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- •Foreword
- •Preface
- •Contents
- •Editors and Contributors
- •About the Editors
- •Contributors
- •1.1 Introduction
- •1.2 Conventional Methods
- •1.2.1 Microscopy
- •1.2.2 Culture
- •1.2.3 Germ Tube Test
- •1.2.5 Carbohydrate Assimilation Test
- •1.2.6 Nitrogen Assimilation Test
- •1.2.7 Carbohydrate Fermentation Test
- •1.2.8 Urease Test
- •1.2.9 Tween 80 Opacity Test
- •1.3 Nonculture-Based Conventional Methods
- •1.3.1 Serological Methods
- •1.3.1.2 ß-d-Glucan
- •1.3.1.3 C. albicans Germ Tube Antibody Assay (CAGTA)
- •1.4 Nucleic Acid-Based Detection
- •1.4.1 Polymerase Chain Reaction (PCR)
- •1.4.3 Peptide Nucleic Acid FISH (PNA-FISH)
- •1.4.4 PCR-Based Innovative Diagnosis
- •1.4.5 FilmArray System
- •1.4.6 Sepsis Flow Chip
- •1.4.7 ePlex System
- •1.4.8 The T2 Candida Assay
- •1.5 Rapid Identification Systems
- •1.5.1 Manual Rapid Identification System
- •1.5.1.1 The API System
- •1.5.1.2 The VITEK System
- •1.5.2 Automatic Rapid Identification System
- •1.5.2.1 MALDI-TOF MS
- •1.5.2.2 The MALDI Sepsityper IVD Kit
- •1.5.2.3 The BioFire FilmArray BCID2 Panel
- •1.5.2.4 The Accelerate Pheno BC Panel
- •1.6 Advanced Diagnostics
- •1.6.2 Biosensor-Based Tests
- •1.6.3 Next-Generation Sequencing (NGS)
- •1.7 Conclusion
- •References
- •2.1 Introduction
- •2.2.1.2 Echinocandins
- •First-Generation Echinocandin
- •Second-Generation Echinocandin
- •2.2.1.3 Other Cell Wall Inhibitors
- •2.2.2.1 Azoles
- •Imidazole
- •Triazole
- •Second-Generation Azole
- •Third-Generation Azole
- •2.2.2.2 Polyenes
- •Other Polyene Under Development
- •2.2.2.3 Allylamines
- •2.2.3 Flucytosine
- •2.3 Conclusion
- •References
- •3.1 Introduction
- •3.2.1 Control Diet
- •3.2.3 Toxification
- •3.2.4 Alternative Treatments
- •3.3.1 Prophylaxis
- •3.3.2 Preemptive Therapies
- •3.3.3 Empirical Therapies
- •3.4 Therapeutic Approach
- •3.4.1 Azoles
- •3.4.2 Echinocandins
- •3.4.3 Polyenes
- •References
- •4.1 Introduction
- •4.3 Eukarya Domain
- •4.4.1 Cryptococcus
- •4.4.2 Aspergillus
- •4.4.3 Mucorales
- •4.4.4 Candida
- •4.5.1 Candida albicans
- •4.5.2 Morphogenesis
- •4.5.3 Pathogenesis
- •4.5.4 Adherence
- •4.5.5 Morphological Switching
- •4.5.6 Invasion
- •4.6 Induced Endocytosis
- •4.7 Active Penetration
- •4.8.2 Biofilm Formation
- •4.8.4.1 Antifungals
- •4.8.4.2 Antifungal Resistance
- •References
- •5.1 Introduction
- •5.2.3.1 Serum
- •5.2.3.2 Low Nitrogen
- •5.2.3.5 Carbon Source
- •5.2.3.6 pH
- •5.2.3.7 N-acetylglucosamine (GlcNAc)
- •5.2.3.8 Quorum Sensing Molecule
- •5.5.5 Surface Colonization Factor1 (SCF1)
- •5.5.6 Other Putative Adhesins
- •5.6.1 Phospholipases
- •5.6.2 Proteinases
- •5.6.3 Hemolysins
- •5.6.4 Lipases
- •5.7 Secreted Cytolytic Peptide: Candidalysin
- •5.5.1 ALS Family
- •5.5.2 HWP Adhesin
- •5.5.3 HYR/IFF Family
- •5.5.4 EPA Family
- •5.9.2 Low Molecular Weight Hsp/Small Heat Shock Proteins
- •5.10.1 Amino Acid/Nitrogen Metabolism
- •5.10.1.1 Amino Acid Sensing Pathway
- •5.12.1.1 Glycolysis
- •5.12.1.2 Gluconeogenesis
- •5.12.1.3 Glyoxylate Cycle
- •5.12.1.4 Fatty Acid Oxidation
- •5.12.3.2 Iron Metabolism
- •5.12.3.3 Candida Iron Transport
- •5.12.3.4 Reductive System
- •5.12.3.5 Siderophore Uptake System
- •5.12.3.6 Haemoglobin-Iron Uptake System
- •5.13.2 Zinc Metabolism
- •References
- •6.1 Introduction
- •6.2 Morphological Switching
- •6.3 Phenotypic Switching
- •6.4 Biofilm Formation
- •6.5 Metabolic Flexibility
- •6.8.1 Hemolysin
- •6.8.2 Phospholipases
- •6.8.3 Proteinase
- •6.8.4 Candidalysin
- •6.12 Conclusion
- •References
- •7.1 Introduction
- •7.2.4 Polymorphism
- •7.2.5.1 Secreted Aspartyl Proteinases
- •7.2.5.2 Phospholipase
- •7.2.6 Calcineurin-Signalling Pathway
- •7.2.7 Ion Homeostasis
- •7.2.7.1 Iron
- •7.2.7.2 Copper
- •7.2.8.1 Capsule
- •7.2.8.2 Melanin
- •7.2.8.3 Heat Shock Proteins
- •7.3 Conclusions
- •References
- •8.1 Introduction
- •8.4.1 ATP-Binding Cassette (ABC) Transporters
- •8.4.2 Major Facilitator Superfamily (MFS) Transporter
- •8.5.1 Biofilm Architecture Among Candida Species
- •References
- •9.1 Introduction
- •References
- •10.1 Introduction
- •10.3 Biofilm
- •10.5 Adherence
- •10.6 Maturation
- •10.8 Dispersion
- •10.11 Animal Models
- •10.18 Photodynamic Therapy
- •References
- •11.1 Introduction
- •11.9 Concluding Remarks
- •References
- •12.1 Introduction
- •12.2 Epidemiology
- •12.3.1 Humoral Response
- •12.3.2 Cellular Immunity
- •12.4 Virulence Factors
- •12.6.1 Fluconazole
- •12.6.2 Polyenes
- •12.6.3 Echinocandins
- •12.7 Drug Resistance
- •12.8 Future Prospects
- •12.9 Conclusions
- •References
- •13.1 Introduction
- •13.4 Translation Research
- •13.4.1 Disease-Oriented Translational Research
- •13.4.2 Lab-Oriented Translational Research
- •13.4.3 Patient-Oriented Translational Research
- •13.5 Conclusion
- •References
- •14.1 Introduction
- •14.2.3 Cutaneous Aspergillosis
- •14.2.4 Ocular Aspergillosis
- •14.2.5 Aspergillus Endocarditis
- •14.2.6 Aspergillus Osteomyelitis
- •14.2.7 Sinus Aspergillosis
- •14.3.2 Histopathology
- •14.3.3 Serological
- •14.3.4 Breath Testing
- •14.3.5 Monoclonal Antibody (mAbs)-Mediated Methods
- •14.4.1 Conventional Therapeutics
- •14.4.1.1 Azoles
- •14.4.1.2 Polyenes
- •14.4.1.3 Echinocandins
- •14.4.1.4 Fluoropyrimidines
- •14.5 Nonconventional Therapeutics
- •14.5.1 Vaccine
- •14.5.2 Monoclonal Antibodies (mAbs)
- •14.5.3 Nanotechnology-Based Therapeutics
- •14.5.4 Immune Therapy
- •14.5.5 Combination Therapy
- •14.8 Conclusion
- •References
- •15: Aspergillus Therapeutics: Future Agents
- •15.1 Introduction
- •15.2.1 Fosmanogepix
- •15.2.2 Ibrexafungerp
- •15.2.3 Olorofim
- •15.2.4 Opelconazole
- •15.2.5 Rezafungin
- •15.2.6 MGCD290
- •15.2.7 Tetrazoles (VT-1129/VT-1161/VT-1598)
- •15.2.8 Nikkomycin Z
- •15.2.9 VL-2397
- •15.2.10 T-2307/ATI-2307
- •15.2.11 Encochleated Amphotericin-B
- •15.2.12 SUBA-Itraconazole
- •15.2.13 Immunotherapy
- •15.2.14 Drug Repurposing
- •References
- •16.1 Introduction
- •16.2 Antifungal Agents
- •16.2.1 Azoles
- •16.2.2 Posaconazole
- •16.2.3 Isavuconazole
- •16.2.4 SUBA—Itraconazole
- •16.2.5 Nanovoriconazole
- •16.2.6 Adverse Effects
- •16.3 Liposomal Amphotericin B (LAMB)
- •16.3.1 Echinocandins
- •16.4 Combination Antifungal Therapy
- •16.5 Therapeutic Drug Monitoring (TDM)
- •16.5.1 Azole-Resistant Aspergillus Spp.
- •16.6 Guideline Recommendations
- •16.10 Conclusion
- •References
- •17.1 Introduction
- •17.3 Potent Antifungal Molecules Under Investigations
- •References
- •19.2 Host–A. fumigatus Interactions
- •19.3.1 Hydrophobicity or Rodlet Layer
- •19.3.2 Conidiation
- •19.3.3 DHN Melanin
- •19.3.5 Siderophores
- •19.3.6 Biofilm Formation
- •19.4 Conclusion
- •References

SaifHameed·
PoojaVijayaraghavanEditors
Recent
Advances in
Human Fungal
Diseases
Progress and Prospects

Recent Advances in Human Fungal Diseases

Saif Hameed • Pooja Vijayaraghavan
Editors
Recent Advances
in Human Fungal Diseases
Progress andProspects

Editors
Saif Hameed
Amity Institute of Biotechnology
Amity University Haryana
Gurugram, Haryana, India
Pooja Vijayaraghavan
Amity Institute of Biotechnology
Amity University
Noida, Uttar Pradesh, India
ISBN 978-981-97-4908-9 ISBN 978-981-97-4909-6 (eBook)
https://doi.org/10.1007/978-981-97-4909-6
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore
Pte Ltd. 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specic statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional afliations.
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
If disposing of this product, please recycle the paper.

Foreword
This comprehensive book provides an insightful approach to the current advances in
the area of fungal diseases, namely Candidiasis and Aspergillosis. The fungi causing these diseases, namely the yeast genera Candida and lamentous Aspergillus
species, are ubiquitously present in the environment and also comprise the human
body ora. We are constantly exposed to these fungi that rarely cause infection
among normal hosts. However, a change in host immune status to an immunocompromised one increases the susceptibility to fungal diseases. During the recent
COVID pandemic, which impacted the entire world, several immunosuppressed
patients were affected with secondary fungal infections. Fungal infections were
brought to the forefront, and we were caught on our back foot regarding the comprehensive treatments and therapies for fungal infections.
There are several features of fungal diseases, including epidemiology, diagnostics, pathogenesis, virulence, host–pathogen interaction, drug resistance, and therapeutic aspects. The knowledge and understanding of these aspects are necessary to
understand the management of fungal diseases. This book presents a compilation of
articles for updated management of Candidiasis and Aspergillosis. First, the authors
have presented a comprehensive approach to the traditional therapeutic strategies
and the newly evolving strategies for disease management. Drug resistance of these
fungi is a hurdle in treatment due to overexposure to antifungals and the extensive
use of antifungals in poultry and dairy farms. The development of effective fungal
mechanisms like drug efux to overcome the drug is a challenging aspect. Another
unique challenge during the treatment and therapy of fungi is the development of
fungal biolms that are multi-structured morphological units displaying drug resistance and persistence. These aspects are addressed in adequately in this book.
Moreover, the authors have included a section on the host–pathogen interaction to
discern the aspects of microbial pathogenicity and design better treatment options
and prevent infectious fungal disease.
Another troubling aspect is the increasing incidence of multidrug-resistant fungal pathogens. Candida auris is being increasingly reported worldwide for its multidrug resistance. Global tracking and the genomic study of such organisms can help
to develop strategies to tackle these incidences. Virulence attributes of the multidrugresistant organisms can be studied to identify molecular targets and provide assistance to the suffering. Similarly, the spectrum of infectious and allergic syndromes
related to Aspergillus infections is rather heterogeneous, with incidences of
v

vi
Foreword
restricted colonization in immunocompetent hosts. Incidences of allergic bronchopulmonary aspergillosis, rhinitis, farmer’s lung, localized aspergilloma, and more
invasive and disseminated infections are seen in the immunocompromised patients.
It is worrying that these diseases are often associated with high mortalities. The
range of diseases is disturbing and requires a rational approach to treat and manage
such diseases.
Diagnostics can be the rst approach for the correct identication of fungal
pathogens to proceed with their timely treatment. Diagnostics of fungal disease
depend on traditional methods of culturing in several laboratories and clinics.
Proven cases are often conrmed by microbiological identication and presence of
clinical symptoms. Evolving early detection techniques can denitely contribute to
improved management of fungal disease. The authors have addressed these needs in
this volume. This book comprises contributory chapters written by well-respected
authors. The information present in this book will be helpful to scientists, researchers, and medical practitioners and will also serve as a valuable reference text for the
university students.
VandanaGhormade
Pune, India

Preface
The book titled Recent Advances in Human Fungal Diseases: Progress and
Prospects aims to comprehensively explore various aspects of mycology, with a
specic focus on advancements and ongoing research related to human fungal
pathogens. The eld of clinical research on fungal infections is often overlooked,
particularly in health care settings in Asian countries and the Indian subcontinent.
Invasive fungal infections have a signicant global impact on human health, causing
approximately 1.5 million deaths annually, comparable to well-known infectious
diseases like tuberculosis or malaria. The primary culprits, Candida and Aspergillus,
are responsible for over 75% of human fungal infections.
Candidiasis, characterized by supercial or systemic infections caused by
Candida species, can affect various parts of the body, including the skin, intestinal
tracts, host tissues, and blood. C. albicans is the predominant cause of both supercial and systemic candidiasis in humans. Similarly, Aspergillus infections, primarily
caused by A. fumigatus acquired from the environment, lead to pulmonary complications such as allergic bronchopulmonary aspergillosis and invasive aspergillosis,
particularly in immunocompromised individuals. Mortality rates in vulnerable populations range from 40% to 90%. The emergence of drug resistance further complicates the treatment landscape.
Addressing drug resistance is a signicant challenge for clinicians, given its multifactorial nature with various contributing mechanisms. Recently identied
C. auris, the rst fungal pathogen recognized as a public health threat, exhibits
intrinsic resistance to antifungals. Hence, there is an urgent social need to comprehend the epidemiology, diagnostics, drug resistance, and therapeutics of these major
human fungal pathogens.
To meet this need, a comprehensive reference book has been compiled to present
an up-to-date perspective on mycological research, consolidating recent developments into a state-of-the-art framework. This book focuses on the biology of human
fungal infections, specically targeting the most common fungal pathogens—Can-
dida and Aspergillus. This book is structured into two sections, “Candida and
Candidiasis” and “Aspergillus and Aspergillosis,” each summarizing key themes
such as epidemiology, diagnostics, pathogenesis, virulence, host–pathogen interaction, drug resistance, and therapeutic aspects.
Contributions from selected experts and renowned veterans in the eld enrich the
book with cutting-edge research. It serves as a valuable research-based reference for
vii

viii
Preface
biomedical scientists, researchers, and professionals in the healthcare industry
involved in various aspects of human fungal diseases. Additionally, students in the
elds of biomedicine, pathology, and pharmacy will nd this book benecial. The
editors express their gratitude to the esteemed contributors for their valuable and
timely input, acknowledging their pivotal role in making this compilation a ready
reference for researchers in the eld.
Gurugram, Haryana, India SaifHameed
Noida, Uttar Pradesh, India PoojaVijayaraghavan

Contents
Part I Candida and Candidiasis
1 Diagnostics of Candida and Candidiasis: Current Methods
and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Sukalyani Banik
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies
of the Past, Present, and Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Biswambhar Biswas and Anil Thakur
3 Candidiasis Treatment: An Evolutionary Journey from Past
to Present and a Glimpse into the Future . . . . . . . . . . . . . . . . . . . . . . . . 65
Md Nazmul Islam Bappy, Tanjin Barketullah Robin, and Kazi Md.
Ali Zinnah
4 MDR in Candida: The Real Storm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Prashansha
Srivastava, Shashikant Tiwari, Manoj Kumar, Manoj V. Murhekar,
and Gaurav Raj Dwivedi
5 Surviving the Storm: How Candida Species Master Adaptation
for Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Aishwarya Rana, Nidhi Gupta, Shumaiza Asif, and Anil Thakur
6 Molecular Cues and Mechanisms of Pathogenesis in Candida . . . . . . 157
Somnath Sahoo and Kongara Hanumantha Rao
7 Factors Affecting Drug Resistance and Virulence
in Fungal Pathogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Preeti Sharma, Deepika Kumari, Pammi Kumari, Antresh Kumar,
and Ritu Pasrija
8 Unravelling Drug Resistance in Candida Species: Genetic,
Biofilm, Transcriptional, and Epigenetic Perspectives . . . . . . . . . . . . . 203
Ajeet Kumar, Ashik Francis, Sandeep Hans, and Anil Thakur
9 Biofilm Formation in Candida Species . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Mba Ifeanyi Elibe and Nweze Emeka Innocent
ix

x
Contents
10 Dissemination of Candida auris Biofilms: A Medical Abrosia . . . . . . . 261
Garima Gangwar, Bharti Singh, and Rekha Puria
11 Polymicrobial Biofilms of C. albicans with Bacterial Species:
An Insight into Intergenus Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Purvi Joshi, Pinal Trivedi, Rohit Bhattacharjee, Muskan Sahu,
and Devarshi Gajjar
12 Decoding the Complex Terrain of Candida tropicalis-Induced
Candidiasis: Insights into Epidemiology, Infection Mechanisms,
Therapeutics, and Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Monalika Gupta, Sana Akhtar Usmani, Khushboo Arya, Shikha
Chandra, Saumya Chaturvedi, Nitin Bhardwaj, Rajendra Prasad,
and Ashutosh Singh
13 Candidiasis, Drug Resistance, and Translational Research . . . . . . . . . 319
Anubhuti Jha and Awanish Kumar
Part II Aspergillus and Aspergillosis
14 Therapeutic Strategies and Challenges in the Management
of Aspergillus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Deotima Das, Ayan Prasad Mukherjee, Saurabh Kumar Jha,
and Rashmi Minocha
15 Aspergillus Therapeutics: Future Agents . . . . . . . . . . . . . . . . . . . . . . . . 365
Yashik Bansal, Reetu Kundu, and Nidhi Singla
16 Recent Advances in the Management of Aspergillosis . . . . . . . . . . . . . . 383
Chhavi Gupta and Sajad Ahmad Dar
17 Drug-Resistance Patterns in Opportunistic Aspergilli:
A Molecular Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Sonia Kumari Shishodia, Raman Thakur, Priya Gautam, Saurav,
Neha, and Jata Shankar
18 A Comprehensive and Intricate Dynamics of Aspergillus:
Implications, Therapeutic Challenges, and Drug Resistance . . . . . . . . 427
Nabajit Kumar Borah, Yukti Tripathi, Aditi Parashar, Seneha
Santoshi, and Hina Bansal
19 Understanding Molecular Pathogenesis of Aspergillus fumigatus . . . . 457
Pooja Sen, Lovely Gupta, Aman Singh, Lokesh Kumar, Rajan
Kumar Mishra, and Pooja Vijayaraghavan
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