Early Oral Switch for Uncomplicated Gram-negative Bacteraemia

Phase 4CompletedNCT05199324

Tan Tock Seng Hospital720 enrolled

Overview

Current management of uncomplicated Gram-negative bacteraemia entails prolong intravenous (IV) antibiotic therapy with limited evidence to guide oral conversion. This trial aim to evaluate the clinical efficacy and economic impact of early switch to oral antibiotics (within 72 hours from index blood culture collection) versus continuing standard of care IV therapy (for at least another 24 hours post-randomisation) for clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia.

This is an international, multicentre, randomised controlled, open-label, phase IV, non-inferiority trial with a non-inferiority margin of 6%. Eligible participants must be clinically stable / non-critically ill inpatients over the age of 18 years old (in Singapore, 21 years and above) with uncomplicated Gram-negative bacteraemia. Randomisation into the intervention or standard arms will be performed with 1:1 allocation ratio according to a randomisation list prepared in advance using a secure online randomisation system. Randomisation will be stratified by country and random sequence will be generated using random permuted blocks of unequal length. Participants randomised to the intervention arm (within 72 hours from index blood culture collection) will be immediately converted to oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole. In the event of microbiological or clinical failure of the oral antibiotic treatment, escalation to IV antibiotics may be initiated at any time point post-randomisation. Participants randomised to the standard arm will continue to receive an active IV therapy for at least another 24 hours post-randomisation. All the study drugs (and dosage) would be routinely used in clinical practice and will be ordered/dispensed from the hospital pharmacy as per site institutional practice. The recommended treatment duration by the study team is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Participants may be discharged home or to outpatient parenteral antimicrobial therapy (OPAT) at any time post-randomisation.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

720

Conditions

Gram-negative Bacteraemia

Interventions

Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazoleDRUG

Clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia randomised to the intervention arm will immediately be switched to oral antibiotics (within 72 hours from index blood culture collection)

Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)DRUG

Clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia randomised to the standard arm will continue to receive an active intravenous antibiotic therapy for at least another 24 hours post-randomisation

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. One or more set(s) of blood cultures positive for Gram-negative bacteria (GNB) associated with evidence of infection 2. Able to be randomised within 72 hours of index blood culture collection 3. Age ≥18 years (≥21 in Singapore) 4. Latest Pitt bacteraemia score \<4 5. Patient or legal representative is able to provide informed consent Exclusion Criteria: 1. Established uncontrolled focus of infection, including but not limited to: * Undrained abdominal abscess, deep seated intra-abdominal infection and other unresolved abdominal sources requiring surgical intervention * Central nervous system abscess (patients with focal neurology should have cranial CT prior to enrolment) * Undrained moderate-to-severe hydronephrosis 2. Complicated infections, including but not limited to: * Necrotising fasciitis * Empyema * Central nervous system infections and meningitis * Endocarditis / endovascular infections 3. Septic shock as defined by systolic blood pressure \<90 or mean arterial pressure \<70 mmHg despite adequate fluid resuscitation or need for inotropic/vasopressor support 4. Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as either growth of 2 or more different microorganism species in the same blood culture, or growth of different species in 2 or more separate blood cultures within the same episode \[\<48 hours\] and with clinical or microbiological evidence of the same source) 5. Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular graft) that cannot be removed 6. Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella spp. 7. Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole 8. Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, urticaria, angioedema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration 9. Unable to consume or absorb oral medications for any reason or unsuitable for ongoing IV therapy (e.g. no intravenous access) 10. Severely immunocompromised in the opinion of the treating doctor, including but not limited to, medical conditions such as: * Active leukaemia or lymphoma * Aplastic anaemia * Bone marrow transplant within two years of transplantation or transplants of longer duration still on immunosuppressive drugs or with graft-versus-host disease * Congenital immunodeficiency * HIV/AIDS with CD4 lymphocyte count \<200 * Neutropenia or expected post-chemotherapy neutropenia within 14 days from the time of screening, defined as absolute neutrophil count \< 500 cells/μL 11. Women who are known to be pregnant or breast-feeding 12. Treatment is not with intent to cure the infection (i.e. palliative care) 13. Unable to collect patient's follow-up data for at least 30 days post-randomisation for any reason 14. Treating doctor deems enrolment into the trial is not in the best interest of the patient 15. Previous enrolment in this trial

Locations (25)

Gold Coast University Hospital

Southport, Queensland, Australia

Outcomes

Primary Outcomes

All-cause mortality at day 30 post-randomisation

Percentage of all-cause mortality at day 30 from the time of randomisation

Time frame: 30 days

Secondary Outcomes

All-cause mortality at day 14 and day 90 post-randomisation

Percentage of all-cause mortality at day 14 and day 90 from the time of randomisation

Time frame: 14 days and 90 days, respectively

Duration of survival (in days) up to day 90 post-randomisation

Hazard rate of survival from the time of randomisation until day 90

Time frame: 90 days

Number of days on IV antibiotic therapy in the total index hospitalisation until (i) hospital discharge and (ii) day 90

Median number of days on IV antibiotic therapy in the total index hospitalisation (including outpatient parenteral antibiotic therapy \[OPAT\]) for surviving participants from the time of randomisation until i) hospital discharge and ii) day 90

Time frame: Up to 90 days

Number of days alive and free of antibiotics (i. for all antibiotics, and ii. for IV antibiotics) between the time of randomisation and day 90

Median total days alive and free from antibiotics (both oral and IV) for surviving participants; median total days alive and free from IV antibiotics for surviving participants; median proportion of days alive and free from antibiotics (both oral and IV) for surviving participants who discontinued the study; median proportion of days alive and free from IV antibiotics for surviving participants who discontinued the study; median proportion of days alive and free from antibiotics (both oral and IV) for non-surviving participants; and median proportion of days alive and free from IV antibiotics for non-surviving participants.

Time frame: 90 days

Data from ClinicalTrials.gov

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