Official Title: “Treatment With Cotrimoxazole vs. Vancomycin for Infections Caused by Methicillin-Resistant Staphylococcus Aureus: Randomized Controlled Trial”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2010

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. In-vitro, it is active against SA, including methicillin-resistance Staphylococcus aureus (MRSA) strains and its activity against SA is bacteridicidal.

Trimethoprim alone is bactericidal against SA, while sulphamethoxazole alone is relatively inactive and their combination is synergistic both in-vitro and in-vivo. 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(s) in this Clinical Trial

• Drug: Cotrimoxazole
  • 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.
• Drug: Vancomycin
  • 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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Cotrimoxazole
• Active Comparator: B
  • Vancomycin

Primary Measures

• 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
  • Time Frame: 7 days
    Safety Issue?: Yes
• Primary safety: 30-day all cause mortality
  • Time Frame: 30 days
    Safety Issue?: Yes

Secondary Measures

• Improved or cure without antibiotic modifications
  • Time Frame: 7 days
    Safety Issue?: No
• Modification of the anti-staphylcoccal treatment within 1 week of treatment onset for perceived failure of therapy
  • Time Frame: 7 days
    Safety Issue?: No
• Survival at 7 days post randomization without the need for modification of the anti-staphylcoccal antibiotic
  • Time Frame: 7 days
    Safety Issue?: Yes
• Bacteriological failure, defined as persistent isolation of Staphylococcus aureus with the same phenotype 7 days after or more after treatment onset
  • Time Frame: 7 days
    Safety Issue?: No
• Need for surgical intervention or other invasive procedures
  • Time Frame: 30 days
    Safety Issue?: No
• Need for central catheter removal
  • Time Frame: 30 days
    Safety Issue?: No
• Persistent bacteremia
  • Time Frame: 30 days
    Safety Issue?: No
• All-cause mortality in ICU and in-hospital
  • Time Frame: 30 days
    Safety Issue?: Yes
• Adverse events
  • Time Frame: 30 days
    Safety Issue?: Yes
• Durations of fever, assigned antibiotic treatment, mechanical ventilation, ICU and hospital stay
  • Time Frame: 30 days
    Safety Issue?: Yes
• Resistance development
  • Time Frame: 30 days
    Safety Issue?: No

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
• 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Rabin Medical Center

Overall Clinical Trial Officials and Contacts

Mical Paul, MD Principal Investigator Rabin Medical Center  

Overall Contact: Mical Paul, MD 972-50-4065575 pil1pel@zahav.net.il

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00427076

Study ID Number: Protocol V.1, dated 22.7.06

ClinicalTrials.gov Identifier: NCT00427076

Health Authority: Israel: Ethics Commission