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Cotrimoxazole Versus Vancomycin for Invasive Methicillin-resistant Staphylococcus Aureus Infections

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Mical Paul, Rabin Medical Center
ClinicalTrials.gov Identifier:
NCT00427076
First received: January 24, 2007
Last updated: July 13, 2014
Last verified: July 2014
  Purpose

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
Staphylococcal Infections
Meningitis
Sepsis
Pneumonia
Drug: Cotrimoxazole
Drug: Vancomycin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment With Cotrimoxazole vs. Vancomycin for Infections Caused by Methicillin-resistant Staphylococcus Aureus: Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Rabin Medical Center:

Primary Outcome 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 ] [ Designated as safety issue: Yes ]
  • Primary safety: 30-day all cause mortality [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Improved or cure without antibiotic modifications [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Modification of the anti-staphylococcal treatment within 1 week of treatment onset for perceived failure of therapy [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Survival at 7 days post randomization without the need for modification of the anti-staphylococcal antibiotic [ Time Frame: 7 days ] [ Designated as 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 ] [ Designated as safety issue: No ]
  • Need for surgical intervention or other invasive procedures [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • Need for central catheter removal [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • Persistent bacteremia [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • All-cause mortality in ICU and in-hospital [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • Adverse events [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • Durations of fever, assigned antibiotic treatment, mechanical ventilation, ICU and hospital stay [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • Resistance development [ Time Frame: 30 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 250
Study Start Date: June 2007
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Cotrimoxazole
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.
Active Comparator: B
Vancomycin
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00427076

Locations
Israel
Rambam Health Care Campus
Haifa, Israel
Rabin Medical Center; Beilinson Hospital and Davidoff Cancer Center
Petah Tikva, Israel, 49100
Sponsors and Collaborators
Rabin Medical Center
Investigators
Principal Investigator: Mical Paul, MD Rabin Medical Center
Principal Investigator: Jihad Bishara, MD Rabin Medical Center
  More Information

No publications provided

Responsible Party: Mical Paul, Dr., Rabin Medical Center
ClinicalTrials.gov Identifier: NCT00427076     History of Changes
Other Study ID Numbers: Protocol V.3, dated 01.06.09
Study First Received: January 24, 2007
Last Updated: July 13, 2014
Health Authority: Israel: Ethics Commission

Keywords provided by Rabin Medical Center:
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

Additional relevant MeSH terms:
Communicable Diseases
Infection
Meningitis
Pneumonia
Staphylococcal Infections
Bacterial Infections
Central Nervous System Diseases
Central Nervous System Infections
Gram-Positive Bacterial Infections
Lung Diseases
Nervous System Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Methicillin
Sulfamethoxazole
Trimethoprim-Sulfamethoxazole Combination
Vancomycin
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Infective Agents, Urinary
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Pharmacologic Actions
Renal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014