nature of the yeast! therapeutic approach to common ... · 13/03/2019 · •recognize antifungals...
TRANSCRIPT
ASCENSION TEXAS
Austin Area Society of Health-Systems Pharmacists
March 13, 2019
Mike McAlister, PharmD
PGY2 Infectious Diseases Pharmacy Resident
Seton Healthcare Family, Austin TX
Nature of the Yeast! Therapeutic Approach to Common Invasive Yeast
Infections
• 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
Pharmacist 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
Pharmacy Technician Objectives
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 10/2018Social History: SNF resident Allergies: None
Labs
WBC: 12,400
SCr: 2.0 mg/dL
Tmax: 103°F
BP: 110/60
Microbiology
Blood Culture #1: Yeast (GS)
Blood Culture #2: Yeast (GS)
Urine Culture: NG
Stool Culture: NG
• 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
Epidemiology of Invasive Candidiasis
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 CandidiasisIn
cid
en
ce p
er
10
0,0
00
pe
rso
n-y
ears
Year of surveillance
9
14 14 14
119
24
31
2523
14 14
78
0
5
10
15
20
25
30
35
1991 - 1993 1998 - 2000 2008 - 2009 2009 - 2010 2010 - 2011 2011 - 2012 2012 - 2013
Candidemia incidence rates per 100,000 persons-years by area and surveillance period
Atlanta Baltimore Connecticut San Francisco
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:
Yapar N. Ther Clin Risk Manag. 2014;10:95-105.Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
Candida albicans
Candida glabrata
Candida parapsilosis
Candida tropicalis
Candida krusei
Candida auris
Candida species Colonization in the Non-neutropenic Adult
Yapar N. Ther Clin Risk Manag. 2014;10:95-105.Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
Lower respiratory tract
Genitourinary tract
Skin and oropharynx
Gastrointestinal tract
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
Pendleton KM et al. Pathog Dis. 2017;75(3).Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
How to differentiate colonization from pneumonia?
Genitourinary Colonization
• Patients most likely to have candiduria
• 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)
Elderly Female DiabeticIndwelling
Urinary Device
Antibiotic Exposure
Urological Procedure
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
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.
How to differentiate colonization from true infection?
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
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.
How to differentiate colonization from true infection?
Antifungal Therapy – Azoles
Mechanism of action: Inhibit conversion of lanosterol to ergosterol• Fungistatic against Candida species
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
Organism FLU ITR VOR POS ISA
C. albicans ++ ++ ++ ++ ++
C. glabrata + + ++ ++ ++
C. parapsilosis ++ ++ ++ ++ ++
C. tropicalis ++ ++ ++ ++ ++
C. krusei - + ++ ++ ++
FLU: fluconazoleITR: itraconazole
VOR: voriconazolePOS: posaconazole
ISA: isavuconazonium sulfate
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.
Antifungal Therapy – Azoles
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 Metabolism
CYP2C19 CYP3A4 CYP2C19Non-CYP Mediated
CYP3A4
UniqueCharacteristics
High bioavailability
Penetrates many body tissues well
Renal excretion: 60 – 80%
unchanged
Cap: 55% absorbed in
acidic environment
Sol: 80% absorbed
unaffected by pH
High bioavailability
Variances in metabolism via CYP2C19 effect
metabolism
Susp: high fat meal & acidic pH
required
DR Tab: unaffected by
gastric pH
High bioavailability
H2O soluble prodrug of
isavuconazole
Causes QT shortening
Adverse EffectsClass-wide: GI upset, rash, HA, & hepatoxicityQT prolongation amongst all agents except ISA
Contraindicated in pregnancy due to established link to birth defects
Cost $ $$ $$ $$$ $$$
FLU: fluconazoleITR: itraconazole
VOR: voriconazolePOS: posaconazole
ISA: isavuconazonium sulfate
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.
Antifungal Therapy – Echinocandins
Mechanism of Action: Inhibits 1,3-beta-D glucan synthase• Fungicidal against Candida species
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%
Organism Micafungin Anidulafungin Caspofungin
C. albicans ++ ++ ++
C. glabrata ++ ++ ++
C. parapsilosis + + +
C. tropicalis ++ ++ ++
C. 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.
Antifungal Therapy – Echinocandins
Micafungin Anidulafungin Caspofungin
Formulations IV IV IV
Pharmacokineticconsiderations
Poorly absorbed via GI tract resulting in IV administration
t½ = 10 – 24 hours
Micafungin and caspofungin undergo hepatic metabolism
No therapeutic drug monitoring required
Highly protein bound 96 – 99%
Adverse Effects
Well tolerated overall
Class-wide: Elevation of LFTs, infusion-reactions, GI upset & HA
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.
Pelz et al. (2001)
DesignProspective, randomized,
placebo-controlled, single-center study
InterventionPO Fluconazole 400 mg or
placebo
Primary Endpoint
Time to occurrence of fungal infection during the
surgical ICU stay
• 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).
Invasive Candidiasis Prophylaxis
Kaplan-Meier curves showing time to proven infection, intent-to-treat analysis
Garbino et al.
DesignProspective, double-blind, placebo-controlled single-
center study
InterventionPO Fluconazole 100 mg or
placebo
Primary Endpoint
Development of severe Candida species infection
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.
Kaplan-Meier estimates of the percentages of fluconazole-and placebo-treated patients who remained free of candidemia.
Symptomatology and Presentation
• Commonly present in patients already sick with other
medical conditions
• Symptoms vary based on infection site and severity
Yapar N. Ther Clin Risk Manag. 2014;10:95-105.Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
Candidemia Intra-abdominal Endophthalmitis
Endocarditis Osteomyelitis Meningitis
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 treatment in non-neutropenic critically ill patients with
Candida colonization (2006)
DesignProspective, cohort, observational, multicenter
study
Methods
Sampled tracheal aspirates, pharyngeal exudates, gastric aspirates and urine & other foci at discretion
of the attending physician
Results
Four risk factors identified as independently associated with greater risk for proven Candida
species infection
Definitions:Colonization defined as persistence of Candida positive cultures at two weekly consecutive setsMultifocal colonization: simultaneous isolation from various noncontiguous foci
Candida Score Points
Surgery 1
TPN 1
Severe sepsis 2
Multifocal colonization
1
Patients with a score >2.5 are 7.75 times as likely to have a
proven infection than patients with a score up to 2.5
(RR = 7.75; 95% CI, 4.47 – 12.66)
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
MethodsSampling of tracheal aspirates and urine – other foci tested at discretion of the attending
physician
Results
Candida Score N% of patients with proven
invasive candidiasis
2 44 0
3 29 0
4 17 17.6
5 2 50
ConclusionThe association between increasing values of the “Candida score” and the rate of invasive
candidiasis was statistically significant (p < 0.0001)
Leroy G et al. Ann Intensive Care. 2011;1(1):50.
Identifying Invasive Candidiasis
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.
•50% sensitivity for Candida species
•Median time to positivity 2 – 3 days
Blood Culture
•May decrease time to positivity for some Candida species
Fungal Blood Culture
•Not specific to Candida species
•Limited by sensitivity and specificity which varies widely
•Potential for false positives
1-3-β-D-glucan
•Role not yet established in clinical practice
Candida PCR
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
25
Empiric Invasive Candidiasis Treatment
• Echinocandins recommended as initial therapy
• Fluconazole is an acceptable alternative in patients who are not critically ill & unlikely to have fluconazole-resistant
Initial Empiric Therapy for Non-neutropenic ICU Patients
• 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
Management without Definite Infection
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
ObjectiveDetermine the non-inferiority of anidulafungin to fluconazole for the
treatment of invasive candidiasis in adults patients
Sample Patients >16 years of age with invasive candidiasis
Exclusion Criteria
• >48 hours of systemic antifungal therapy for the current episode• Prophylactic administration of azole for >1 week, within 30 days before
enrollment• Refractory Candida species infection• Elevated levels of hepatic enzymes• Candida krusei infection, osteomyelitis, endocarditis, or meningitis
Primary Endpoint
Percent of patients achieving global response defined as both clinical success and microbiologic success
Reboli AC et al. N Engl J Med. 2007;356(24):2472-82.
Clinical success1: resolution of signs/symptoms & no need for additional therapyMicrobiologic success2: eradication of Candida species present as baseline from follow-up culture
Empiric Invasive Candidiasis Treatment
Anidulafungin versus fluconazole for invasive candidiasis (2007)
Design Randomized, double-blind, non-inferiority trial
ObjectiveDetermine the non-inferiority of anidulafungin to fluconazole for
the treatment of invasive candidiasis in adults patients
Results Anidulafungin Fluconazole
Primary
Endpoint75.6% 60.2% 95% (CI 3.9 – 27.0)
Observed
Failure13% 24% P = 0.49
ConclusionAnidulafungin is non-inferior to fluconazole for the treatment of
invasive candidiasis
Reboli AC et al. N Engl J Med. 2007;356(24):2472-82.
Clinical success1: resolution of signs/symptoms & no need for additional therapyMicrobiologic success2: eradication of Candida species present as baseline from follow-up culture
28
Empiric Invasive Candidiasis Treatment
• Echinocandins recommended as initial therapy
• Fluconazole is an acceptable alternative in patients who are not critically ill & unlikely to have fluconazole-resistant
Initial Empiric Therapy for Non-neutropenic ICU Patients
• 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
Management without Definite Infection
Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
• 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
Azole Step-down
• Two weeks of therapy from clearance of bloodstream without evidence of metastatic complications
Duration of Therapy
29
Definitive Management of Invasive Candidiasis
Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
Candidemia Intra-Abdominal
Preferred Empiric Therapy
Anidulafungin 200mg x1, then 100mg qDayCaspofungin 70mg x1, then 50mg qDay
Micafungin 100mg qDay
Alternative for Non-ICU Low Risk Patients
Fluconazole 800mg (12mg/kg) x1, then 400mg (6mg/kg) qDay
Duration Two weeks from negative cultureDetermined by achievement of
source control
Organism Specific Considerations
C. glabrataFluconazole 800mg (12mg/kg) daily OR
Voriconazole 400mg (6mg/kg) BID x1 day,then 200 – 300mg (3 – 4mg/kg) BID
Azole and/or Echinocandin
Resistant
Liposomal Amphotericin B (3 - 5mg/kg) qDay
Treatment Summary
Pappas PG et al. Clin Infect Dis. 2016;62(4):e1-50.
Invasive Candidiasis Case
Day #1
WBC: 12,400
Tmax: 103°F
Fluconazole 800mg IV once
Blood Culture x2: Yeast (Gram Stain)Urine: Pending
Day #2
WBC: 10,700
Tmax: 100.6°F
Fluconazole 400mg IV q24 hr
Blood Culture: No Growth x2Urine: Pending
Day #3
WBC: 9,900
Tmax: 99.2°F
Fluconazole 400mg IV q24 hr
Blood Culture: Yeast x2Repeat Blood Culture: Pending
Day #4
WBC: 7,700
Tmax: Afebrile
Fluconazole 400mg IV q24 hr
Day1 Blood Culture: Candida parapsilosisRepeat Blood Culture: NG
•Document bloodstream clearance
•Remove CVC when able
•Rule out endophthalmitis
Managing Candidemia
32
Final Considerations
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 qDay2. Obtain repeat sputum cultures to prove true infection3. 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
CSF Analysis
Clarity: Cloudy
WBC: 540
Lymphocytes: 79
Glucose: 33 mg/dL
Protein: 64 mg/dL
Cryptococcal Ag: Positve
Labs
WBC: 9,100
SCr: 0.9 mg/dL
Tmax: 98.6°F
BP: 119/72
CD4: 39 (3%)
HIV VL: Undetectable
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
• 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.
Non-pulmonary or
MeningealPulmonary CNS
Symptomatology and Presentation
Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019.
• Headache
• Fever
• Neck pain
• Nausea & Vomiting
• Light sensitivity
• Confusion or behavioral changes
Meningoencephalitis
• 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
42
Identifying Cryptococcal Meningoencephalitis
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 deoxycholate
(AmB Deoxycholate)
Liposomal amphotericin B
(L-AmB)
Amphotericin B lipid complex
(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
Pharmacokinetics
Poor CNS penetration
t½ = 15 days
Improved ability for CNS penetration
t½ = 5 – 50 days
Vd: 131 L/kg
t ½ = 5 – 10 days
Adverse Effects
Class-wide: Nephrotoxicity, electrolyte imbalances, infusion reactions, & hepatotoxicity
Concomitant IV fluid administration utilized to help prevent the 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
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.
Flucytosine
Formulation PO
Pharmacokinetics
80% absorbed orally
t½ = 2 – 5 hours
90% excreted in urine as unchanged drug
Adverse Effects
Dose dependent bone marrow toxicities (anemia, leukopenia, thrombocytopenia)
Hepatotoxicity, gastrointestinal upset, and rashContraindicated in pregnancy
46
Cyptococcal Meningoencephalitis Treatment in HIV
• AmB deoxycholate 0.7 – 1.0mg/kg qDay + Flucytosine 25mg/kg QID
• Alternative: Substitute AmB deoxycholate for liposomal formulation
Induction (2 Weeks)
• Fluconazole 400mg (6mg/kg) qDay
Consolidation (8 Weeks)
• Fluconazole 200mg qDay
• Alternative: Itraconazole 200mg BID
Maintenance (Suppressive & Prophylactic Therapy)
Perfect JR et al. Clin Infect Dis. 2010;50(3):291-322.
47
Cyptococcal Meningoencephalitis Treatment in HIV
Combination Antifungal Therapy for Cryptococcal Meningitis (2013)
Design Randomized, three-group, open-label trial
ObjectiveDetermine outcomes of patients that receive AmB deoxycholate
monotherapy, AmB deoxycholate + flucytosine, and AmBdeoxycholate + fluconazole
Patient Population
Patients >14 years of age with HIV, S&S of cryptococcalmeningoencephalitis, & either positive CSF stain, CSF or blood
cryptococcal Ag, CSF or blood culture
Co-Primary Endpoint
14-day and 70-day all-cause mortality
Secondary Endpoints
Moraltiy at 6 monthsTime to CSF sterilization
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.
48
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 AmBdeoxycholate 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!
• 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
Immune Reconstitution Inflammatory Syndrome (IRIS) & ART Initiation
• 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
Duration of Maintenance Therapy
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.
50
Cryptococcus Case
Maintenance
Fluconazole 200 mg qDayART held upon diagnosis and planned to re-
initiate outpatient between four to ten weeks
Consolidation
Fluconazole 400 mg qDay for 8 weeks
Induction
AmB deoxycholate 1mg/kg + Flucytosine 25 mg/kg QID for 2 weeks
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
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
Assessment Questions
References
1. Yapar N. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014;10:95-105.
2. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.
3. Centers for Disease Control. Invasive Candidiasis Statistics. https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html#five. Accessed February 21, 2019.
4. León C, Ruiz-santana S, Saavedra P, et al. A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. CritCare Med. 2006;34(3):730-7.
5. Leroy G, Lambiotte F, Thévenin D, et al. Evaluation of "Candida score" in critically ill patients: a prospective, multicenter, observational, cohort study. Ann Intensive Care. 2011;1(1):50.
6. Pendleton KM, Huffnagle GB, Dickson RP. The significance of Candida in the human respiratory tract: our evolving understanding. Pathog Dis. 2017;75(3)
7. Kaya D, Aldirmaz agartan C, Yucel M. Fungal Agents as a Cause of Surgical Wound Infections: An Overview of Host Factors. Wounds. 2007;19(8):218-22.
8. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-52.
9. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt). 2010;11(1):79-109.
10. Hallen-adams HE, Suhr MJ. Fungi in the healthy human gastrointestinal tract. Virulence. 2017;8(3):352-358.
11. Nawrot U, Kowalska-krochmal B, Sulik-tyszka B, et al. Evaluation of blood culture media for the detection of fungi. Eur J Clin Microbiol Infect Dis. 2015;34(1):161-167.
12. Nett JE, Andes DR. Antifungal Agents: Spectrum of Activity, Pharmacology, and Clinical Indications. Infect Dis Clin North Am. 2016;30(1):51-83.
13. Pelz RK, Hendrix CW, Swoboda SM, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg. 2001;233(4):542-8.
14. Garbino J, Lew DP, Romand JA, Hugonnet S, Auckenthaler R, Pittet D. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med. 2002;28(12):1708-17.
15. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24):2472-82.
16. Centers for Disease Control. C. neoformans Infection Statistics. https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html. Accessed February 25, 2019.
17. Panel on Opportunistic Infections in HIV-Infected Adults andAdolescents. Guidelines for the prevention and treatment ofopportunistic infections in HIV-infected adults andadolescents:recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV MedicineAssociation of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 2nd, 2019.
18. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291-322.
19. Bellmann R, Egger P, Wiedermann CJ. Differences in pharmacokinetics of amphotericin B lipid formulations despite clinical equivalence. Clin Infect Dis. 2003;36(11):1500-1.
20. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291-302.
21. Eshun-wilson I, Okwen MP, Richardson M, Bicanic T. Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis. Cochrane Database Syst Rev. 2018;7:CD009012.
ASCENSION TEXAS
Austin Area Society of Health-Systems Pharmacists
March 13, 2019
Mike McAlister, Pharm.D.
PGY2 Infectious Diseases Pharmacy Resident
Seton Healthcare Family, Austin TX
Nature of the Yeast! Therapeutic Approach to Common Invasive Yeast
Infections