Can Keflex and Sulfa Antibiotics Be Used for MRSA and Streptococcus?
No, Keflex (cephalexin) alone cannot treat MRSA, but trimethoprim-sulfamethoxazole (sulfa) can cover MRSA—however, sulfa alone cannot reliably treat Streptococcus and must be combined with a beta-lactam like Keflex when streptococcal coverage is needed. 1, 2, 3
Understanding the Coverage Gap
Keflex (Cephalexin) Coverage
- Cephalexin provides excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA), but has zero activity against MRSA 1, 4
- Cephalexin is the preferred oral beta-lactam for typical nonpurulent cellulitis where MRSA is not suspected, dosed at 500 mg orally every 6 hours for 5 days 1
Trimethoprim-Sulfamethoxazole (TMP-SMX/Bactrim/Septra) Coverage
- TMP-SMX provides reliable coverage against most community-acquired MRSA strains and is recommended as a first-line oral option by the Infectious Diseases Society of America (A-II evidence) 3, 5
- Critical limitation: TMP-SMX does not reliably cover beta-hemolytic streptococci, which commonly cause skin infections 6, 2, 3
- The American Academy of Pediatrics explicitly states that trimethoprim-sulfamethoxazole should not be used as a single agent in the initial treatment of cellulitis because of the possibility it is caused by group A Streptococcus and the possibility of intrinsic resistance 6
When to Use Combination Therapy (Keflex PLUS Sulfa)
Combination therapy with TMP-SMX plus cephalexin is appropriate when both streptococcal and MRSA coverage are needed, specifically in these situations 1:
- Cellulitis associated with penetrating trauma 1
- Presence of purulent drainage or exudate 1, 3
- Injection drug use 1
- Evidence of MRSA infection elsewhere or nasal MRSA colonization 1
- Cellulitis with systemic inflammatory response syndrome (SIRS) 1
Dosing for Combination Therapy
- TMP-SMX: 1-2 double-strength tablets (160/800 mg) orally twice daily 1
- PLUS Cephalexin: 500 mg orally every 6 hours 1
- Duration: 5 days if clinical improvement occurs, extending only if symptoms have not improved 1
Alternative Single-Agent Option
Clindamycin monotherapy (300-450 mg orally every 6 hours) provides coverage for both streptococci and MRSA, avoiding the need for combination therapy—but only if local MRSA clindamycin resistance rates are less than 10% 1, 3, 4
Critical Evidence Against Unnecessary Combination
A landmark randomized controlled trial demonstrated that combination therapy with TMP-SMX plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage 1, 7. Among 146 patients with nonpurulent cellulitis, 85% were cured with combination therapy versus 82% with cephalexin alone (risk difference 2.7%, P=0.66) 7.
Common Pitfalls to Avoid
- Never use TMP-SMX as monotherapy for typical cellulitis without adding a beta-lactam, as streptococcal coverage will be inadequate 6, 1, 3
- Do not reflexively add MRSA coverage for typical nonpurulent cellulitis—beta-lactam monotherapy is successful in 96% of cases 1
- Assess for specific MRSA risk factors before prescribing combination therapy, as overtreatment increases antibiotic resistance without improving outcomes 1
- In the emergency department setting, surrounding erythema may simply be an extension of the MRSA infection rather than streptococcal cellulitis requiring additional coverage 8
Treatment Algorithm
- Assess for purulent drainage, penetrating trauma, injection drug use, or MRSA colonization 1
- If MRSA risk factors present: Use TMP-SMX PLUS cephalexin, OR clindamycin monotherapy (if local resistance <10%) 1, 3
- If no MRSA risk factors: Use cephalexin alone—do not add TMP-SMX 1, 7
- Treat for 5 days if clinical improvement occurs; extend only if symptoms persist 1
- Reassess within 24-48 hours to verify clinical response 1