Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia
- Conditions
- Staphylococcus Aureus Bacteremia
- Interventions
- Drug: IV Cloxacillin, IV Cefazolin, IV Vancomycin, or IV CeftarolineDrug: Tab. Trimethoprim-sulfamethoxazole, Tab. Clindamycin, Tab. Cephalexin, or Tab. Linezolid
- Registration Number
- NCT06336824
- Lead Sponsor
- Clinical Research Centre, Malaysia
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 290
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Blood culture positive for Staphylococcus aureus (S. aureus).
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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).
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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.
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Achieved defervescence, defined as sustained body temperature ≤37.5°C within 48 hours before randomization.
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Able to provide written informed consent to participate trial.
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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.
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Septic shock, defined as hypotension requiring vasopressors to maintain MAP ≥65 mmHg despite adequate volume resuscitation.
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Received more than 5 days of non-study antibiotics as empirical therapy prior to enrolment.
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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.
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Known history of S. aureus infection within the past 3 months.
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Inability to tolerate oral therapy or poor absorption of oral medications, or not suitable for ongoing IV therapy (for example, difficult intravenous access)
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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.
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Patient is concomitantly receiving oral antibiotics which are active against S. aureus. For example, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prophylaxis.
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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
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Failure or inability to remove intravascular catheter that is present when first positive blood culture was drawn.
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Known comorbidity that increased the risk of complicated infections:
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End-stage renal disease
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Severe liver disease (Child-Pugh class C)
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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
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13.Short life expectancy < 3 months
14.Pregnancy (for women of childbearing potential)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard IV therapy (SIV) IV Cloxacillin, IV Cefazolin, IV Vancomycin, or IV Ceftaroline 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 Early Oral Switch Therapy (EOS) Tab. Trimethoprim-sulfamethoxazole, Tab. Clindamycin, Tab. Cephalexin, or Tab. Linezolid 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
- Primary Outcome Measures
Name Time Method Rate of SAB-relapse 90 days defined as any new positive blood culture with S. aureus, and/or newly diagnosed metastatic S. aureus infection resulting from hematogenous dissemination
- Secondary Outcome Measures
Name Time Method Number of days of hospitalization 90 days Number of calendar days of hospitalisation after the first positive blood culture for S. aureus.
Rate of complications related to IV therapy 90 days Any complications related to insertion or usage of peripheral branula or central catheter, and administration of IV drugs
Rate of Clostridium difficile diarrhoea 90 days A diagnosis of diarrhoea with ≥1 stool sample tested positive for C. difficile toxin or toxin gene.
Rate of all-cause mortality 90 days Any death occurred within 90 days of randomization.
Rate of adverse events 30 days Any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have a causal relationship with treatment.
Trial Locations
- Locations (12)
Hospital Sultanah Bahiyah
🇲🇾Alor Setar, Kedah, Malaysia
Hospital Sultan Idris Shah Serdang
🇲🇾Kajang, Selangor, Malaysia
Hospital Sultan Abdul Halim
🇲🇾Sungai Petani, Kedah, Malaysia
Hospital Tuanku Ja'afar
🇲🇾Seremban, Negeri Sembilan, Malaysia
Hospital Raja Permaisuri Bainun
🇲🇾Ipoh, Perak, Malaysia
Hospital Tengku Ampuan Rahimah
🇲🇾Klang, Selangor, Malaysia
Hospital Melaka
🇲🇾Melaka, Malaysia
Hospital Sultanah Aminah
🇲🇾Johor Bahru, Johor, Malaysia
Hospital Seberang Jaya
🇲🇾Seberang Jaya, Penang, Malaysia
Hospital Pulau Pinang
🇲🇾George Town, Penang, Malaysia
Hospital Selayang
🇲🇾Selayang Baru Utara, Selangor, Malaysia
Hospital Ampang
🇲🇾Ampang, Selangor, Malaysia