Trial Information

Treatment With Cotrimoxazole vs. Vancomycin for Infections Caused by Methicillin-resistant Staphylococcus Aureus: Randomized Controlled Trial

Staphylococcus aureus (SA) is a major pathogen causing community-acquired and health-care
associated infections. In hospitals, SA infections are associated with a significant burden;
in-hospital mortality during the last 15 years following SA bacteremia in Beilinson hospital
was 38% and did not decrease in recent years. Resistance to beta-lactams is widely prevalent
in hospitals (57% of all SA isolates causing bacteremia at our center). The drug of choice
currently recommended for these infections is a glycopeptide (vancomycin or teicoplanin).

Cotrimoxazole (trimethoprim-sulfamethoxazole) is a relatively 'old' drug commonly used for
urinary tract infections. Invitro, it is active against SA, including methicillin-resistance
Staphylococcus aureus (MRSA) strains and its activity against SA is bactericidal.
Trimethoprim alone is bactericidal against SA, while sulphamethoxazole alone is relatively
inactive and their combination is synergistic both in-vitro and invivo. The prevalence of
cotrimoxazole-susceptible SA varies locally. At our center, 97% of SA strains causing
bacteremia in 2004 were susceptible to cotrimoxazole. Community-acquired MRSA, prevalent in
the United States as a cause for severe skin and soft tissue infections, has not been
described in Israel.

Several reasons exist to search for antibiotics other than vancomycin for MRSA infections.
Vancomycin is less effective that beta-lactam drugs for SA infections susceptible to both
agents. It is the last resort antibiotic for MRSA infections out of the currently
recommended bactericidal antibiotics for invasive infections. Use of vancomycin has led to
the development of SA strains with partial or complete resistance to vancomycin (VISA and
VRSA, respectively). Vancomycin use is associated with the appearance of
vancomycin-resistant enterococcus (VRE) species. Nosocomial infections with VISA and VRE are
difficult to treat and may spread rapidly in the hospital. 10 Finally, vancomycin cannot be
administered orally.

Limited evidence supports the efficacy of cotrimoxazole for MRSA infections, with paucity of
data for high-burden invasive infections. Cotrimoxazole is probably inferior to vancomycin
for methicillin-susceptible SA. ; thus we may infer indirectly its inferiority to
methicillin and drugs alike for MRSA infections. Cotrimoxazole may be less effective than
glycopeptides and oxacillin for left-sided endocarditis. No evidence exists to support the
use of cotrimoxazole empirically for the treatment of suspected SA infections in the
hospital.

We plan an open label single-center pragmatic randomized controlled trial to compare
cotrimoxazole to vancomycin. We will include patients with documented or highly suspected
MRSA infections, according to pre-defined risk factors. We chose to target this patient
population to assess the efficacy of cotrimoxazole both empirically and for documented
infections.