Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia

Staphylococcus Aureus Bacteremia Clinical Trial

— EVOS  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06336824
• Other study ID #: EVOS 1.2 dated 25/10/2023
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: May 2024
• Est. completion date: June 2025

Study information

• Verified date: April 2024
• Source: Clinical Research Centre, Malaysia
• Contact: Steven Lim, MBBS, MRCP
• Phone: +60133620081
• Email: stevenlimcl[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 290
• Est. completion date: June 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Bacteremia
• Staphylococcal Infections
• Staphylococcus Aureus Bacteremia

Intervention

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.
• 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.

Locations

Country	Name	City	State
Malaysia	Hospital Sultanah Bahiyah	Alor Setar	Kedah
Malaysia	Hospital Ampang	Ampang	Selangor
Malaysia	Hospital Pulau Pinang	George Town	Penang
Malaysia	Hospital Raja Permaisuri Bainun	Ipoh	Perak
Malaysia	Hospital Sultanah Aminah	Johor Bahru	Johor
Malaysia	Hospital Sultan Idris Shah Serdang	Kajang	Selangor
Malaysia	Hospital Tengku Ampuan Rahimah	Klang	Selangor
Malaysia	Hospital Melaka	Melaka
Malaysia	Hospital Seberang Jaya	Seberang Jaya	Penang
Malaysia	Hospital Selayang	Selayang Baru Utara	Selangor
Malaysia	Hospital Tuanku Ja'afar	Seremban	Negeri Sembilan
Malaysia	Hospital Sultan Abdul Halim	Sungai Petani	Kedah

Sponsors (1)

Lead Sponsor	Collaborator
Clinical Research Centre, Malaysia

Country where clinical trial is conducted

Malaysia, 

Outcome

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