Gram-negative Bacteraemia
Conditions
Keywords
uncomplicated bacteraemia, gram-negative bacteria, early oral switch, fluoroquinolones, ciprofloxacin, trimethoprim-sulfamethoxazole, oral antibiotics
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.
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.
Interventions
DRUGOral 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)
DRUGStandard 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
Sponsors
Tan Tock Seng Hospital
Singapore Clinical Research Institute
Consorzio per Valutazioni Biologiche e Farmacologiche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality at day 30 post-randomisation | 30 days | Percentage of all-cause mortality at day 30 from the time of randomisation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality at day 14 and day 90 post-randomisation | 14 days and 90 days, respectively | Percentage of all-cause mortality at day 14 and day 90 from the time of randomisation |
| Duration of survival (in days) up to day 90 post-randomisation | 90 days | Hazard rate of survival from the time of randomisation until day 90 |
| Number of days on IV antibiotic therapy in the total index hospitalisation until (i) hospital discharge and (ii) day 90 | Up to 90 days | 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 |
| 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 | 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. |
| Treatment-emergent adverse events from the time of randomisation until day 90 | 90 days | 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. |
| 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 | 30 days | 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. |
| Time (in days) to being discharged alive from the total index hospitalisation between the time of randomisation and day 90 | 90 days | 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') |
| Number of days alive and not in hospital (including OPAT) up to day 90 post-randomisation | 90 days | Median number of days alive and not in hospital (including OPAT) between the time of randomisation and day 90 |
| Readmission or extended index hospitalisation between the time of randomisation and day 90 | 90 days | 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. |
| 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 | 90 days | 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". |
| 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 | 90 days | 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. |
| Health economic evaluation up to day 90 post-randomisation | 90 days | 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. |
Countries
Australia, Greece, Israel, Italy, Lebanon, Malaysia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye)
Contacts
PRINCIPAL_INVESTIGATORDavid Lye, MBBS
Tan Tock Seng Hospital
Outcome results
None listed