Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia (EVOS)

July 2, 2024 updated by: Steven Lim Chee Loon, Clinical Research Centre, Malaysia

Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia: The EVOS Randomized Controlled Trial

The Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus aureus Bacteraemia (EVOS) study is a multicentre, randomized, open-label, parallel group, phase 3, non-inferiority trial of early intravenous to oral antibiotic switch in comparison with standard intravenous antibiotic regime among patients with uncomplicated Staphylococcus aureus bacteraemia (SAB). The study is based on the hypothesis that an early switch from IV to oral antimicrobial therapy is non-inferior and safe compared to conventional minimum 14-day course of IV therapy in patients with low-risk uncomplicated SAB.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The study is conducted at 12 government tertiary hospitals with infectious diseases physicians in Malaysia. The study population comprises of 290 patients with uncomplicated SAB who have received 3 to 7 days of definitive IV antimicrobial therapy. Eligible participants are randomized 1:1 into 2 groups, early oral antibiotic switch versus standard IV antibiotic therapy, following the inclusion and exclusion criteria.

The study consists of 3 stages for each patient with a duration of approximately 12 weeks: screening and enrolment, open-label treatment with 7 to 11 days of study antibiotics, and follow-up until day 90 post-randomization. Phone call or inpatient follow up will be conducted at Day 7-11, Day 30, and Day 90 post- randomization to review patient's condition.

Study Type

Interventional

Enrollment (Estimated)

290

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Malaysia
      • Melaka, Malaysia, 75400
    • Johor
      • Johor Bahru, Johor, Malaysia, 80100
    • Kedah
      • Alor Setar, Kedah, Malaysia, 05460
      • Sungai Petani, Kedah, Malaysia, 08000
    • Negeri Sembilan
      • Seremban, Negeri Sembilan, Malaysia, 70300
    • Penang
      • George Town, Penang, Malaysia, 10450
      • Seberang Jaya, Penang, Malaysia, 13700
    • Perak
      • Ipoh, Perak, Malaysia, 30450
    • Selangor
      • Ampang, Selangor, Malaysia, 68000
      • Kajang, Selangor, Malaysia, 43000
        • Recruiting
        • Hospital Sultan Idris Shah Serdang
        • Contact:
      • Klang, Selangor, Malaysia, 41200
        • Recruiting
        • Hospital Tengku Ampuan Rahimah
        • Contact:
      • Selayang Baru Utara, Selangor, Malaysia, 68100

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Blood culture positive for Staphylococcus aureus (S. aureus).

  2. Received 3 to 7 days of definitive IV antimicrobial therapy, defined as:

    • Cloxacillin or cefazolin for methicillin-sensitive staphylococcus aureus (MSSA); Vancomycin or ceftaroline for methicillin-resistant staphylococcus aureus (MRSA).
    • Proven in-vitro susceptibility and adequate dosing given (as determined by the principal investigator).
  3. Achieved clearance of bacteraemia, defined as at least one documented latest negative follow-up blood culture obtained within 72 hours after the initiation of definitive IV antimicrobial therapy.
  4. Achieved defervescence, defined as sustained body temperature ≤37.5°C within 48 hours before randomization.
  5. Able to provide written informed consent to participate trial.

Exclusion Criteria:

  1. Evidence of metastatic infection of S. aureus: for example, infective endocarditis, intraabdominal abscess, lung empyema, and osteomyelitis. Radiological investigations such as chest X-ray, ultrasound, echocardiogram, and CT scan are not mandatory prior to enrolment, but should be done at the discretion of the treating physician if clinically indicated.
  2. Septic shock, defined as hypotension requiring vasopressors to maintain MAP ≥65 mmHg despite adequate volume resuscitation.
  3. Received more than 5 days of non-study antibiotics as empirical therapy prior to enrolment.
  4. Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained prior to randomization. Common skin contaminants such as coagulase-negative staphylococci, Bacillus spp., and diphtheroid will not be considered to represent polymicrobial infection.
  5. Known history of S. aureus infection within the past 3 months.
  6. Inability to tolerate oral therapy or poor absorption of oral medications, or not suitable for ongoing IV therapy (for example, difficult intravenous access)

  7. No options of oral antibiotic available for patient due to:

    • In vitro resistance of S. aureus to all oral study drugs.
    • Known contraindications to receive the active oral study drugs. For example, hypersensitivity reaction to trimethoprim-sulfamethoxazole, thrombocytopenia secondary to linezolid etc.
    • Non-availability of oral study drugs at the study sites.
  8. Patient is concomitantly receiving oral antibiotics which are active against S. aureus. For example, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis.
  9. Presence of a non-removable foreign body such as prosthetic heart valve, vascular graft, pacemaker, automated implantable cardioverter-defibrillator, ventriculoperitoneal shunt, prosthetic joint, and fracture fixation implant
  10. Failure or inability to remove intravascular catheter that is present when first positive blood culture was drawn.

  11. Known comorbidity that increased the risk of complicated infections:

    • End-stage renal disease
    • Severe liver disease (Child-Pugh class C)

    • Severe immunodeficiency:

      • HIV-positive patients with CD4<200 cells/uL or AIDS
      • primary immunodeficiency disorders
      • high-dose steroid therapy (>1 mg/kg prednisone or equivalent doses given for > 4 weeks or planned during intervention)
      • immunosuppressive therapy
      • neutropenia (<500 neutrophils/μl) at randomization or neutropenia expected during intervention phase due to immunosuppressive treatment
      • solid organ or hematopoietic stem cell transplantation within the past 6 months or planned during treatment period

13.Short life expectancy < 3 months

14.Pregnancy (for women of childbearing potential)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Early Oral Switch Therapy (EOS)

Patients will switch from IV therapy to oral antibiotics for 7 to 11 days to achieve a total 14 days of definitive antimicrobial therapy for SAB.

First choice oral antibiotics for MSSA and MRSA: Tab. Trimethoprim-sulfamethoxazole (TMP 10mg/kg/day)

Alternative oral antibiotics for MSSA: Tab. Clindamycin 600mg TDS, Tab. Cephalexin 1gm QID, Tab Linezolid 600mg BD

Alternative oral antibiotics for MRSA: Tab. Linezolid 600mg BD
Drug: Tab. Trimethoprim-sulfamethoxazole, Tab. Clindamycin, Tab. Cephalexin, or Tab. Linezolid

The choice of study drug will depend on the susceptibility of the respective isolate, expected drug interactions, contraindications, and expected side effects.

Investigators will assess whether the "first-choice" regimen can be given and then consider the alternative regimen. The antibiotics can be switched from first choice to the respective alternative medications during the intervention period if clinically necessary. The route of administration must be maintained according to the randomized group.

Other Names:
  • Zyvox
  • Dalacin
  • Bactrim
  • Ospexin
Active Comparator: Standard IV therapy (SIV)

Patients will continue with IV therapy for 7 to 11 days to achieve a total 14 days of definitive antimicrobial therapy for SAB.

First choice IV antibiotics for MSSA: IV Cloxacillin 2g every 4 or 6 hours

Alternative IV antibiotics for MSSA: IV Cefazolin 2g TDS

First choice IV antibiotics for MRSA: IV Vancomycin 15-20mg/kg BD

Alternative IV antibiotics for MRSA: IV Ceftaroline 600mg TDS
Drug: IV Cloxacillin, IV Cefazolin, IV Vancomycin, or IV Ceftaroline

The choice of study drug will depend on the susceptibility of the respective isolate, expected drug interactions, contraindications, and expected side effects.

Investigators will assess whether the "first-choice" regimen can be given and then consider the alternative regimen. The antibiotics can be switched from first choice to the respective alternative medications during the intervention period if clinically necessary. The route of administration must be maintained according to the randomized group.

Other Names:
  • Zinforo
  • Cloxacillin Sodium
  • Cefazolin Sandoz
  • Vancotex

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of SAB-relapse
Time Frame: 90 days
defined as any new positive blood culture with S. aureus, and/or newly diagnosed metastatic S. aureus infection resulting from hematogenous dissemination
90 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of days of hospitalization
Time Frame: 90 days
Number of calendar days of hospitalisation after the first positive blood culture for S. aureus.
90 days
Rate of all-cause mortality
Time Frame: 90 days
Any death occurred within 90 days of randomization.
90 days
Rate of complications related to IV therapy
Time Frame: 90 days
Any complications related to insertion or usage of peripheral branula or central catheter, and administration of IV drugs
90 days
Rate of Clostridium difficile diarrhoea
Time Frame: 90 days
A diagnosis of diarrhoea with ≥1 stool sample tested positive for C. difficile toxin or toxin gene.
90 days
Rate of adverse events
Time Frame: 30 days
Any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have a causal relationship with treatment.
30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Clinical Research Centre, Malaysia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 28, 2024

Primary Completion (Estimated)

May 1, 2025

Study Completion (Estimated)

June 1, 2025

Study Registration Dates

First Submitted

March 22, 2024

First Submitted That Met QC Criteria

March 22, 2024

First Posted (Actual)

March 29, 2024

Study Record Updates

Last Update Posted (Actual)

July 5, 2024

Last Update Submitted That Met QC Criteria

July 2, 2024

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EVOS 1.3 dated 12 March 2024

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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