Clinical trial NCT02283905: Amphotericin-B and Voriconazole for Pulmonary Blastomycosis
Official title: Case Series of Continuously-infused Amphotericin-B and Follow-up Voriconazole Therapy for Severe Blastomycosis Pulmonary Infections
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Blastomycosis
Keywords: amphotericin-B
continuously infused
voriconazole
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2014-11-05
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: The concentration-time profile of antifungals during treatment relative to the level of susceptibility of the infecting organism
timeFrame: within the first month of therapy
Secondary outcomes:
measure: Clinical recovery - as assessed by time to fever defervescence; and white blood cell (WBC) count resolution
timeFrame: 2 to 3 days
measure: Clinical recovery - time to discontinuation of mechanical ventilation
timeFrame: less than 7 days
measure: Clinical recovery - time to respiratory dysfunction resolution
timeFrame: less than 4 days
Other outcomes:
Locations:
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
Study officials:
affiliation: St. Boniface Hospital
name: Robert E. Ariano, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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. doi: 10.1086/313828.
citation: Ariano RE, Mitchelmore BR, Lagace-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.
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. doi: 10.1136/bmj.322.7286.579.