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Three Years After the SECURE Trial – Are We Still Feeling Secure with Isavuconazole?
Chase Ayres, PharmD PGY-1 Pharmacy Resident
Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center, UT Health San Antonio November 22nd, 2019
Learning Objectives
1. Describe pathophysiology and diagnosis of invasive pulmonary aspergillosis (IPA) 2. Review current practices for treatment of IPA 3. Evaluate recent evidence for and against isavuconazole use for IPA 4. Identify preferred agent for primary treatment of IPA
08 Fall
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Assessment Questions 1. Which of the following comorbidities confers the highest risk for developing IPA?
A. HIV-positive B. Allogeneic stem cell transplant C. Type II diabetes mellitus D. Colorectal cancer
2. True or False? Treatment of IPA should be initiated only after a pathogen has been isolated from sterile culture.
A. True B. False
3. Which of the following agents is NOT an appropriate first-line option for treatment of IPA?
A. Isavuconazole B. Liposomal Amphotericin B C. Voriconazole D. Caspofungin
***To obtain CE credit for attending this program please sign in. Attendees will be
emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at [email protected] ***
Faculty (Speaker) Disclosure: Chase Ayres has indicated he has no relevant financial relationships to disclose relative to the content of his presentation
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Background
I. Invasive Aspergillosis (IA)1-3 a. Potentially life-threatening infection caused by environmental molds, most
commonly affecting immunocompromised patients b. Epidemiology
i. Approximately 15,000 hospitalizations in the US attributed to IA yearly ii. Annual healthcare cost estimated at $1.2 billion
iii. Mortality rate >25-90% 1. If left untreated, 100%
iv. Incidence of 0.5-11% in at-risk populations II. Aspergillus species4
a. Genus of spore-forming, filamentous fungus found naturally in soil, water, air, decaying vegetation, and other organic debris
b. Favors warm, damp habitats c. Inhaled regularly but not pathogenic in most immunocompetent individuals d. Most common species isolated in human infections include A. fumigatus, A. flavus, A.
terreus, and A. niger1 Figure 1. Overview of Fungi4
III. Spectrum of disease a. Allergic bronchopulmonary, chronic, and invasive aspergillosis infections1-4
i. Pulmonary disease is most common due to direct environmental exposure 1. Conidia small enough (2.5 to 3 microns) to reach alveoli 2. Spores may eventually germinate into invasive hyphae, causing
infection ii. Invasive pulmonary aspergillosis (IPA) is the most common manifestation
IV. Invasive pulmonary aspergillosis (IPA)1-6 a. Accounts for >90% of all IA b. Advanced infection may disseminate elsewhere in the body, including the central
nervous system c. Patients with underlying pulmonary disease or immune compromise are at higher
risk (Figure 2)
Fungi
Yeasts
Candida Cryptococcus
Molds
Septate Fungi
Aspergillus Fusarium
Mucorales
Mucor Rhizopus
Dimorphic Fungi
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d. Pathogenesis1,7 i. Immunocompetent
1. Aspergillus conidia regularly inhaled from environment 2. Respiratory epithelial cells provide physical barrier to infection 3. Alveolar macrophages help clear conidia and promote secondary
inflammation a. Recruit neutrophils and natural killer cells to site of infection
ii. Immunocompromised 1. Immune deficiency allows germination from conidia into hyphae,
subsequently leading to invasive fungal disease 2. Neutrophils are the main defense against invasive hyphae
a. Patients with severe, prolonged neutropenia are particularly vulnerable
i. ANC <500 cells/mcL for > 10 days Figure 2. Risk categories for IPA8
e. Diagnosis9,10 i. No gold standard diagnostic test available
ii. Clinical diagnosis based on multiple factors and classified as proven, probable, or possible (Appendix 1)
iii. Microbiological (Table 1) 1. Isolation of Aspergillus coupled with clinical manifestations of infection
a. Cultured from respiratory source (e.g. bronchoalveolar lavage) b. Risk factors must be accounted for with clinical presentation
2. Visualized via microscopy a. Morphology described as septated hyaline hyphae branching at
45 degree angles b. Sometimes confused other hyaline molds such as Fusarium spp
Highest Risk
•Chronic granulomatous disease •Allogenic stem cell transplant with graft-versus-host disease •Lung transplantation •Acute myeloid leukemia/myelodysplastic syndrome with induction therapy or in
relapse
Intermediate Risk
•Allogeneic stem cell transplant without graft-versus-host disease •Non-lung, non-kidney solid organ transplant •Acute lymphoblastic leukemia •Acute myeloid leukemia (consolidation phase) •Chronic lymphoblastic leukemia •Myelodysplastic syndrome
Low Risk
•Multiple myeloma •Chronic obstructive pulmonary disease acute exacerbation •Acquired immunodeficiency syndrome •Non-hodgkins's lymphoma •Autologous stem cell transplant •Kidney transplant •Solid tumor •Autoimmune disorder
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3. Respiratory culture should be evaluated in conjunction with histopathology or culture from sterile site
a. Both cultures and tissue microscopy have low sensitivities iv. Radiographic
1. Computed tomography (CT) scan of chest recommended when IPA suspected
2. Nodules with surrounding ground-glass opacities (halo-sign) common with early IPA and represent alveolar hemorrhage
v. Additional Laboratory Tests Table 1. Laboratory Diagnostics
Galactomannan (GM) antigen detection
Beta-D-glucan assay
Nucleic acid detection via polymerase chain reaction
(PCR)
Polysaccharide found in cell walls of Aspergillus
Presence of GM antigen in serum or bronchoscopy acts as an indirect marker of Aspergillus
Cross-reaction with other fungi may produce false-positive results
1,3-Beta-D-glucan is found in many fungi cell walls
May indicate presence of invasive fungal infection
Best utilized early if infection suspected
Recommended in hematologic malignancy and HSCT, but not specific for Aspergillus
May result positive for Candida spp or Pneumocystis jiroveci
Remains negative for Mucor and Cryptococcus
Evidence lacking to form consensus, should be employed alongside other diagnostic modalities, if at all
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Table 2. Available Mold-Active Antifungals10-18
Drug Mechanism
of Action Dosing and
Formulations Half-life (h)
Enzyme Inhibition
Therapeutic Drug Monitoring
Adverse Effects Cost ($/d)
PRIMARY THERAPY Voriconazole (VRC)
Inhibits ergosterol synthesis
6 mg/kg Q12H IV for 1 d, then 4 mg/kg IV q12h (IV solution);
200-300 mg PO Q12H or 3-4
mg/kg PO Q12H (tablets and PO
suspension)
Variable, dose-dependent
CYP3A4 (strong) CYP2C19
(moderate)
Target trough 1.5-5 mcg/mL
Visual hallucinations, QTc prolongation,
hepatotoxicity, hyperkalemia and
hypokalemia, skin rash, hypertension
PO: 35 IV: 56
ALTERNATIVE THERAPY
Isavuconazole (ISA) Inhibits
ergosterol synthesis
200 mg Q8H for 6 doses, then 200 mg daily
(IV solution, PO capsules)
130 CYP3A4
(moderate) Not recommended
Hepatotoxicity, hypokalemia, QTc
shortening, skin rash, edema
PO:172 IV: 290
Amphotericin B (AmB)
Binds ergosterol
3-5 mg/kg/day (liposomal
suspension); 1-1.5 mg/kg/day (conventional
solution); 5 mg/kg/day
(lipid complex suspension)
7-10 on initial dosing, 100-153
terminally (liposomal); 15-
48 on initial dosing, 15 days
terminally (conventional);
170 (lipid complex)
N/A N/A
Nephrotoxicity, hypokalemia,
hypomagnesemia, hypotension, infusion
related reactions (chills, fever)
Conv’l: 35 Lipo: 300-540
SALVAGE THERAPY
Caspofungin Inhibits 1,3-beta-D-glucan
synthesis
70 mg/day x1, then 50 mg/day
(IV solution) 27-50 N/A N/A
Hypotension, edema, skin rash,
thrombocytopenia, neutropenia,
IV: 60
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hepatotoxicity
Micafungin Inhibits 1,3-beta-D-glucan
synthesis
100-150 mg/day (IV
solution 14-17.2 N/A N/A
Anemia, hepatotoxicity, phlebitis
IV: 62
Posaconazole (POS)
Inhibits ergosterol synthesis
300 mg BID on day 1, then 300
mg daily (IV solution,
delayed-release tablet)
26-31 CYP3A4 (strong)
Prophylaxis: target trough ≥0.7 mcg/mL
Treatment: target trough ≥1 mcg/mL
Thrombophlebitis, rigors, QTc
prolongation, hypertension, edema,
skin rash, thrombocytopenia,
neutropenia, hepatotoxicity
PO:191 IV: 490
Itraconazole Inhibits
ergosterol synthesis
200 mg PO Q12H (PO
suspension) 25-50
CYP3A4 (strong)
0.5 – 3 mcg/mL
Edema, hypertension, skin rash, fever,
headache, hepatotoxicity
PO:20-64
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Treatment of Invasive Pulmonary Aspergillosis10
I. Infectious Diseases Society of America (IDSA) 2016 Aspergillosis Guidelines recommend voriconazole for primary treatment of IPA (strong recommendation, high-quality evidence)
II. Isavuconazole, liposomal amphotericin B (L-AmB), and amphotericin B lipid complex (ABLC) recommended as alternatives (ISA, L-AmB: strong recommendation, moderate-quality evidence; ABLC: weak recommendation, low-quality evidence)
Figure 3. History of Treatment
III. Amphotericin B11
a. Polyene antifungal brought to market in 1959 b. Broad spectrum of activity against molds and yeasts alike c. Considered first-line treatment prior to 2000s
i. Lack of available agents with in vitro activity against Aspergillus ii. Significant adverse effect (AE) profile limited use
iii. Mortality rates with amphotericin B deoxcholate (AmB-D) remained high d. Improved liposomal formulations developed in the late 1990s
i. Widened therapeutic index and enhanced tolerability IV. Voriconazole
a. Compared to AmB-D for treatment of IA in randomized controlled trial by Herbrecht and colleagues in 2002 (Table 2)19
Table 2. VRC versus AmB-D Design Overview
i. VRC patients achieved successful outcome in 52.8% compared to 31.6% of
AmB-D patients (95% CI, 10.4-32.9) ii. VRC patients experienced significantly fewer adverse events
Development of amphotericin B (conventional)
1958
1990s
Liposomal formulations of amphotericin B
emerge
Voriconazole proven superior to amphotericin
B
for IPA
2002
2015
Isavuconazole approved
(SECURE trial)
Design Patient Population Intervention Primary Outcome Randomized control trial (RCT) comparing VRC to AmB-D as primary therapy for IA
≥ 12 years of age immunocompromised Definite or probable IA
Voriconazole (n=144)
Amphotericin B
deoxycholate (n=133)
Response rate at Week 12
Complete or partial response
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1. Superior safety profile for renal impairment, hypokalemia, systemic events (fever, chills, anaphylaxis, asthenia, or myalgia), dyspnea
2. Fewer treatment discontinuations in VRC arm a. VRC 13.4% vs AmB-D 24.3%, p=0.008
iii. Non-inferiority trial showed VRC to be superior to AmB-D 1. VRC supplanted amphotericin B as drug of choice for IA 2. Rapid shift in standard of care for IPA
a. Ease of administration (oral therapy) b. Tolerable c. Efficacious
V. Isavuconazole15,21 a. Newest triazole antifungal
i. Approved in 2015 ii. Activity against Aspergillus and other molds, including Mucorales
b. Formulated as prodrug, isavuconazonium sulfate
Table 3. SECURE Trial Design Overview
c. Results i. All-cause mortality
1. Day 42: ISA 19%, VRC 20% a. Adjusted treatment difference -1.0%, 95% CI -7.8 to 5.7
2. Day 84: ISA 29%, VRC 31% a. Adjusted treatment difference -1.4%, 95% CI -9.2 to 6.3
ii. Overall response at end of treatment 1. Complete or partial success: ISA 35%, VRC 36%
d. ISA met noninferiority endpoints compared to VRC e. ISA patients experienced significantly fewer drug-related AE overall (42% vs 60%,
p<0.001) i. Treatment-emergent AE: significantly fewer skin and subcutaneous skin
disorders (33% vs 42%, p=0.037), eye disorders (15% vs 27%, p=0.002), and hepatobiliary disorders (9% vs 16%, p=0.016)
ii. Drug discontinuation rates lower in ISA arm (significance not reported) 1. Discontinuation due to treatment-emergent AE: ISA 14% vs VRC
23% 2. Discontinuation due to drug-related AE: ISA 8% vs VRC 14%
f. ISA granted FDA approval for treatment of IA i. VRC remains primary treatment recommendation in 2016 aspergillosis
guidelines 1. Older option with evidence and experience supporting its use 2. Therapeutic drug monitoring available and validated 3. Significant drug-drug interactions and side effect profile
ii. ISA recommended as alternative therapy based on SECURE22 1. Less evidence outside clinical trials to lend confidence to its use
Design Patient Population Intervention Primary Outcome
Double-blind, RCT conducted in population of primarily IA patients
≥ 18 years of age Criteria for proven,
probable, or possible invasive mold disease
Isavuconazole (n=258)
Voriconazole
(n=258)
All-cause mortality by day 42
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2. Therapeutic drug monitoring not validated, but also may not be necessary23,24
3. Fewer drug-drug interactions and significantly more favorable safety profile compared to VRC25
SECURE Case
reports Real-world
studies
Clinical Question: Should isavuconazole be preferred therapy in the treatment of IPA?
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Abbreviations: HCT, hematopoietic stem cell transplant; HM, hematologic malignancy; IFI, invasive fungal infection; ISA, isavuconazole; L-AmB, liposomal amphotericin B
ISA affected by hepatic function o No dosing recommendations currently available o Insufficient data to compare to VRC in hepatic failure
Early breakthrough data concerning o ISA expected to be equal with VRC based on SECURE results o Requires more thorough investigation
Table 4. Early Real-World Experience with Isavuconazole
Article Design/Purpose Population Drug Regimen Results (Efficacy/Safety)
Arsiè E, et al. 201826 Case report
58 year old male with history of
HBV-cirrhosis (Child Pugh Score
class C). Treated for possible IPA.
L-AmB x1 dose, then
ISA 200 mg daily post
loading regimen x1
week, followed by 200
mg every other day
ISA concentration after 1 week
200 mg daily = 7.5 mg/L
ISA concentration after 1 week
200 mg every other day = 9.5
mg/L
Patient eventually died of
multiorgan failure in setting of
worsening infection
Dadwal S, et al.
201627
Abstract report HM and HCT patients who received
≥7 days ISA for IFI treatment
n=131
ISA (dosing not
reported) 6 patients (4.6%) developed
breakthrough IFI
4 with Aspergillus, 1
with Rhizopus spp., and 1
with Candida
norvegensis
All patients had detectable
trough levels (range 1.4-4.8
mg/L)
Fung M, et al. 201828 Single-center
retrospective
observational report
≥18 years old with HM or solid
organ transplant with confirmed
breakthrough IFI while on ISA
n=5
ISA 200 mg daily,
with or without
loading dose, for
either prophylaxis or
treatment
All patients presented with
pneumonia
2 patients with Aspergillus niger
1 each of Rhizopus spp.,
Scedosporium apiospermum,
Aspergillus fumigatus
3 of 5 patients died
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Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole
Rausch CR, DiPippo AJ, Bose P, et al. Clin Infect Dis. 201829
Objective Report evidence of breakthrough invasive fungal infections (b-IFI) in patients receiving isavuconazole
Methods Design Single-center retrospective observational case series Patient Population
681 bed academic medical center in Houston, Texas Inclusion Criteria Exclusion Criteria
Adult patients in leukemia service Received ISA for prophylaxis or treatment of IFIs ≥ 7 days
Concomitant antifungal agent for IFI treatment
Results Demographics (n=100)
Male gender, 73 (73%) Median age, 68 years [range 24-91] Neutropenia at time of ISA initiation, 69 (69%); > 14 days, 61 (61%) Malignancy types: AML (70%), ALL (10%), CML blast crisis (2%), CLL (6%), other
(12%) Treatment of aspergillosis, 57 (57%) Primary prophylaxis, 27 (27%) Secondary prophylaxis, 16 (16%) ISA started in 39 patients previously on posaconazole
o Switched due to intolerance or failure to reach therapeutic levels
Results
Total b-IFI rate of 13% o Treatment, n=6/13 (46%) o Primary prophylaxis, n=5/13 (39%) o Secondary prophylaxis, n=2/13 (15%)
Mold-causing b-IFI, n=6 (46%) o Mortality rate, 50% o Aspergillus spp. rate, 7.7%
Rate of b-IFIs nonneutropenic at diagnosis, n=4 (31%) Additional 7 patients had possible breakthrough fungal pneumonia
Table 1. Occurrence of proven or probable breakthrough IFIs Patient Age/Sex
ANC, cells/mcL
ISA indication
Duration of ISA, d
b-IFI Breakthrough pathogen
ISA MIC, mcg/mL
45/F <100 Secondary
prophylaxis 146 Esophagitis
Candida albicans
N/A
71/M 500-1000 Treatment 7 Fungemia Candida
parapsillosis N/A
52/M <100 Primary
prophylaxis 53 Fungemia
Trichosporon asahii
0.5
76/M 500-1000 Primary
prophylaxis 14
Disseminated
Rhizopus spp. 2
61/F <100 Primary
prophylaxis 34 Pneumonia
Mucorales spp.
N/A
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o Real-world data necessary to evaluate ISA’s place in therapy o Breakthrough infections a concern for anti-fungal agents
Isavuconazole b-IFI rates ranged 4.6-13% Previously reported b-IFI rates across retrospective studies30-35
Posaconazole: 7.5% Voriconazole: 2.4-14%
o ISA and VRC are likely equally efficacious for IPA What other evidence has emerged since ISA approved?
30/M <100 Secondary
prophylaxis 63 Fungemia
Candida guilliermondii
1
76/F 100-500 Treatment 81 Pneumonia Fusarium spp. N/A
54/F <100 Treatment 160 Disseminat
ed Candida
krusei 4
34/M <10 Primary
prophylaxis 24 Fungemia
Candida glabrata
4
51/F >1000 Primary
prophylaxis 41 Fungemia
Candida glabrata
4
60/F 500-1000 Treatment 157 Pneumonia,
fungemia
Rhizopus spp.; C.
glabrata N/A
61/M 100-500 Treatment 194 Pneumonia Rhizomucor
spp. N/A
78/F <100 Treatment 26 Disseminat
ed Aspergillus
spp. N/A
ANC, absolute neutrophil count (at time of b-IFI diagnosis); b-IFI, breakthrough invasive fungal infection; ISA, isavuconazole; MIC, minimum inhibitory concentration; N/A, nonapplicable
Author’s Conclusions
Single-agent ISA resulted in higher than expected rate of breakthrough infection Breakthrough infections occurred primarily in non-Aspergillus spp.
Reviewer’s Critique Strengths Most comprehensive report to date for b-IFIs on ISA Limitations Retrospective, observational
Small, single-center Previous posaconazole exposure in many patients ISA MICs not tested for all patients Limited to leukemia patients No comorbidities reported
Overall Conclusions
ISA associated with relatively high rates of b-IFI Candida spp. represent most common b-IFI pathogens on ISA
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Studies conducted with isavuconazole since SECURE
Lack of Toxicity With Long-term Isavuconazole Use in Patients With Hematologic Malignancy
DiPippo A, Kontoyiannis D. Clin Infect Dis. 201936
Objective Present real-world tolerability data in hematologic malignancy patients on long-term isavuconazole
Methods Design Single-center retrospective report Patient Population
681 bed academic medical center in Houston, Texas Inclusion Criteria Exclusion Criteria
Consecutive patients receiving isavuconazole continuously for ≥ 6 months
Diagnosed with hematologic malignancy
N/A
Results Demographics (n=50)
Male gender, n=35/50 (70%) Median age, 61 years (range, 23-91) Malignancy types: AML/MDS (60%), ALL (12%), B-cell lymphomas (8%), CLL (6%),
CML (6%), MM (4%), aplastic anemia (4%) Median ISA duration, 356 days (range, 180-832) Indication for ISA
o Possible or presumed infection (66%) o Mold-active prophylaxis (34%)
Results Table 1. Toxicity Indicators of Chronic (≥6 Months) ISA Use
Indicator Baseline 3 Months 6 Months 12 Monthsa 24 Monthsa
ECG QTc 421 (324-
531)b 405 (371–
473)d 400 (372–
476)f 425.5
(371–471)h 391 (362–
399)k Endocrine SBP, mm Hg 124.5 (94–
171)
126 (96–155)
122.5 (88–163)
125.5 (90–
149)i
119.5
(102–154)l
Serum potassium,
mg/dL
3.8 (2.7–5.7)
4.1 (3–5.3)
4.25 (3.1–5.2)
4.2 (3.1–
5.9)i
3.9 (3.3–
5.1)l
Liver function tests ALT, U/L 37 (12–
426) 33 (12–
155) 33.5 (14–
224)
33 (16–
460)i
26 (6–63)l
AST, U/L 31 (12-245)c
29.5 (15-185)e
29 (17-184)g
29 (13-325)j
26 (11-83)m
Alkaline phosphatase, U/L
103 (38–570)
86 (52–357)
90.5 (43–240)
97.5 (48–
434)i
83.5 (58–
330)l
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Total bilirubin, mg/dL
0.8 (0.2–3.7)
0.7 (0.3–4.2)
0.6 (0.2–5.9)
0.6 (0.2–
14.1)i
0.5 (0.2–1.4)l
All values presented as median (range) Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; SBP, systolic blood pressure. aOr last date of isavuconazole (ISA) as appropriate. bn = 33.. cn = 34. dn = 24. en = 44. fn = 21. gn = 49. hn = 27. in = 46. jn = 38. kn = 6. ln = 18. mn = 15. Sixteen occurrences of toxicity possibly related to ISA use
o Hepatotoxicity: 4 (8%) o Skin rash: 6 (12%) o Blurry vision: 3 (6%) o Squamous cell carcinoma: 2 (4%) o Neurologic toxicity: 1 (2%)
Author’s Conclusions
First real-world data assessing long-term tolerability of ISA ISA was well tolerated overall
Reviewer’s Critique Strengths First real-world report of effects of chronic ISA use
Spectra of ISA-attributed toxicity largely consistent with SECURE o Primarily hepatobiliary, skin, ophthalmic events
Limitations No comparator group Retrospective, single-center
o Incidence of adverse events lower than reported in clinical trials Small sample size Comorbidities not reported
Overall Conclusions
Practical evidence of successful long-term use of ISA
Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center
Van Matre ET, Evans SL, Mueller SW, et al. Ann Clin Microbiol Antimicrob. 201937
Objective Compare safety end points between triazole antifungals in the treatment of IFIs Methods
Design Single-center retrospective matched cohort study Patient Population
678-bed academic hospital in Aurora, Colorado Inclusion Criteria Exclusion Criteria
Adult patients > 18 years of age Receipt of isavuconazole (ISA), voriconazole (VRC), or
posaconazole (POS) for active treatment of confirmed
Patients in vulnerable category such as pregnancy, prisoners
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or suspected fungal infection Intervention Compared patients who received ISA vs VRC vs PSC Outcome Primary: Composite safety outcome
QTc prolongation (>470 ms for females, >450 ms for males) Liver function tests five times the upper limit of normal (ALT > 260 units/L, AST > 195
units/L) Any documented antifungal treatment related adverse event based on primary team
documentation Secondary:
Individual components of composite outcome (percent change in QTc length from baseline, percent change in calcineurin inhibitor serum concentration)
Total cost of inpatient antifungal therapy per day All-cause in-hospital mortality In hospital and ICU LOS
Statistics 30 patients needed in each group to detect 30% difference in primary outcome between groups with 80% power and 5% alpha
Categorical data compared using chi-squared test, with pairwise comparisons if statistical significance was found
Continuous, normally distributed data compared with analysis of variance test followed by pairwise t-test
Non-normally distributed data with Kruskal-Wallis test, then Mann-Whitney U tests Results
Demographics n = 100
Characteristic Total
(n=100) ISA (n=33) VRC (n=34) POS (n=33) P-value
Age, years ± SD 55.9 ± 13.7
58.8 ± 14.0 56.9 ± 11.4 52.1 ± 15.1 0.124
Primary diagnosis of oncology, n (%)
62 (62) 17 (51.5) 23 (67.6) 22 (66.7 0.097
Hematologic malignancy, n (%)
58 (93.6)
16 (94.1) 22 (95.6) 20 (90.9) 0.806
Primary diagnosis of solid organ transplant, n (%)
26 (26) 14 (42.4) 5 (14.7) 7 (21.2) 0.097
Baseline AST, units/L ± SD
27.3 ± 36.0
22.0 ± 17.7 21.9 ± 15.5 36.4 ± 41.8 0.053
Baseline ALT, units/L ± SD
26.8 ± 28.2
22.2 ± 22.0 22.5 ± 22.1 37.1 ± 53.3 0.160
Baseline QTc, ms ± SD
457 ± 40 478 ± 46 445 ± 29 450 ± 35 0.001
Concurrent echinocandin therapy, n(%)
23 (23) 8 (24.2) 5 (14.7) 10 (30.3) 0.298
Concurrent QTc prolonging medications, n (%)
83 (83) 24 (72.7) 28 (82.35) 31 (93.9) 0.057
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Concurrent immunosuppression, n (%)
52 (52) 20 (60.6) 17 (50.0) 15 (45.4) 0.447
Formal infectious disease team consultation, n (%)
71 (71) 28 (84.8) 20 (58.8) 23 (69.7) 0.055
Indication for use Primary, n (%) 58 (58) 10 (30.3) 28 (82.4) 20 (60.6) < 0.001 Refractory, n (%) 24 (24) 13 (39.4) 4 (11.8) 7 (21.2) 0.027 Intolerance, n (%) 16 (16) 9 (27.3) 1 (2.9) 6 (18.2) 0.011 Other, n (%) 2 (2) 1 (3.0) 1 (2.9) 0 (0) 0.444 Treatment diagnosis Zygomycosis, n (%)
8 (8.33) 3 (9.1) 0 (0) 5 (15.2) 0.101
Aspergillosis, n (%)
30 (31.2)
12 (36.4) 10 (33.3) 8 (24.2)
Empiric treatment, n (%)
58 (60.4)
18 (54.6) 20 (66.7) 20 (60.6)
Results Clinical Outcomes
Characteristic Total
(n=100) ISA (n=33) VRC (n=34)
POS (n=33)
P-value
Primary outcome: Composite safety, n (%)
40 (40) 8 (24.2) 19 (55.9) 13 (39.4) 0.028
QTc prolongation following drug initiation, n (%)
28 (28) 4 (12.1) 13 (38.2) 11 (33.3) 0.037
LFT elevation, n (%)
8 (8.0) 2 (6.1) 3 (8.8) 3 (9.1) 0.876
Adverse reaction, n (%)
9 (9) 2 (6.1) 5 (15.2) 2 (6.1) 0.356
Change in QTc, ms ± SD
7.5 ± 42.0
-18.0 ± 37.6 20.5 ± 37.8 22.6 ± 38.6 0.001
Max QTc, ms ± SD 464.2 ± 35.1
460.0 ± 29.5 465.4 ±
33.8 467.4 ± 42.2 0.739
Change in ALT, units/L ± SD
93.2 ± 393.6
95.1 ± 440.3 105.6 ± 448.5
78.5 ± 281.2 0.964
Change in AST, units/L ± SD
192.4 ± 894.7
159.5 ± 717.3 259.2 ± 1226.2
155.4 ± 629.8 0.875
Mortality, n (%) 48 (48) 15 (45.5) 16 (47.1) 17 (51.5) 0.878 Hospital LOS, days ± SD
32.9 ± 37.4
31.8 ± 25.9 28.2 ± 19.5 38.7 ± 56.7 0.515
30 day readmission, n (%)
29 (42) 8 (34.78) 7 (30.4) 14 (60.9) 0.077
Recurrent infection, n (%)
9 (14.1) 1 (4.5) 4 (19.1) 4 (19.1) 0.230
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Percent change in immunosuppression dose [IQR]
-46.1 [-27.8, -57.8]
-34.3 [-4.04, -46.5]
-48.4 [-35.1, -65.9]
-46.4 [-35.1, -65.9]
0.029
Primary outcome pairwise comparison
o ISA < VRC, p=0.008 Cost Outcomes
Characteristic Total
(n=100) ISA (n=33) VRC (n=34) POS (n=33) P-value
Total drug cost, $ [IQR]
3912 [2499-6635]
3570 [2476-6458]
3891 [3013-4904]
4798 [2546-8011]
0.360
Total drug cost per day, $ [IQR]
478 [369-625]
500 [396-625]
369 [302-474]
624 [485-787]
<0.001
Therapeutic drug monitoring, n (%)
22 (22)
0 (0)
14 (41.2)
8 (24.2)
<0.001
Total cost, $ [IQR]
4032 [2499- 6703]
3571 [2476- 6458]
4011 [3013- 4904]
4798 [2546- 8131]
0.360
Author’s Conclusions
Primary outcome difference was driven by ISA’s lower incidence of QTc prolongation Increase in transaminases with ISA numerically lower than VRC, although not compared 1:1
for significance ISA required less immunosuppressive dose reduction than other triazoles Drug cost and overall total cost were similar across drug groups, but cost per day was lowest
with voriconazole Reviewer’s Critique
Strengths Cohort mostly well-matched at baseline Representation of patients outside of hematologic malignancy
Limitations Retrospective single-center study o Inherent bias in baseline drug selection o Limited external validity
Small population Adverse effects not well-characterized Reliance on biomarkers as surrogates for safety outcomes Potential confounders with echinocandin therapy Unable to follow up with patients past 30 days from discharge
Overall Conclusions
Evidence from a practical setting that generally validates previous data regarding outcomes with ISA compared to other triazoles for treatment of invasive fungal infections
19 | Ayres
Conclusions
I. Efficacy data outside of clinical trials for ISA are limited a. Evidence suggests ISA is similarly effective to its comparators
II. Therapeutic drug monitoring may be warranted in select populations (e.g. hepatic failure)
III. Role of prophylaxis in settings outside IPA remain unclear IV. Breakthrough rates appear consistent with VRC and POS V. Safety data continue to favor ISA over VRC
Summary
I. Recent evidence upholds the conclusions of SECURE II. ISA has comparable efficacy and a clearly favorable adverse effect profile relative to VRC
III. ISA is a compelling first line option for treatment of IPA
Recommendations
I. Recommend ISA for primary IPA II. Recommend VRC for extrapulmonary IA
Voriconazole
Practical experience
Isavuconazole
Tolerability
Safety
20 | Ayres
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Appendix 1. Invasive fungal disease (IFD) criteria
Category Diagnostic Criteria Proven IFD 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 IFD 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 allogeneic stem cell transplant, prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for > 3 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 IFD One Host Factor and one Clinical Criteria as defined above