Amphotericin-B and Voriconazole for Pulmonary Blastomycosis

Blastomycosis Clinical Trial

— BLASTO  

Official title:

Case Series of Continuously-infused Amphotericin-B and Follow-up Voriconazole Therapy for Severe Blastomycosis Pulmonary Infections

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02283905
• Other study ID #: B2014:032
• Status: Terminated
• Phase: Phase 4
• Start date: June 2015
• Est. completion date: September 25, 2020

Study information

• Verified date: September 2020
• Source: University of Manitoba
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: September 25, 2020
• Est. primary completion date: September 25, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Blastomycosis

Intervention

Drug:
• amphotericin-B
continuously infused
• voriconazole
intravenously or orally administered

Locations

Country	Name	City	State
Canada	St. Boniface General Hospital	Winnipeg	Manitoba

Sponsors (2)

Lead Sponsor	Collaborator
University of Manitoba	Pfizer

Country where clinical trial is conducted

Canada, 

References & Publications (4)

Ariano RE, Mitchelmore BR, Lagacé-Wiens PR, Zelenitsky SA. Successful treatment of pulmonary blastomycosis with continuously infused amphotericin B deoxycholate after failure with liposomal amphotericin B. Ann Pharmacother. 2013 Jun;47(6):e26. doi: 10.1345/aph.1R703. Epub 2013 May 14. — View Citation

Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, Kauffman CA; Infectious Diseases Society of America. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008 Jun 15;46(12):1801-12. doi: 10.1086/588300. — View Citation

Chowfin A, Tight R, Mitchell S. Recurrent blastomycosis of the central nervous system: case report and review. Clin Infect Dis. 2000 Jun;30(6):969-71. Review. — View Citation

Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ. 2001 Mar 10;322(7286):579-82. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Clinical recovery - as assessed by time to fever defervescence; and white blood cell (WBC) count resolution	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.	2 to 3 days
Secondary	Clinical recovery - time to discontinuation of mechanical ventilation	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.	less than 7 days
Secondary	Clinical recovery - time to respiratory dysfunction resolution	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	less than 4 days