sign in sign up
<<
Home , Candida glabrata, Candida krusei, Candida tropicalis

Epidemiology of Invasive Fungal Infections:

• Candida: Most common and frequently most severe source of fungal infection • 5 principal : , , , , • Multiple species are antimicrobial resistant to 1 or more agents (eg, Candida glabrata, Candida krusei, Candida parapsilosis) Candida albicans • Therapeutic selection varies by species-level susceptibility • Key Takeaways: • Candida glabrata has innate resistance to ; emerging resistance (15-20%) to in some centers (eg, large cancer centers) • Candida parapsilosis has relative resistance to echinocandins versus other strains, but these agents may still be used effectively against it

Candida glabrata : Key Knowledge Points • Aspergillus • Multiple species: Aspergillus fumigatus (dominant), Aspergillus flavus, Aspergillus niger, Aspergillus tereus, others

• Aspergillus has become -resistant in Europe, and in some parts of USA • Cause: Environmental impact of azole use in agriculture/related industries (eg, European flower farming)

• Development of increased azole resistance across Aspergillus strains an ongoing clinical concern /

• Many different fungal species can cause Mucormycosis • Uncontrolled patients are especially at risk • Immunosuppressed patients (eg, hematologic malignancies) also at risk • Can cause severe invasive fungal sinusitis infection as well as severe pulmonary infection • Often affects eyes, face, sinuses, nasal passages • Surgical debridement often required • Requires alternate therapeutic selection versus other organisms Mucormycosis Caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species

Syncephalastrum racemosum Syncephalastraceae Syncephalastrum Apophysomyces Saksenaeaceae Apophysomyces elegans complex Saksenaea Saksenaea vasiformis

Cunninghamella Cunninghamella bertholletiae Cunninghamellacea Mucorales e Actinomucor Actinomucor elegans Mucor Mucoraceae Rhizopus Rhizomucor Rizomucor pusillus

Cokeromyces Thamnidiaceae Cokeromyces recurvatus

Lichtheimia Lichtheimiaceae (former Absidia)

Order Family Genus Unusual species Patient Risk Assessment: Mucormycosis • Poorly controlled diabetes/ketoacidosis • Trauma/burn patients • IV drug abusers • Neonates

Dangers of Mucormycosis: • Necrotizing skin infections • Rhinocerebral infections with necrotizing lesions • Pulmonary mucormycoses in transplant patients • Resistant to most available agents, requires surgical management Community Practice Approach to Invasive Fungal Infections (IFIs): Initial Diagnostics

IV Drug Users: • Identify Patient-Specific Risk Factors, • Mucormycosis and And: other Diabetic Ketoacidosis, • Duration of Risk Cutaneous Lesions on • Any Travel? Burn Patients, Trauma Site Infections: • Prior ? • Mucormycosis and other molds

Post-Hematopoietic Stem Cell Solid Organ Transplants (SOTs): Transplant: • Detailed history and physical ≤ 30 Days→ more likely Candida • Response to antibacterials? > 30 Days→ Invasive Infections • Use of non-invasive diagnostics & need for biopsy? ICU/Critical Care Patients: • Candida • Mold infections=less common • IV drug users/burn patients are a subset of this population

Source: Thompson GR. Expert clinical consultation to ACHL, March 2018. Diagnostics, Susceptibility Testing, and Preventive Therapy Selection in IFIS • Noninvasive Tests for organism identification • Start Treatment BEFORE diagnostic results are in • Some infections require invasive testing for definitive diagnosis • Some organisms are drug resistant: Candida glabrata, Candida krusei, Candida propsilosis • Use radiographic findings for possible and Mucormycosis; revisit after 14 days New IDSA Guidelines 2016

• Infectious Diseases Society of America (IDSA) released 2 new guidelines in 2016:

– remains primary treatment for Invasive Aspergillosis (IA)

– and isavuconazole listed as alternatives for IA – Echinocandins now first-line therapy for (IC)

– Fluconazole now alternative or step- down therapy for IC

Pappas PG, et al. Clin Infect Dis. 2016;62(4):e1-e50. Patterson TF et al. Clin Infect Dis. 2016 Aug 15;63(4):433-42. New IDSA Guidelines 2016

• Voriconazole and Isavuconazole are NOT equivalent in their action against Mucorales • Voriconazole is NOT a treatment option for mucormycosis Links to All Current IFI Guidelines (USA and Europe):

• IDSA Candidiasis Guideline 2016: http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_By_Organism- 28143/Fungi/Candidiasis/ • IDSA Aspergillosis 2016: http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_By_Organism-28143/Fungi/Aspergillus/ • European Mucormycosis Guideline 2013-14 (No U.S. guideline is available): https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)60228-7/fulltext

• European Candidiasis Guideline 2012: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)60763-1/fulltext • European Aspergillosis Guideline 2016: https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(18)30051-X/fulltext?code=cmi-site Why are Echinocandins Preferred for Candidiasis?

• A 2012 study did a head-to head retrospective comparison of Echinocandins, Fluconazole, and Amphotericin B in non-neutropenic patients with candidemia. • Data from 1915 patients from seven randomized trials were compared. • Overall mortality was 31.4% • Rate of treatment success was 67.4% • Treatment with an echinocandins reduced mortality by one-third

Andes DR, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: A patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110-1122. General Susceptibility/Drug Resistance Patterns of Candida Species

Fluconazole Voriconazole Candins AmB

Candida S S S S S S albicans

Candida S-DD to R S-DD to R S-DD to R S-DD to R S S to I glabrata

Candida S S S S S S tropicalis

Candida S S S S S to R S parapsilosis

Candida R S-DD to R S S S S to I krusei

AmB = amphotericin B; S = susceptible; SDD = susceptibility-dose dependent; R = resistant; I = intermediate. Pappas PG, et al. Clin Infect Dis. 2009;48(5):503-535. Mechanism of Action: Voriconazole and Isavuconazole

Mechanism of Action inhibits Substrate – Inhibitor Substrate – Inhibitor Vori Flu Vori Flu isozymes: Itra Vori • 2C9 Vori • 2C19

• 3A4 2C9 2C19 Enzyme System • Isavuconazole is a prodrug P-GP 3A4

Substrate – Inhibitor Substrate – Inhibitor Itra Flu Posa Itra Vori Itra Posa Isa Vori Isa Posa Isa

Bruggemann RJM, et al. Clin Infect Dis. 2009;48:1441. US Food and Drug Administration. Advisory Committee Briefing Document. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiInfective DrugsAdvisoryCommittee/UCM430748.pdf. Accessed February 29, 2016. Molecular Structure: Isavuconazole Spectrum of Activity: Voriconazole and Isavuconazole

• Voriconazole lacks activity against Mucorales • Isavuconazole is effective against Mucorales • Voriconazole possesses more drug-interaction complexity versus Isavuconazole Voriconazole vs. Isavuconazole vs. Posaconazole

• Both drugs available as both PO and IV, BUT… • Voriconazole requires therapeutic drug monitoring • Isavuconazole has more predictable pharmacokinetics= no therapeutic drug monitoring required • Isavuconazole and Posaconazole have similar spectrums of activity (Candida, Aspergillus, Mucorales) – Principal difference: Posaconazole’s clinical data is in prophylaxis, while Isavuconazole’s clinical is in primary treatment • NONE of these drugs are considered interchangeable Head to Head Comparison for Voriconazole vs Isavuconazole: IA and Other Mold

100

90

80 P=<.05

70 59.8 60

50 42.4 40 35 36.4 Percent (%) 30 23.3 18.6 20.2 19.6 20

10

0 All-Cause Proven / Probable Overall Related Adverse Mortality IFI Mortality Response Drug Events

Isavuconazole Voriconazole

Maertens JA, et al. Lancet. 2016;387:760-769.