Methee_Chayakulkeeree.pptx

New Update in Lung Mycosis Management:
Focus on Mold Infections
Methee Chayakulkeeree, MD, PhD, FECMM
Division of Infectious Diseases and Tropical Medicine
Department of Medicine
Faculty of Medicine Siriraj Hospital
Mahidol University

Common Fungal Pathogens of The Respiratory Tract
Yeast
• Cryptococcus spp.
Mold
• Aspergillus spp.
• Mucor spp.
• Other molds
Dimorphic
• Histoplasma capsulatum
Nonculturable
• Pneumocystis jirovecii

A 68-Year-Old Man
• Type 2 DM
• Post kidney transplant 16 years ago
• Baseline creatinine 1.45
• Current medication
• Prograf 1.5 mg/day, Prednisolone 2.5 mg/day, MMF 1000 mg/day
• Presented with URI symptom for 9 days and progressive dyspnea
• NP swab- detected SARS-CoV-2 PCR (CT = 24.3)
• Desaturation - O2 saturation 91% room air
• CXR: RML and RLL infiltration

Medication
• Favipiravir initially, change to remdesivir IV
• Dexamethasone IV
• Meropenem, vancomycin, levofloxacin (treatment of HAP)
Supportive care
• ET tube D3 post admission
• Hemoperfusion D11 post admission
• ECMO D12 post admission
Management

Chest CT Scan
Multiple pulmonary nodules
with ground glass opacities
and cavity

Progress
• PF ratio 77  severe ARDS
• Cr 1.56 > 2.35, Procalcitonin 9.61, lactate 1.7
• Serum galactomannan = 1.55 (positive)
Covid-19-associated pulmonary aspergillosis (CAPA)
• Start Voriconazole 470 mg IV q 12 hrs x 1 day, 300 mg IV q 12 hr
• Actual BW 95 Kg; adjusted BW = 77 kg (load 6 mg/kg then 4 mg/kg)
• Voriconazole level 3.5 µg/mL before ECMO
• Voriconazole TDM required

• The incidence of CAPA - 19.6% to 33.3% in severe COVID-19
• High mortality 64.7%
• The conventional risk factors of invasive aspergillosis were not common
• Risk factors: ARDS on MV, corticosteroid, IL-6 inhibitor
• Pathogen: Aspergillus fumigatus, followed by Aspergillus flavus
• Voriconazole - used carefully in the concern of drug-drug interaction and
enhancing cardiovascular toxicity on anti-SARS-CoV-2 agents
COVID-19-Associated
Pulmonary Aspergillosis (CAPA)
Lai CC., et al. J Microbiol Immunol Infect 2021;54: 46-53

Invasive Pulmonary Aspergillosis

Updates and Challenges
• Diagnosis of IPA
• “Classical” and non-classical (novel) risks?
• Small molecule kinases inhibitor used in cancer treatment
• Severe influenza (Influenza-associated pulmonary aspergillosis - IAPA)
• Severe COVID-19 (COVID-19-associated pulmonary aspergillosis - CAPA)
• How to diagnose? – definite (proven) vs. probable
• Management
• Drug-drug interaction
• Dose adjustment in different host settings and TDM in individual patient
• Novel agents: new azoles - less drug interaction and broader spectrum

Invasive Pulmonary Aspergillosis
• Most common (70%) of invasive mold infections
• Commonly caused by Aspergillus fumigatus
“Classic” Risk Factors
• Neutropenia and stem cell transplant**
• Corticosteroid use
• Solid organ transplants recipients
Emerging of novel risk factors

Non-Classical/New Risks of IMDs
Latgé JP., et al. Clin Microbiol Rev 2019;33:e00140-18
2020
COVID-19
Ibrutinib
(Bruton’s tyrosine kinase inhibitor)

• ICU patients admitted 2009 - 2016
• Respiratory failure from CAP (non-
immunocompromised) or influenza (cohort)
• IPA 16/315 (5%) of control group (non-influenza
respiratory failure)
• IPA in 83/432 (19%) with influenza (14% in non-
immunocompromised)
• Median of 3 days after admission to the ICU
• Influenza A (71/355; 20%) and B (12/77; 15.6%)
• 90-day mortality 51% (influenza + IPA) vs. 28% (influenza
only), p = 0.001
Forest plots of risk factors for the development of
invasive pulmonary aspergillosis
A. Within influenza cohort; B. Compared influenza group
and control group
Schauwvlieghe AF., et al. Lancet Respir Med 2018;6:782–92

Diagnosis of Invasive Aspergillosis
• Definite (proven) case required tissue obtained for histopathology
• Histopathology: septate hyphae with acute angle branching
(Differential diagnosis: Fusarium and Scedosporium)
• Serum or BAL galactomannan
• Culture: A. fumigatus (>90%), A. flavus (5%), A. terreus
ธนภัทร นุ่นสังข์,
Thanapat Nunsang,
Thanapat Nunsang,
46024371
46024371
Age: 29 year(s)
Age: 29 year(s)
11/8/2523
11/8/2523
M
M
Siriraj Hospital
Siriraj Hospital
Definition
Definition
CHEST+WHOLE ABDOMEN
CHEST+WHOLE ABDOMEN
Chest IV 7.0 B40f
Chest IV 7.0 B40f
22/7/2553 14:42:13
22/7/2553 14:42:13
21874723
21874723
ULTRAVIST 370
ULTRAVIST 370
LOC: 189.9
LOC: 189.9
THK: 7
THK: 7
FFS
FFS
IV contrast
Late Arterial Phase
IV contrast
Late Arterial Phase
R
R L
L
A
A

Imaging and Invasive Procedures
Chest CT
• Should be performed regardless CXR results
• Routine contrast NOT recommended (neutropenics)
• Except when lesions near a large vessel
Bronchoscopy with bronchoalveolar lavage (BAL)
• Recommended in patients suspected IPA (except risk > benefit)
• Yield of BAL is low for peripheral nodular lesions
• Percutaneous or endobronchial lung biopsy preferred
Patterson TF., et al. Clin Infect Dis 2016;63(4):e1–60

Chest Computed Tomography
Thanapat Nunsang,
Thanapat Nunsang,
46024371
46024371
Age: 29 year(s)
Age: 29 year(s)
11/8/2523
11/8/2523
M
M
Page: 21 of 43
Page: 21 of 43
Acq: 4
Acq: 4
KVp: 120
KVp: 120
mA: 123
mA: 123
Siriraj Hospital
Siriraj Hospital
Definition
Definition
CHEST+WHOLE ABDOMEN
CHEST+WHOLE ABDOMEN
Chest IV 7.0 B40f
Chest IV 7.0 B40f
22/7/2553 14:42:13
22/7/2553 14:42:13
21874723
21874723
ULTRAVIST 370
ULTRAVIST 370
LOC: 189.9
LOC: 189.9
THK: 7
THK: 7
FFS
FFS
IV contrast
Late Arterial Phase
IV contrast
Late Arterial Phase
IM: 21
IM: 21
W: 1800
W: 1800
C: -585
C: -585
R
R L
L
A
A
P
P
cm
cm
Jarupa Toobjantuek,
Jarupa Toobjantuek,
Page: 80 of 212
Page: 80 of 212 IM: 80 SE: 3
IM: 80 SE: 3
cm
cm
ประจิน โพธิ์ระมาตร,
ประจิน โพธิ์ระมาตร,
Pajin Phoramard,
Pajin Phoramard,
52982066
52982066
Age: 56 YEAR
Age: 56 YEAR
7/10/2498
7/10/2498
F
F
Page: 16 of 41
Page: 16 of 41
Acq: 3
Acq: 3
KVp: 120
KVp: 120
mA: 122
mA: 122
Siriraj Hospital
Siriraj Hospital
Definition
Definition
CHEST
CHEST
Chest IV 7.0 B40f
Chest IV 7.0 B40f
14/9/2555 14:36:20
14/9/2555 14:36:20
22688098
22688098
IOPAMIRO 370
IOPAMIRO 370
LOC: 106.90
LOC: 106.90
THK: 7
THK: 7
FFS
FFS
IV contrast
IV contrast
---
---
IM: 16
IM: 16
W: 1800
W: 1800
C: -585
C: -585
R
R L
L
A
A
P
P
cm
cm
Ground-
glass halo
Nodules
Air
crescent
Cavities

CT Scan of Kidney Transplant Recipient with
Invasive Mold Infections
Chayakulkeeree M, et al. Transplant Proc. 2014;46(2):595-7
Aspergillosis Mucormycosis

• Radiological patterns - nonspecific in non-neutropenics
• Single nodular lesions
• Masses
• Diffuse bilateral pulmonary infiltrates
• Pleural effusion
• Abnormalities masked by underlying acute processes
• Halo sign and the air crescent sign - uncommon in nonneutropenics
• Sensitivity 5–24%
Taccone FS, et al. Crit Care 2015;19:7., Dai Z, et al. Respirology 2013;18:323–31.
Aspergillosis in Nonneutropenic: Imaging

Vessel Occlusion Signs (VOS)
Henzler, C., et al. Sci Rep 2017;7:4483
High resolution computed
tomography
pulmonary angiography (CTPA)

Galactomannan
Galactomannan for diagnosis
• Serum and BAL galactomannan
• Sensitivity and specificity 70-80% (hematologic malignancies)
• Decreased sensitivity in patients receiving mold-active agents
• BAL galactomannan can be used in patients receiving mold-
active antifungal agents
• Single serum or BAL GM ≥ 0.5 or 1.0 (depends on guidelines)
• Serum GM ≥ 0.7 and BAL GM ≥ 0.8 is significant
• Less sensitive in non-neutropenics
• Used for treatment monitoring
Patterson TF., et al. Clin Infect Dis 2016;63(4):e1–60

• Serum galactomannan meta-analysis (27 studies)1
• Hematologics:
• Sensitivity 71% and specificity 89%
• Non-hematologics:
• Sensitivity 22% and specificity 84%
• Nonneutropenics2:
• Sensitivity 37.8%, specificity 87.1% and PPV 60.8%
• Bronchoalveolar lavage (BAL), cutoff value 0.53
• Sensitivity up to 100%
• Specificity 75% to 92%
1Pfeiffer CD, et al. Clin Infect Dis 2006;42:1417–27,2Zhou W, et al. J Clin Microbiol 2017;55:2153–61,3Guinea J, et al. Mycopathologia 2014;178:403–16
Aspergillosis in Nonneutropenic
Diagnosis: Galactomannan

COVID-19-Associated
Pulmonary Aspergillosis (CAPA)
Imaging Clinical Factors Microbiology
Probable • Pulmonary infiltrates
• Cavitating infiltrate
• Refractory fever
• Pleural rub
• Chest pain
• Hemoptysis
• BAL microscopy +
• BAL culture +
• Serum GM EIA > 0.5
• BAL GM EIA ≥ 1
• Serum PCR + (x2)
• BAL PCR + (CT<36)
• Serum and BAL PCR +
Possible • Non-BAL microscopy +
• Non-BAL culture +
• Non-BAL GM EIA > 4.5
• Non-BAL GM EIA > 1.2 (x2)
• Non-BAL GM EIA > 1.2 AND non-BAL GM LFA+ or PCR+
Koehler P., et al. Lancet Infect Dis 2021;21: e149-62
Pulmonary form
Entry criteria: COVID-19 admitted in ICU with ARDS
Proven: Histopathology, Aspergillus from culture, microscopy, PCR from material that was obtained by a sterile aspiration or biopsy

ESCMID-ECMM-ERS guideline:
First-line targeted therapy of pulmonary Aspergillus disease
Intervention SoR QoE1 QoE2 QoE3 Comment
Isavuconazole 200 mg IV tid day 1–2, then 200 mg qd oral A I IIt IIt D III, if mold active azole prophylaxis;
fewer adverse effects than voriconazole
Voriconazole 2 x 6 mg/kg IV (oral 400 mg bid) on day 1, then 2–4
mg/kg IV (oral 200–300 mg bid)
A I IIt IIt C III for start with oral;
D III, if prior mold active azole prophylaxis; TDM
L-AmB 3 mg/kg B II IIt IIt
Combination of voriconazole 6/4 mg/kg bid (after 1 week oral
possible [300 mg bid]) + anidulafungin 200/100 mg
C I IIt IIt No significant difference compared to voriconazole, in
GM-positive (subgroup) better survival; TDM
Caspofungin 70 mg qd day 1, followed by 50 mg qd (if body weight
<80 kg)
C II II II
Itraconazole 200 mg q12 h IV on day 1, then 200 mg/qd C III IIt,a IIt,a D III for start with oral, TDM
D III, if mold active azole prophylaxis
AmB lipid complex 5 mg/kg C III III III
Micafungin 100 mg C III III III
AmB colloidal dispersion 4–6 mg/kg D I IIt IIt
Conventional AmB 1–1.5 mg/kg D I IIt IIt
Other combinations D III III III Efficacy unproven
Population
1. Neutropenia (non-allo HSCT recipients), 2. Allo-HSCT (during neutropenia), 3. Allo-HSCT (w/o neutropenia) or other nonneutropenic patients
Ullmann AJ, et al. Clin Microbiol Infect. 2018;24(Suppl. 1):e1–38; , Tissot F, et al. Haematologica. 2017;102:433–444.

ECIL-6 guidelines: First-line treatment of IA
Grade Comments
Voriconazole A I Daily dose: 2x6 mg/kg on day 1 then 2x4 mg/kg
(initiation with oral therapy: C III)
Isavuconazole A I As effective as voriconazole and better tolerated
Liposomal AmB B I Daily dose: 3 mg/kg
AmB lipid complex B II Daily dose: 5 mg/kg
AmB colloidal dispersion C I Not more effective than d-AmB but less nephrotoxic
Caspofungin C II
Itraconazole C III
Combination voriconazole* + anidulafungin** C I
Other combinations C III
Recommendation against use:
d-AmB deoxycholate
A I Less effective and more toxic
Tissot F, et al. Haematologica. 2017;102:433–444.

The Limitations of Voriconazole
Non-linear pharmacokinetics
• Concentrations vary up to 100-fold in patients receiving fixed dose
• Reached steady state in 5-6 days (24 hours with loading)
• Required therapeutic drug monitoring (TDM)
Hepatotoxicity, CNS toxicity, photopsia, prolonged QTc and cutaneous adverse reactions
• May or may not relate to blood voriconazole level
Significant drug interaction due to metabolism via CYP2C19 and CYP3A4
• Rifampicin (caution), sirolimus - contraindicated
• Cyclosporin, tacrolimus, statin, calcium channel blockers – used with caution
• Omeprazole (CYP2C19) inhibitor increases voriconazole level
Cyclodextrin in IV form limit the use in patients with renal insufficiency
Limitation for treatment of IFD of uncertain etiologic agents
 Aspergillosis vs. mucormycosis
Purkins L., et al. Antimicrob Agents Chemother 2002; 46(8): 2546-53, Denning DW., et al. Clin Infect Dis 2002; 34(5):563-71

*As determined by the data review committee
IA, invasive aspergillosis; IMD, invasive mold disease; ITT, intention-to-treat; mITT, modified intention-to-treat; myITT, mycological intent-to-treat
Maertens JA, et al. Lancet. 2016;387:760–769.
ITT
N = 516
Isavuconazole
N = 258
mITT
N = 143
myITT
N = 123
Voriconazole
N = 258
mITT
N = 129
myITT
N = 108
• ITT: All randomized patients who received at least one dose of study drug
• mITT: Patients who had proven or probable IMD*
• myITT: Patients with proven or probable IA*
SECURE Study:
Voriconazole vs. Isavuconazole for IMD

SECURE Study: Mortality at Day 42-ITT
(primary endpoints)
Isavuconazole
N = 258
Voriconazole
N = 258
All-cause mortality, n (%) 48 (19) 52 (20)
Adjusted treatment difference, % (95% CI)a −1.0 (−7.8, 5.7)
Deaths, n (%) 45 (17) 50 (19)
Unknown survival status, n (%)b 3 (1) 2 (1)
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72 84
Isavuconazole (N = 143)
Voriconazole (N = 129)
mITT
Study day
Survival from first dose of study drug to Day 84
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72 84
Voriconazole (N = 258)
Study day
ITT
Survival
probability

Treatment-emergent AEs
AE, adverse event; TEAE, treatment-emergent adverse event
• Significantly fewer drug-related AEs with isavuconazole vs voriconazole (109 [42%] vs 155 [60%]; P < 0.001)
• Less frequent discontinuation due to TEAEs with isavuconazole vs voriconazole (37 [14%] vs 59 [23%])
System organ class (%)
Isavuconazole
(N = 257)
Voriconazole
(N = 259)
p-value
Patients with any AE 247 (96%) 255 (98%) 0.122
Skin and subcutaneous tissue
disorders
86 (33%) 110 (42%) 0.037
Eye disorders 39 (15%) 69 (27%) 0.002
Hepatobiliary disorders 23 (9%) 42 (16%) 0.016
Other AEs were not significantly different between
isavuconazole and voriconazole

Antifungal Options for Invasive Aspergillosis
Voriconazole Isavuconazole
Forms IV, PO IV, PO
Cyclodextrin in IV form Yes No
IV form for renal failure patients No Yes
Activity for Mucormycosis No Yes
Approved as 1st-line therapy for
aspergillosis
Yes Yes
Pharmacokinetics Non-linear Linear
Drug-drug interaction +++ +/-
CYP 2C19, 2C9, 3A4 (inhibitor/substrate) Mild-mod 3A4 (inhibitor/substrate)
Adverse effect +++ +
Therapeutic drug monitoring Yes No
Chen L et al. Drugs.2020;80:671-695, Natesan SK and Chandrasekar PH. Infect Drug Resist 2016;9:291–300

A 50-year-old man post KT 6 weeks
Culture: Mucor spp.

A 42-Year-Old Woman Post KT
กนกพร สุภาพ,
KANOKPORN SUPAP
KANOKPORN SUPAP
49189448
49189448
31/1/2514
31/1/2514
Age: 42 YEAR
Age: 42 YEAR
F
F
Page: 1 of 1
Page: 1 of 1
SIRIRAJ HOSPITAL (OPD2)
SIRIRAJ HOSPITAL (OPD2)
CHEST,GENERAL AP
CHEST,GENERAL AP
10/2/2556 11:08:27
22848794
22848794
---
---
---
---
---
---
IM: 1002
IM: 1002
W: 1024
W: 1024
C: 442
C: 442
Z: 0.48
Z: 0.48
S: 124
S: 124
cm
cm
Kanokporn Supap,
Kanokporn Supap,
49189448
49189448
Age: 42 YEAR
Age: 42 YEAR
31/1/2514
31/1/2514
F
F
Page: 1 of 275
Page: 1 of 275
Acq: 2
Acq: 2
KVp: 120
KVp: 120
mA: 79
mA: 79
Siriraj Hospital
Siriraj Hospital
Definition
Definition
ABDOMEN, WHOLE
ABDOMEN, WHOLE
whole Abd NC 1.5 B30f
whole Abd NC 1.5 B30f
8/2/2556 16:16:03
22847588
22847588
---
---
LOC: -15.60
LOC: -15.60
THK: 1.50
THK: 1.50
FFS
FFS
Non contrast
Non contrast
---
---
IM: 1
IM: 1
W: 1800
W: 1800
C: -585
C: -585
R
R L
L
A
A
P
P
cm
cm
Cunninghamella bertholletiae

A 44-Year-Old Man with Car Accident and
Near Drowning
Chest CT:
- Multiple air-filled cavities
- Intracavitary segmental
consolidation in apical and
posterior segments of RUL
- Scattered multi-focal
consolidations in all
segments of both lungs

Tracheal Aspirates
• Serum Aspergillus galactomannan > 6
• Cultures:
• Aspergillus flavus
• Aspergillus fumigatus
• Rhizopus microsporus
• Lichtheimia corymbifera

Mucormycosis: Predisposing Factors
Wide and heterogeneous population
• Diabetes type 1 and 2 (with ketoacidosis)
• Hematological malignancy
• Bone marrow transplantation (esp. with GvHD)
• Neutropenia
• Corticosteroid use
• Solid organ transplantation***
• Iron overload
• Deferoxamine therapy (disseminated disease)
• IVDU
• Trauma/burns
Pulmonary form

Diagnosis
• Aspergillosis and mucormycosis share similar clinical and radiological
presentations
• Blood cultures usually negative
• Antigen tests for Aspergillus galactomannan is NOT useful
Need high index of suspicion
• Prolonged acidosis such as poorly controlled diabetics
• Renal failure, immunosuppressed patients, persons on deferoxamine
therapy

Aspergillosis vs. Mucormycosis
Susceptible Hosts
Hematological patients
Small molecule kinase inhibitors
Immunosuppressive agents
Diabetes mellitus
Severe COVID-19 pneumonia
 COVID-19-associated mucormycosis (CAM)
 Rhinocerebral mucormycosis
 Pulmonary mucormycosis
 Linked to high-dose corticosteroid use
Mucor
Aspergillus
Thanapat Nunsang,
Thanapat Nunsang,
46024371
46024371
Age: 29 year(s)
Age: 29 year(s)
11/8/2523
11/8/2523
M
M
Page: 21 of 43
Page: 21 of 43
Acq: 4
Acq: 4
KVp: 120
KVp: 120
mA: 123
mA: 123
Siriraj Hospital
Siriraj Hospital
Definition
Definition
CHEST+WHOLE ABDOMEN
CHEST+WHOLE ABDOMEN
Chest IV 7.0 B40f
Chest IV 7.0 B40f
22/7/2553 14:42:13
22/7/2553 14:42:13
21874723
21874723
ULTRAVIST 370
ULTRAVIST 370
LOC: 189.9
LOC: 189.9
THK: 7
THK: 7
FFS
FFS
IV contrast
Late Arterial Phase
IV contrast
Late Arterial Phase
IM: 21
IM: 21
W: 1800
W: 1800
C: -585
C: -585
R
R L
L
A
A
P
P
cm
cm
Lin CY et al. Microorganisms. 2019;7(11):531
Reverse halo sign

COVID-19-Associated Mucormycosis (CAM)
• 0.27% in hospitalized COVID-19 patients in India (2.1-fold rise)
Species
Rhizopus arrhizus
Rhizomucor pusillus
Apophysomyces variabilis
Lichtheimia corymbifera
Others
Patel A., et al. Emerging Infectious Disease journal 2021;27(9)

• Uncontrolled DM - most common underlying disease
• COVID-19 - only underlying disease in 32.6% of CAM
• Hypoxemia and improper glucocorticoid use - independently risk factors
• Rhinocerebral mucormycosis 52.8%
• Case-fatality rate at 12 weeks = 45.7%
• Age, rhino-orbital-cerebral involvement, and ICU admission associated
with increased mortality

8
8
13
Early CAM
Late CAM
Median day 18
Early CAM – DKA more often
Late CAM – Hypoxemia and steroids
8 days

Therapeutic Approach to Mucormycosis
• Multimodal approach (equally important)
• Antifungal agents
• Liposomal amphotericin B
• Maintenance: posaconazole, isavuconazole
• Surgical debridement***
• Correction of the underlying condition predisposing the patient
to the disease
• Control DM
• Corticosteroids should be discontinued
• Other immunosuppressive drugs should be tapered as much as possible
Cornely OA, et al. Lancet Infect Dis. 2019 Dec;19(12):e405-e421

Isavuconazole Phase III studies
1. Maertens JA, et al. Lancet. 2016;387:760–769; 2. Marty FM, et al. Lancet Infect Dis. 2016;16:828–837. 43
*In VITAL, the ITT population consisted of 146 patients treated with isavuconazole, and the mITT population consisted of 37 of these patients who had a confirmed diagnosis of mucormycosis
AmB, amphotericin B; IA, invasive aspergillosis; ITT, intention to treat; mITT, modified intention to treat
Phase III, double-blind,
global, multicentre
Isavuconazole (n=258)
Voriconazole (n=258)
Patients with invasive fungal
disease caused by
Aspergillus spp. or other
filamentous fungi
SECURE1
Phase III, single-arm,
open-label, global,
multicentre
Isavuconazole (n=146*)
Patients with invasive fungal
infection caused by Mucorales,
or other rare molds
VITAL2 FungiScope™ case-control2
Isavuconazole (n=21)
Amphotericin B (n=33)
Patients who received primary
treatment for mucormycosis with
isavuconazole (VITAL) matched
with patients who received AmB
(FungiScope™ registry)
Prospective, observational,
case-control

Vital Study
44
DRC, Data-Review Committee
Marty FM, et al. Lancet Infect Dis. 2016;16:828–837.
Mucormycosis infection
only
N = 37
Mucormycosis
N = 46
DRC assessed
Proven/probable
N = 37
Intolerant
N = 5
Refractory
N = 11
Primary
N = 21

Vital Study: Efficacy outcomes
AmB, amphotericin B; CI, confidence interval; CNS, central nervous system
Marty FM, et al. Lancet Infect Dis. 2016;16:828–837.
Kaplan–Meier analysis of patients who received isavuconazole as primary treatment (VITAL) compared
with AmB-treated matched controls (FungiScope)
Days
Survival
probability
Number of subjects at risk
21 17 17 16 16 14 14 14 14 13 12 12 12
33 26 26 25 22 20 20 20 18 16 16 14 14
AmB formulation (N = 33)
1.0
0.8
0.6
0.4
0.2
0.0
0 1 7 14 21 28 35 42 49 56 84
77
70
63
Case matching criteria:
• Severe disease (CNS
involvement or
disseminated)
• Hematologic malignancy
• Surgery (resection or
debridement)
Isavuconazole
AmB
Case-control analysis of day 42 weighted all-cause mortality (%; 95% CI):
Isavuconazole: 33%; 13.2–53.5
AmB: 41%; 20.2–62.3 P = 0.595

Take home messages
• Common mold pathogens in respiratory tract are Aspergillus and
Mucorales
• Pulmonary aspergillosis, mucormycosis and other mold infections
share similar clinical features and require diagnostic procedures
• Novel risk factors for aspergillosis are emerging, including severe viral
pneumonia (influenza, COVID-19)
• Timely and accurate diagnosis are crucial for management of invasive
mold infections
• Several factors should be considered for appropriate choice of anti-
mold agents

Methee_Chayakulkeeree.pptx

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