Amphotericin-B and Voriconazole for Pulmonary Blastomycosis

Phase 4

Terminated

• Conditions: Blastomycosis
• Interventions: Drug: amphotericin-B; Drug: voriconazole

• Registration Number: NCT02283905
• Lead Sponsor: University of Manitoba

Brief Summary

All patients with pulmonary blastomycosis requiring mechanical ventilation will have their blood concentrations measured for the antifungal drugs, amphotericin-B and voriconazole; as well as an analysis of the susceptibility of their infecting species of blastomyces. This information will then be analyzed relative to their rate of clinical recovery from this serious fungal infection.

Detailed Description

To evaluate six intensively studied patients admitted to medical intensive care with pulmonary blastomycosis requiring mechanical ventilation. Interventionally, all patients will receive continuously infused amphotericin-B (1 mg/kg/d); and then stepped down to oral or i.v. voriconazole once clinically responding. Blood will be sampled for amphotericin-B concentrations for the 3 first days (i.e. one blood sample per day); and when eventually changed over to voriconazole (i.e. generally after a total dose of 1 g has been reached of Amphotericin-B; as per usual practice). Once switched to oral or intravenous voriconazole, at the treating physicians discretion, then blood would once again be sampled for the next 3 days for voriconazole concentrations. MIC's of the infecting blastomyces would also be analyzed. The fungal isolate would be sent off to the Fungus Testing Laboratory at the University of Texas in San Antonio for susceptibility testing.

Clinical response to therapy relative to their initial pharmacokinetic and pharmacodynamic indices for amphotericin-B (i.e. daily free maximal concentration divided by the MIC) would be assessed in these 6 intensively studied patients. Clinical parameters assessed would be 1). time to fever defervescence; 2). time to white cell count resolution, and 3). improvements in respiratory gas exchange (i.e. specifically the rate of rise of the pressure of arterial oxygen (Pa02) divided by the fraction of inspired oxygen (Fi02) delivered through the ventilator (or PF ratio).

Study Timeline

• Study First Submitted: 2014-10-31
• Study First Submitted QC: 2014-11-04
• Study First Posted: 2014-11-05
• Study Start: 2015-06
• Status Verified: 2020-09
• Primary Completion: 2020-09-25
• Study Completion: 2020-09-25
• Last Update Submitted: 2020-09-25
• Last Update Posted: 2020-09-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2

Inclusion Criteria

• All adult patients 18 years of age or older admitted to the intensive care units of St. Boniface General Hospital with a diagnosis of acute pulmonary blastomycosis requiring mechanical ventilation.

Exclusion Criteria

• The patient's data will be excluded if they die within 3 days of hospital admission.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Amphotericin-B and Voriconazole	amphotericin-B	Treatment with a 24 hour continuous infusion of amphotericin B deoxycholate at 1.0 mg/kg/day for a total dose of at least 1 g (i.e. \~ 14 days); and then the patient is stepped down to voriconazole 6 mg/kg i.v. q12h for 2 doses, then 4 mg/kg q12h either i.v. or orally as appropriate. The oral dose will be rounded for convenience to either the 200 mg or 400 mg tablet twice daily.
Amphotericin-B and Voriconazole	voriconazole	Treatment with a 24 hour continuous infusion of amphotericin B deoxycholate at 1.0 mg/kg/day for a total dose of at least 1 g (i.e. \~ 14 days); and then the patient is stepped down to voriconazole 6 mg/kg i.v. q12h for 2 doses, then 4 mg/kg q12h either i.v. or orally as appropriate. The oral dose will be rounded for convenience to either the 200 mg or 400 mg tablet twice daily.

Primary Outcome Measures

Name	Time	Method
The concentration-time profile of antifungals during treatment relative to the level of susceptibility of the infecting organism	within the first month of therapy

Secondary Outcome Measures

Name	Time	Method
Clinical recovery - time to discontinuation of mechanical ventilation	less than 7 days	Defined as the interval between initiation of amphotericin-B infusion and when the patient was considered ready for extubation. A patient was considered ready for extubation if awake or arousable, neurologically intact, cooperative and comfortable, fraction of inspired oxygen (FiO2) \< or = 0.4, positive end-expiratory pressure (PEEP) \< or = 5 cm water (H2O); and at the attending physicians discretion. Patient status will be assessed for extubation at least once daily.
Clinical recovery - time to respiratory dysfunction resolution	less than 4 days	The daily assessment of the lowest pressure of arterial oxygen divided by the fraction of inspired oxygen (PF ratio = Pa02/Fi02) to detect the time until the PF ratio exceeds 200
Clinical recovery - as assessed by time to fever defervescence; and white blood cell (WBC) count resolution	2 to 3 days	Temperature would be assessed at least 4 times daily; and once there was a sustained temp \< 38 degrees Celsius the timing would stop. WBC would be assessed at least twice daily and once the count fell less than 12,000 the timing would stop.

Trial Locations

Locations (1)

St. Boniface General Hospital; 🇨🇦 Winnipeg, Manitoba, Canada