This document discusses management of mold infections, focusing on Aspergillus. It describes a case of a kidney transplant recipient presenting with COVID-19 who developed invasive pulmonary aspergillosis. Imaging showed multiple pulmonary nodules and cavities. Treatment with voriconazole was started based on positive serum galactomannan and CT findings consistent with aspergillosis. The risk of aspergillosis is increased in patients with severe COVID-19, especially those receiving corticosteroids and with ARDS. Diagnosis relies on imaging, galactomannan testing and culture/pathology when possible. Voriconazole and other azoles are first-line treatments but require monitoring for
respiratory inspections are common in elderly people and often times,that tickles into the lungs.More often than not they have comorbiidites,like Diabetes,hypertension etc.Hence,the treatment has to be different and some times the prognosis is guarded
Neutrophilic granulocytes or
polymorphonuclear neutrophils
(PMNs) account for 40% to 75%
of white blood cells.
They are first WBCs recruited to sites
of acute inflammation, in response to
chemotactic cues such as CXCL8
(interleukin-8, IL-8) produced by stressed tissue cells and tissue-resident immune cells such as macrophages.
respiratory inspections are common in elderly people and often times,that tickles into the lungs.More often than not they have comorbiidites,like Diabetes,hypertension etc.Hence,the treatment has to be different and some times the prognosis is guarded
Neutrophilic granulocytes or
polymorphonuclear neutrophils
(PMNs) account for 40% to 75%
of white blood cells.
They are first WBCs recruited to sites
of acute inflammation, in response to
chemotactic cues such as CXCL8
(interleukin-8, IL-8) produced by stressed tissue cells and tissue-resident immune cells such as macrophages.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Are There Any Natural Remedies To Treat Syphilis.pdf
Methee_Chayakulkeeree.pptx
1. 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
2. Common Fungal Pathogens of The Respiratory Tract
Yeast
• Cryptococcus spp.
Mold
• Aspergillus spp.
• Mucor spp.
• Other molds
Dimorphic
• Histoplasma capsulatum
Nonculturable
• Pneumocystis jirovecii
3. 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
5. 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
8. 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
9. • 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
11. 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
12. 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
13. 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)
14. • 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
15. 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,
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
16. 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
17. Chest Computed Tomography
ธนภัทร นุ่นสังข์,
ธนภัทร นุ่นสังข์,
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
18. CT Scan of Kidney Transplant Recipient with
Invasive Mold Infections
Chayakulkeeree M, et al. Transplant Proc. 2014;46(2):595-7
Aspergillosis Mucormycosis
19. • 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
20. Vessel Occlusion Signs (VOS)
Henzler, C., et al. Sci Rep 2017;7:4483
High resolution computed
tomography
pulmonary angiography (CTPA)
21. 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
22. • 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
23. 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
24. 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.
25. 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.
26. 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
27. *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
28. 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
Isavuconazole (N = 258)
Voriconazole (N = 258)
Study day
ITT
Survival
probability
Maertens JA, et al. Lancet. 2016;387:760–769.
29. 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
Maertens JA, et al. Lancet. 2016;387:760–769.
30. 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
33. A 42-Year-Old Woman Post KT
กนกพร สุภาพ,
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
กนกพร สุภาพ,
กนกพร สุภาพ,
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
34. 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
36. 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
37. 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
38. 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
ธนภัทร นุ่นสังข์,
ธนภัทร นุ่นสังข์,
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
39. 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)
40. COVID-19-Associated Mucormycosis (CAM)
• 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
Patel A., et al. Emerging Infectious Disease journal 2021;27(9)
41. 8
8
13
Early CAM
Late CAM
Median day 18
Early CAM – DKA more often
Late CAM – Hypoxemia and steroids
COVID-19-Associated Mucormycosis (CAM)
Patel A., et al. Emerging Infectious Disease journal 2021;27(9)
8 days
42. 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
43. 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
44. 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
45. 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
Isavuconazole (N = 21)
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
46. 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
47. 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