Can cephalexin (Keflex) be used as an alternative treatment for infections susceptible to cefazolin (Ancef)?

Can Cephalexin Be Used to Treat Cefazolin-Susceptible Infections?

Yes, cephalexin can generally be used as an oral alternative for infections susceptible to cefazolin, particularly for mild-to-moderate skin and soft tissue infections, though the clinical context and infection severity must guide this decision.

Pharmacologic Rationale

Both cefazolin and cephalexin are first-generation cephalosporins with similar antimicrobial spectra, covering methicillin-susceptible Staphylococcus aureus (MSSA) and streptococci 1, 2. However, there are important pharmacokinetic and potency differences:

• Cephalexin demonstrates higher MIC values (MIC50 of 2 μg/mL, MIC90 of 4 μg/mL) compared to cefazolin (MIC50 of 0.5 μg/mL) against MSSA isolates, indicating cefazolin is approximately 4-8 times more potent in vitro 3
• CLSI now recommends cefazolin-cephalexin surrogate testing, which has recategorized many isolates from resistant to susceptible for cephalexin, supporting its broader use 4

Clinical Evidence Supporting Interchangeability

Skin and Soft Tissue Infections

For mild-to-moderate uncomplicated SSTIs, cephalexin is non-inferior to cefazolin:

• A randomized controlled trial comparing cephalexin 500 mg orally four times daily versus cefazolin 2 g IV daily plus probenecid showed equivalent failure rates at 72 hours (4.2% vs 6.1%, risk difference 1.9%, 95% CI -3.7% to 7.6%) and clinical cure at 7 days (100% vs 97.7%) 5
• Multiple studies demonstrate clinical cure rates of 87-89% for cephalexin in mild-to-moderate SSTIs, statistically equivalent to comparators 6, 7
• Notably, cephalexin showed 92% clinical cure rates even for MRSA infections (35/38 patients), though this likely reflects the contribution of incision and drainage rather than antibiotic activity, as cephalosporins lack clinically relevant in vitro activity against MRSA 6

Guideline Support

Major infectious disease guidelines list both agents as acceptable alternatives for similar indications:

• For purulent skin and soft tissue infections (likely S. aureus): both cefazolin and cephalexin are recommended options 8
• For non-purulent cellulitis: cefazolin or cephalexin are listed as alternatives to penicillin 8
• For incisional surgical site infections of trunk/extremities: oxacillin, nafcillin, cefazolin, and cephalexin are all recommended 8
• For diabetic wound infections (mild): cephalexin is specifically listed as an appropriate oral option 8

Pediatric Considerations

In pediatric populations, cephalexin serves as the preferred oral step-down therapy:

• For methicillin-susceptible S. aureus pneumonia: cephalexin 75-100 mg/kg/day in 3-4 divided doses is the preferred oral therapy after parenteral cefazolin 8

Important Caveats and Limitations

When NOT to Substitute Cephalexin for Cefazolin

Do not use cephalexin in the following scenarios:

• Severe or life-threatening infections requiring parenteral therapy (sepsis, endocarditis, severe pneumonia, necrotizing fasciitis) 8, 1
• Infections requiring high tissue penetration where oral bioavailability is insufficient (osteomyelitis, deep abscesses without drainage)
• Confirmed MRSA infections - despite paradoxical clinical responses in some studies, cephalosporins lack reliable anti-MRSA activity and should not be relied upon 6
• Infections with high bacterial burden where the lower potency of cephalexin (4-8x higher MICs) may be clinically significant 3

Dosing Considerations

Cephalexin requires more frequent dosing than cefazolin:

• Standard cephalexin dosing: 500 mg orally four times daily for adults 5, 7
• Alternative dosing: 500 mg twice or three times daily may be acceptable for uncomplicated infections based on PK/PD modeling 4
• Pediatric dosing: 75-100 mg/kg/day divided into 3-4 doses 8

Practical Algorithm for Decision-Making

Use this approach when considering cephalexin as an alternative to cefazolin:

1. Assess infection severity: Mild-to-moderate infections are appropriate for oral therapy; severe infections require IV therapy 5
2. Verify susceptibility: Confirm MSSA (not MRSA) and check cefazolin or cephalexin susceptibility if available 4
3. Consider infection type: SSTIs, uncomplicated UTIs, and step-down therapy for pneumonia are appropriate; endocarditis and osteomyelitis are not 8, 1, 2
4. Ensure adequate source control: For abscesses, incision and drainage must be performed; antibiotics alone are insufficient 6
5. Monitor clinical response: Reassess at 48-72 hours; failure to improve warrants culture-directed therapy or escalation 5

FDA-Approved Indications

Both agents share overlapping FDA-approved indications:

• Cefazolin: respiratory tract infections, UTIs, skin/skin structure infections, bone/joint infections, septicemia, endocarditis 1
• Cephalexin: respiratory tract infections, otitis media, skin/skin structure infections, bone infections, genitourinary infections 2

The key distinction is that cefazolin is approved for parenteral use in severe infections and surgical prophylaxis, while cephalexin is limited to oral treatment of mild-to-moderate infections 1, 2.