Candida spp. Bloodstream Infections Infections and Infestations
Conditions
Interventions
Current interventions as of 16/06/2026:
Step 1 – Dose-selection
Micafungin 100 mg/d IV plus flucytosine 50 mg/kg PO/NG (split QDS)
Micafungin 100 mg/d IV plus flucytosine 100 mg/kg PO/NG (split QDS)
Sponsors
Wits Health Consortium
Eligibility
Sex/Gender
All
Age
18 Years to 110 Years
Inclusion criteria
Inclusion criteria: Current key inclusion criteria: 1. Age =18 years 2. Evidence of microscopy-confirmed yeast bloodstream infection 3. =1 Systemic signs of infection during a 24-hour period before or after blood culture draw Previous key inclusion criteria: 1. Age =18 years 2. Evidence of microscopy-confirmed yeast bloodstream infection 3. =1 Systemic signs of infection during a 24 hour period before and after blood culture draw
Exclusion criteria
Exclusion criteria: Current key exclusion criteria: 1. Yeast growing in blood culture is confirmed not to be a Candida spp (late exclusion criterion - may take up to 3 days to identify the organism) 2. Invasive candidiasis with complex organ or prosthetic involvement (e.g. infection involving material that cannot be removed within 5 days of randomisation, osteomyelitis, endocarditis or myocarditis, endophthalmitis, chorioretinitis or any central nervous system involvement) identified as likely to present within 5 days of Candida BSI (late exclusion criterion) 3. Pregnancy or breastfeeding 4. Receipt of a systemic antifungal, at treatment-dose, to which the Candida spp causing bloodstream infection is susceptible (> 3 doses of a once daily or >5 doses of a twice daily drug within 4 days of randomisation). This will be a late exclusion criteria once antifungal susceptibility testing results are available. 5. Micafungin or flucytosine resistant Candida spp (by EUCAST breakpoint) in initial bloodstream isolate (late exclusion criteria) 6. A known hypersensitivity to trial drugs 7. Co-administration of cytarabine 8. Known complete dihydropyrimidine dehydrogenase deficiency 9. Alanine transferase or aspartate aminotransferase level >10-fold upper limit of normal, or history of chronic cirrhosis (Child-Pugh score >9) 10. Neutrophil count 3 doses of a once daily or >5 doses of a twice daily drug within 4 days of randomisation). This will be a late exclusion criteria once antifungal susceptibility testing results are available. 4. Micafungin or flucytosine resistant Candida spp (by EUCAST breakpoint) in initial bloodstream isolate (late exclusion criteria) 5. A known hypersensitivity to trial drugs 6. Co-administration of cytarabine 7. Known complete dihydropyrimidine dehydrogenase deficiency 8. Alanine transferase or aspartate aminotransferase level >10-fold upper limit of normal, or history of chronic cirrhosis (Child-Pugh score >9) 9. Neutrophil count <500 x10^6/L or platelet count <50,000 x 10^6/L 10. Previous participation in this trial or in another trial for the same indication 11. The principal investigator (PI) is of the opinion that the individual is not suitable for participation in the study due to any other medical factors 12. For Step 1 only, an estimated Glomerular Filtration Rate (eGFR) of <50mL/min/1.73 m^2, haemoglobin <8g/dL, or participants without adequate intravenous access for regular blood draws during the first 24 hours of treatment. Late Exclusion Criteria: 1. Yeast growing in blood culture is confirmed not to be a Candida spp (may take up to 3 days to identify the organism) 2. Evidence of Candida eye i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| STEP 1 – Dose-selection: A target flucytosine exposure of >45% time/MIC derived from prior work will be used. A population pharmacokinetic model of flucytosine plasma concentrations will be developed. This model will be used to simulate the probability of target attainment. The lowest dose achieving the PKPD target in >90% of patients will be taken forward to step 2. This is measured using PK blood sampling at day 1 and day 7.;STEP 2 – Primary efficacy outcome (hierarchical composite at 30 days): 1) time to death (all-cause mortality, measured in ordinal blocks of 5 days); 2) breakthrough during treatment (binary – whether or not any blood cultures taken after blood culture sterility, become positive with Candida spp); 3) relapse within 30 days after end of treatment (binary - whether or not a blood culture taken following the end of treatment is positive with the same Candida spp as grown from the initial blood culture); 4) time-to-blood culture-sterility (measured in ordinal blocks of 12 hour periods); 5) time to emergence of micafungin resistance (MIC > EUCAST breakpoint) in any commensal Candida species. This is measured using the Win Ratio (Hierarchical Composite) at day 30;Previous primary outcomes as of 16/06/2026: 1. STEP 1 – Dose-selection: population pharmacokinetic modelling of flucytosine plasma concentrations to assess for achievement of target drug exposure of flucytosine in plasma measured using PK blood sampling at day 1 and day 7 2. STEP 2 – Primary efficacy outcome (hierarchical composite at 30 days): 1) time to death (all-cause mortality, measured in ordinal blocks of 5 days); 2) breakthrough Candida BSI during treatment (binary – whether or not any blood cultures taken subsequent to blood culture sterility for =48 hours, become positive with Candida spp); 3) Candida BSI relapse within 30 days after end of treatment (binary - whether or not a blood culture taken following the end of treatment is positive with the same Candida spp as grown from the | — |
Secondary
| Measure | Time frame |
|---|---|
| All-cause mortality measured using number of deaths (site records) at day 30 and day 90;Time to all-cause mortality measured using time-to-event at day 30 and day 90;Candida BSI breakthrough during treatment measured using proportion of patients with a positive blood culture indicating a new Candida bloodstream infection at scheduled timepoints until EOT+5;Relapse of Candida BSI after treatment measured using proportion of participants with a positive blood culture from the same Candida spp at day 14, EOT +5, day 30 and EOT +30;Time to blood culture sterility measured using time to negative blood culture with no subsequent positive within 48 hours at scheduled timepoints until EOT +5;Time to micafungin resistance in colonising or invasive Candida spp measured using time to detection of micafungin resistance (MIC above EUCAST breakpoint) in a colonising or invasive Candida spp at every 3/4 days until day 30;Proportion of participants who have micafungin resistance detected measured using resitance (MIC above EUCAST breakpoint) detected in any colonising or invasive Candida spp at day 14, EOT+5 & day 30;Duration of ICU admission and hospitalisation measured using time spent in ICU/hospital from site records at up until day 90;Rate of change in fungal biomarkers measured using serum beta-D-glucan & blood Candida qPCR at until day 30;Serious adverse events (SAEs) measured using proportion with grade 3 cytopaenias, other grade 4 adverse events and other SAEs at up until EOT +5 | — |
Countries
South Africa
Contacts
Public ContactLauriane Fomete
Outcome results
None listed