Clinical trial NCT06336824: Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia
Official title: Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia: The EVOS Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Staphylococcus Aureus Bacteremia
Keywords: bacteremia
oral antibiotics
Staphylococcus aureus
Lead sponsor: Clinical Research Centre, Malaysia
Sponsor class: OTHER
First posted: 2024-03-29
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Rate of SAB-relapse
timeFrame: 90 days
Secondary outcomes:
measure: Number of days of hospitalization
timeFrame: 90 days
measure: Rate of all-cause mortality
timeFrame: 90 days
measure: Rate of complications related to IV therapy
timeFrame: 90 days
measure: Rate of Clostridium difficile diarrhoea
timeFrame: 90 days
measure: Rate of adverse events
timeFrame: 30 days
Other outcomes:
Locations:
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah
state: Johor
city: Alor Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
state: Kedah
city: Sungai Petani
country: Malaysia
facility: Hospital Sultan Abdul Halim
state: Kedah
city: Seremban
country: Malaysia
facility: Hospital Tuanku Ja'afar
state: Negeri Sembilan
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
state: Penang
city: Seberang Jaya
country: Malaysia
facility: Hospital Seberang Jaya
state: Penang
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun
state: Perak
city: Ampang
country: Malaysia
facility: Hospital Ampang
state: Selangor
city: Kajang
country: Malaysia
facility: Hospital Sultan Idris Shah Serdang
state: Selangor
city: Klang
country: Malaysia
facility: Hospital Tengku Ampuan Rahimah
state: Selangor
city: Selayang Baru Utara
country: Malaysia
facility: Hospital Selayang
state: Selangor
city: Melaka
country: Malaysia
facility: Hospital Melaka
Study officials:
References: