Combination Therapy with Keflex and Bactrim
The combination of Keflex (cephalexin) and Bactrim (trimethoprim-sulfamethoxazole) is generally not recommended as routine therapy, as there is limited evidence supporting superior outcomes compared to monotherapy for most common infections. 1
When Combination Therapy May Be Considered
Skin and Soft Tissue Infections with Mixed Pathogens
For cellulitis with concern for both streptococcal and MRSA involvement, combination therapy with a beta-lactam (like cephalexin) plus Bactrim may be warranted. 2
- The American Academy of Pediatrics specifically notes that Bactrim should not be used alone for cellulitis due to poor activity against Group A Streptococcus, which may have intrinsic resistance 2
- When cellulitis is present alongside purulent infection, adding a beta-lactam to Bactrim provides coverage for streptococci 2
- However, a large randomized trial found that cephalexin plus trimethoprim-sulfamethoxazole did not result in statistically significant higher cure rates compared to cephalexin alone for uncomplicated cellulitis (83.5% vs 85.5%, difference -2.0%) 1
Diabetic Foot Infections
For mild diabetic foot infections without complicating features, either cephalexin or trimethoprim-sulfamethoxazole can be used as monotherapy rather than in combination. 3
- The IWGDF/IDSA 2023 guidelines list first-generation cephalosporins (cephalexin) as appropriate for mild infections with gram-positive cocci 3
- Trimethoprim-sulfamethoxazole is listed as an alternative for patients with beta-lactam allergy or when MRSA risk is high 3
- For moderate-to-severe infections, broader spectrum agents are preferred over this combination 3
Evidence Against Routine Combination Use
Urinary Tract Infections
For urinary tract infections, either agent alone is typically sufficient; combination therapy offers no proven advantage. 4, 5
- Historical trials comparing these agents showed similar efficacy when used as monotherapy 4, 5
- A 1972 trial found trimethoprim alone was as effective as other agents including cephalexin for various urinary infections 4
- A 1981 study demonstrated no difference in efficacy between cefaclor (similar to cephalexin) and trimethoprim-sulfamethoxazole for acute lower UTIs 5
Respiratory Infections
For respiratory tract infections, monotherapy with either agent is standard; combination therapy is not supported by evidence. 6
- A comparative study found both agents equally effective when used individually for respiratory infections 6
- Co-trimoxazole was suggested for first-line therapy with cephalexin reserved for non-responders 6
Safety Considerations
Adverse Event Profile
The safety profile of combination therapy has not been well-studied, but individual agent risks should be considered cumulatively. 7
- Trimethoprim-sulfamethoxazole carries risks of serious skin reactions including Stevens-Johnson syndrome (4 of 7 cases in one large study) 7
- The risk of serious liver disease is similar between TMP-SMZ (5.2/100,000) and cephalexin (2.0/100,000) 7
- Blood disorders are rare with both agents 7
- Combination therapy in the cellulitis trial showed no significant difference in adverse events compared to monotherapy 1
Clinical Decision Algorithm
Choose monotherapy based on the most likely pathogen:
- For purulent skin infections (abscesses, furuncles): Use Bactrim alone after drainage 2
- For non-purulent cellulitis: Use cephalexin alone 1
- For mixed infections with both purulent and non-purulent features: Consider adding cephalexin to Bactrim 2
- For urinary tract infections: Use either agent as monotherapy based on local resistance patterns 3, 4
Key Pitfalls to Avoid
- Do not use Bactrim alone for cellulitis without purulent drainage due to inadequate streptococcal coverage 2
- Do not routinely combine these agents expecting superior outcomes, as evidence does not support this practice 1
- Consider local resistance patterns, particularly for trimethoprim-sulfamethoxazole, which has high resistance rates among S. pneumoniae (>40%) and H. influenzae (27%) 3