Nature of the Yeast! Therapeutic Approach to Common ... · 13/03/2019 · •Recognize antifungals utilized in the treatment of infections due Candida species and Cryptococcus species

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

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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


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


Variances in metabolism via CYP2C19 effect

metabolism

Susp: high fat meal & acidic pH

required

DR Tab: unaffected by

gastric pH


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


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


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


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


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

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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



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


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

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• 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


• 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


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


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


Blood Culture: Yeast x2Repeat Blood Culture: Pending

Day #4

WBC: 7,700

Tmax: Afebrile


Day1 Blood Culture: Candida parapsilosisRepeat Blood Culture: NG

•Document bloodstream clearance

•Remove CVC when able

•Rule out endophthalmitis

Managing Candidemia

32

Final Considerations


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


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


Disease Spectrum

• Cryptococcus meningoencephalitis carries the highest

morbidity and mortality associated with disease

• Three month mortality rate of approximately 20%


Non-pulmonary or

MeningealPulmonary CNS

Symptomatology and Presentation


• 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.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf

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


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


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


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


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


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


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.

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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

Documents

Nature of the Yeast! Therapeutic Approach to Common ... · 13/03/2019 · •Recognize antifungals utilized in the treatment of infections due Candida species and Cryptococcus species