Early Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia

  • STATUS
    Recruiting
  • End date
    Mar 1, 2025
  • participants needed
    720
  • sponsor
    Tan Tock Seng Hospital
Updated on 4 October 2022

Summary

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 step-down 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.

Description

This is an international, multicentre, randomised controlled, open-label, phase III, 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 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 should continue to receive an active IV therapy for at least another 24 hours post-randomisation before clinical re-assessment and decision making by the treating doctor. 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 minimum treatment duration should be 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 OPAT at any time post-randomisation.

Details
Condition Gram-negative Bacteraemia
Treatment Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole, Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)
Clinical Study IdentifierNCT05199324
SponsorTan Tock Seng Hospital
Last Modified on4 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

One or more set(s) of blood cultures positive for Gram-negative bacteria (GNB) associated with evidence of infection
Able to be randomised within 72 hours of index blood culture collection
Age ≥18 years (≥21 in Singapore)
Latest Pitt bacteraemia score <4
Patient or legal representative is able to provide informed consent

Exclusion Criteria

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 computed tomography scan prior to enrolment)
Undrained moderate-to-severe hydronephrosis
Complicated infections, including but not limited to
Necrotising fasciitis
Empyema
Central nervous system infections and meningitis
Endocarditis / endovascular infections
Sepsis as defined by infection with consequent acute organ dysfunction or septic shock
as defined by systolic blood pressure <90 or mean arterial pressure <70 mmHg
despite adequate fluid resuscitation
Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as either growth of 2 different microorganism species in the same blood culture, or growth of different species in 2 separate blood cultures within the same episode [<48 hours] and with clinical or microbiological evidence of the same source)
Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular graft) that cannot be removed
Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella spp
Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole
Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, urticaria, angiodema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration
Unable to consume or absorb oral medications for any reason or unsuitable for ongoing intravenous therapy (e.g. no intravenous access)
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
Current radiation therapy
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
Women who are known to be pregnant or breast-feeding
Treatment is not with intent to cure the infection (i.e. palliative care)
Unable to collect patient's follow-up data for at least 30 days post-randomisation for any reason
Treating doctor deems enrolment into the trial is not in the best interest of the patient
Previous enrolment in this trial
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