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Freydière AM, Guinet R (1997) Rapid methods for identication of the most frequent clinical
yeasts. Revista iberoamericana de micologia 14(3):85–89
Frickmann H, Loderstaedt U, Racz P, Tenner-Racz K, Eggert P, Haeupler A etal (2015) Detection
of tropical fungi in formalin-xed, parafn-embedded tissue: still an indication for microscopy
in times of sequence-based diagnosis? Biomed Res Int 2015:938721
Galiana L, Arena F, Oliver A, Sansó N, Benito E (2017) Compassion satisfaction, compassion
fatigue, and burnout in Spain and Brazil: ProQOL validation and cross-cultural diagnosis. J
Pain Symptom Manag 53(3):598–604
Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS etal (2006) Time to initiation of
uconazole therapy impacts mortality in patients with candidemia: a multi-institutional study.
Clin Infect Dis 43(1):25–31
Ghannoum MA (2000) Potential role of phospholipases in virulence and fungal pathogenesis. Clin
Microbiol Rev 13(1):122–143. table of contents
Guarner J, Brandt ME (2011) Histopathologic diagnosis of fungal infections in the 21st century.
Clin Microbiol Rev 24(2):247–280
Hamer EC, Moore CB, Denning DW (2006) Comparison of two uorescent whiteners, calcouor
and Blankophor, for the detection of fungal elements in clinical specimens in the diagnostic
laboratory. Clin Microbiol Infect 12(2):181–184
Hammarström H, Kondori N, Friman V, Wennerås C (2015) How to interpret serum levels of beta-
glucan for the diagnosis of invasive fungal infections in adult high-risk hematology patients:
optimal cut-off levels and confounding factors. Eur J Clin Microbiol Infect Dis 34(5):917–925
Hanson KE, Pfeiffer CD, Lease ED, Balch AH, Zaas AK, Perfect JR etal (2012) β-D-glucan sur-
veillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients:
a randomized pilot study. PLoS One 7(8):e42282
Hay R, Denning DW, Bonifaz A, Queiroz-Telles F, Beer K, Bustamante B etal (2019) The diag-
nosis of fungal neglected tropical diseases (fungal NTDs) and the role of investigation and
laboratory tests: an expert consensus report. Trop Med Infect Dis 4(4):122
Hayden RT, Qian X, Procop GW, Roberts GD, Lloyd RV (2002) In situ hybridization for the iden-
tication of lamentous fungi in tissue section. Diagn Mol Pathol 11(2):119–126
Hilmioglu S, Ilkit M, Badak Z (2007) Comparison of 12 liquid media for germ tube production of
Candida albicans and C. tropicalis. Mycoses 50(4):282–285
Hsu MC, Chen KW, Lo HJ, Chen YC, Liao MH, Lin YH etal (2003) Species identication of
medically important fungi by use of real-time LightCycler PCR. J Med Microbiol 52(Pt
12):1071–1076
Huang TD, Melnik E, Bogaerts P, Evrard S, Glupczynski Y (2019) Evaluation of the ePlex blood
culture identication panels for detection of pathogens in bloodstream infections. J Clin
Microbiol 57(2):e01597–e01518
Huppert M, Harper G, Sun SH, Delanerolle V (1975) Rapid methods for identication of yeasts. J
Clin Microbiol 2(1):21–34
Huseyin CE, O’Toole PW, Cotter PD, Scanlan PD (2017) Forgotten fungi-the gut mycobiome in
human health and disease. FEMS Microbiol Rev 41(4):479–511
Hussain KK, Malavia D, Johnson EM, Littlechild J, Winlove CP, Vollmer F etal (2020) Biosensors
and diagnostics for fungal detection. J Fungi (Basel, Switzerland) 6(4):349
Jensen HE (2021) Histopathology in the diagnosis of invasive fungal diseases. Curr Fungal Infect
Rep 15(1):23–31
Kakoschke TK, Kleinemeier C, Langenmayer MC, Ebel F (2019) Tape mount immunostaining:
a versatile method for immunouorescence analysis of fungi. Future Microbiol 14:275–282
Kali A, Srirangaraj S, Charles PM (2015) A cost-effective carbohydrate fermentation test for yeast
using microtitre plate. Indian J Med Microbiol 33(2):293–295
Klingspor L, Lindbäck E, Ullberg M, Özenci V (2018) Seven years of clinical experience with
the Yeast Trafc Light PNA FISH: assay performance and possible implications on antifungal
therapy. Mycoses 61(3):179–185
Klis FM (1994) Review: cell wall assembly in yeast. Yeast (Chichester, England) 10(7):851–869
S. Banik
1 Diagnostics of Candida and Candidiasis: Current Methods and Future…
Kordalewska M, Zhao Y, Lockhart SR, Chowdhary A, Berrio I, Perlin DS (2017) Rapid and accu-
rate molecular identication of the emerging multidrug-resistant pathogen Candida auris. J
Clin Microbiol 55(8):2445–2452
Kwasny D, Tehrani SE, Almeida C, Schjødt I, Dimaki M, Svendsen WE (2018) Direct detection
of Candida albicans with a membrane based electrochemical impedance spectroscopy sensor.
Sensors (Basel, Switzerland) 18(7):2214
Lamoth F, Alexander BD (2014) Nonmolecular methods for the diagnosis of respiratory fungal
infections. Clin Lab Med 34(2):315–336
Land GA, Vinton EC, Adcock GB, Hopkins JM (1975) Improved auxanographic method for yeast
assimilations: a comparison with other approaches. J Clin Microbiol 2(3):206–217
León C, Ruiz-Santana S, Saavedra P, Castro C, Loza A, Zakariya I etal (2016) Contribution
of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU
patients with severe abdominal conditions. Crit Care 20(1):149
Li HT, Lin BC, Huang ZF, Yang CZ, Huang WM (2019) [Clinical value of droplet digital PCR
in rapid diagnosis of invasive fungal infection in neonates]. Zhongguo dang dai er ke za zhi =
Chin J Contemp Pediatr. 21(1):45–51
Lipperheide V, Andraka L, Pontón J, Quindós G (1993) Evaluation of the albicans IDR plate
method for the rapid identication of Candida albicans. Mycoses 36(11–12):417–420
Lockhart SR (2014) Current epidemiology of Candida infection. Clin Microbiol Newsl
36(17):131–136
Loefer J, Dorn C, Hebart H, Cox P, Magga S, Einsele H (2003) Development and evaluation
of the nuclisens basic kit NASBA for the detection of RNA from Candida species frequently
resistant to antifungal drugs. Diagn Microbiol Infect Dis 45(3):217–220
Lott TJ, Kuykendall RJ, Reiss E (1993) Nucleotide sequence analysis of the 5.8S rDNA and
adjacent ITS2 region of Candida albicans and related species. Yeast (Chichester, England)
9(11):1199–1206
Lynch DP (1994) Oral candidiasis. History, classication, and clinical presentation. Oral Surg Oral
Med Oral Pathol 78(2):189–193
Martin MV, Schneidau JD Jr (1970) A simple and reliable assimilation test for the identication of
candida species. Am J Clin Pathol 53(6):875–879
Martínez-Jiménez MC, Muñoz P, Guinea J, Valerio M, Alonso R, Escribano P etal (2014) Potential
role of Candida albicans germ tube antibody in the diagnosis of deep-seated candidemia. Med
Mycol 52(3):270–275
Martínez-Jiménez MC, Muñoz P, Valerio M, Vena A, Guinea J, Bouza E (2015) Combination
of Candida biomarkers in patients receiving empirical antifungal therapy in a Spanish ter-
tiary hospital: a potential role in reducing the duration of treatment. J Antimicrob Chemother
70(11):3107–3115
Martín-Mazuelos E, Loza A, Castro C, Macías D, Zakariya I, Saavedra P etal (2015) β-D-Glucan
and Candida albicans germ tube antibody in ICU patients with invasive candidiasis. Intensive
Care Med 41(8):1424–1432
Marty M, Bourrat E, Vaysse F, Bonner M, Bailleul-Forestier I (2015) Direct microscopy: a useful
tool to diagnose oral candidiasis in children and adolescents. Mycopathologia 180(5–6):373–377
McCombie WR, McPherson JD (2019) Future promises and concerns of ubiquitous next-
generation sequencing. Cold Spring Harb Perspect Med 9(9):a025783
McCullough MJ, Clemons KV, Stevens DA (1999) Molecular and phenotypic characterization of
genotypic Candida albicans subgroups and comparison with Candida dubliniensis and Candida
stellatoidea. J Clin Microbiol 37(2):417–421
Mendonça A, Santos H, Franco-Duarte R, Sampaio P (2022) Fungal infections diagnosis—past,
present and future. Res Microbiol 173(3):103915
Mennink-Kersten MA, Ruegebrink D, Verweij PE (2008) Pseudomonas aeruginosa as a cause of
1,3-beta-D-glucan assay reactivity. Clin Infect Dis 46(12):1930–1931
Mickelsen PA, McCarthy LR, Propst MA (1977) Further modications of the auxanographic
method for identication of yeasts. J Clin Microbiol 5(3):297–301
37
38
Mikulska M, Calandra T, Sanguinetti M, Poulain D, Viscoli C (2010) The use of mannan antigen
and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the
Third European conference on infections in leukemia. Critical Care 14(6):R222
Mohr JF, Sims C, Paetznick V, Rodriguez J, Finkelman MA, Rex JH etal (2011) Prospective sur-
vey of (1→3)-beta-D-glucan and its relationship to invasive candidiasis in the surgical intensive
care unit setting. J Clin Microbiol 49(1):58–61
Monday LM, Parraga Acosta T, Alangaden G (2021) T2Candida for the diagnosis and manage-
ment of invasive Candida infections. J Fungi (Basel, Switzerland) 7(3):178
Moore KJ, Johnson MG, McClary SP (1988) Disk inoculum-solid medium method to test carbon
and nitrogen assimilation by yeast isolates. Appl Environ Microbiol 54(12):3185–3186
Moragues MD, Ortiz N, Iruretagoyena JR, García-Ruiz JC, Amutio E, Rojas A et al (2004)
Evaluation of a new commercial test (Candida albicans IFA IgG) for the serodiagnosis of inva-
sive candidiasis. Enfermedades infecciosas y microbiologia clinica 22(2):83–88
Moran GP, Coleman DC, Sullivan DJ (2012) Candida albicans versus Candida dubliniensis: why
is C. albicans more pathogenic? Int J Microbiol 2012:205921
Morrell M, Fraser VJ, Kollef MH (2005) Delaying the empiric treatment of candida bloodstream
infection until positive blood culture results are obtained: a potential risk factor for hospital
mortality. Antimicrob Agents Chemother 49(9):3640–3645
Neely LA, Audeh M, Phung NA, Min M, Suchocki A, Plourde D etal (2013) T2 magnetic reso-
nance enables nanoparticle-mediated rapid detection of candidemia in whole blood. Sci Transl
Med 5(182):182ra54
Neppelenbroek KH, Seó RS, Urban VM, Silva S, Dovigo LN, Jorge JH etal (2014) Identication
of Candida species in the clinical laboratory: a review of conventional, commercial, and molec-
ular techniques. Oral Dis 20(4):329–344
Nichols JA, Herbert Chan HW, Baker MAB (2019) Machine learning: applications of articial
intelligence to imaging and diagnosis. Biophys Rev 11(1):111–118
Nickerson WJ (1953) Reduction of inorganic substances by yeasts. I.Extracellular reduction of
sulte by species of Candida. J Infect Dis 93(1):43–56
Odds FC (1991) Sabouraud(’s) agar. J Med Vet Mycol. Bi-monthly publication of the International
Society for Human and Animal Mycology 29(6):355–359
Oliveri S, Trovato L, Betta P, Romeo MG, Nicoletti G (2008) Experience with the Platelia Candida
ELISA for the diagnosis of invasive candidosis in neonatal patients. Clin Microbiol Infect
14(4):391–393
Omidfar K, Ahmadi A, Syedmoradi L, Khoshfetrat SM, Larijani B (2020) Point-of-care biosensors
in medicine: a brief overview of our achievements in this eld based on the conducted research
in EMRI (endocrinology and metabolism research Institute of Tehran University of medical
sciences) over the past fourteen years. J Diabetes Metab Disord:1–5. https://doi.org/10.1007/
s40200- 020- 00668- 0
Ostrosky-Zeichner L, Alexander BD, Kett DH, Vazquez J, Pappas PG, Saeki F et al (2005)
Multicenter clinical evaluation of the (1→3) β-D-glucan assay as an aid to diagnosis of fungal
infections in humans. Clin Infect Dis 41(5):654–659
Pagano J, Levin JD, Trejo W (1957) Diagnostic medium for differentiation of species of Candida.
Antibiot Annu 5:137–413
Pancholi P, Carroll KC, Buchan BW, Chan RC, Dhiman N, Ford B etal (2018) Multicenter
evaluation of the accelerate PhenoTest BC kit for rapid identication and phenotypic anti-
microbial susceptibility testing using morphokinetic cellular analysis. J Clin Microbiol
56(4):e01329–e01317
Parra-Sánchez M, Zakariya-Yousef Breval I, Castro Méndez C, García-Rey S, Loza Vazquez
A, Úbeda Iglesias A et al (2017) Candida albicans germ-tube antibody: evaluation of a
new automatic assay for diagnosing invasive candidiasis in ICU patients. Mycopathologia
182(7–8):645–652
Pasqualotto AC, Denning DW (2005) Diagnosis of invasive fungal infections–current limita-
tions of classical and new diagnostic methods. Eur Oncol Rev 11. https://doi.org/10.17925/
EOH.2005.0.0.1p
S. Banik
1 Diagnostics of Candida and Candidiasis: Current Methods and Future…
Patel S, Nanda R, Sahoo S, Mohapatra E (2016) Biosensors in health care: the milestones achieved
in their development towards lab-on-chip-analysis. Biochem Res Int 2016:3130469
Pfaller MA, Preston T, Bale M, Koontz FP, Body BA (1988) Comparison of the Quantum II,
API Yeast Ident, and AutoMicrobic systems for identication of clinical yeast isolates. J Clin
Microbiol 26(10):2054–2058
Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M (2011) Candida bloodstream infec-
tions: comparison of species distribution and resistance to echinocandin and azole antifun-
gal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial
Surveillance Program (2008–2009). Int J Antimicrob Agents 38(1):65–69
Pfaller MA, Wolk DM, Lowery TJ (2016) T2MR and T2Candida: novel technology for the rapid
diagnosis of candidemia and invasive candidiasis. Future Microbiol 11(1):103–117
Pfeiffer CD, Samsa GP, Schell WA, Reller LB, Perfect JR, Alexander BD (2011) Quantitation of
Candida CFU in initial positive blood cultures. J Clin Microbiol 49(8):2879–2883
Pincus DH, Orenga S, Chatellier S (2007) Yeast identication—past, present, and future methods.
Med Mycol 45(2):97–121
Pini P, Colombari B, Marchi E, Castagnoli A, Venturelli C, Sarti M etal (2019) Performance of
Candida albicans germ tube antibodies (CAGTA) and its association with (1 → 3)-β-D-glucan
(BDG) for diagnosis of invasive candidiasis (IC). Diagn Microbiol Infect Dis 93(1):39–43
Pospísil L, Kabátová A (1976) Lipolytic activity in some Candida strains (author’s transl).
Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene Zweite
naturwissenschaftliche Abt: Allgemeine, landwirtschaftliche und technische Mikrobiologie
131(8):692–696
Posteraro B, Efremov L, Leoncini E, Amore R, Posteraro P, Ricciardi W etal (2015) Are the con-
ventional commercial yeast identication methods still helpful in the era of new clinical micro-
biology diagnostics? A meta-analysis of their accuracy. J Clin Microbiol 53(8):2439–2450
Racil Z, Kocmanova I, Lengerova M, Weinbergerova B, Buresova L, Toskova M etal (2010)
Difculties in using 1,3-{beta}-D-glucan as the screening test for the early diagnosis of inva-
sive fungal infections in patients with haematological malignancies—high frequency of false-
positive results and their analysis. J Med Microbiol 59(Pt 9):1016–1022
Radic M, Goic-Barisic I, Novak A, Rubic Z, Tonkic M (2016) Evaluation of PNA FISH® Yeast
Trafc Light in identication of Candida species from blood and non-blood culture specimens.
Med Mycol 54(6):654–658
Rimek D, Fehse B, Göpel P (2008) Evaluation of Mueller-Hinton-agar as a simple medium for the
germ tube production of Candida albicans and Candida dubliniensis. Mycoses 51(3):205–208
Rüchel R, Schaffrinski M (1999) Versatile uorescent staining of fungi in clinical specimens by
using the optical brightener Blankophor. J Clin Microbiol 37(8):2694–2696
Rudek W (1978) Esterase activity in Candida species. J Clin Microbiol 8(6):756–759
Salimnia H, Fairfax MR, Lephart PR, Schreckenberger P, DesJarlais SM, Johnson JK etal (2016)
Evaluation of the FilmArray blood culture identication panel: results of a multicenter con-
trolled trial. J Clin Microbiol 54(3):687–698
Samaranayake LP, MacFarlane TW, Williamson MI (1987) Comparison of Sabouraud dextrose
and Pagano-Levin agar media for detection and isolation of yeasts from oral samples. J Clin
Microbiol 25(1):162–164
Sardi JCO, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJS (2013) Candida
species: current epidemiology, pathogenicity, biolm formation, natural antifungal products
and new therapeutic options. J Med Microbiol 62(Pt 1):10–24
Seeliger HP (1956) Use of a urease test for the screening and identication of cryptococci. J
Bacteriol 72(2):127–131
Sexton DJ, Bentz ML, Welsh RM, Litvintseva AP (2018) Evaluation of a new T2 Magnetic
Resonance assay for rapid detection of emergent fungal pathogen Candida auris on clinical
skin swab samples. Mycoses 61(10):786–790
Sherry NL, Porter JL, Seemann T, Watkins A, Stinear TP, Howden BP (2013) Outbreak investiga-
tion using high-throughput genome sequencing within a diagnostic microbiology laboratory. J
Clin Microbiol 51(5):1396–1401
39
40
Slatko BE, Gardner AF, Ausubel FM (2018) Overview of next-generation sequencing technolo-
gies. Curr Protoc Mol Biol 122(1):e59
Slifkin M (2000) Tween 80 opacity test responses of various Candida species. J Clin Microbiol
38(12):4626–4628
Song N, Li X, Liu W (2021) Metagenomic next-generation sequencing (mNGS) for diagnosis
of invasive fungal infectious diseases: a narrative review. J Lab Precis Med 6:29. https://doi.
org/10.21037/jlpm- 21- 25
Sonneborn A, Tebarth B, Ernst JF (1999) Control of white-opaque phenotypic switching in
Candida albicans by the Efg1p morphogenetic regulator. Infect Immun 67(9):4655–4660
Spanu T, Posteraro B, Fiori B, D’Inzeo T, Campoli S, Ruggeri A etal (2012) Direct maldi-tof mass
spectrometry assay of blood culture broths for rapid identication of Candida species causing
bloodstream infections: an observational study in two large microbiology laboratories. J Clin
Microbiol 50(1):176–179
Stender H (2003) PNA FISH: an intelligent stain for rapid diagnosis of infectious diseases. Expert
Rev Mol Diagn 3(5):649–655
Sullivan DJ, Henman MC, Moran GP, O’Neill LC, Bennett DE, Shanley DB etal (1996) Molecular
genetic approaches to identication, epidemiology and taxonomy of non-albicans Candida spe-
cies. J Med Microbiol 44(6):399–408
Sullivan DJ, Moran G, Donnelly S, Gee S, Pinjon E, McCartan B etal (1999) Candida dublinien-
sis: an update. Revista iberoamericana de micologia 16(2):72–76
Taira CL, Okay TS, Delgado AF, Ceccon ME, de Almeida MT, Del Negro GM (2014) A multiplex
nested PCR for the detection and identication of Candida species in blood samples of criti-
cally ill paediatric patients. BMC Infect Dis 14:406
Taschdjian CL, Burchall JJ, Kozinn PJ (1960) Rapid identication of Candida albicans by lamen-
tation on serum and serum substitutes. AMA J Dis Child 99:212–215
Thévenot DR, Toth K, Durst RA, Wilson GS (2001) Electrochemical biosensors: recommended
denitions and classication. Biosens Bioelectron 16(1–2):121–131
Tierno PM Jr, Milstoc M (1977) Germ Tube-positive Candida tropicalis. Am J Clin Pathol
68(2):294–295
Timmins EM, Howell SA, Alsberg BK, Noble WC, Goodacre R (1998) Rapid differentiation
of closely related Candida species and strains by pyrolysis-mass spectrometry and Fourier
transform- infrared spectroscopy. J Clin Microbiol 36(2):367–374
Tirunarayanan MO, Lundbeck H (1968) Investigations on the enzymes and toxins of staphylococci.
Assay of lipase using Tween as the substrate. Acta Pathol Microbiol Scand 72(2):263–276
Trost A, Graf B, Eucker J, Sezer O, Possinger K, Göbel UB etal (2004) Identication of clinically
relevant yeasts by PCR/RFLP.J Microbiol Methods 56(2):201–211
Turner SA, Butler G (2014) The Candida pathogenic species complex. Cold Spring Harb Perspect
Med 4(9):a019778
Vendele I, Willment JA, Silva LM, Palma AS, Chai W, Liu Y etal (2020) Mannan detecting C-type
lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phyloge-
netic heterogeneity in fungal cell walls. PLoS Pathog 16(1):e1007927
Vogelstein B, Kinzler KW, Digital PCR (1999) Proc Natl Acad Sci USA 96(16):9236–9241
Wadlin JK, Hanko G, Stewart R, Pape J, Nachamkin I (1999) Comparison of three commercial
systems for identication of yeasts commonly isolated in the clinical microbiology laboratory.
J Clin Microbiol 37(6):1967–1970
Wain J, Mavrogiorgou E (2013) Next-generation sequencing in clinical microbiology. Expert Rev
Mol Diagn 13(3):225–227
White PL, Price JS, Cordey A, Backx M (2021) Molecular diagnosis of yeast infections. Curr
Fungal Infect Rep 15(3):67–80
Wickerham LJ (1943) A simple technique for the detection of melibiose-fermenting yeasts. J
Bacteriol 46(6):501–505
Wickerham LJ (1946) A critical evaluation of the nitrogen assimilation tests commonly used in the
classication of yeasts. J Bacteriol 52:293–301
S. Banik
1 Diagnostics of Candida and Candidiasis: Current Methods and Future…
Wickerham LJ, Burton KA (1948) Carbon assimilation tests for the classication of yeasts. J
Bacteriol 56(3):363–371
Wills ED (1965) Lipases. Adv Lipid Res 3:197–240
Wright WF, Overman SB, Ribes JA (2011) (1–3)-β-D-glucan assay: a review of its laboratory and
clinical application. Lab Med 42(11):679–685
Yao Y, Shi L, Zhang C, Sun H, Wu L (2019) Application of fungal uorescent staining in oral
candidiasis: diagnostic analysis of 228 specimens. BMC Microbiol 19(1):96
Zhang SX, Carroll KC, Lewis S, Totten M, Mead P, Samuel L etal (2020) Multicenter evalua-
tion of a PCR-based digital microuidics and electrochemical detection system for the rapid
identication of 15 fungal pathogens directly from positive blood cultures. J Clin Microbiol
58(5):e02096–e02019
Zieliński B, Sroka-Oleksiak A, Rymarczyk D, Piekarczyk A, Brzychczy-Włoch M (2020) Deep
learning approach to describe and classify fungi microscopic images. PLoS One 15(6):e0234806
41
Fungal Fighters: AComprehensive Guide
toAntifungal Therapies ofthePast,
Present, andFuture
BiswambharBiswas andAnilThakur
Abstract
Candida, an opportunistic fungal group, thrives in areas like skin, gut, and ears,
deriving nutrition from hosts. Its ability to transition from tissue colonization to
systemic candidiasis varies globally due to healthcare practices, antifungal use,
and Candida species distribution. Understanding the ever-changing epidemiol-
ogy, inuenced by factors like host immunity and medical interventions, proves
vital for effective prevention and management. Advancements in antifungal
research have resulted in successive generations of drugs targeting fungal vulner-
abilities. Nevertheless, the limited availability of druggable targets in fungi pres-
ents formidable challenges. Antifungals of various generations have been
developed to address emerging fungi or combat resistance to existing drugs,
enhancing efcacy and efciency. Like rst-generation echinocandins, such as
anidulafungin and caspofungin, center around β-1,3 glucan synthesis, while
second- generation echinocandins, exemplied by micafungin and rezafungin,
showcase improved solubility and bioavailability. Azole-class drugs, pivotal for
inhibiting ergosterol biosynthesis, have evolved from ketoconazole to third-
generation agents like voriconazole and posaconazole. Despite their historical
success, concerns persist regarding resistance development, particularly with u-
conazole. The emergence of resistant Candida species, such as C. glabrata,
C. krusei, and C. auris, poses signicant challenges to existing antifungal agents.
The limitations inherent in current drug options emphasize the pressing need for
innovative antifungal therapies. Ongoing research on drug development and
identication of resistance patterns is crucial for the evolution of the next genera-
tion of antifungals. Addressing vulnerabilities specic to certain host conditions,
2
B. Biswas · A. Thakur (*)
Laboratory of Protein Translation and Fungal Pathogenesis, Regional Centre for
Biotechnology, Faridabad, Haryana, India
e-mail: anil.thakur@rcb.res.in
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
S. Hameed, P. Vijayaraghavan (eds.), Recent Advances in Human Fungal
Diseases, https://doi.org/10.1007/978-981-97-4909-6_2
43
44
B. Biswas and A. Thakur
such as diabetes and HIV, complements antifungal strategies. Proactive
approaches, including vaccination, provide new therapeutic avenues. This chap-
ter will delve into the chronological development of various antifungals and their
effectiveness against fungi. This exploration aims to lay the foundation for the
evolution of the existing drugs for the advancement of next-generation
antifungals.
Keywords
Antifungal · Azole · Echinocandin · Polyene · Allylamine · Erg11 · Ergosterol ·
Cell-wall · Biosynthesis · Candidiasis · Therapeutic-design · Inhibitors
2.1 Introduction
Fungal diseases are a serious threat to humanity as it kills more than 1.5million
people every year. Candida is a group of opportunistic fungal species that derives its
nutrition from its host while on the epidermal layers of the skin, gut, and sometimes
in the ear. As an opportunistic organism, it can infect the tissues it colonizes and can
disseminate further to cause systemic candidiasis (Vázquez-González et al. 2013;
Murphy and Bicanic 2021). Candida infections exhibit variations in prevalence
across geographical regions. Healthcare practices, antifungal misuse, and regional
differences in Candida species distribution inuence the global burden of Candida
infections. The epidemiology of Candida infections is dynamic and inuenced by
factors such as host immunity, medical interventions, and environmental conditions.
Insights into the epidemiological patterns and risk factors associated with Candida
infections are crucial for effective prevention and management. Advancements in
antifungal research have led to the development of multiple generations of antifungal drugs, each designed to target specic vulnerabilities in the fungal life cycle. As
a eukaryotic organism, fungi present a unique challenge in drug development due to
their limited number of druggable targets compared to prokaryotes. Unlike prokaryotes, fungi share substantial homology with mammalian systems, making the design
of drugs against fungi challenging, as homologous targets may impact both the
pathogen and the host. One signicant distinction between fungi and mammals is
the presence of the fungal cell wall. This structural feature becomes a focal point for
drug design efforts, as disrupting the cell wall integrity can be a promising strategy
for combating fungal infections. Additionally, differences in sterol chemistry contribute to the divergence between fungal and mammalian systems. However, mammals contain cholesterol, fungi, including pathogenic species, are characterized by
the presence of ergosterol. And also, azole drugs achieve their therapeutic effect by
impeding the activity of Erg11, resulting in the inhibition of the ergosterol pathway.
In contrast, polyene drugs operate by binding to ergosterol within the fungal cell.
Echinocandin drugs, on the other hand, function through the inhibition of Fks1, the
gene encoding the β-1,3-glucan synthase enzyme. This enzyme plays a critical role
in the synthesis of β-1,3-glucan, a pivotal fungal cell wall component. Available
2 Fungal Fighters: A Comprehensive Guide to Antifungal Therapies of the Past…
45
antifungal medications, including polyenes (e.g., nystatin and amphotericin), imidazoles (such as clotrimazole), and triazoles (including uconazole and itraconazole), are pivotal in the management of Candidiasis. Among these, uconazole, a
water-soluble bis-triazole, emerges as a favorable choice for treating Candidiasis in
HIV-infected patients due to its outstanding tolerance level, low toxicity, and favorable pharmacokinetics. The global antifungal drug market allocates a signicant
share to uconazole, accounting for one-fourth of the market. Despite its widespread use, concerns have arisen regarding treatment failure, relapse, and the emergence of resistance. The development of drug resistance is linked to factors such as
low CD4 lymphocyte count and prolonged exposure to uconazole. A notable
mechanism contributing to resistance involves the replacement of uconazolesusceptible Candida albicans strains with less uconazole-sensitive species like
C. glabrata and C. krusei. As the incidence of fungal infections rises, the limitations
of current antifungal agents become increasingly apparent. Many existing drugs
exhibit undesirable side effects, inefcacy against emerging fungi, or contribute to
the rapid development of resistance. Understanding the mechanisms of action and
resistance patterns of these antifungals is pivotal for the development of new antifungal drugs. This underscores the urgent need for the next generation of antifungal
agents that can address these shortcomings and provide effective solutions to combat the growing challenges posed by fungal infections. The quest for innovative
antifungal therapies becomes imperative in ensuring the continued efcacy of treatments and improving outcomes for patients facing Candidiasis and other fungalrelated conditions.
Additionally, the chapter highlights the challenges posed for the development of
antifungal drugs and their efcacy. The resistance to existing drugs with Candida
species necessitates ongoing research and innovation in antifungal drug development. Insights into current literature provide a foundation for future directions in
combating Candida infections, emphasizing the importance of surveillance, novel
therapeutic targets, and the development of next-generation antifungals to mitigate
the impact of these fungal pathogens on global health.
2.2 Vulnerabilities ofFungus
Being a eukaryotic organism, it has very a small number of druggable targets unlike
in the case of prokaryotes. As fungi share a large homology with mammalian systems, designing drugs against fungi will have homologous targets. The majority of
the difference lies in the presence of the cell wall in fungus. A difference also lies in
the sterol chemistry, cholesterol is found in mammals but ergosterol is found in the
fungus (Sanglard etal. 2003). An enzyme of the salvage pathway found in prokaryotes and lower eukaryotes is absent in higher eukaryotes which makes fungi vulnerable to the uorinated pyrimidine analogue class of antifungal (Tassel and Madoff
1968; Bellmann and Smuszkiewicz 2017). Thus, the current antifungal regime tar-
gets either the cell wall synthesizing machinery the ergosterol synthesizing machinery or the ergosterol itself.
46
B. Biswas and A. Thakur
2.2.1 Cell Wall Biosynthesis andEchinocandins
2.2.1.1 Budding andCell Wall Synthesis
Deposition of cell and division cycle gene products, together called septins, invites
Bud3 (Sanders and Field 1995). Myosin 5 and Kinesin bring chitin synthases and
β-1,3 glucan synthase into the bud site. RSR1 and BUD5 are Ras GTPase and GEF
proteins that are deposited on the bud site by kinesins over the microtubules (Pulver
etal. 2013). Bem1 is an SH3 domain-containing protein, and it acts as a docking site
where many different proteins will come and bind (Gow etal. 2017). Septins like
CDC3, CDC10, CDC11, and CDC12 will bind to the bud site which forms the neck
lament (Byers and Goetsch 1976a, b; Haarer and Pringle 1987; Ford and Pringle
1991; Kim etal. 1991). Vesicles containing chitin synthase (CHS6, MCS1), glucan
synthase (FKS1), cdc42 (RHO1), and GEF (BUD3) proteins are brought in towards
the bud site (Fernandes etal. 2016). The binding of Rho1 causes actin polarization
and the deposition of the chitin and glucan synthases on the cell membrane which
starts the cell wall synthesis of the new cell or bud (Sanders and Field 1995). Rho1
also acts as the regulatory subunit of FKS1 (Pulver etal. 2013). Echinocandins bind
to the cell wall synthases, specically the β-1,3 glucan synthases. The exact binding
site of echinocandins in the FKS1 is not clearly dened, but it is believed to bind at
the same location as the regulatory domain.
2.2.1.2 Echinocandins
FKS1 is composed of catalytic, activating, and regulatory subunits. It functions by
hydrolyzing the UDP-glucose and causes the branching and elongation of β-(1,3)
glucans. GPI-anchored transglycosidase or hydrolases that are present on the membrane act on the synthesized sugar chain to adapt the sugar chain onto them.
Echinocandins are a class of antifungal that is biochemically a lipopeptide and targets the FKS1 to stop glucan synthesis.Echinocandins have undergone signicant
evolution, we have tried to capture the evolution which we havesummarised in the
text below and also illustrated in (Fig.2.1).
First-Generation Echinocandin
Anidulafungin Echinocandin-B is the rst drug of its class discovered in the year
1974 and was patented by Eli Lilly and Co. (Nyfeler and Keller-Schierlein 1974). It
is a cyclic hexapeptide made up of 4,5-dihydroxyornithine, two threonines,
3-hydroxyproline, 3-hydroxy-4-methylproline, 3,4-dihydroxyhomotyrosine, and a
linoleoyl side chain α acylated with the 4,5-dihydroxyornithine. Echinocandin-B is
a natural byproduct of A. nidulans. This drug had a toxic side effect of hemolysis,
which is due to the presence of the linoleoyl side chain. Thus, the side chain was
changed to 4-octyloxybenzoate, and the drug candidate was named cilofungin
(Nyfeler and Keller-Schierlein 1974). Cilofungin did not have any hemolytic activity but it had very low solubility, and the polyethylene glycol solvent used was toxic
for human administration and thus failed in clinical trial phase II.Later, the fatty
acyl sidechain was changed to alkoxytriphenyl which increased water solubility,
forming the drug anidulafungin which was approved as an antifungal in
2006in the US.