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Sponsored by: |
Rabin Medical Center |
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Information provided by: | Rabin Medical Center |
ClinicalTrials.gov Identifier: | NCT00427076 |
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.
Condition | Intervention | Phase |
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Staphylococcal Infections Meningitis Sepsis Pneumonia |
Drug: Cotrimoxazole Drug: Vancomycin |
Phase III |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study |
Official Title: | Treatment With Cotrimoxazole vs. Vancomycin for Infections Caused by Methicillin-Resistant Staphylococcus Aureus: Randomized Controlled Trial |
Estimated Enrollment: | 250 |
Study Start Date: | June 2007 |
Estimated Study Completion Date: | January 2011 |
Estimated Primary Completion Date: | December 2010 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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A: Experimental
Cotrimoxazole
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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.
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B: Active Comparator
Vancomycin
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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.
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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.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Exclusion before randomization:
Exclusions after randomization:
Contact: Mical Paul, MD | 972-50-4065575 | pil1pel@zahav.net.il |
Contact: Jihad Bishara, MD | 972-3-9377511 | jihadb@clalit.org.il |
Israel | |
Rabin Medical Center; Beilinson Hospital and Davidoff Cancer Center | Recruiting |
Petah Tikva, Israel, 49100 | |
Contact: Leonard Leibovici, MD 972-3-9376501 leibovic@post.tau.ac.il | |
Sub-Investigator: Ynon Lischinsky, MD | |
Sub-Investigator: Moshe Garty, MD | |
Sub-Investigator: Silvio Pitlik, MD | |
Sub-Investigator: Zmira Samra, Prof. | |
Sub-Investigator: Pierre singer, MD | |
Sub-Investigator: Leonard Leibovici, MD |
Principal Investigator: | Mical Paul, MD | Rabin Medical Center |
Principal Investigator: | Jihad Bishara, MD | Rabin Medical Center |
Responsible Party: | Infectious diseases unot, Rabin Medical Center, Beilinson Campus ( Mical Paul ) |
Study ID Numbers: | Protocol V.1, dated 22.7.06 |
Study First Received: | January 24, 2007 |
Last Updated: | May 21, 2008 |
ClinicalTrials.gov Identifier: | NCT00427076 |
Health Authority: | Israel: Ethics Commission |
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 |
Bacterial Infections Systemic Inflammatory Response Syndrome Trimethoprim Sulfamethoxazole Bacteremia Central Nervous System Diseases Trimethoprim-Sulfamethoxazole Combination Foreign Bodies Pneumonia, Ventilator-Associated Inflammation Meningitis |
Staphylococcal Infections Gram-Positive Bacterial Infections Sepsis Methicillin Central Nervous System Infections Respiratory Tract Diseases Respiratory Tract Infections Lung Diseases Vancomycin Pneumonia |
Communicable Diseases Anti-Infective Agents Antiprotozoal Agents Nervous System Diseases Anti-Infective Agents, Urinary Infection Renal Agents |
Pharmacologic Actions Anti-Bacterial Agents Antimalarials Antiparasitic Agents Pathologic Processes Therapeutic Uses |