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Isavuconazole to the Rescue? A New Treatment Option for Critically Ill Patients with Invasive Pulmonary Aspergillosis

Sarah McDaniel, PharmD PGY-1 Pharmacy Practice Resident

Methodist Hospital and Methodist Children’s Hospital, San Antonio TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

November 11th, 2016

Learning objectives 1. Describe characteristics, epidemiology, and clinical impact of Aspergillus2. Discuss the current pharmacotherapy options for invasive pulmonary aspergillosis (IPA)3. Review the current literature supporting the use of isavuconazole in IPA4. Formulate an evidence based recommendation regarding antifungal agent selection for IPA

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I. Background and Microbiology1, 2

A. History a. In 1729, Micheli of Florence first characterized Aspergillus and noted a resemblance of

the species to an aspergillum, an instrument used to sprinkle holy waterb. In 1856, Virchow published the first complete microscopic description of the organismc. IPA was first described in a case report in 1953

B. Pathogenic Fungi Figure 1: Pathogenic Fungi Classification1

C. Morphology2 a. Aspergillus is a mold that, if isolated from pathological samples, is readily cultured with

rapid growth on a variety of media in 24 to 72 hours b. Aspergillus is characterized microscopically by hyaline and septate acute branching

hyphae that are 3 to 6 µm in width

Figure 2: Labeled diagram of Aspergillus fumigatus

Fungi

Yeast

CandidaCryptococcusTrichosporon

Mold

AspergillusFusarium

ScedosporiumZygomycetes

Dimorphic

HistoplasmaBlastomycesCoccidioides

ParacoccidiodesSporothrix

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II. Epidemiology1 - 7 A. Aspergillus is found in soil, water, air, and decaying vegetation B. Aspergillosis refers to an illness caused by the genus Aspergillus C. Aspergillus is implicated in colonization, allergic response, and semi-invasive, invasive, or chronic

infections D. Invasive aspergillosis (IA) is characterized by pathogenic invasion across tissue planes and

potential dissemination either by hematogenous spread or by direct extension E. Potential sites of dissemination include the central nervous system, thyroid, liver, spleen,

kidneys, bones, and heart F. IPA is the most common type of IA G. Risk factors for IPA and patient populations commonly affected include4:

a. Neutropenia (< 500 cells/mm3 for > 10 days) i. Hematopoietic stem cell transplant (HSCT) recipients

ii. Solid organ transplant (SOT) recipients iii. Prolonged corticosteroid use equivalent to 0.3 mg/kg/day of prednisone

for > 3 weeks iv. Immunodeficiency syndromes

b. Reduced pulmonary host defenses i. Prolonged corticosteroid use equivalent to 0.3 mg/kg/day of prednisone

for > 3 weeks ii. Structural lung disease

AIDS: Acquired immune deficiency syndrome; ALL: acute lymphocytic leukemia; AML: acute myeloid leukemia; CLL: chronic lymphocytic leukemia; COPD: chronic obstructive pulmonary disease; GVHD: graft-versus-host disease; MDS: myelodysplastic syndrome; SOT: solid organ transplant

H. Incidence and Mortality8,9

a. Hospital discharges with diagnosis of Aspergillus have increased from 4.8 per million patients in 1976 to 38 per million patients in 1997

b. In a large review of IPA cases reported up to 1995, the case fatality rate was estimated to be approximately 85%

c. The estimated mortality rate of IPA in HSCT recipients exceeds 90%

Low risk

Multiple myelomaCOPD acute exacerbationAIDSNon-hodgkins's lymphomaAutologous HSCTSolid tumorAutoimmune disorder

Intermediate risk

ALLCLLAllogenic HSCTNon-lung SOTAML Myelodysplastic syndrome

High risk

Chronic granulomatous diseaseAllogenic HSCT with GVHDLung transplantationAML/MDS with induction therapy or in relapse

Figure 3. Classification of At Risk Populations for IPA3

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III. Pathogenesis and Host Defense1,2,5

A. Several hundred species of Aspergillus have been identified; however, fewer than 40 cause disease in humans and animals

Table 1. Clinically Relevant Aspergillus Species2

Species Frequency of Isolation in Infection (%)

Significance

A. fumigatus 50 – 67 Most common invasive species; a prevalent human allergen

A. flavus 8 – 14 Causes sinusitis, skin infection; produces aflatoxin

A. niger 5 – 9 Uncommon in invasive disease; implicated in colonization and superficial otic disease

A. terreus 3 – 5 Increasingly prevalent in immunocompromised hosts; inherently resistant to amphotericin B

B. Route of Infection

a. Infection is commonly thought to occur through inhalation of Aspergillus conidia into the lower respiratory tract or paranasal sinuses

b. IA is uncommon in immunocompetent hosts but can occur

Figure 4. Response to Aspergillus Pulmonary Inoculation in Immunocompetent Patients2

C. Inhaled conidia enlarge and germinate into hyphal forms that can invade vascular tissue and lead to IPA

D. Most IPA cases arise from chronic colonization coupled with new onset neutropenia E. Many Aspergillus species produce toxins including aflatoxin, ochratoxin, and gliotoxin; however,

the role of these toxins in pathogenicity has not been elucidated

IV. Clinical Presentation1,2,5,6

A. IPA can present with progressive dry cough, dyspnea, pleuritic chest pain, hemoptysis, or fever despite broad spectrum antibiotic coverage

B. Radiologic findings of the lungs depend upon the duration and extent of disease and can include dense nodular infiltrates, pleural-based wedge-shaped densities, or a “halo” sign surrounding nodular lesions

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Figure 5. Chest CT Scan Depicting Halo Sign6

C. Absence of findings should not discourage IPA diagnosis as neutropenic and critically ill patients often have nonspecific clinical symptoms and radiographic features

D. Symptomatic presentation and histopathological and radiologic findings of IPA can resemble that of other molds including Mucorales, Fusarium, and Scedosporium

V. Diagnosis of IPA4,10

A. The gold standard for diagnosis includes a tissue biopsy demonstrating hyphal invasion plus a positive culture for Aspergillus that was obtained from the same site

B. Due to variable culture sensitivities between patient populations and the limited feasibility of obtaining a tissue biopsy in critically ill patients, varying levels of diagnostic certainty are clinically utilized

Table 2. Criteria for Diagnosis of Invasive Lower Respiratory Tract Fungal Disease4

Diagnosis certainty

Findings

Proven Diagnosis

One of the following: 1) Microscopic analysis: Histopathologic, cytopathologic, or direct microscopic examination obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage 2) Culture: recovery of a mold or “black yeast” from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, cranial sinus cavity specimen, and urine

Probable Diagnosis

One from each of the following three categories: 1) Host Factors: Recent history of neutropenia temporally related to the onset of fungal disease, receipt of an allogenic stem cell transplant, prolonged used of corticosteroids at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > three weeks, treatment with other recognized T cell immunosuppressants in the past 90 days, or inherited severe immunodeficiency 2) Clinical Criteria: Dense well-circumcised lesions with or without a halo sign, air-crescent sign, or cavity 3) Mycologic Criteria: Mold in sputum, bronchoalveolar lavage (BAL) fluid, bronchial brush, or aspirate samples indicated by presence of fungal elements indicating a mold or recovery by culture of a mold, galactomannan antigen detected in plasma, serum, BAL fluid, or cerebrospinal fluid

Possible Diagnosis

One Host Factor and one Clinical Criteria as defined above

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C. Newer Diagnostic Methods1,6,10,11 a. Galactomannan Antigen

i. Tests for a polysaccharide that is a major constituent of Aspergillus cell walls ii. Serum and BAL galactomannan are recommended for the diagnosis of IA in

HSCT and hematologic malignancy patients iii. Results from BAL fluid testing are more sensitive than serum and less affected

by antifungal therapy; therefore, only BAL galactomannan should be utilized in patients receiving mold-active antifungal therapy or prophylaxis

iv. A positive result is defined as an optical density (OD) ratio ≥ 0.5 v. Sensitivity and specificity of results are affected by multiple variables including

the use of mold-active antifungal therapy or piperacillin-tazobactam therapy b. 1, 3-β-D-Glucan

i. A cell wall component of many fungi ii. Serum assays are recommended for diagnosing IA in hematologic malignancy

and allogenic HSCT patients iii. A positive result is defined as an optical density > 80 pg/mL iv. Sensitivity and specificity of results are affected by multiple variables such as

the use of intravenous immunoglobulin and infections with bacteria that contain cellular beta-glucans such as Pseudomonas aeruginosa

c. Nucleic Acid Testing i. Currently no standardized recommendations for use

VI. Pharmacotherapy Options

Table 3. Antifungal Spectrum of Activity for Aspergillus spp12

Organism Antifungal agent Polyenes Mold-active azoles Echinocandins*

Amp-B Isavu Vori Itra Posa Caspo Mica Anidula A. fumigatus + + + + + + + + A. flavus ± + + + + + + + A. terreus + + + + + + + + A. niger - + + ± + + + + * Echinocandins are not currently recommended as primary therapy or monotherapy for treatment of IPA Amp B: amphotericin B; Anidula: anidulafungin; Capso: caspofungin; Isavu: isavuconazole; Itra: itraconazole; Mica: micafungin; Posa: posaconazole; Vori: voriconazole

A. Antifungal therapy should be initiated if clinical suspicion for IPA arises B. Amphotericin B1-3,10,13

a. Originally formulated in 1955 from Streptomyces nodosus b. FDA approved in 1958 c. A polyene that is fungicidal to most Aspergillus spp through ergosterol binding and

leakage of cell components d. Available in multiple formulations e. Adverse events include electrolyte wasting, nephrotoxicity and infusion related

reactions

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f. Considered the standard of care for IPA until a landmark New England Journal of Medicine trial in 2002 by Herbrect et al.14

i. Overall treatment success was defined as complete response (clinical improvement and > 90% resolution of lesions) and partial response (clinical improvement and > 50% resolution of lesions)

ii. Results: 1. Overall treatment success: voriconazole 52.8%, deoxycholate amp-B

31.6% (absolute difference 21.2%; 95% CI, 10.4 – 32.9) 2. Survival rates: voriconazole 70.8%, deoxycholate amp-B 57.9% (HR,

0.59; 95% CI 0.40 – 0.88) 3. Voriconazole-treated patients had significantly fewer severe drug-

related adverse events C. Voriconazole1-3,10,13-18

a. Approved by the FDA in 2002 for the treatment of fungal infections b. A mold-active, second-generation triazole that is fungicidal to most Aspergillus spp

through inhibition of the synthesis of ergosterol, a cell wall component c. Available in both IV and PO formulations d. Adverse events include liver function test abnormalities, nausea, vomiting, diarrhea,

skin rashes, hallucinations, visual abnormalities and QTc prolongation e. Multiple cohort studies released after Herbrecht et al. support an approximate 15%

improved survival observed at 12 weeks in all patient types treated with voriconazole compared to those treated with other mold-active IV therapies

f. Metabolism associated with interpatient variability due suboptimal pharmacokinetic parameters (see Appendix I) and CYP2C19 phenotypic differences

g. A meta-analysis by Luong et al. found that patients at therapeutic concentrations of voriconazole are more likely to have a successful treatment outcome (OR: 2.81; 95% CI, 1.12 – 7:04; i2=69%) and are less likely to experience an adverse event (17.8% vs 81.4%; p < 0.001)

h. The 2016 IDSA guideline update for IA recommends TDM with a goal trough > 0.5 – 1 µg/mL and < 5 – 6 µg/mL for patients receiving voriconazole therapy for IA, prolonged azole prophylaxis, or other therapies for which interactions with azoles are anticipated

i. Due to accumulation of sulfobutylether-β-cyclodextrin (SBECD), a solubilizing agent present in IV voriconazole, the manufacturer suggests that IV therapy be used in patients with an estimated creatinine clearance of < 50 mL/min or a serum creatinine > 2.5 mg/dL if benefit outweighs the risk of potential accumulation

j. Clinical trials and animal studies suggest that SBECD may not contribute to nephrotoxicity

k. Although oral voriconazole is an evidence-based treatment option, oral therapy is not feasible for all critically ill patients with reduced renal function

l. Compared to the IV formulation, the PO formulation of voriconazole has been associated with lower therapeutic drug levels and a higher rate of treatment failure15

D. Isavuconazole10,20 a. Approved by the FDA in 2015 for the treatment of fungal infections b. A mold-active, second-generation triazole that is fungicidal against most Aspergillus spp

through inhibiting the synthesis of ergosterol, a cell wall component c. Available in IV and PO formulations

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d. Associated with adverse events such as nausea, vomiting, diarrhea, liver function test abnormalities and QTc shortening

e. Current pharmacokinetic and pharmacodynamic data do not indicate a need for TDM (See appendix I)

f. Limited data on use E. The 2016 IDSA guidelines provided a strong recommendation for both voriconazole and

isavuconazole as single agent monotherapies for the treatment of IPA

Table 4. 2016 IDSA Guideline Recommended Agents for the Treatment of IPA10

Grade of Recommendation Agent Dose Strong recommendation; high-quality evidence

Voriconazole 6 mg/kg every 12 hours x 2 doses then 4 mg/kg every 12 hours for at least 7 days of IV therapy followed by 4 mg/kg IV or 200 mg PO q12h

Strong recommendation; moderate-quality evidence

Isavuconazole IV or PO: 372 mg q8h x 6 doses then 372 mg daily

Strong recommendation; moderate-quality evidence

Liposomal AMP-B IV: 3 – 5 mg/kg/day

Figure 6: Prescribing Considerations for Two First-line Treatment Agents for IPA

VIII. Clinical Question Considering the large amount of data available supporting the use of voriconazole for the treatment of IPA, in which populations would treatment with isavuconazole be preferred?

Voriconazole Isavuconazole

• TDM recommended • Cyclodextrin IV formulation • Substrate and inhibitor of CYP2C19

(major), CYP3A4 (minor), and CYP2C9 (minor)

• Moderate burden of adverse events

• Ample literature supporting safety and efficacy

• $$$

• TDM not currently recommended • No cyclodextrin in the IV

formulation • Substrate and inhibitor of CYP3A4

and p-glycoprotein • Low burden of adverse events • Scant literature supporting safety

and efficacy • $$$$$

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IX. Literature Summary Table 5: SECURE trial21 Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-9. Objective To establish non-inferiority of ISAVU to VORI for the primary treatment of invasive

mold disease Population 532 patients reviewed between 2007 to 2013

Inclusion criteria • ≥ 18 years • Proven,

probable or possible invasive mold disease caused by Aspergillus spp or other filamentous fungi

Exclusion criteria • Hepatic dysfunction • eCrCl < 50 mL/min • High risk for QTc prolongation • Concomitant use of certain anti-epileptics, anti-rejection

agents, and CYP450 inducers within 5 days of first dose of study drug

• Invasive fungal infections other than Aspergillus spp., Mucormycosis or Scedosporium prolificans

• ≥ 4 doses of mold active azoles within 7 days prior to the first dose of study drug

• CD4 count < 200 or an AIDS defining condition • Patients unlikely to survive 30 days or on a ventilator

Study Design n= 516

• Phase 3, randomized, double blind, international, multicenter, non-inferiority study • Independent committee of infectious disease experts determined diagnosis and

clinical, mycological, radiological and overall responses • ITT population: all patients enrolled, randomly assigned, received ≥ 1 dose of drug • mITT population: ITT patients with proven or probable invasive mold disease • myITT population: mITT patients with proven or probable invasive aspergillosis

Outcomes • Primary endpoint: all-cause mortality from first dose to day 42 in the ITT population

• Key secondary endpoint: overall response at end of treatment (≤ 84 days of therapy) in the mITT population

• Other secondary endpoints: all-cause mortality, overall clinical mycological and radiological responses, safety and tolerability

Methods • 255 patients per group required for an 80% power to demonstrate that the upper limit of the 95% CI for a treatment difference was 10% or less

• 20% mortality rate was assumed for both drugs in the primary efficacy population • Historical ACM with VORI to day 42 was estimated at 18.8% (95% CI, 12.4 – 25.1) • Adjusted treatment difference was calculated by stratified Cochran-Mangel-

Haenszel method and Fisher’s exact test was used for assessment of adverse effects

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SECURE Trial (continued) Results

Table 6: Demographics of ITT population VORI ISAVU # of patients 258 258 Age, years 51.2 51.1 Proven invasive mold disease (%) 14 11 Probable invasive mold disease (%) 36 44 Possible invasive mold disease (%) 42 34

Table 7: Demographics of mITT population

VORI ISAVU # of patients 129 143 Aspergillus spp only (%) 30 34 Non-Aspergillus spp only (%) 5 3 LRTD only (%) 83 81

Table 8: All-cause mortality endpoints

VORI ISAVU Difference (95% CI)

Day 42 ACM in ITT pop (%) 20 19 -1% (-7.8 – 5.7) Day 42 ACM in mITT pop (%) 23 20 -2.6% (-12.2 – 6.9)

Day 42 ACM in myITT pop (%) 22 19 -2.7% (-12.9 – 7.5) Day 84 ACM in ITT pop (%) 31 29 -1.4% (-9.2 – 6.3) Day 84 ACM in mITT pop (%) 37 30 -5.5% (-16.1 – 5.1) Day 84 ACM in myITT pop (%) 36 28 -5.7% (-17.1 – 5.6)

Table 9. Data Review Committee Assessed Response at End of Treatment

VORI ISAVU Difference (95% CI)

Overall response at EOT, n 129 143 Complete success (%) 36 35 1.6 (-9.3 – 12.6) Partial success (%) 10 12 Progression of disease (%) 38 36 Clinical response (%) 60 62 0.4 (-10.6 – 11.5) Mycological response (%) 41 38 3.8 (-7.4 – 15.1) Radiological response (%) 33 29 5.7 (-4.90 – 16.3)

• In the mITT population, complete response was seen in 35% and 36% of ISAVU and

VORI patients with an estimated difference of 1.6% (95% CI, -9.3 – 12.6) • Permanent drug discontinuation due to treatment-emergent adverse events were

less common with ISAVU (14%) than VORI (23%) • Permanent drug discontinuation due to drug-related adverse events was lower for

ISAVU (8%) than VORI (14%)

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SECURE Trial (continued) Author’s Conclusion

ISAVU is non-inferior to VORI in patients suspected of having invasive mold disease and showed significantly fewer drug related adverse events and fewer drug discontinuations.

Strengths • Large size geographic spread • Evaluation criteria decided by infectious disease experts; required consensus of

three to assess diagnosis and responses • Stratification of patients into multiple groups • Primary outcome supported in multiple populations • Duration of follow-up

Limitations • Did not perform therapeutic drug monitoring for VORI • Not randomized by certainty of diagnosis • Extensive exclusion criteria • Did not clearly describe the DRC’s definition of overall response or “unlikely to

survive 30 days” AIDS: acquired immunodeficiency syndrome; ACM: all-cause mortality; ALT: alanine aminotransferase; AST: aspartate aminotransferase; eCrCl: estimated creatinine clearance; DRC: data review committee, EOT: end of treatment; HIV: human immunodeficiency virus; IFD: invasive fungal disease; ISAVU: isavuconazole; ITT: intent-to-treat; LRTD: lower respiratory tract disease; mITT: modified intent-to-treat; myITT: mycological intent-to-treat; pop: population; VORI: voriconazole Table 10. Neofytos et al.22 Neofytos D, Lombardi LR, Shields RK et al. Administration of voriconazole in patients with renal dysfunction. Clin Infect Dis 2012;54:913-21. Objective • Prove that VORI is well tolerated and safe in patients with renal dysfunction

• Assess the rate of renal dysfunction among patients treated with VORI • Identify risk factors for renal dysfunction among patients treated with VORI

Population n = 166

Inclusion criteria • ≥ 18 years • VORI use for ≥ 3 days with the

same formulation

Exclusion criteria • Administration of VORI within 30 days • Requirement for hemodialysis • eCrCl > 50 for the PO therapy treatment arm

Study Design

• Retrospective observational study of patients at John Hopkins Hospital and University of Pittsburgh Medical Center

Figure 7. Division of Patient Groups

Outcomes • Primary endpoint: Significant renal function change defined as an increase in SCr >

1.5 x baseline or a decrease in eCrCl by > 25% • Secondary endpoints: Risk factors significantly associated with renal dysfunction • Collected information on doses, routes and frequency of VORI utilized, presence of

additional nephrotoxic medications, comorbidities and other patient characteristics

Grou

p 1 IV VORI

eCrCl < 50 mL/minn = 42 Gr

oup

2 PO VORIeCrCl < 50 mL/min

n = 47 Grou

p 3 IV VORI

eCrCl ≥ 50 mL/minn = 77

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Neofytos et al. (Continued) Methods • Route of VORI administration and baseline renal function were added to a univariate

analysis and pairwise group comparisons were made • Variables that had a p value < 0.20 were added stepwise into a multivariate logistic

regression to assess risk factors for renal impairment progression adjusted for the other risk factors in the models

• ORs and 95% CIs were performed for all logistic regression analysis results Results Table 11. Characteristics of Study Populations

Variable Group 1 Group 2 Group 3 P value Age, mean, years 57.3 56.5 48 <0 .05 Ethnicity, white (%) 83.3 93.6 83.1 0.21 Hematologic malignancy (%) 33.3 40.2 38.9 0.76 HSCT recipient (%) 11.9 8.5 14.3 0.63 SOT recipient (%) 38.1 48.9 22.1 0.007 VORI loading dose (%) 76.2 31.9 80.5 <0.0001 VORI ≤ 7 days (%) 47.6 36.2 46.7 0.44 Prophylactic use (%) 28.6 59.5 29.9 0.002 Baseline liver impairment (%) 21.9 21.7 17.3 0.97 Vanc trough ≥ 20 (%) 54.5 45.4 28.9 0.13 Aminoglycoside use (%) 4.8 6.4 7.8 0.77 Vasopressor use (%) 28.6 17.0 26.0 0.39 Immunosuppressant use (%) 38.1 53.2 28.6 0.02 Corticosteroid use (%) 59.5 55.3 49.3 0.55 Mechanical ventilation (%) 33.3 31.9 44.1 0.31

Figure 8. Mean Serum Creatinine Trend

• Significant changes in renal function observed in 19 (11.4%), 14 (8.4%) and 28

(16.9%) of patients on days 3, 7 and EOT respectively.

0

0.5

1

1.5

2

2.5

Day 1 Day 3 Day 7 EOT

Seru

m c

reat

inin

e

Group 1

Group 2

Group 3

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Neofytos et al. (continued) Results Table 12. Univariate Analysis of VORI Associated Variables for Renal Dysfunction

Predictor Day 3 Day 7 End of treatment OR P value OR P value OR P value

IV vs oral 0.84 0.75 2.52 0.24 2.01 0.19 Loading dose 1.15 0.79 0.94 0.91 1.38 0.48 Dose > or ≤ 4 mg/kg BID 0.69 0.73 0.94 0.91 1.38 0.48 Duration > or ≤ 7 days 0.40 0.07 3.00 0.10 0.85 0.69 Level ≥ 5 or < 5 NA NA 8.0 0.2 18 0.02

Table 13. Significant Risk Factors for Renal Dysfunction Per Multivariate Analysis

Predictor Day 3 Day 7 End of treatment OR P value OR P value OR P value

White vs non-white NS NS NS NS 0.36 0.04 Hematologic malignancy 5.09 0.01 NS NS NS NS Fluconazole within 30 days 6.2 0.008 NS NS NS NS Baseline liver impairment NS NS 5.30 0.004 NS NS Duration > or ≤ 7 days 0.19 0.01 NS NS NS NS Concomitant penicillins 6.12 0.03 NS NS 2.39 0.04 Concomitant immunosuppressive agent

7.00 0.002 NS NS NS NS

Concomitant vasopressor 0.13 0.02 NS NS NS NS

Author’s Conclusion

• Factors correlated with renal dysfunction are likely markers of disease severity • No correlation of renal dysfunction with baseline renal dysfunction or route of

administration of VORI Strengths • RIFLE criteria definition for significant renal function change utilized

• 37.9% of population had hematologic malignancy, 12% were HSCT recipients, and 33.7% were SOT recipients

• PO VORI population served as a control group Limitations • Observational design

• VORI levels were only available for 27 patients (22% of IV VORI patients) • Median duration of treatment was 9 days, 10 days and 9 days respectively for

groups 1, 2 and 3; minimum duration of treatment recommended is 6 to 12 weeks AmpB: amphotericin B; BID: twice daily; CI: confidence interval; eCrCl: estimated creatinine clearance; HSCT: hematopoietic stem cell transplant; IV: intravenous; NS: not significant; SCr: serum creatinine; Vanc: vancomycin; VORI: voriconazole

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Table 14. Alverez-Lerma et al.23

Alvarez-lerma F, Allepuz-palau A, Garcia MP, et al. Impact of intravenous administration of voriconazole in critically ill patients with impaired renal function. J Chemother. 2008;20(1):93-100. Objective To assess the possible renal and liver damage related to the accumulation of SBECD in

critically ill patients with renal insufficiency treated with the IV VORI Population n = 69

Inclusion Criteria: • ≥ 18 years • Treated in the ICU • Proven, probable or possible fungal infection • ≥ 3 days of IV VORI therapy

Exclusion Criteria: • None listed

Study Design

Figure 9. Division of Patient Groups • Open-label, non-comparative, observational study of ICU patients in 21 hospitals

in Spain

• Impaired renal function was defined as a SCr > 1.5, an eCrCl < 50, or the need for

hemodialysis Outcomes Primary Outcome: Renal or hepatic damage associated with IV voriconazole use

The following variables were assessed: • Renal function variables from 1 day prior to VORI administration to 5 days after

EOT • Concomitant use of potentially nephrotoxic drugs • Renal and liver function-related variables Normal renal function was defined as: • SCr < 1.5 or eCrCl > 50 mL/min Renal damage was defined as one of the following: • Increase in SCr to > 1.5 or decrease in eCrCl to < 50 mL/min in patients with

normal baseline renal function • SCr increase to ≥ 2 times baseline or a decrease in eCrCl to ≤ ½ baseline • Initiation of hemodialysis during treatment Liver damage was defined as: • Increase ≥ 4 times the initial serum concentration of liver enzymes or ≥ 2 times the

initial serum concentration if impaired liver function present at baseline Methods • Variables compared between renal function groups using Student’s t test or Mann-

Whitney U test for continuous variables and chi-square or Fisher’s exact for categorical data

• P values were two-sided with significance set at p < 0.05 • Variables independently associated to renal damage analyzed by logistic

regression

Grou

p 1 Normal Renal

Function n = 43 Gr

oup

2 Impaired Renal Functionn = 26

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Alvarez-lerma et al. Results

Table 15. Characteristics of Study Population Variable Normal RF Impaired RF P value Mean age, years 55.9 58.8 0.490 Mean APACHE II Score 20.9 24.0 0.146 SOT recipient (%) 7.0 11.5 0.665 Hematologic malignancy (%) 14.0 15.4 1.000 Use of immunosuppressants (%) 18.6 23.1 0.760 Use of vasopressors (%) 70.0 92.0 0.036 Treated with ≥ 1 nephrotoxic agent (%) 65.0 50.0 0.312 Mean duration of IV VORI use, days 13.0 11.2 0.332

Table 16. Organ Function Changes and Overall Mortality Outcomes

Variable Normal RF Impaired RF P value Underwent dialysis (%) 6.9 38.5 NR New dialysis requirement (%) 6.9 3.8 NR Renal damage (%) 30.2 15.4 0.257 Liver damage (%) 27.9 11.5 0.281 Overall Mortality (%) 48.8 61.5 NR

Table 17. Mortality with focus on renal outcomes

Normal renal function at baseline Outcome Mortality rate P Value Renal Damage 84.6% 0.0028 No Renal Damage 33.3%

Impaired renal function at baseline Outcome Mortality rate P value Renal Damage 75% 0.385 No Renal Damage 60%

Table 18. Variables associated with renal dysfunction

Variable OR (95% CI) P value Age ≥ 70 years 6.80 (1.61 – 28.68) 0.009 APACHE II Score ≤ 15 2.72 (0.40 – 18.63) 0.307 Nephrotoxic drug use 1.85 (0.46 – 7.47) 0.385 Impaired RF prior to VORI 0.23 (0.05 – 1.07) 0.061

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Alverez-Lerma et al. continued Results Figure 10. Mean serum creatinine trend

Author’s Conclusions

IV VORI use in critically ill patients with baseline renal insufficiency is not associated with a further deterioration of renal function, the presence of liver dysfunction, or an increase in ICU mortality rate.

Strengths • Included patients with significant renal dysfunction and on dialysis Limitations • Observational design with small sample size

• Use of threshold values to define renal damage; may cause overestimation in normal renal function patients

• Significant baseline differences between groups • Did not report VORI levels • Mean duration of IV VORI therapy 13 and 11 days • Multi-center with many investigators

APACHE: acute physiology and chronic health evaluation; eCrCl: estimated creatinine clearance; ICU: intensive care unit; IV: intravenous; NR: not reported; OR: odds ratio; RF: renal function; SBECD: sulfobutylether-β-cyclodextrin; SCr: serum creatinine; VORI: voriconazole

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X. Recommendations for Use

A. In most patients, voriconazole should be utilized for the treatment of IPA due to the abundance of robust data supporting its use

B. However, some patient populations may benefit from the use of isavuconazole

Figure 11. Patient characteristics that warrant consideration of isavuconazole use

Figure 12. Focus upon Cyclodextrin and Renal Function Changes

IV or PO isavuconazole

should be considered

Patient is unable to tolerate voriconazole

≥ 3 consecutive voriconazole trough measurements

outside of goal of 1.0 - 6.0 mcg/mL Patient has congenital or

acquired QT syndrome, sinus bradycardia, or preexisting symptomatic arrhythmias

ORPatient has QTc > 450 ms

If patient can tolerate PO therapy, strongly consider voriconazole formulations

If IV therapy is necessary, consider limiting IV voriconazole to a maximum of 10

consecutive days of therapy

If a longer duration of IV therapy is necessary,

consider switching to IV isavuconazole

If on IV Voriconazole and eCrCl < 50 mL/min

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XI. References 1. Richardson MD, Warnock DW. Fungal Infection, Diagnosis and Management. John Wiley & Sons;

2012. 2. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of

Infectious Diseases, Expert Consult. Saunders; 2014. 3. Cadena J, Thompson GR, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis

and Management. Infect Dis Clin North Am. 2016;30(1):125-42. 4. De pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the

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XI. Appendices

Appendix I: Pharmacokinetic and pharmacodynamic properties of azole antifungals 11

Characteristic Antifungal agent Isavuconazole Voriconazole Itraconazole Posaconazole Fluconazole

Available formulations

Oral and IV Oral and IV Oral Oral Oral and IV

Bioavailability Very high Up to 95% 30% capsules, 50% solution

54% capsules, low/variable solution

95%

Protein binding 98% 58% > 99% 99% 10% Food effect No effect Negative effect Positive effect

capsules, negative effect solution

Positive effect Negative effect

Volume of distribution

High High Very High High Low

CNS penetration

Low CNS, high brain

High > 50% Low < 10% Low High > 60%

Clearance (L/h) Low High Very High Very High Low Half-life (h) 56 – 104 6 – 12 24 – 30 16 – 35 24 – 30 Probability of interactions

Moderate High High Moderate Moderate

Use in hepatic insufficiency

Reduce dose; avoid in severe hepatic disease

Reduce dose; avoid in severe hepatic disease

No dose adjustment; avoid in severe hepatic disease

No dose adjustment; avoid in severe haptic disease

Reduce dose; avoid in severe hepatic disease

TDM Not currently recommended

Yes Yes Yes No