An Update in the Management of Candidiasis Daniel B. Chastain, Pharm.D., AAHIVP Infectious Diseases Pharmacy Specialist Phoebe Putney Memorial Hospital Adjunct Clinical Assistant Professor UGA College of Pharmacy July 16, 2016
Disclosures I have nothing to disclose. Management of Candidiasis 2
Objectives: Pharmacists Review the epidemiology and risk factors for candidiasis Identify new diagnostic approaches for candidiasis Discuss major differences in treatment recommendations Create an evidence based treatment and monitoring plan for invasive candidiasis Management of Candidiasis 3
Objectives: Technicians Identify concerns with increasing rates of candidiasis Review the treatment for candidiasis List 2-3 medications used to treat candidiasis Management of Candidiasis 4
Guideline Development Last updated in 2009 Multidisciplinary panel of 12 experts Reviewed recent literature Data discussed over a 2yr period Management of Candidiasis 5
Guideline Development New data on diagnosis, prevention, and treatment for invasive candidiasis Significant changes in treatment recommendations Endorsed by AAP, PIDS, and Mycoses Study Group Management of Candidiasis 6
Candida sp. Diverse spectrum of diseases 4th most common healthcare-associated bloodstream infection (BSI) 40-60% mortality, higher if septic shock 15 distinct species causing human infection > 90% caused by top 5 1. C. albicans 2. C. glabrata 3. C. tropicalis 4. C. parapsilosis 5. C. krusei Management of Candidiasis 7
Antifungal Therapy No randomized controlled trials to support superiority of one therapeutic agent over another Previous exposure Intolerance Comorbidities Severity of illness Involvement of CNS, cardiac valves Dominant species BMC Infect Dis 2011; 11:261. Clin Microbiol Infect 2012; 18:680-7. Am J Med 1996; 101:170-6. N Engl J Med 1994; 331:1325-30. Clin Infect Dis 2003; 36:1221-8. Lancet 2005; 366:1435-42. Clin Infect Dis 2004; 39:770-5. N Engl J Med 2002; 347:2020-9. Lancet 2007; 369:1519-27. N Engl J Med 2007; 356:2472-82. Clin Infect Dis 2007; 45:883-93. Clin Infect Dis 2009; 48:1676-84. Mycoses 2014; 57:12-8. BMC Infect Dis 2014; 14:97. Management of Candidiasis 8
Antifungal Resistance 7% of all BSI are resistant to fluconazole No echinocandin resistance before 2004 3-5% in C. glabrata Prevalence > 10% at some facilities Clin Infect Dis 2012;55:1352-61. J Clin Microbiol 2012;50:3435-42. J Clin Microbiol 2004;42:1519-27. Clin Infect Dis1999;29:1164-70. Clin Infect Dis 2012;55:1352-1361. Clin Infect Dis 2013;56:1724-1732. Open Forum Infect Dis 2015;2:ofv163. Management of Candidiasis 9
Multidrug Resistance Growing concern of isolates resistant to both fluconazole and echinocandins Few treatment options Likely worse outcomes J Antimicrob Chemother 2014;69:2210-4. J Antimicrob Chemother 2010;65:1042-51. Microbiol Immunol 2009;53(1):41-4. http://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html Management of Candidiasis 10
When to consider candidiasis Clinical deterioration with no obvious cause Fever of unknown origin (FUO), leukocytosis Recently undergone abdominal surgery Presence of central venous catheter (CVC) Management of Candidiasis 11
Risk Factors Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores Mechanical ventilation Surgery (abdominal surgery) Broad spectrum antibiotics Presence of CVC Parenteral nutrition Diabetes mellitus Renal insufficiency/hemodialysis Pancreatitis Immunosuppressive agents BMC Infect Dis 2013;13:10. Int J Antimicrob Agents 2009;33:554-7. Mycoses 2007;50:302-10. Crit Care Med 2006;34:730-7. Crit Care Med 2009;37:1624-33. Intensive Care Med 2015;41:285-05. Management of Candidiasis 12
Diagnosis of Candidiasis
Blood Cultures Gold standard Insensitive for markers of disease Positive in 50-70% of candidemias Rarely positive with deep-seated candidiasis Significant turn around time Delay in appropriate therapy Clin Infect Dis 2013;56:1284-92. J Clin Microbiol 2014;52:3082-4. Eur J Clin Microbiol Infect Dis 2013;32:917-22. Antimicrob Agents Chemother 2005;49:3640-5. J Antimicrob Chemother 2011;66:2146-51. Management of Candidiasis 14
β-d-glucan assays Cell wall component of Candida sp., Aspergillus sp., and others Positive results lack specificity Antifungal therapy reduces sensitivity Most useful if risk factors suggest candidiasis Med Mycol 2000;38:147-59. Clin Infect Dis 2004;39:199-205. Clin Infect Dis 2005;14:654-9. Clin Infect Dis 2008;46:1864-70. J Clin Microbiol 2011;49:58-61. Management of Candidiasis 15
T2 Biosystems T2 Magnetic Resonance (T2MR ) Shorten time to diagnosis and initiation of antifungal therapy BSI caused by top 5 Candida sp. < 3-5hrs from blood specimen Sens/Spec: 96.4%; 99.4% www.t2biosystems.com Sci Transl Med 2013;5:182ra54. Clin Infect Dis 2015;60:892-9. Future Microbiol 205;10:1133-44. Clin Infect Dis 2015;60:892-9. Management of Candidiasis 16
Antifungal Susceptibility Testing (AST)
AST Overview Consensus documents describing standardized methods Broth- and agar-based Guides therapeutic decision making Aids in drug development studies Tracking antifungal resistance CLSI M27-A3 CLSI M38-A2 CLSI M44-A CLSI M44-S2 CLSI M51-P Clin Infect Dis 2002;35(8):982-9. Clin Infect Dis 2008;46(1):120-8. Clin Microbiol Rev 2006;19(2):435-47. Management of Candidiasis 18
AST Objectives Relative activities of antimicrobial agents against the pathogen of interest Correlate with in vivo activity and to predict the likely outcome of therapy Provide a quantitative means by which to survey the development of resistance Predict the therapeutic potential and spectrum of activity Clin Infect Dis 2002;35(8):982-9. Clin Infect Dis 2008;46(1):120-8. Clin Microbiol Rev 2006;19(2):435-47. Management of Candidiasis 19
AST Recommendations All bloodstream and other clinically relevant isolates Echinocandin susceptibility Previously treated with an echinocandin Infected with C. glabrata or C. parapsilosis Management of Candidiasis 20
Etest Management of Candidiasis 21 http://life-worldwide.org/media-centre/article/resistance-detection-straight-from-the-blood-culture-bottle
Sensititre YeastOne Panel http://www.mycology.adelaide.edu.au/gallery/yeast-like_fungi/# Management of Candidiasis 22
VITEK 2 Yeast Susceptibility Test http://www.mycology.adelaide.edu.au/laboratory_methods/antifungal_susceptibility_testing/overview.html Management of Candidiasis 23
MicroScan Rapid Yeast ID Panel http://www.mycology.adelaide.edu.au/laboratory_methods/antifungal_susceptibility_testing/overview.html Management of Candidiasis 24
C. albicans Antifungal Agent Clinical Breakpoint (mcg/ml) S SSD I R Fluconazole <2 4 > 8 Itraconazole <0.12 0.25-0.5 > 1 Voriconazole <0.12 0.25-0.5 > 1 Posaconazole Anidulafungin <0.25 0.5 > 1 Caspofungin <0.25 0.5 > 1 Micafungin <0.25 0.5 > 1 Management of Candidiasis 25
C. glabrata Antifungal Agent Clinical Breakpoint (mcg/ml) S SSD I R Fluconazole 32 > 64 Itraconazole Voriconazole Posaconazole Anidulafungin <0.25 0.5 > 1 Caspofungin <0.25 0.5 > 1 Micafungin <0.25 0.5 > 1 Management of Candidiasis 26
C. parapsilosis Antifungal Agent Clinical Breakpoint (mcg/ml) S SSD I R Fluconazole <2 4 > 8 Itraconazole Voriconazole <0.12 0.25-0.5 > 1 Posaconazole Anidulafungin <2 4 > 8 Caspofungin <2 4 > 8 Micafungin <2 4 > 8 Management of Candidiasis 27
C. tropicalis Antifungal Agent Clinical Breakpoint (mcg/ml) S SSD I R Fluconazole <2 4 > 8 Itraconazole Voriconazole <0.12 0.25-0.5 > 1 Posaconazole Anidulafungin <0.25 0.5 > 1 Caspofungin <0.25 0.5 > 1 Micafungin <0.25 0.5 > 1 Management of Candidiasis 28
C. krusei Antifungal Agent Clinical Breakpoint (mcg/ml) S SSD I R Fluconazole Itraconazole Voriconazole <0.5 1 > 2 Posaconazole Anidulafungin <0.25 0.5 > 1 Caspofungin <0.25 0.5 > 1 Micafungin <0.25 0.5 > 1 Management of Candidiasis 29
Candidemia
Neutropenic and Nonneutropenic patients: Empiric Therapy Significant change from 2009 Echinocandin initially Caspofungin 70mg LD, then 50mg/day Micafungin 100mg/day Anidulafungin 200mg LD, then 100mg/day Management of Candidiasis 31
Echinocandins Initially? Fungicidal activity Favorable safety profile Limited drug-drug interactions Success in randomized, comparative clinical trials Clin Infect Dis 2004; 39:770-5. N Engl J Med 2002; 347:2020-9. Lancet 2007; 369:1519 27. N Engl J Med 2007; 356:2472-82. Clin Infect Dis 2007; 45:883-93. BMC Infect Dis 2011; 11:261. Clin Infect Dis 2009; 48:1676-84. Management of Candidiasis 32
Anidulafungin vs. Fluconazole Manufacturer, sponsored, randomized, multicenter trial Anidulafungin vs. fluconazole x > 14d Invasive candidiasis Global response at the end of IV therapy Resolution of signs and symptoms and eradication of candida N Engl J Med 2007; 356:2472-82. Management of Candidiasis 33
Anidulafungin vs. Fluconazole N Engl J Med 2007; 356:2472-82. Management of Candidiasis 34
Anidulafungin vs. Fluconazole N Engl J Med 2007; 356:2472-82. Management of Candidiasis 35
Impact of Treatment Strategy on Invasive Candidiasis Outcomes Quantitative review of 7 randomized trials Assessed impact of factors on mortality and clinical cure Treatment-related factors associated with improved survival and greater clinical success: Echinocandin Central venous catheter (CVC) removal Clin Infect Dis 2012;54:1110-22. Management of Candidiasis 36
Neutropenic and Nonneutropenic patients: Alternative Therapy Fluconazole 800mg (12mg/kg) LD, then 400mg (6mg/kg)/day Select patients, not critically ill Unlikely to have fluconazole-resistant Candida sp. Voriconazole (neutropenic patients) Azole intolerance, limited availability or resistance Lipid formulation of amphotericin B Management of Candidiasis 37
Neutropenic and Nonneutropenic patients: Step Down Therapy Step down therapy with an azole (PO or IV) within 5-7 days Not critically ill Unlikely to have azole-resistant isolate Negative repeat blood cultures Susceptibility testing recommended for all bloodstream isolates Management of Candidiasis 38
Early Step-Down Strategy Open-label noncomparative trial Anidulafungin > 5 days, followed by step-down therapy to fluconazole or voriconazole Once clinically stable and negative blood cultures No difference in outcomes BMC Infect Dis 2014; 14:97. Management of Candidiasis 39
Neutropenic and Nonneutropenic patients: Step Down Therapy Fluconazole 400mg/day Voriconazole 6mg/kg twice daily x 2 doses, then 3-4mg/kg PO twice daily Additional mold coverage Management of Candidiasis 40
Neutropenic and Nonneutropenic patients Early removal of CVC is optimal Ophthalmology consult Repeat blood cultures daily or every other day 14 days from first negative if no metastatic complications All symptoms resolved Resolution of neutropenia N Engl J Med 2007; 356:2472-82. Clin Infect Dis2007; 45:883-93. Clin Microbiol Infect 2012; 18:680-7. Clin Infect Dis 2009;48:1676-84. BMC Infect Dis 2014; 14:97. Antimicrob Agents Chemother 2012; 56:3133-7. Clin Infect Dis 2012; 54:1110-22. Crit Care Med 2008;36:2967 72. J Hosp Infect 2012; 82:281 5. J Antimicrob Chemother 2013; 68:206 13. Clin Infect Dis 1995; 21:994 6. Arch Intern Med 1995; 155:2429 35. J Infect 2009;58:154 60. N Engl J Med 1994; 331:1325-30. Clin Infect Dis 2003; 36:1221-8. Lancet 2005; 366:1435-42. Lancet 2007; 369:1519-27. Clin Infect Dis 2012; 54:1739-46. Management of Candidiasis 41
Endophthalmitis Ocular involvement in < 16% Dilated retinal exam Nonneutropenic: < 7 days Neutropenic: once resolved Treatment decisions made by ophthalmologist Antimicrob Agents Chemother 2012; 56:3133-7. Management of Candidiasis 42
Candida krusei Intrinsic resistance to fluconazole Voriconazole 200-300mg (3-4mg/kg) twice daily Echinocandin Lipid formulation of amphotericin B Antimicrob Agents Chemother 1998;42:2645-9. Antimicrob Agents Chemother 2003;47:1213-9. J Clin Microbiol 2008;46:515-21. Antimicrob Agents Chemother 2006;50:2522-4. Med Mycol 2005;43:559-64. Antimicrob Agents Chemother 2007;51:1876-8. Management of Candidiasis 43
Candida glabrata Resistant to azoles via drug efflux Higher dose fluconazole (800mg/day) Voriconazole 200-300mg (3-4mg/kg) twice daily Echinocandins Lipid formulation of amphotericin B Clin Infect Dis 2006;42:244-51. J Clin Microbiol 2012;50:1199-203. Antimicrob Agents Chemother 2008;52:3783-5. Antimicrob Agents Chemother 2011;55:1312-4. J Clin Microbiol 2010;48:2373-8. Antimicrob Agents Chemother 2004;48:2477-82. Management of Candidiasis 44
Candida parapsilosis? Fluconazole > echinocandin Decreased in vitro activity Reports of echinocandin resistance No data demonstrating superiority of fluconazole over echinocandins Antimicrob Agents Chemother 2011; 55:561-6. J Clin Microbiol 2011; 49:396-9. N Engl J Med 2002; 347:2070-2. N Engl J Med 2006; 355:1154-9 J Clin Microbiol 2013; 51:4167-72. Clin Microbiol Infect 2014; 20:698-705. Management of Candidiasis 45
Neutropenic patients Sources other than CVC predominate GI tract CVC removal, if applicable G-CSF considered with prolonged neutropenia Management of Candidiasis 46
ID Consult Early identification of Candida sp. Optimal antifungal treatment Better patient outcomes Management of Candidiasis 47
Take Home Points ID consult Early therapy decreases mortality Echinocandins initially for invasive candidiasis CVC removal Antifungal susceptibility testing Step-down approach Management of Candidiasis 48
Self-Assessment Questions
What is the empiric drug of choice for candidemia in non-neutropenic patients? A. Fluconazole 800mg IV x 1 dose, then 400mg IV q24hrs thereafter B. Amphotericin B lipid complex 5mg/kg IV q24hrs C. Micafungin 100mg IV q24hrs D. Voriconazole 6mg/kg IV q12hrs x 2 doses, then 4mg/kg IV q12hrs thereafter Management of Candidiasis 50
What is the recommended treatment duration for candidemia without metastatic complications in neutropenic patients? A. 14 days, after documented clearance of Candida from the bloodstream B. 14 days total C. 21 days, after documented clearance of Candida from the bloodstream D. 21 days total Management of Candidiasis 51
Non-medication treatment recommendations for candidemia include which of the following? A. Infectious diseases consult B. Ophthalmology consult C. Central venous catheter (CVC) removal, if applicable D. All of the above Management of Candidiasis 52
Thank you! Daniel B. Chastain, Pharm.D., AAHIVP Infectious Diseases Pharmacy Specialist Phoebe Putney Memorial Hospital Adjunct Clinical Assistant Professor UGA College of Pharmacy dchastain@ppmh.org