Candidemia
Conditions
Keywords
candidemia, echinocandin, micafungin, caspofungin
Brief summary
The purpose of this pharmacokinetic (PK) and pharmacodynamic (PD) study is: To study the rate and duration of serum cidal activity of caspofungin (CFG) and micafungin (MFG) against Candida isolates from the subject and against Candida glabrata with varying degrees of caspofungin susceptibilities. This investigation will provide clinicians information supporting the use of caspofungin and micafungin in situations where Candida strains may be a cause of infection.
Detailed description
Methods: Patients - Adult patients with presumptive candidemia. Patients with severe neutropenia (\<500) APACHE II scores \> 20, or significant liver disease will be excluded. All will give written informed consent (Pappas et al. CID. Oct 1, 2007). Drugs - Patients will receive either CFG: 70 mg loading dose (LD) followed by 50 mg once daily (qd) (8 patients), MFG: 100 mg qd (8 patients) or MFG: 200 mg qd (8 patients). All agents will be given by slow IV infusion (MFG will be supplied by Astellas). Sera - Blood samples will be collected at the end of the infusion (peak) and at 12 h and 24 h (trough) after the beginning of an infusion (day 3-4). Each patients sera will be tested (MIC and cidal activity) against their own Candida isolate (if isolated). In addition, recent clinical isolates of C. glabrata will also be tested against patient sera (time-kill) to verify previous in vitro and animal PD studies (Cota. AAC. Nov. 2006; Wiederhold. AAC. May 2007). Results: * Patient outcome, including Candida eradication, will be documented for each patient by repeat culture. * Serum concentrations (lab to be determined) and PK analysis of each echinocandin will be determined for each patient. * Serum cidal titers will be measured against each of the Candida isolates for each agent at each time period. Median and geometric mean Peak and duration of cidal activity will then be determined and compared.
Interventions
DRUGmicafungin
100 mg qd by slow IV infusion for 24 h
DRUGMicafungin
200 mg qd by slow IV infusion for 24 h
DRUGCaspofungin
70 mg LD followed by 50 mg qd by slow IV infusion for 24 h
Sponsors
Astellas Pharma US, Inc.
Gary E. Stein, Pharm.D.
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
* Adult patients with presumptive candidemia
Exclusion criteria
* Patients with severe neutropenia (\<500) * Patients with APACHE II scores \> 20 * Patients with severe liver disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | Pre-treatment, 1.5 hour (h), 12 h and 24 h after receiving the drug | Serum cidal activity of serum collected at different timepoints from the patients will be tested against various Candida isolates and the ex-vivo effect reported as log inhibition (logrithmic measurement of the decrease in microbiological growth). These Candida isolates had a range of minimum inhibitory concentrations (MIC) to Caspofungin (C) and Micafungin (M). |
Countries
United States
Participant flow
Recruitment details
Subjects were inpatients (Sparrow Hospital) with probable fungal infections that required treatment with an antifungal; referral base was infectious disease consultations. The first subject was enrolled 12/24/08, with the last subject enrolled on 1/15/10.
Participants by arm
| Arm | Count |
|---|---|
| Micafungin (M) 100 Patients receive Micafungin (M) 100 mg once daily (qd) | 8 |
| Micafungin (M) 200 Patients receive 200 mg Micafungin (M) once daily | 8 |
| Caspofungin (C) 50 Patients receive caspofungin 70 mg loading dose (LD) followed by 50 mg once daily (qd) | 5 |
| Total | 21 |
Baseline characteristics
| Characteristic | Micafungin (M) 200 | Caspofungin (C) 50 | Micafungin (M) 100 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
| Age, Continuous | 57.81 years STANDARD_DEVIATION 17.38585 | 44.0 years STANDARD_DEVIATION 20.43282 | 64.62 years STANDARD_DEVIATION 16.13282 | 57.6 years STANDARD_DEVIATION 18.65374 |
| Region of Enrollment United States | 8 participants | 5 participants | 8 participants | 21 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 5 |
| serious Total, serious adverse events | 1 / 8 | 1 / 8 | 0 / 5 |
Outcome results
Primary
Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth)
Serum cidal activity of serum collected at different timepoints from the patients will be tested against various Candida isolates and the ex-vivo effect reported as log inhibition (logrithmic measurement of the decrease in microbiological growth). These Candida isolates had a range of minimum inhibitory concentrations (MIC) to Caspofungin (C) and Micafungin (M).
Time frame: Pre-treatment, 1.5 hour (h), 12 h and 24 h after receiving the drug
Population: Each subject received drug and had serum samples drawn at pre-treatment, 1.5h, 12h, and 24h after dosing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans MIC: C, M 0.016 mg/L | 3 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.06 mg/L | 3 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.25 mg/L | 0.5 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 119 FKS mutant MIC:C 1, M 0.16 mg/L | 0.5 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 90 FKS mutant MIC: C 1, M 0.25 mg/L | 0 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans A-15 FKS mutant MIC: C 2, M0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C 2, M 0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 50 mg/Day Caspofungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 117 FKS mutant MIC: C 8, M 0.83 mg/L | 0 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.25 mg/L | 1 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C 2, M 0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 119 FKS mutant MIC:C 1, M 0.16 mg/L | 0.5 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 90 FKS mutant MIC: C 1, M 0.25 mg/L | 0.5 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans A-15 FKS mutant MIC: C 2, M0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans MIC: C, M 0.016 mg/L | 0.5 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.06 mg/L | 1.5 Log inhibition |
| Log Inhibition of 100 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 117 FKS mutant MIC: C 8, M 0.83 mg/L | 0 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.25 mg/L | 0.5 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C, M 0.06 mg/L | 0.5 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans MIC: C, M 0.016 mg/L | 0 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 119 FKS mutant MIC:C 1, M 0.16 mg/L | 1.5 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. glabrata MIC: C 2, M 0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans A-15 FKS mutant MIC: C 2, M0.5 mg/L | 0 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 90 FKS mutant MIC: C 1, M 0.25 mg/L | 2 Log inhibition |
| Log Inhibition of 200 mg/Day Micafungin on Candida Spp. | Serum Cidal Activity as Tested Against Various Candida Isolates and Reported as Ex-vivo Effect (Log Inhibition of Growth) | C. albicans 117 FKS mutant MIC: C 8, M 0.83 mg/L | 0 Log inhibition |