Early Oral Switch for Uncomplicated Gram-negative Bacteraemia

NCT05199324 | Recruiting Phase 4 DMC

• 1 other identifier: DSRB 2021/00764
• Study Type: interventional
• Target: 720
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Gram-negative Bacteraemia

Keywords

uncomplicated bacteraemia; gram-negative bacteria; early oral switch; antibiotics; fluoroquinolones; ciprofloxacin; trimethoprim-sulfamethoxazole

Outcome Measures

Primary Outcomes (1)

• All-cause mortality at day 30 post-randomisation

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

  30 days

Secondary Outcomes (12)

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

  14 days and 90 days, respectively

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

  90 days

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

  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

  90 days

• Treatment-emergent adverse events from the time of randomisation until day 90

  90 days

Study Arms (2)

Early switch to oral antibiotic therapy

EXPERIMENTAL

The oral antibiotic options are fluoroquinolones (most commonly, ciprofloxacin) or trimethoprim-sulfamethoxazole. The recommended doses for patients with normal renal function would be ciprofloxacin 750 mg twice daily (if body weight ≥70 kg) or ciprofloxacin 500 mg twice daily (if body weight \<70 kg) or trimethoprim-sulfamethoxazole 5 mg/kg (for trimethoprim component) every 12 hourly or trimethoprim-sulfamethoxazole (160 mg / 800 mg; double strength) two tablets twice daily. Doses may be adjusted in the setting of renal dysfunction. 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 due to regimen extension or requirement for prolonged regimen as clinically indicated.

Drug: Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole

Continuing intravenous antibiotic therapy

ACTIVE COMPARATOR

The intravenous antibiotics to be administered will be determined by the treating doctor according to what would be considered standard of care in the hospital site. Commonly used intravenous antibiotics (and doses) for treatment of Gram-negative bacteraemia include ceftriaxone 2 g daily or cefazolin 2 g three times daily. 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 due to regimen extension or requirement for prolonged regimen as clinically indicated.

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

Interventions

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

Also known as: Rocephin, Kefzol

Continuing intravenous antibiotic therapy

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

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)

Also known as: Ciprofloxacin, Bactrim, Co-Trimoxazole

Early switch to oral antibiotic therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Complicated infections, including but not limited to:
• Necrotising fasciitis
• Empyema
• Central nervous system infections and meningitis
• Endocarditis / endovascular infections
• 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
• 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)
• 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, angioedema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration

Sponsors & Collaborators

• Tan Tock Seng Hospital: lead
• National University Hospital, Singapore: collaborator
• Singapore General Hospital: collaborator
• Changi General Hospital: collaborator
• Sengkang General Hospital: collaborator
• Ng Teng Fong General Hospital: collaborator
• University of Malaya: collaborator
• Hospital Sungai Buloh, Selangor: collaborator
• Universiti Kebangsaan Malaysia Medical Centre: collaborator
• Taichung Veterans General Hospital: collaborator
• Melbourne Health: collaborator
• Gold Coast Hospital and Health Service: collaborator
• Princess Alexandra Hospital, Brisbane, Australia: collaborator
• Istanbul Medipol University Hospital: collaborator
• Sheba Medical Center: collaborator
• University Hospital of Pisa: collaborator
• Seoul National University Bundang Hospital: collaborator
• Samsung Medical Center: collaborator
• University Hospital of Patras: collaborator
• Hospital del Mar: collaborator
• Singapore Clinical Research Institute: collaborator
• KPJ Ampang Puteri Specialist Hospital: collaborator
• Rambam Hospital, Haifa, Israel: collaborator
• IRCCS San Raffaele: collaborator
• IRCCS Azienda Ospedaliero-Universitaria di Bologna: collaborator
• American University of Beirut Medical Center: collaborator
• Consorzio per Valutazioni Biologiche e Farmacologiche: collaborator

Study Sites (1)

Tan Tock Seng Hospital

Singapore, Singapore, 308433, Singapore

RECRUITING

Related Publications (1)

• Lee IR, Tong SYC, Davis JS, Paterson DL, Syed-Omar SF, Peck KR, Chung DR, Cooke GS, Libau EA, Rahman SBA, Gandhi MP, Shi L, Zheng S, Chaung J, Tan SY, Kalimuddin S, Archuleta S, Lye DC. Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial. Trials. 2022 Jul 19;23(1):572. doi: 10.1186/s13063-022-06495-3.

  PMID: 35854360 BACKGROUND

Related Links

• Related Info

MeSH Terms

Interventions

Fluoroquinolones; Ciprofloxacin; Trimethoprim, Sulfamethoxazole Drug Combination; Cefazolin; Ceftriaxone

Intervention Hierarchy (Ancestors)

4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Drug Combinations; Pharmaceutical Preparations; Cephalosporins; beta-Lactams; Lactams; Thiazines; Cefotaxime; Cephacetrile

Study Officials

• David Lye, MBBS

  Tan Tock Seng Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Lye, MBBS

CONTACT

(65) 63577457; david.lye@nhghealth.com.sg

I. Russel Lee, PhD

CONTACT

(65) 65115060; lee.mc.ivor.russel@nhghealth.com.sg

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2021
• First Posted: January 20, 2022
• Study Start: June 3, 2022
• Primary Completion: May 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: April 16, 2026

Record last verified: 2026-04

Locations

SG (1)