Can I use Keflex (cephalexin) to treat an uncomplicated soft‑tissue infection in an adult with normal renal function, and what dosing regimen and duration are recommended, including considerations for penicillin allergy, MRSA risk, and renal impairment?

Cephalexin (Keflex) for Soft Tissue Infections

First-Line Recommendation

Cephalexin 500 mg orally every 6 hours for 5 days is the preferred first-line treatment for uncomplicated soft tissue infections in adults with normal renal function, achieving approximately 96% clinical success when the infection is non-purulent and lacks MRSA risk factors. 1, 2

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Standard Dosing Regimens

Adults with Normal Renal Function

• Cephalexin 500 mg orally every 6 hours (four times daily) for 5 days is the standard regimen for typical non-purulent cellulitis 3, 2, 4
• The FDA-approved adult dosage range is 1–4 grams daily in divided doses, with 250 mg every 6 hours as the usual dose and 500 mg every 12 hours as an alternative for uncomplicated skin infections 4
• Treatment duration should be exactly 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, absence of fever); extend only if symptoms persist 1, 2
• High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 2

Pediatric Dosing

• 25–50 mg/kg/day divided into 3–4 doses is the standard pediatric regimen 1, 4
• For streptococcal pharyngitis and skin infections in children over 1 year, the total daily dose may be divided and given every 12 hours 4
• In severe infections, the pediatric dosage may be doubled 4

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When Cephalexin Is Appropriate

Ideal Clinical Scenarios

• Non-purulent cellulitis without drainage, exudate, or abscess formation 2
• Absence of MRSA risk factors including penetrating trauma, injection drug use, purulent drainage, known MRSA colonization, or systemic inflammatory response syndrome 1, 2
• Uncomplicated skin and soft tissue infections in otherwise healthy adults 5, 6

Microbiological Coverage

• Cephalexin provides excellent activity against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-susceptible Staphylococcus aureus 3, 2
• Beta-lactam monotherapy achieves 96% clinical success in typical non-purulent cellulitis because these are the predominant pathogens 1, 2

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Critical Situations Where Cephalexin Is INADEQUATE

MRSA Risk Factors Requiring Alternative Therapy

Do NOT use cephalexin alone when any of the following are present:

• Purulent drainage or exudate at the infection site 1, 2
• Penetrating trauma or injection drug use 1, 2
• Known MRSA colonization or prior MRSA infection 1, 2
• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 breaths/min) 1, 2
• Failure to respond to beta-lactam therapy after 48–72 hours 1, 2

Organisms NOT Covered by Cephalexin

• MRSA – cephalexin has no activity against methicillin-resistant strains 3
• Anaerobes – inadequate coverage for polymicrobial infections 3
• Gram-negative rods – limited activity against most species 3
• Pasteurella multocida – important in animal bite wounds 3

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Alternative Regimens When MRSA Coverage Is Needed

Oral Options for Purulent Cellulitis

• Clindamycin 300–450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, but use only if local MRSA clindamycin resistance is <10% 1, 2
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) ensures dual coverage 1, 2
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam is appropriate for patients ≥8 years old 1, 2

Intravenous Options for Hospitalized Patients

• Vancomycin 15–20 mg/kg IV every 8–12 hours is first-line for complicated cellulitis requiring hospitalization (A-I evidence) 1, 2
• Linezolid 600 mg IV twice daily or daptomycin 4 mg/kg IV once daily are equally effective alternatives (A-I evidence) 1, 2

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Penicillin Allergy Considerations

Cross-Reactivity Risk

• Cross-reactivity between penicillins and cephalosporins is only 2–4%, primarily based on R1 side chain similarity rather than the beta-lactam ring 2
• Cephalexin shares identical R1 side chains with amoxicillin, so avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy 2

Safe Use in Non-Immediate Reactions

• For patients with non-immediate penicillin allergy (e.g., maculopapular rash, drug-induced fever), cephalexin remains an appropriate option 2
• Avoid all cephalosporins in patients with anaphylaxis, angioedema, or urticaria to penicillins due to potential severe cross-reactivity 2

Alternative for True Penicillin Allergy

• Clindamycin 300–450 mg orally every 6 hours is the preferred alternative for penicillin-allergic patients, providing coverage for both streptococci and MRSA if local resistance is <10% 2

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Renal Impairment Dosing

Dose Adjustment Required

• Cephalexin should be administered with caution in markedly impaired renal function, with careful clinical observation and laboratory monitoring 4
• For patients with CrCl 30–70 mL/min, standard dosing may be appropriate but therapeutic drug monitoring is recommended 2
• In end-stage renal disease on hemodialysis, serum cephalexin concentrations should be monitored approximately 2 hours and 6 hours after a timed dose to guide adjustments 2

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Special Clinical Scenarios

Diabetic Foot Infections

• Diabetic foot infections are typically polymicrobial and require broader coverage than simple cellulitis 2
• For mild diabetic foot infections, amoxicillin-clavulanate, levofloxacin, or combination therapy is preferred over cephalexin alone 1, 2
• For moderate-to-severe diabetic foot infections, use ceftriaxone, ampicillin-sulbactam, ertapenem, or broader-spectrum agents 1, 2

Bite-Related Cellulitis

• Cephalexin is inadequate for animal or human bite wounds due to lack of anaerobic and Pasteurella coverage 1, 3
• Amoxicillin-clavulanate 875/125 mg twice daily is the preferred oral agent for bite-associated cellulitis 1, 2

Severe Cellulitis with Systemic Toxicity

• Vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours is mandatory for severe cellulitis with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis 1, 2

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Common Pitfalls to Avoid

Overtreatment Errors

• Do NOT routinely add MRSA coverage for typical non-purulent cellulitis without specific risk factors—this overtreats ~96% of cases and drives resistance 1, 2
• Do NOT automatically extend therapy to 7–10 days based on tradition; extend only if warmth, tenderness, or erythema persist after 5 days 1, 2
• Do NOT use combination therapy (e.g., cephalexin plus TMP-SMX) when monotherapy is appropriate—this increases adverse effects without improving outcomes 2

Undertreatment Errors

• Do NOT use cephalexin alone for purulent cellulitis with visible drainage—MRSA coverage is required 1, 2
• Do NOT delay surgical consultation when signs of necrotizing infection are present (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue, gas or bullae) 1, 2
• Do NOT treat simple abscesses with antibiotics alone—incision and drainage is the primary treatment 2

Monitoring Failures

• Reassess patients within 24–48 hours to verify clinical response; treatment failure rates of ~21% have been reported with some oral regimens 2
• If no improvement after 48–72 hours, consider resistant organisms (MRSA), undrained abscess, deeper infection, or alternative diagnoses 2

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Adjunctive Measures to Accelerate Recovery

Physical Management

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and inflammatory substances 1, 2

Predisposing Condition Management

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration and treat if present to eradicate colonization and reduce recurrence 1, 2
• Address underlying venous insufficiency, lymphedema, and chronic edema as these increase recurrence risk 1, 2

Prevention of Recurrent Cellulitis

• For patients with 3–4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics such as penicillin V 250 mg orally twice daily or erythromycin 250 mg twice daily 2

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Evidence Quality Summary

• The 2014 IDSA guidelines provide A-I level evidence (strong recommendation, high-quality evidence) supporting beta-lactam monotherapy for uncomplicated cellulitis 1
• Randomized controlled trials demonstrate that cephalexin achieves >95% clinical cure rates in appropriately selected patients 5, 7, 8, 6, 9
• Pediatric studies show no significant difference between cephalexin and clindamycin for uncomplicated SSTIs caused predominantly by CA-MRSA when appropriate drainage is performed 8