Nature of the Yeast! Therapeutic Approach to Common Invasive Yeast Infections

ASCENSION TEXAS Nature of the Yeast! Therapeutic Approach to Common Invasive Yeast Infections

Austin Area Society of Health-Systems Pharmacists March 13, 2019 Mike McAlister, PharmD PGY2 Infectious Diseases Pharmacy Resident Seton Healthcare Family, Austin TX Pharmacist Objectives • Describe the epidemiology, populations at risk, and presentation for infections due to Candida species and Cryptococcus species. • Recognize colonization versus infection with Candida species at various anatomical sites. • Distinguish the differences in antifungal pharmacotherapy including variances in spectrum of coverage, mechanism of action, pharmacokinetics/pharmacodynamics, and adverse effects. • Identify first-line treatment options for infections due to clinically relevant yeasts.

2 Pharmacy Technician Objectives

• Recognize antifungals utilized in the treatment of infections due Candida species and Cryptococcus species. • List sites at which a person may be colonized with Candida species. • Describe the signs and symptoms of systemic infection due to yeasts. • Identify appropriate treatment options for patients with an infection due to Candida species or Cryptococcus species.

3 Outline

Invasive Candidiasis • Background and Epidemiology • Candida Colonization • Antifungal Review • Prophylaxis • Risk Factors • Signs & Symptoms • Diagnosis • Empiric Therapy • Definitive Management Invasive Candidiasis Case

KC is a 52 year old M with PMH of diabetes and necrotizing pancreatitis (10/2018). The patient is presenting to the hospital from skilled nursing facility (SNF) with fever, hypotension, and concern for sepsis. The patient has been receiving intermittent TPN for the previous month. Past Surgical History: surgical debridement of pancreas 10/2018 Social History: SNF resident Allergies: None

Labs Microbiology WBC: 12,400 Blood Culture #1: Yeast (GS) SCr: 2.0 mg/dL Blood Culture #2: Yeast (GS) Tmax: 103°F Urine Culture: NG BP: 110/60 Stool Culture: NG Epidemiology of Invasive Candidiasis

• Common healthcare-associated infection with 46,000

• Candidemia is the most common type invasive candidiasis

• According to the Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network (NHSN) • Fourth most common cause of hospital-acquired bloodstream infection • Fifth most common hospital-acquired infection

6 Yapar N. Ther Clin Risk Manag. 2014;10:95-105. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Epidemiology of Invasive Candidiasis

Candidemia incidence rates per 100,000 persons-years by area and surveillance period 35 31

30 years - 25 24 25 23

15 14 14 14 14 14 11 9 9 10 8 7

Incidence per 100,000 person 100,000 per Incidence 5

0 1991 - 1993 1998 - 2000 2008 - 2009 2009 - 2010 2010 - 2011 2011 - 2012 2012 - 2013 Atlanta Baltimore Connecticut San Francisco Year of surveillance

Centers for Disease Control. Invasive Candidiasis Statistics. https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html#five. Accessed February 21, 2019. Epidemiology of Invasive Candidiasis

• Greater than 150 Candida species exist, roughly 95% of infections are due to the following organisms:

Candida Candida Candida albicans glabrata parapsilosis

Candida Candida tropicalis krusei

Candida auris

Yapar N. Ther Clin Risk Manag. 2014;10:95-105. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Candida species Colonization in the Non-neutropenic Adult

Lower Genitourinary respiratory tract tract

Skin and Gastrointestinal oropharynx tract

Yapar N. Ther Clin Risk Manag. 2014;10:95-105. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Respiratory Tract Colonization

• Candida species colonize up to ½ of all healthy persons respiratory tract

• Biopsies & BAL specimens in ventilated patients has isolated Candida species in 40 – 50% of patients

• No prospective human studies exist displaying the efficacy of treating Candida species colonization of the respiratory tract

How to differentiate colonization from pneumonia?

Pendleton KM et al. Pathog Dis. 2017;75(3). Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Genitourinary Colonization

• Patients most likely to have candiduria

Indwelling Elderly Female Diabetic Urinary Device

Antibiotic Urological Exposure Procedure

• Treatment of candiduria is recommended for following populations: • Symptomatic Candida cystitis or pyelonephritis • Patients undergoing a urological procedure

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Pendleton KM et al. Pathog Dis. 2017;75(3) Skin and Oropharynx Colonization

• Candida species are considered normal host microbiota of the oral cavity and skin

• Rarely a pathogen in the immunocompetent individual

• Can be implicated in surgical site infections or other deep-seated skin soft tissue infections How to differentiate colonization from true infection?

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Pendleton KM et al. Pathog Dis. 2017;75(3). Kaya D et al. Wounds. 2007;19(8):218-22. Stevens DL et al. Clin Infect Dis. 2014;59(2):e10-52. Gastrointestinal Tract Colonization

• Estimated 30 – 60% of healthy individuals carry Candida species

• Candida species are cultured from ~20% with perforations

• Isolation of Candida species on culture may not always necessitate the need for antifungal therapy

How to differentiate colonization from true infection?

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Solomkin JS et al. Surg Infect (Larchmt). 2010;11(1):79-109. Hallen-adams HE, Suhr MJ. Virulence. 2017;8(3):352-358. FLU: fluconazole ITR: itraconazole VOR: voriconazole POS: posaconazole Antifungal Therapy – Azoles ISA: isavuconazonium sulfate

Mechanism of action: Inhibit conversion of lanosterol to ergosterol • Fungistatic against Candida species

Organism FLU ITR VOR POS ISA C. albicans ++ ++ ++ ++ ++ C. glabrata + + ++ ++ ++ C. parapsilosis ++ ++ ++ ++ ++ C. tropicalis ++ ++ ++ ++ ++ C. krusei - + ++ ++ ++

Key Points: • Fluconazole is active against many clinically significant yeasts • Candida glabrata minimum inhibitory concentrations (MICs) are often higher for fluconazole • Fluconazole is not active against Candida krusei

Nett JE et al. Infect Dis Clin North Am. 2016;30(1):51-83. Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online, Hudson, Ohio:Wolters Kluwer Clinical Drug Information, Inc.; 2013; February 26, 2019. FLU: fluconazole ITR: itraconazole VOR: voriconazole POS: posaconazole Antifungal Therapy – Azoles ISA: isavuconazonium sulfate

FLU ITR VOR POS ISA Formulations PO/IV PO PO/IV PO/IV PO/IV t½ 20 – 50 hours 16 – 28 hours 6 hours 24 hours 72 hours Primary Non-CYP CYP2C19 CYP3A4 CYP2C19 CYP3A4 Metabolism Mediated High Cap: 55% Susp: high fat High bioavailability absorbed in High meal & acidic pH bioavailability acidic bioavailability required Penetrates many environment H O soluble Unique 2 body tissues well Variances in DR Tab: prodrug of Characteristics Sol: 80% metabolism via unaffected by isavuconazole Renal excretion: absorbed CYP2C19 effect gastric pH 60 – 80% unaffected by pH metabolism Causes QT unchanged shortening Class-wide: GI upset, rash, HA, & hepatoxicity Adverse Effects QT prolongation amongst all agents except ISA Contraindicated in pregnancy due to established link to birth defects Cost $ $$ $$ $$$ $$$

Mechanism of Action: Inhibits 1,3-beta-D glucan synthase • Fungicidal against Candida species

Organism Micafungin Anidulafungin Caspofungin C. albicans ++ ++ ++ C. glabrata ++ ++ ++ C. parapsilosis + + + C. tropicalis ++ ++ ++ C. krusei ++ ++ ++

Key Points: • Echinocandins demonstrate very similar activity against Candida species • Candida parapsilosis often exhibits higher MICs • Rates of Candida glabrata resistance to echinocandins range from <2 – 14%

Micafungin Anidulafungin Caspofungin Formulations IV IV IV Poorly absorbed via GI tract resulting in IV administration

t½ = 10 – 24 hours Pharmacokinetic Micafungin and caspofungin undergo hepatic metabolism considerations No therapeutic drug monitoring required

Highly protein bound 96 – 99% Well tolerated overall Adverse Effects Class-wide: Elevation of LFTs, infusion-reactions, GI upset & HA

• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, could be used in high-risk patients in adult ICUs with a high rate (>5%) of invasive candidiasis (weak recommendation; moderate-quality evidence).

Garbino et al. Pelz et al. (2001)

Prospective, double-blind, Prospective, randomized, Design placebo-controlled single- Design placebo-controlled, single- center study center study PO Fluconazole 100 mg or PO Fluconazole 400 mg or Intervention Intervention placebo placebo Time to occurrence of Primary Development of severe Primary fungal infection during the Endpoint Candida species infection Endpoint surgical ICU stay Kaplan-Meier curves showing time to proven infection, Kaplan-Meier estimates of the percentages of fluconazole-and intent-to-treat analysis placebo-treated patients who remained free of candidemia. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Pelz RK et al. Ann Surg. 2001;233(4):542-8. Garbino J et al. Intensive Care Med. 2002;28(12):1708-17. Symptomatology and Presentation

• Commonly present in patients already sick with other medical conditions

• Symptoms vary based on infection site and severity

Candidemia Intra-abdominal Endophthalmitis

Endocarditis Osteomyelitis Meningitis

Yapar N. Ther Clin Risk Manag. 2014;10:95-105. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. At Risk Populations

Host Related Factors Healthcare Associated Factors Immunosuppressive disease Long hospital or ICU stay Neutropenia Receipt of total parenteral nutrition Elderly age Recent major surgery Severity of illness Central venous catheters Candida colonization Previous receipt of antimicrobial therapy Necrotizing pancreatitis Dialysis

Yapar N. Ther Clin Risk Manag. 2014;10:95-105. Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. At Risk Populations

A bedside scoring system (“Candida score”) for early antifungal Candida Score Points treatment in non-neutropenic critically ill patients with Surgery 1 Candida colonization (2006) TPN 1 Prospective, cohort, observational, multicenter Design Severe sepsis 2 study Multifocal 1 Sampled tracheal aspirates, pharyngeal exudates, colonization Methods gastric aspirates and urine & other foci at discretion of the attending physician Patients with a score >2.5 are 7.75 times as likely to have a Four risk factors identified as independently proven infection than patients Results associated with greater risk for proven Candida with a score up to 2.5 species infection (RR = 7.75; 95% CI, 4.47 – 12.66)

Definitions: Colonization defined as persistence of Candida positive cultures at two weekly consecutive sets Multifocal colonization: simultaneous isolation from various noncontiguous foci

León C et al. Crit Care Med. 2006;34(3):730-7. At Risk Populations

Evaluation of “Candida score” in critically ill patients: a prospective, multicenter, observational, cohort study (2011) Design Prospective, observational cohort, observational, multicenter study Sample Adults with hospital-acquired severe sepsis or septic shock amongst 5 ICUs Sampling of tracheal aspirates and urine – other foci tested at discretion of the attending Methods physician % of patients with proven Candida Score N invasive candidiasis 2 44 0 Results 3 29 0 4 17 17.6 5 2 50 The association between increasing values of the “Candida score” and the rate of invasive Conclusion candidiasis was statistically significant (p < 0.0001)

Leroy G et al. Ann Intensive Care. 2011;1(1):50. Identifying Invasive Candidiasis

Blood Culture

•50% sensitivity for Candida species •Median time to positivity 2 – 3 days

Fungal Blood Culture

•May decrease time to positivity for some Candida species

1-3-β-D-glucan

•Not specific to Candida species •Limited by sensitivity and specificity which varies widely •Potential for false positives

Candida PCR

•Role not yet established in clinical practice

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Nawrot U et al. Eur J Clin Microbiol Infect Dis. 2015;34(1):161-167. Audience Question

Which Candida species typically has higher MICs to echinocandins making fluconazole the preferred therapy? 1. Candida albicans 2. Candida glabrata 3. Candida parapsilosis 4. Candida tropicalis 5. Candida krusei

Answer: Candida parapsilosis Empiric Invasive Candidiasis Treatment

Initial Empiric Therapy for Non-neutropenic ICU Patients

• Echinocandins recommended as initial therapy • Fluconazole is an acceptable alternative in patients who are not critically ill & unlikely to have fluconazole-resistant

Management without Definite Infection

• Patients without clinical response at 4 – 5 days & do not have further evidence of infection after therapy initiation or have negative non-culture- based diagnostic assay with a high negative predictive value, consideration should be given to stopping antifungal therapy

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Empiric Invasive Candidiasis Treatment

Anidulafungin versus fluconazole for invasive candidiasis (2007) Design Randomized, double-blind, non-inferiority trial Determine the non-inferiority of anidulafungin to fluconazole for the Objective treatment of invasive candidiasis in adults patients Sample Patients >16 years of age with invasive candidiasis • >48 hours of systemic antifungal therapy for the current episode • Prophylactic administration of azole for >1 week, within 30 days before Exclusion enrollment Criteria • Refractory Candida species infection • Elevated levels of hepatic enzymes • Candida krusei infection, osteomyelitis, endocarditis, or meningitis Primary Percent of patients achieving global response defined as both clinical Endpoint success and microbiologic success

Clinical success1: resolution of signs/symptoms & no need for additional therapy Microbiologic success2: eradication of Candida species present as baseline from follow-up culture

Reboli AC et al. N Engl J Med. 2007;356(24):2472-82. Empiric Invasive Candidiasis Treatment

Results Anidulafungin Fluconazole

Primary 75.6% 60.2% 95% (CI 3.9 – 27.0) Endpoint Observed 13% 24% P = 0.49 Failure Anidulafungin is non-inferior to fluconazole for the treatment of Conclusion invasive candidiasis

Clinical success1: resolution of signs/symptoms & no need for additional therapy Microbiologic success2: eradication of Candida species present as baseline from follow-up culture

Reboli AC et al. N Engl J Med. 2007;356(24):2472-82. Empiric Invasive Candidiasis Treatment

Initial Empiric Therapy for Non-neutropenic ICU Patients

• Echinocandins recommended as initial therapy • Fluconazole is an acceptable alternative in patients who are not critically ill & unlikely to have fluconazole-resistant

Management without Definite Infection

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Definitive Management of Invasive Candidiasis

Azole Step-down

• Transition to fluconazole (usually within 5 – 7 days) is recommended for clinically stable patients with isolates susceptible to fluconazole, and have negative repeat blood cultures

Duration of Therapy

• Two weeks of therapy from clearance of bloodstream without evidence of metastatic complications

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Treatment Summary Candidemia Intra-Abdominal

Anidulafungin 200mg x1, then 100mg qDay Preferred Caspofungin 70mg x1, then 50mg qDay Empiric Therapy Micafungin 100mg qDay

Alternative for Non-ICU Low Fluconazole 800mg (12mg/kg) x1, then 400mg (6mg/kg) qDay Risk Patients Determined by achievement of Duration Two weeks from negative culture source control Organism Specific Considerations

Fluconazole 800mg (12mg/kg) daily OR C. glabrata Voriconazole 400mg (6mg/kg) BID x1 day, then 200 – 300mg (3 – 4mg/kg) BID

Azole and/or Liposomal Amphotericin B Echinocandin (3 - 5mg/kg) qDay Resistant

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Invasive Candidiasis Case

Day #1 Day #2 WBC: 12,400 WBC: 10,700 Tmax: 103°F Tmax: 100.6°F Fluconazole 800mg IV once Fluconazole 400mg IV q24 hr

Blood Culture x2: Yeast (Gram Stain) Blood Culture: No Growth x2 Urine: Pending Urine: Pending

Day #3 Day #4

WBC: 9,900 WBC: 7,700

Tmax: 99.2°F Tmax: Afebrile

Fluconazole 400mg IV q24 hr Fluconazole 400mg IV q24 hr

Blood Culture: Yeast x2 Day1 Blood Culture: Candida parapsilosis Repeat Blood Culture: Pending Repeat Blood Culture: NG Final Considerations

Managing Candidemia

•Document bloodstream clearance •Remove CVC when able •Rule out endophthalmitis

Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50. Audience Question

A 32 year old male with no PMH presents to the ED with SOB and a RLL consolidation on CXR. Sputum cultures obtained grow Haemophilus influenzae and scant Candida albicans. The patient has been receiving ampicillin/sulbactam, and the resident wants to know how they should proceed with treatment.

What is the most appropriate response? 1. Initiate fluconazole PO 800 mg x1, then 400 mg qDay 2. Obtain repeat sputum cultures to prove true infection 3. Ignore the Candida and monitor for improvement as it likely represents colonization and not true infection

Answer: Ignore and monitor for improvement Outline

Invasive Candidiasis • Background and Epidemiology • Risk Factors • Signs & Symptoms • Diagnosis • Treatment Cryptococcosis Case

IR is 28 year old Male with PMH vertically transmitted HIV who has been on ART approximately 6 months after entering a committed relationship. Patient was at work when he experienced 2 seizure like episode prompting coworkers to call EMS. Past Surgical History: None Allergies: None

Labs CSF Analysis WBC: 9,100 Clarity: Cloudy SCr: 0.9 mg/dL WBC: 540 Tmax: 98.6°F Lymphocytes: 79 BP: 119/72 Glucose: 33 mg/dL CD4: 39 (3%) Protein: 64 mg/dL HIV VL: Undetectable Cryptococcal Ag: Positve Epidemiology - Cryptococcosis

• Cryptococcus species are yeasts found ubiquitous in the environment • Soil • Decaying wood • Tree Bark • Bird droppings

• Two species of Cryptococcus have been identified as causing infection in humans • Cryptococcus neoformans (C. neoformans) • Cryptococcus gattii (C. gattii)

Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019. C. neoformans vs C. gattii

• Infections due to C. gattii occur primarily seen in healthy hosts

• Meningoencephalitis infection with C. gattii: • ↑ Neurological complications • Delayed response to therapy • ↑ Incidence of neurosurgical intervention

• Pharmacotherapy does not differ based on causative organism

Nett JE et al. Infect Dis Clin North Am. 2016;30(1):51-83. Epidemiology - Cryptococcosis

• Infection rates have decreased significantly since the 1990s with the advent of antiretroviral therapy (ART)

• Estimated 100 million cases of cyptococcosis annually worldwide • Cryptococcal meningitis responsible for 181,000 deaths per year

• Infection is remarkably more common in resource-limited countries

Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019. At Risk Patients

• Infection is rare among people with healthy immune systems

• Patient populations at greatest risk: • HIV/AIDS • Bone marrow transplant • On immunosuppressive therapies

Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019. Disease Spectrum

Non- pulmonary or Pulmonary CNS Meningeal

• Cryptococcus meningoencephalitis carries the highest morbidity and mortality associated with disease • Three month mortality rate of approximately 20%

Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019. Symptomatology and Presentation

Meningoencephalitis

• Headache • Fever • Neck pain • Nausea & Vomiting • Light sensitivity • Confusion or behavioral changes

• Cryptococcal disease can be diagnosed through culture, CSF microscopy, or by cryptoccocal antigen (Ag)

• Serum cryptococcal Ag can be positive in both meningeal and non- meningeal disease

• CSF cryptococcal Ag is often positive in patients with CNS disease

• Typical CSF: • ↑ Protein • Low - normal glucose • Pleocytosis with lymphocytic predominance

Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 2nd, 2019. Antifungal Therapy - Polyenes

Mechanism of Action: Bind ergosterol within fungal cell membrane • Fungicidal against Candida species and Cryptococcus species Amphotericin B Liposomal Amphotericin B deoxycholate amphotericin B lipid complex (AmB Deoxycholate) (L-AmB) (ABLC) Cryptococcus species ++ ++ ++ C. albicans ++ ++ ++ C. glabrata ++ ++ ++ C. paropsilosis ++ ++ ++ C. tropicalis ++ ++ ++ C. krusei ++ ++ ++

Nett JE et al. Infect Dis Clin North Am. 2016;30(1):51-83. Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322. Antifungal Therapy - Polyenes

Mechanism of Action: Bind ergosterol within fungal cell membrane • Fungicidal against Candida species and Cryptococcus species AmB deoxycholate L-AmB ABLC Poor CNS Improved ability for Vd: 131 L/kg penetration CNS penetration Pharmacokinetics t½ = 15 days t½ = 5 – 50 days t ½ = 5 – 10 days Class-wide: Nephrotoxicity, electrolyte imbalances, infusion reactions, & hepatotoxicity Concomitant IV fluid administration utilized to help prevent the Adverse Effects development of nephrotoxicity Pre-treatment with NSAIDs, antihistamines, & steroids may help prevent infusion reactions Cost $$ $$$ $$$

Nett JE et al. Infect Dis Clin North Am. 2016;30(1):51-83. Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322. Bellmann R et al. Clin Infect Dis. 2003;36(11):1500-1. Antifungal Therapy – Flucytosine

Mechanism of Action: Impairs fungal nucleic acid synthesis • Active against Candida and Cryptococcus species • Rarely utilized as monotherapy for Candida species infections due to rapid development of resistance

Flucytosine Formulation PO 80% absorbed orally

Pharmacokinetics t½ = 2 – 5 hours

90% excreted in urine as unchanged drug

Dose dependent bone marrow toxicities (anemia, leukopenia, thrombocytopenia) Adverse Effects Hepatotoxicity, gastrointestinal upset, and rash Contraindicated in pregnancy

Nett JE et al. Infect Dis Clin North Am. 2016;30(1):51-83. Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322. Cyptococcal Meningoencephalitis Treatment in HIV

Induction (2 Weeks)

• AmB deoxycholate 0.7 – 1.0mg/kg qDay + Flucytosine 25mg/kg QID • Alternative: Substitute AmB deoxycholate for liposomal formulation

Consolidation (8 Weeks)

• Fluconazole 400mg (6mg/kg) qDay

Maintenance (Suppressive & Prophylactic Therapy)

• Fluconazole 200mg qDay • Alternative: Itraconazole 200mg BID

Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322. Cyptococcal Meningoencephalitis Treatment in HIV

Combination Antifungal Therapy for Cryptococcal Meningitis (2013) Design Randomized, three-group, open-label trial Determine outcomes of patients that receive AmB deoxycholate Objective monotherapy, AmB deoxycholate + flucytosine, and AmB deoxycholate + fluconazole Patients >14 years of age with HIV, S&S of cryptococcal Patient meningoencephalitis, & either positive CSF stain, CSF or blood Population cryptococcal Ag, CSF or blood culture Co-Primary 14-day and 70-day all-cause mortality Endpoint Moraltiy at 6 months Secondary Time to CSF sterilization Endpoints Adverse events during first 10 weeks of therapy Changes in CSF fungal counts

Day JN et al. N Engl J Med. 2013;368(14):1291-302. Cyptococcal Meningoencephalitis Treatment in HIV

Kaplan–Meier curve estimating survival according to treatment group • Fewer deaths occurred by days 14 and 70 among patients receiving AmB deoxycholate and flucytosine vs those receiving AmB deoxycholate alone • 14 Day: HR 0.57; 95% CI 0.30 to 1.08; p = 0.08 • 70 Day: HR 0.61; 95% CI, 0.39 to 0.97; p = 0.04 • Combination therapy with fluconazole had no significant effect on survival

Day JN et al. N Engl J Med. 2013;368(14):1291-302. Last but not yeast! Immune Reconstitution Inflammatory Syndrome (IRIS) & ART Initiation

• IDSA & AIDS Info Guidelines: Initiate ART between 2 – 10 weeks after diagnosis • Cochrane review of four studies suggest higher rates of mortality when ART initiated within 4 weeks of diagnosis • Consensus: Consider 4 – 10 weeks for ART initiation and ensure close monitoring of intracranial pressures

Duration of Maintenance Therapy

• Discontinuation of maintenance therapy can be considered for patients with sustained absolute CD4 counts >100 cells/uL and undetectable or very low viral loads for >3 months

Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322. Eshun-wilson T et al. Cochrane Database Syst Rev. 2018;7:CD009012. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 2nd, 2019. Cryptococcus Case

Induction

AmB deoxycholate 1mg/kg + Flucytosine 25 mg/kg QID for 2 weeks

Consolidation

Fluconazole 400 mg qDay for 8 weeks

Maintenance ART held upon diagnosis and planned to re- Fluconazole 200 mg qDay initiate outpatient between four to ten weeks

50 Assessment Questions

1. Which Candida species is intrinsically resistant to fluconazole? 1. Candida albicans 2. Candida glabrata 3. Candida parapsilosis 4. Candida tropicalis 5. Candida krusei

Answer: Candida krusei Assessment Questions

2. What class of antifungals is the preferred initial therapy in critically patients with suspected invasive candidiasis? 1. Echinocandin 2. Azole 3. Polyene 4. Pyrimidine analogue

Answer: Echinocandin Assessment Questions

3. At which of the following anatomical sites can Candida species be a colonizer? 1. Urinary tract 2. Gastrointestinal tract 3. Sputum 4. All of the above

Answer: All of the above Assessment Questions

4. The treatment of Cryptococcus meningoencephalitis is broken down into the phases of induction, consolidation, and maintenance. 1. True 2. False

Answer: True Assessment Questions

5. Which treatment regimen is preferred for induction therapy in cryptococcal meningoencephalitis and has been shown to have decreased mortality compared to alternative regimens? 1. AmB deoxycholate monotherapy 2. AmB deoxycholate plus flucytosine 3. AmB deoxycholate plus fluconazole

Answer: AmB deoxycholate plus flucytosine

55 References

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Austin Area Society of Health-Systems Pharmacists March 13, 2019 Mike McAlister, Pharm.D. PGY2 Infectious Diseases Pharmacy Resident Seton Healthcare Family, Austin TX