Sulfamethoxazole-Trimethoprim for Skin and Soft Tissue Infections: 1 or 2 Tablets BID?

The 2014 Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections (SSTI) recommend sulfamethoxazole-trimethoprim (SMX-TMP) for purulent infections where methicillin-resistant S. aureus (MRSA) is a likely pathogen. ¹ But, what dose of SMX-TMP should we be prescribing? Both the SSTI and MRSA guidelines say 1-2 double strength tablets twice a day. ^1,2 So, which is it, 1 tablet or 2?

Brief Pharmacokinetics

Based on the properties of SMX-TMP, why might you want to use a higher dose?

• SMX-TMP works by blocking bacterial folate biosynthesis at two distinct sites which leads to defective biosynthesis of thymidine. Thymidine release from infected and inflamed tissue could lead to clinical failure of SMX-TMP. ³
• The pharmacodynamics of SMX-TMP have not been clearly determined, but in vitro models suggest that SMX-TMP has concentration dependent antibacterial activity against MRSA meaning that higher doses of drug are associated with higher rates of bactericidal activity. ⁴
• However, a study of serum and tissue concentrations of SMX-TMP in patients with mild diabetic foot infections found similar log kill rates against S. aureus with both doses of 1 DS tablet twice daily and 2 DS tablets twice daily. ⁵

Clinical/Real World Studies

1. In a prospective, single center study, investigators evaluated clinical outcomes associated with treatment of positive MRSA SSTIs in 170 patients who received standard-dose SMX-TMP (160 mg/800 mg twice daily) versus 121 patients who received high-dose SMX-TMP (320 mg/1600 mg twice daily) for a period of 7 to 15 days. ⁶
   • Demographics across both treatment groups were relatively similar at baseline with the exception of history of trauma leading to the SSTI; in this subgroup, a greater proportion of patients received high-dose SMX-TMP compared to standard-dose SMX-TMP (7.4% versus 2.4%, p = 0.046).
   • There was no difference in clinical resolution between the standard and high-dose groups: Clinical resolution was achieved in 73% of patients treated with high-dose SMX-TMP versus 75% of patients treated with SMX-TMP (OR, 0.96; 95% CI, 0.76 to 1.2; p =0.79).
   • Although surgical drainage was performed in more patients who received high-dose SMX-TMP compared to standard-dose SMX-TMP (74.5% versus 60.7%), this was not demonstrated to have any effect on resolution of infection.
2. In a retrospective review of 106 hospitalized patients treated for cellulitis with and without abscess, risk factors for clinical outcomes and treatment failures were evaluated. ⁷
   • Although patients included in the analysis had a greater incidence of comorbidities (40.6% of patients evaluated had diabetes mellitus while 13.2% of patients had a history of immunosuppression), it was demonstrated that 15.7% of all isolates were positive for MRSA.
   • The majority of patients (90.5%) received empiric parenteral antimicrobial upon admission, and 20% of all patients were prescribed SMX-TMP upon hospital discharge.
   • A subgroup analysis demonstrated that morbidly obese patients prescribed standard-dose SMX-TMP at discharge (160 mg/800 mg twice daily) experienced clinical failure (p = 0.002). The authors recommended that higher doses of SMX-TMP may be indicated in the treatment of cellulitis and cutaneous abscesses in larger patients.

Final recommendations

• Most patients can probably receive SMX-TMP 1 DS tablet twice a day for MRSA SSTIs.
• Higher dose of SMX-TMP (2 DS tablets BID) may be appropriate in:
  • Larger patients (weight > 100 kg)
  • Trauma-induced SSTI
  • Immunosuppressed
• Higher dose SMX-TMP (4 tablets/day) may be associated with more adverse effects than standard dose SMX-TMP (2 tablets/day), such as hyperkalemia. ⁸

Bonus clinical pearl: Neither SMX-TMP nor doxycycline have great coverage for skin streptococcal species. So, if you’re concerned for staph and strep, consider adding on an additional antimicrobial for strep coverage such as cephalexin.

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