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

Phase 3
18 Years
Open (Enrolling)
Staphylococcal Infections, Meningitis, Sepsis, Pneumonia

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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

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

Inclusion Criteria:

- Adults >18 years

- providing signed informed consent or, if unable, having a legal guardian or a
caretaker that will sign informed consent

- Patients with documented MRSA infections:

- MRSA bacteremia

- Other microbiologically documented MRSA infections defined as a clinical source of
infection (CDC criteria) plus microbiological documentation of MRSA from the source
of infection

- Patients with highly probable MRSA infections, prior to microbiological documentation
of the pathogen:

- Suspected neurosurgical meningitis (including VP-shunt meningitis)

- Sepsis during hemodialysis

- Ventilator-associated pneumonia with prior antibiotic treatment within 48 hours

- Catheter-related or suspected catheter-related infections

- Surgical site infection in the presence of a foreign body

Exclusion Criteria:

Exclusion before randomization:

- Previous antibiotic treatment directed against MRSA >48 hours (including vancomycin,
fucidic acid, rifampicin or cotrimoxazole)

- Known allergy to either study drug

- Acute leukemia and/ or BMT with neutropenia <500/mm3 or <1000/mm3 and expected to
decrease below 500/mm3

- Pregnancy, lactation

- Previous enrollment in this study

- Concurrent participation in another trial

Exclusions after randomization:

- Documented Staphylococcal infection resistant to cotrimoxazole or VISA or VRSA

- Documented MSSA

- Documented left-sided endocarditis

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Primary efficacy: Improved or cure with or without antibiotic modifications, defined as: survival at 7 days post randomization with resolution of fever and resolution of hypotension

Outcome Time Frame:

7 days

Safety Issue:


Principal Investigator

Mical Paul, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Rabin Medical Center


Israel: Ethics Commission

Study ID:

Protocol V.3, dated 01.06.09



Start Date:

June 2007

Completion Date:

January 2015

Related Keywords:

  • Staphylococcal Infections
  • Meningitis
  • Sepsis
  • Pneumonia
  • 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
  • Meningitis
  • Pneumonia
  • Sepsis
  • Staphylococcal Infections