Addressing Challenges to Optimal Diagnosis and Treatment ...

This CME activity is provided by Integrity Continuing Education.This CEU/CNE activity is co-provided by Postgraduate Institute for Medicine and Integrity Continuing Education.

Supported by an educational grant from Astellas Pharma US, Inc.

Addressing Challenges to Optimal Diagnosis and Treatment of Invasive Fungal Infections

Faculty

Peter G. Pappas, MD, FACPWilliam E. Dismukes Professor of Medicine

PI, Mycoses Study GroupUniversity of Alabama at Birmingham

Birmingham, Alabama

Research: Amplyx Pharmaceuticals, Astellas Pharma US, Cidara Therapeutics, Gilead Sciences, Inc., IMMY, Merck, Scynexis, T2 Biosystems, Vical

Faculty Disclosures

Identify challenges in the diagnosis of common invasive fungal infections (IFIs) and recognize clinical circumstances that require empirical treatment

Review the emerging patterns and underlying mechanisms of fungal resistance

Describe current guideline recommendations for the treatment of IFIs

Learning Objectives

Introduction

IFIs are a significant cause of serious illness and mortality in immunocompromised patients

Estimated annual incidence in the US:

Transplant and ICU patients, and patients with cancer undergoing chemotherapy, are at extremely high risk for IFIs

Each day appropriate antifungal therapy is delayed is associated with a 50% increase in mortality and an additional $5000 in healthcare costs

Overview

ICU, intensive care unit.Pfaller MA, et al. Future Microbiol. 2015;11(1),103-117; Pfaller MA, et al. Clin Infect Dis. 2006;43(suppl 1):S3-S14.

IFI Infections per million populationCandidiasis 72 to 228

Aspergillosis 12 to 34

Candida – C. albicans

– C. glabrata

– C. tropicalis

– C. parapsilosis

– C. krusei

Aspergillus– A. fumigatus

Mucorales Cryptococcus Histoplasma Coccidioides Blastomyces Phaeohyphomycosis

Common IFIs

IFI Incidence Among Organ Transplant Patients

Kontoyiannis DP, et al. Clin Infect Dis. 2010 Apr 15;50(8):1091-100; Pappas PG, et al. Clin Infect Dis. 2010;50(8):1101-1111.

Transplant-Associated Infection Surveillance Network (TRANSNET)

Cum

ulat

ive

Inci

denc

e (%

)

0 90 180 270 360Days From Transplant

141210

86420

Small BowelLungLiver

PancreasHeartKidney

Overall

IFI Incidence Among Allogeneic Hematopoietic Stem Cell Transplant Patients

Corzo-Leon et al. Mycoses. 2015;58(6):325-36.

TRANSNET: Cumulative Incidence of IFIPr

obab

ility

of I

FI

0 3 6 9 12 15 18 21 24Months After Transplant

0.15

0.10

0.05

0.00

Any IFIAspergillosis

CandidiasisNC/NA IFI

Impact of IFIs in the Hospital Setting

Source: Healthcare Cost and Utilization Project 2004-2005. HSC/BMT, hematopoietic stem cell or bone marrow transplant; SE, standard error, SOT, solid organ transplant.Menzin et al. Am J Infect Control. 2011;39(4):e15-e20.

MeasurePatients With an IFI Patients Without an IFI Difference (All P < .05)

N Mean N Mean MeanMortalityAll patients 187 22.0% 187 4.3% 17.6%SOT 78 20.3% 78 5.1% 15.1%HSCT/BMT 109 23.2% 109 3.8% 19.4%

Lengths of stayAll patients 186 45.6 187 26.3 19.2SOT 77 46.3 78 22.8 23.5HSCT/BMT 109 45.1 109 28.8 16.2

CostsAll patients 162 $165,026 183 $109,587 $55,439SOT 63 $185,253 75 $122,556 $62,697HSCT/BMT 99 $152,360 108 $100,705 $51,655

05

1015202530354045

Culture Day Day 1 Day 2 Day ≥3

Mor

talit

y (%

)

Days to Start of Fluconazole

Importance of Early Diagnosis and Treatment for Invasive Candidiasis

Garey KW, et al. Clin Infect Dis. 2006;43(1):25-31.

Diagnosis

Signs and symptoms are nonspecific

Invasive disease is difficult to distinguish from colonization

Available tests are limited by suboptimal sensitivity and/or specificity

Diagnostic Challenges

Culture and Direct MicroscopyDirect Microscopy

• Frequent false negatives and positives

• Lower sensitivity relative to culture

• Often requires expertise

Culture• Tissue

- Acquisition is challenging• Blood

- Suitable for fragile patients- ~50% sensitivity for

candidemia - Lower for Aspergillus

• Can be time-consuming • Often requires expertise

Guarner J, et al. Clin Microbiol Rev. 2011;24(2):247-280.

Culture-independent Diagnostic Tests: Sensitivity and Specificity

Organism Diagnostic Test Sensitivity (%) Specificity (%)

Candidaspecies

β-D-glucan* 75.3 85.0

Mannan/Anti-mannan* 83.0 86.0

PCR* 95.0 92.0

T2Candida 91.1 99.4

Aspergillusspecies

Galactomannan* 71.0/90.0 (serum/BAL) 89.0/94.0 (serum/BAL)

β-D-Glucan* 77.0 85.0

Lateral-flow device 81.8 98.0

PCR* 88.0/90.2 (serum/BAL) 75.0/96.4 (serum/BAL)

*Meta-analysisBAL, bronchoalveolar fluid.Pfaller MA. Invasive fungal infections and approaches to their diagnosis. In: Andrew S, Tang Y-W, eds. Methods in Microbiology. Philadelphia, PA: Elsevier; 2015.

Relative Advantages and Disadvantages of Diagnostic Tests

Technique Advantages Disadvantages

Culture Methods Gold standard; allows susceptibilities Delay in diagnosis; low sensitivity

PCR Methods Highest accuracy Low commercial ability

β-D-glucan Panfungal marker; high sensitivity and specificity

Many false-positive results; methodological concerns

GalactomannanIncreased accuracy for detection of Aspergillus in hematologic illnesses

Only for Aspergillus; many false-positive results; not useful for non-hematologic illnesses

Mannan + Antimannan

Good specificity and sensitivity with combined use Variable results; limited experience

Pemán J, et al. Mycoses. 2009;53(5):424-433.

Pharmacologic Treatment Options

Timeline of Antifungal Development

1957

Amphotericin B (AMB)

1989

Lipid AMB

2005

Micafungin

1979

Miconazole

1992

Itraconazole

2001

Caspofungin

2006

Anidulafungin

1964

Flucytosine

1980

Ketoconazole

1990

Fluconazole

2002

Voriconazole

1995-97

Lipid AMB SalvageAspergillosis

2015

Isavuconazole

2006

Posaconazole

Adapted from: Chapman SW, et al. Trans Am Clin Climatol Assoc. 2008;119:197-215.

Antifungal Indications by ClassClass Agent Candidiasis Aspergillosis Mucormycosis

Polyenes Amphotericin B

Triazoles

Fluconazole

Itraconazole

Voriconazole

Posaconazole

Isavuconazole Not approved

EchinocandinsCaspofungin

Anidulafungin

Micafungin

Nucleic acid analogues Flucytosine

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

Sites of Therapeutic Action

Adapted from: Moriyama B, et al. Mycoses. 2014;57(12):718-733.

Cell wall synthesisEchinocandins

Membrane functionPolyenes Ergosterol synthesis

Azoles

Nucleic acid synthesis5-Fluorocytosine

Isavuconazole vs Voriconazole for Invasive Aspergillosis

Maertens JA, et al. Lancet. 2016;387(10020):760-769.

Surv

ival

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Study Day

100908070605040302010

0

IsavuconazoleVoriconazole

Treatment difference (95% CI)-1.1 (-8.9 to 6.7) P=.744

Isavuconazole vs Amphotericin B for Invasive Mucormycosis

Marty FM, et al. Lancet Infect Dis. 2016;16(7):828-837.

Surv

ival

Pro

babi

lity

(%) 100

908070605040302010

0

Isavuconazole (n=21)Amphotericin B (n=33)

0 7 14 21 28 35 42 49 56 63 70 77 84

Treatment Day

HR 0.831(95% CI 0.367-1.882); P=.653

Combined Azole and Echinocandin Therapy vs Azole Monotherapy in Invasive Aspergillosis

Marr KA, et al. Ann Intern Med. 2015;162(2):81-89.

Surv

ival

Dis

trib

utio

n Fu

nctio

n 1.00

0.75

0.50

0.25

0.000 1 2 3 4 5 6 7 8 9 10 11 12 13

Time to Death (week)

Voriconazole and anidulafungin (n=135)Voriconazole and placebo (n=142)Censored data

Important Antifungal Drug-Drug InteractionsAntifungal Concerns Drugs to Avoid

Amphotericin B Associated nephrotoxicity Drugs with potential additive nephrotoxicity

Itraconazole*Posaconazole**

Impact of gastric acidity

Medications that alter gastric pH (eg, proton pump inhibitors and histamine-2 blockers)

Azole Class

Role as CYP450 enzyme substrates and inhibitors

Antiarrhythmics, antipsychotics, immunosuppressants, migraine medications, antibiotics, anticoagulants, antidepressants, antiepileptics, antiretrovirals, chemotherapies, antihypertensives, lipid-lowering agents, narcotics, sedatives, hormonal therapies, and diabetes drugs

Caspofungin Use of OATP-1B1 transporter

Immunosuppressants, antiepileptics, antiretrovirals, and rifampin

*Oral capsule; **oral solution.CYP450, cytochrome P450; OATP1B1, organic anion transporting polypeptide 1B1.

Initial therapy– An echinocandin

– Fluconazole in select patients (not critically ill and unlikely to be infected with a fluconazole-resistant strain)

Susceptibility testing– Azole in clinically relevant Candida isolates

– Echinocandin with prior echinocandin treatment, or C. glabrata or C. parapsilosis

Treatment Recommendations for Invasive Candidiasis

Pappas PG, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;62(4):409-417.

L-AmB for neutropenic patients (although toxicity is a concern)

Empiric therapy:– Fluconazole for high-risk patients in adult ICUs with >5% rate of invasive

candidiasis

– High-risk patients:

• Intra-abdominal infection • Recent abdominal surgery• Anastomotic leaks• Necrotizing pancreatitis

Treatment Recommendations for Invasive Candidiasis (cont’d)

L-AmB, liposomal amphotericin B.

Pappas PG, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;62(4):409-417.

For suspected infection, initiate therapy during diagnostic evaluation

Triazoles preferred for invasive aspergillosis treatment and prevention

Voriconazole as initial therapy for invasive pulmonary infection– Consider combination with an echinocandin for high-risk patients

Routine susceptibility testing not recommended except for suspected azole-resistance or lack of therapeutic response

Continue therapy for at least 6 to 12 weeks

Treatment Recommendations for Invasive Aspergillosis

Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1-e60.

AmB-d or L-AmB for initial and salvage therapy if voriconazole cannot be administered

Echinocandins as salvage therapy (alone or combination; not for routine initial monotherapy)

Prophylaxis – Initiate posaconazole, voriconazole, and/or micafungin for prolonged

neutropenia – Consider aerosolized AmB with prolonged neutropenia and lung transplant

Treatment Recommendations for Invasive Aspergillosis (cont’d)

Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1-e60.

Therapeutic Drug Monitoring

Additional studies needed to assess role of TDM for isavuconazole and posaconazole extended-release tablet and intravenous formulations.CNS, central nervous system; GI, gastrointestinal; TDM, therapeutic drug monitoring.Patterson TF, et al. 2016 IDSA Guidelines. Clin Infect Dis. 2016;63(4):e1–e60.

Clinical Scenarios Where Antifungal TDM Is Useful Comments

Populations with increased pharmacokinetic variability

• Impaired GI function; hepatic (voriconazole, posaconazole, itraconazole); pediatric patients, elderly patients, obese patients, critically ill patients

Changing pharmacokinetics • Intravenous-to-oral switch, changing GI function, changing hepatic or renal function, physiological instability

Interacting medications • Patient receiving medication that induces CYP3A4, antacids, proton pump inhibitors (itraconazole capsules, posaconazole suspension), antiretroviral medications

• Possibly corticosteroids (voriconazole)Severe disease • Extensive infection, lesions contiguous with critical structures, CNS infection, multifocal or

disseminated infectionCompliance • Important issue with longer-term consolidation therapy or secondary prophylaxisSuspected breakthrough infection

• TDM can help to establish whether fungal disease progression occurred in the setting of inadequate antifungal exposure

Suspected drug toxicity, neurotoxicity (voriconazole)

• Although exposure-response relationships are described for other toxicities (eg, hepatotoxicity, bone disease), the utility of TDM to prevent their occurrence is less well established

Prevention of IFIs

Environmental exposure reduction (frequently not feasible)

Pharmacologic prophylaxis during a period of risk

Strategies for IFI Prevention

Prophylactic Treatment: Low Infection Risk

Prophylactic Treatment: High Infection Risk

General Risk Factors for IFI

Kriengkauykiat J, et al. Clin Epidemiol. 2011;3:175-191.

Environmental factors

Host predisposition

Neutropenia ≥3 weeks

• Colonization

• Central venous catheter

• Hemodialysis

• Clinically unstable presentation (acute renal failure, shock, disseminated intravascular coagulation)

• Surgery (complicated or repeated abdominal)

• Anti-anaerobic antibiotic agents

• Total parenteral nutrition or intralipid agents

• Prolonged ICU stay

Specific Risk Factors for Invasive Candidiasis


• Graft vs host disease (acute grades 2-4 or chronic)

• Hematocrit type (mismatched-related donor at greatest risk)

• Underlying hematologic disease (myelodysplastic syndrome or acute myeloid leukemia)

• Corticosteroid (dose and duration)

• T-cell-depleting therapy

• Cytomegalovirus infection

• Ganciclovir use

• Polymorphisms (TLR4, TNF, or IL-10)

• Hematopoietic cell transplantation in nonlaminar air flow room

Specific Risk Factors for Invasive Aspergillosis

IL, interleukin; TLR4, toll-like receptor 4; TNF, tumor necrosis factor.


Antifungal Resistance

Candida Resistance Patterns in the United States

Percentage ofCandida blood isolates tested showing fluconazole, echinocandin, or multi-drug resistance by surveillance year

0%1%2%3%4%5%6%7%8%9%

10%

2008-2009 2009-2010 2010-2011 2011-2012 2012-2013

Res

ista

nt Is

olat

es (%

)

Years of Surveillance

Fluconazole Echinocandins Multi-drug

Centers for Disease Control and Prevention. Fungal diseases. Invasive candidiasis statistics.https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html. Accessed October 12, 2017.

Azole-resistant Aspergillus fumigatus in the United States 2011-2013

• Most A isolates were itraconazole-susceptible

• ~5% required an MIC > established epidemiologic cutoff value = 1 μg/mL

Pham CD, et al. Emerg Infect Dis. 2014;20(9):1498–1503.

0

50

100

150

200

250

300

350

0.05 0.094 0.1 0.12 0.125 0.19 0.25 0.38 0.5 0.75 1 1.5 2 3 4 6 16 32

Num

ber o

f Iso

late

s

MIC (µg/mL)

Biofilms Drug target modification Decreased intracellular drug levels

– Regulation of drug transporters– Chromosomal anomalies

Mechanisms of Resistance

Antimicrobial Stewardship: Elements of a Successful Program

Andruszko B, et al. Curr Clin Microbiol Rep. 2016;3(3):111-119.

Create a collaborative

group

Provide bedside

interventions

Implement rapid

diagnostics

Perform Daily audits

Implement local

guidelines

Provide educational programs

Identify need via

audit

ID, infectious disease.Adapted from: Agrawal S, et al. J Antimicrob Chemother. 2016;71(suppl 2):ii37-ii42.

The Multidisciplinary Team

ID Specialist

Pediatric ID Specialist

Medical Microbiologist

Hospital PharmacistHematologist

Administrative Support Staff

The Multidisciplinary Team (cont’d)

Adapted from: Agrawal S, et al. J Antimicrob Chemother. 2016;71(suppl 2):ii37-ii42.

• Patient risk factors• Conventional tests• Biomarkers• Molecular diagnostics• Imaging

ID Specialist





The Multidisciplinary Team (cont’d)

Optimal Antifungal Therapy

Adapted from: Agrawal S, et al. J Antimicrob Chemother. 2016;71(suppl 2):ii37-ii42.

• Patient risk factors• Conventional tests• Biomarkers• Molecular diagnostics• Imaging

ID Specialist





Case Evaluations

John is an 18-year-old who underwent a splenectomy following a car accident. He has a central line in place and has been receiving broad-spectrum antibiotics since surgery. He develops a fever of 102° F and has negative blood cultures as part of the workup.

Case Evaluation #1: Patient Description

Case Evaluation #1: Question 1

A. GalactomannanB. T2CandidaC. Lateral flow device

What type of additional testing would you request for John?

A. B. C.

0% 0%0%

:8


A. Very stronglyB. StronglyC. Not at all

How strongly do you agree with the assertion that John should be initiated on antifungal therapy?

A. B. C.

0% 0%0%

:8


A. IsavuconazoleB. MicafunginC. L-AmB

Which of the following would you prescribe as initial therapy for John?

A. B. C.

0% 0%0%

:8

Julia is a 54-year-old woman with a history of obesity and prediabetes, who underwent a liver transplant 2 months ago. She presents with fever, cough, and hypoxia. Her chest CT was positive for nodular infiltrate pattern without a clear halo or crescent sign. Her serum galactomannan assay was just above the reference range and β-D Glucan assay was positive.

Case Evaluation #2: Patient Description


A. IsavuconazoleB. MicafunginC. L-AmB

Which of the following would you prescribe as initial therapy for Julia?

A. B. C.

0% 0%0%

:8


A. 4 to 6 weeksB. 6 to 12 weeksC. 12 to 18 weeks

How long would you continue therapy?

A. B. C.

0% 0%0%

:8

IFIs are a significant cause of morbidity and mortality in immunocompromised patients

Diagnosis is challenging because symptoms are often nonspecific and current diagnostic tests have limited specificity and sensitivity

Approved systemic antifungal therapies, which include polyenes, azoles, and echinocandins, can provide effective treatment of IFIs

By maintaining a high index of suspicion for IFIs in at-risk patients, clinicians can ensure early diagnosis and treatment to prevent poor patient outcomes

Summary

Aggressively evaluate immunocompromised patients for IFI risk and administer appropriate diagnostic testing to pursue early identification of an infection

For at-risk patients with a suspected or proven infection, promptly administer antifungal therapy using diagnostic test results and individualcharacteristics to guide treatment choice

Consider appropriate prophylaxis for selected patients who are at particularly high risk for IFI, such as those with prolonged neutropenia or in ICUs with high rates of invasive candidiasis

Apply principles of antimicrobial stewardship to optimize clinical outcomes and minimize unintended consequences of antifungal misuse or overuse

Clinical Pearls

Thank You

Addressing Challenges to Optimal Diagnosis and Treatment ...

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