Early Oral Switch for Uncomplicated Gram-negative Bacteraemia (INVEST)

Early Oral Step-down Antibiotic Therapy Versus Continuing Intravenous Therapy for Uncomplicated Gram-negative Bacteraemia (the INVEST Trial)

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.

Study Overview

• Status: Completed
• Conditions: Gram-negative Bacteraemia
• Intervention / Treatment: Drug: Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole; Drug: Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)

Detailed Description

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
• Enrollment (Actual): 720
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Greece
  • Pátrai, Greece, 26504
    • University General Hospital of Patras
• Israel
  • Haifa, Israel, 3109601
    • Rambam Hospital
  • Ramat Gan, Israel, 5262000
    • Sheba Medical Center
• Italy
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant'Orsola
  • Milan, Italy, 20132
    • IRCCS Hospital San Raffaele
  • Pisa, Italy, 56124
    • University Hospital of Pisa
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • American University of Beirut Medical center
• Malaysia
  • Ampang, Malaysia, 68000
    • Hospital Ampang
  • Kuala Lumpur, Malaysia, 56000
    • Hospital Universiti Kebangsaan Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Universiti Malaya Medical Centre
  • Sungai Buloh, Malaysia, 47000
    • Sungai Buloh Hospital
• Singapore
  • Singapore
    • Singapore, Singapore, Singapore, 119074
      • National University Hospital
    • Singapore, Singapore, Singapore, 308433
      • Tan Tock Seng Hospital
    • Singapore, Singapore, Singapore, 169608
      • Singapore General Hospital
    • Singapore, Singapore, Singapore, 529889
      • Changi General Hospital
    • Singapore, Singapore, Singapore, 544886
      • Sengkang General Hospital
    • Singapore, Singapore, Singapore, 609606
      • Ng Teng Fong General Hospital
• South Korea
  • Soeul, South Korea, 06351
    • Samsung Medical Center
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bandang Hospital
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
• Taiwan
  • Xitun District
    • Taichung, Xitun District, Taiwan, 407219
      • Taichung Veterans General Hospital
• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye), 34214
    • Medipol Mega University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early switch to oral antibiotic therapy; 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; 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); Other Names: Ciprofloxacin; Bactrim; Co-Trimoxazole
Active Comparator: Continuing intravenous antibiotic therapy; 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); 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; Other Names: Rocephin; Kefzol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality at day 30 post-randomisation	Percentage of all-cause mortality at day 30 from the time of randomisation	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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.	90 days
Treatment-emergent adverse events from the time of randomisation until day 90	Percentage of participants with each treatment-emergent adverse event. Adverse events of special interest include Clostridioides difficile-associated diarrhoea, peripherally inserted central catheter and other central venous catheter complications (e.g. catheter-related bloodstream infection, catheter-related superficial or deep venous thrombosis/thrombophlebitis, catheter blockage, and exit site infection) requiring line removal during index hospitalisation (including OPAT), and liver function test abnormalities or acute kidney injury.	90 days
Change in treatment strategy, either due to an adverse event or presumed lack of efficacy of treatment regimen, between the time of randomisation and day 30	Percentage of participants who experienced a change in treatment strategy (e.g. switch to IV antibiotics from allocated oral antibiotics or vice versa) between the time of randomisation and day 30 due to: i) an adverse event deemed by the doctor to be of sufficient severity to change treatment strategy, or ii) presumed lack of efficacy of treatment strategy according to the judgement of the doctor.	30 days
Time (in days) to being discharged alive from the total index hospitalisation between the time of randomisation and day 90	Hazard rate of discharge alive from the total index hospitalisation (including OPAT and hospital-in-the-home) between the time of randomisation and day 90 (note: any death occurrence within 90 study days will be considered '90 days')	90 days
Number of days alive and not in hospital (including OPAT) up to day 90 post-randomisation	Median number of days alive and not in hospital (including OPAT) between the time of randomisation and day 90	90 days
Readmission or extended index hospitalisation between the time of randomisation and day 90	Percentage of participants who were readmitted or experienced extended index hospitalisation. Readmission is defined as a new hospitalisation for any cause or a return to ambulatory hospital services occurring after discharge from the index hospitalisation. Extended index hospitalisation is defined as >14 days of hospital length of stay starting from the day of randomisation.	90 days
Health economic evaluation up to day 90 post-randomisation	Health economic evaluation includes calculation of estimated total healthcare cost (from healthcare system and patient perspective) up to day 90 post-randomisation. The health economic evaluation component of this study will be performed for participating sites in Singapore and Malaysia only. Results of the health economic evaluation will be published separately from the main trial results manuscript.	90 days
Health-related quality of life (EQ-5D descriptive system) on the day of screening (baseline), on the day of end of treatment, and on day 90 post-randomisation	EQ-5D-5L consists of EQ-5D descriptive system and EQ visual analogue scale (EQ VAS). The descriptive system encompasses five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which has 5-level scale: no problems, slight problems, moderate problems, severe problems, and extreme problems. Participants will be asked to indicate their health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions will be combined into a 5-digit number that describes the participant's health state (e.g. 11211). The health state will then be converted into a utility index score using country specific value set, where 1 = full health and 0 = death. The utility index score can fall below 0 in culture which deems a health state is "worst than death".	90 days
Health-related quality of life (EQ visual analogue scale) on the day of screening (baseline), on the day of end of treatment, and on day 90 post-randomisation	EQ-5D-5L consists of EQ-5D descriptive system and EQ visual analogue scale (EQ VAS). The EQ VAS records the participant's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS will be used as a quantitative measure of health outcome that reflects the participant's own judgement, where 0 indicates the worst health imaginable and 100 indicates the best health imaginable.	90 days

Collaborators and Investigators

• Sponsor: Tan Tock Seng Hospital
• Collaborators: Singapore Clinical Research Institute; Consorzio per Valutazioni Biologiche e Farmacologiche
• Investigators: Principal Investigator: David Lye, MBBS, Tan Tock Seng Hospital

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2022
• Primary Completion (Actual): May 24, 2026
• Study Completion (Actual): July 23, 2026

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: January 16, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Actual): August 10, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: oral antibiotics; ciprofloxacin; fluoroquinolones; trimethoprim-sulfamethoxazole; gram-negative bacteria; uncomplicated bacteraemia; early oral switch
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Bacteremia; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amides; Aniline Compounds; Amines; Pyrimidines; Benzene Derivatives; Drug Combinations; beta-Lactams; Lactams; Cephalosporins; Thiazines; 4-Quinolones; Quinolones; Quinolines; Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Sulfanilamides; Sulfones; Trimethoprim; Cefotaxime; Cephacetrile; Ceftriaxone; Cefazolin; Fluoroquinolones; Trimethoprim, Sulfamethoxazole Drug Combination; Ciprofloxacin
• Other Study ID Numbers: DSRB 2021/00764

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No