 95% in uncomplicated soft tissue infections treated with cephalexin. 3
• Cephalexin demonstrates non-inferiority to IV cefazolin plus probenecid for mild-moderate uncomplicated infections, with failure rates of only 4.2% at 72 hours. 4

Dosing Recommendations

Standard adult dosing is 500 mg orally every 6 hours (four times daily) for 5-7 days. 5, 6

• A 5-day course is as effective as 10 days if clinical improvement is observed by day 5. 5
• Twice-daily dosing at 1 g may be considered for convenience, though standard four-times-daily dosing remains preferred. 6
• Dose reduction is required when creatinine clearance falls below 30 mL/min. 7

Critical Limitations and When NOT to Use Cephalexin

Cephalexin has NO activity against MRSA and should not be used when methicillin-resistant Staphylococcus aureus is suspected or confirmed. 1, 5

For MRSA infections, alternative agents include:

• Oral: trimethoprim-sulfamethoxazole, doxycycline, clindamycin, or linezolid 1
• IV: vancomycin, daptomycin, linezolid, or ceftaroline 1

Cephalexin is contraindicated in neonates (birth to 28 days). 8 For neonatal skin infections, use nafcillin or oxacillin at 50 mg/kg/dose every 6 hours IV instead. 8 Neonates require immediate medical evaluation and often hospitalization due to high risk of rapid progression to sepsis. 8

Specific Clinical Scenarios

Purulent Infections (Likely Staphylococcus aureus)

• The IDSA recommends cephalexin as an option for purulent infections when MRSA is not suspected. 1
• However, if local MRSA prevalence is high or patient has risk factors (recent hospitalization, IV drug use, prior MRSA), choose anti-MRSA coverage instead. 1

Non-Purulent Cellulitis (Likely Streptococcus)

• Cephalexin is highly effective, with beta-lactam success rates of 96% in cellulitis. 5
• The IDSA lists cephalexin among preferred agents for non-purulent infections. 1

Diabetic Foot Infections (Mild)

• The IDSA recommends cephalexin for mild diabetic wound infections. 1
• Moderate-to-severe diabetic infections require broader coverage and cephalexin is inadequate. 1

Surgical Site Infections

• Cephalexin is appropriate for incisional SSIs after surgery of trunk or extremities (away from axilla/perineum). 1
• Not appropriate for SSIs involving intestinal/genitourinary tract or axilla/perineum, which require anaerobic coverage. 1

Necrotizing Fasciitis

• Cephalexin is NOT appropriate for necrotizing infections, which require combination therapy with clindamycin plus piperacillin-tazobactam or ceftriaxone plus metronidazole. 1

Common Pitfalls to Avoid

• Do not add trimethoprim-sulfamethoxazole to cephalexin for simple cellulitis - combination therapy offers no advantage over cephalexin alone. 5
• Obtain cultures before initiating therapy when possible, particularly for moderate-severe infections, diabetic wounds, or treatment failures. 2
• Do not use cephalexin for animal or human bites - these require amoxicillin-clavulanate for anaerobic coverage. 1
• Recognize that cephalexin does not penetrate into host cells, limiting its utility for intracellular pathogens. 7

Advantages Supporting First-Line Use

• Rapid and complete oral absorption in the upper intestine 7
• Does not disturb lower bowel flora 7
• Very low incidence of allergic reactions due to chemical stability 7
• Minimal drug interactions 6
• Low incidence of gastrointestinal side effects 3, 9
• Achieves urinary concentrations 500-1000 mcg/mL, far exceeding MIC for urinary pathogens 7