Cotrimoxazole Versus Vancomycin for Invasive Methicillin-resistant Staphylococcus Aureus Infections

NCT00427076 | Completed Phase 3 DMC

• 1 other identifier: Protocol V.3, dated 01.06.09
• Study Type: interventional
• Target: 252
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Staphylococcal Infections; Meningitis; Sepsis; Pneumonia

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

Outcome Measures

Primary Outcomes (2)

• 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

  7 days

• Primary safety: 30-day all cause mortality

  30 days

Secondary Outcomes (11)

• Improved or cure without antibiotic modifications

  7 days

• Modification of the anti-staphylococcal treatment within 1 week of treatment onset for perceived failure of therapy

  7 days

• Survival at 7 days post randomization without the need for modification of the anti-staphylococcal antibiotic

  7 days

• Bacteriological failure, defined as persistent isolation of Staphylococcus aureus with the same phenotype 7 days after or more after treatment onset

  7 days

• Need for surgical intervention or other invasive procedures

  30 days

Study Arms (2)

A

EXPERIMENTAL

Cotrimoxazole

Drug: Cotrimoxazole

B

ACTIVE COMPARATOR

Vancomycin

Drug: Vancomycin

Interventions

Cotrimoxazole DRUG

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.

A

Vancomycin DRUG

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.

B

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Documented Staphylococcal infection resistant to cotrimoxazole or VISA or VRSA
• Documented MSSA
• Documented left-sided endocarditis

Sponsors & Collaborators

• Rabin Medical Center: lead

Study Sites (2)

Rambam Health Care Campus

Haifa, Israel

Location

Rabin Medical Center; Beilinson Hospital and Davidoff Cancer Center

Petah Tikva, 49100, Israel

Location

Related Publications (1)

• Paul M, Bishara J, Yahav D, Goldberg E, Neuberger A, Ghanem-Zoubi N, Dickstein Y, Nseir W, Dan M, Leibovici L. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ. 2015 May 14;350:h2219. doi: 10.1136/bmj.h2219.

  PMID: 25977146 DERIVED

MeSH Terms

Conditions

Staphylococcal Infections; Meningitis; Sepsis; Pneumonia; Catheter-Related Infections; Pneumonia, Ventilator-Associated

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Neuroinflammatory Diseases; Nervous System Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Healthcare-Associated Pneumonia; Cross Infection; Iatrogenic Disease; Disease Attributes

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Mical Paul, MD

  Rabin Medical Center

  PRINCIPAL INVESTIGATOR

• Jihad Bishara, MD

  Rabin Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: January 24, 2007
• First Posted: January 26, 2007
• Study Start: June 1, 2007
• Primary Completion: May 1, 2014
• Study Completion: June 1, 2014
• Last Updated: September 25, 2015

Record last verified: 2015-09

Locations

IL (2)