Staphylococcal InfectionsPhase 3NCT00427076
Cotrimoxazole Versus Vancomycin for Invasive Methicillin-resistant Staphylococcus Aureus Infections
A Phase 3 study testing Cotrimoxazole and Vancomycin in people with Staphylococcal Infections and Meningitis, run by Rabin Medical Center at 2 sites in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Staphylococcal Infections, Meningitis, Sepsis
- What is being tested?
- Cotrimoxazole and Vancomycin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 252 participants
- Where
- 2 sitesIsrael
- Study dates
- Jun 2007to Jun 2014
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
Show all 11Show fewer
- 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
Who cannot join
- 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
Show all 10Show fewer
- Exclusions after randomization:
- Documented Staphylococcal infection resistant to cotrimoxazole or VISA or VRSA
- Documented MSSA
- Documented left-sided endocarditis
Trial locations and contacts
2 sites in 1 country.
Israel2 sites
Rambam Health Care Campus
Haifa
Rabin Medical Center; Beilinson Hospital and Davidoff Cancer Center
Petah Tikva, 49100
About this study
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.
Read the 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.
- Conditions
- Staphylococcal Infections, Meningitis, Sepsis, Pneumonia
- Being tested
- Cotrimoxazole, Vancomycin
- 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
- Medical subject headings
- Staphylococcal Infections, Meningitis, Sepsis, Pneumonia, Catheter-Related Infections, Pneumonia, Ventilator-Associated
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CotrimoxazoleDrug
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.
VancomycinDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | Cotrimoxazole Receives: Drug: Cotrimoxazole |
| B | Active comparator | Vancomycin Receives: Drug: Vancomycin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 7 days
Primary safety: 30-day all cause mortality
Measured: 30 days
Secondary outcomes (11)
Improved or cure without antibiotic modifications
Measured: 7 days
Modification of the anti-staphylococcal treatment within 1 week of treatment onset for perceived failure of therapy
Measured: 7 days
Survival at 7 days post randomization without the need for modification of the anti-staphylococcal antibiotic
Measured: 7 days
Bacteriological failure, defined as persistent isolation of Staphylococcus aureus with the same phenotype 7 days after or more after treatment onset
Measured: 7 days
Need for surgical intervention or other invasive procedures
Measured: 30 days
Need for central catheter removal
Measured: 30 days
Persistent bacteremia
Measured: 30 days
All-cause mortality in ICU and in-hospital
Measured: 30 days
Adverse events
Measured: 30 days
Durations of fever, assigned antibiotic treatment, mechanical ventilation, ICU and hospital stay
Measured: 30 days
Resistance development
Measured: 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2007 (estimated)
- Study startJun 2007
- Primary completionMay 2014
- Study completionJun 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Staphylococcal InfectionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 252 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rabin Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mical Paul, Rabin Medical Center
- Investigators
- Mical Paul, MD, Principal investigator, Rabin Medical CenterJihad Bishara, MD, Principal investigator, Rabin Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00427076
- Sponsor's protocol ID
- Protocol V.3, dated 01.06.09
- Status last verified
- Sep 2015
- First submitted
- 24 Jan 2007
- Last updated
- 25 Sep 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 25977146
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment With Cotrimoxazole vs. Vancomycin for Infections Caused by Methicillin-resistant Staphylococcus Aureus: Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT00427076
- Acronym / sponsor ID
- Protocol V.3, dated 01.06.09
- 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
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 252 participants (actual)
- Lead sponsor
- Rabin Medical CenterUniversity, hospital or other
- Study start
- Jun 2007
- Primary completion
- May 2014 (actual)
- Study completion
- Jun 2014 (actual)
- First posted
- 26 Jan 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: CotrimoxazoleCotrimoxazole |
| B | Active comparator | Drug: VancomycinVancomycin |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CotrimoxazoleCotrimoxazole 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 | A |
| Vancomycinintravenous 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. | Drug | B |
Primary outcome
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
Primary safety: 30-day all cause mortality
Time frame: 30 days
11 secondary outcomes
Improved or cure without antibiotic modifications
Time frame: 7 days
Modification of the anti-staphylococcal treatment within 1 week of treatment onset for perceived failure of therapy
Time frame: 7 days
Survival at 7 days post randomization without the need for modification of the anti-staphylococcal antibiotic
Time frame: 7 days
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
Need for surgical intervention or other invasive procedures
Time frame: 30 days
Need for central catheter removal
Time frame: 30 days
Persistent bacteremia
Time frame: 30 days
All-cause mortality in ICU and in-hospital
Time frame: 30 days
Adverse events
Time frame: 30 days
Durations of fever, assigned antibiotic treatment, mechanical ventilation, ICU and hospital stay
Time frame: 30 days
Resistance development
Time frame: 30 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2015.
- Derived from this study: PubMed 25977146Paul 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mical Paul, MD principal investigator
Rabin Medical Center
Jihad Bishara, MD principal investigator
Rabin Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Cotrimoxazole and Vancomycin in people with Staphylococcal Infections and Meningitis, run by Rabin Medical Center at 2 sites in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Sep 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary 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 (time frame: 7 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00427076, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2015.