Cotrimoxazole Versus Vancomycin for Invasive Methicillin-resistant Staphylococcus Aureus Infections
Condition: Staphylococcal Infections; Meningitis; Sepsis; Pneumonia
MeSH terms: Infections; Communicable Diseases; Pneumonia; Staphylococcal Infections; Meningitis
Study type: Interventional
Phase: Phase 3

Summary: 
      Methicillin-resistant Staphylococcus aureus (SA) is a major pathogen causing mainly
      health-care associated infections and, lately, also community acquired infections. Few
      treatment choices exist to treat these infections. The currently recommended antibiotics for
      these infections are glycopeptides (vancomycin or teicoplanin). Glycopeptide treatment hs
      several disadvantages. It is a last resort antibiotic family that should be reserved for the
      future; Vancomycin is less effective that beta-lactam drugs for SA infections susceptible to
      both agents; treatment can only be given intravenously; and use of vancomycin has led to the
      development of SA strains with partial or complete resistance to vancomycin. Cotrimoxazole is
      an old antibiotic active against most strains of MRSA, depending on local epidemiology.

      Study hypothesis: The purpose of this study is to show that cotrimoxazole is as effective as
      treatment with vancomycin for invasive MRSA infections.

      We plan a randomized controlled trial comparing treatment with cotrimoxazole vs. vancomycin
      for invasive MRSA infections. The primary efficacy outcome we will assess will be Improvement
      or cure with or without antibiotic modifications, defined as: survival at 7 days post
      randomization with resolution of fever (<38 for two consecutive days) and resolution of
      hypotension (>90 systolic without need for vasopressor support); and physician's assessment
      that the primary infection was improved or cured. The primary safety outcome will be
      all-cause 30-day survival.
    

Detailed description: 
      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.
    

Intervention name(s): Cotrimoxazole; Vancomycin
Intervention type(s): Drug; Drug
Intervention description(s): Cotrimoxazole arm: intravenous cotrimoxazole 4 amp (320 mg trimethoprim/ 1600 mg sulfamethoxazole) diluted in 500 ml D5W or N.S. Q 12 hours. Patients intolerant of volume overload will be given the same dose in 250ml D5W (as in the current recommendations used in the hospital). The dose was selected basing on the existing randomized controlled trial and a pharmacokinetic study . 21 For patients with GFR< 30 the dosage interval will be increased to 4 amp (320 mg trimethoprim/ 1600 mg sulfamethoxazole) diluted in 500 ml D5W or N.S. Q 24 hours. 22 Patients on peritoneal dialysis will be given 2 amp (160 mg trimethoprim/ 800 mg sulfamethoxazole) Q 48 hours. Patients with acute renal failure treated with hemodialysis will be given the 2 amp (160 mg trimethoprim/ 800 mg sulfamethoxazole) after dialysis. Patients on continuous hemofiltration for acute renal failure will be administered the dose for GFR<30.; intravenous vancomycin 1gr Q 12 hours. Adjustment to creatinine clearance: GFR 10-50 1 gr Q 24-96 hours, GFR <10 1gr Q 4-7 days.
Intervention MeSH terms: Vancomycin; Trimethoprim, Sulfamethoxazole Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: vancomycin; cotrimoxazole; trimethoprim/ sulfamethoxazole; methicillin-resistant Staphylococcus aureus; Health care association infections; MRSA bacteremia or other microbiologically documented MRSA infections (defined clinically by CDC criteria); Suspected neurosurgical meningitis; Sepsis during hemodialysis, catheter-associated and catheter-related infections; Ventilator-associated pneumonia; Surgical site infection in the presence of a foreign body