Co esponding au ho : Mohankuma L
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion License 4.0.
The escala ing c isis o an i ungal esis ance: Clinical, molecula and public heal h
pe spec i es
Mohankuma L 1, *, Badapdianghun Rymmai 2, Abigail Kha kongo 2 ,Shi ashanka Go indhan 1 and Mohsin
Ahamed 3
1 Assis an P o esso , Acha ya and BM Reddy college o Pha macy, Bangalo e.
2 In e ns Doc o o Pha macy, Acha ya & BM Reddy college o Pha macy, Bangalo e.
3 Lec u e a School o Pha maceu ical Science and Technology, Kanuwama i, Samagu i,Nagaon(782140).
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
Publica ion his o y: Recei ed on 25 Augus 2025; e ised on 01 Oc obe 2025; accep ed on 03 Oc obe 2025
A icle DOI: h ps://doi.o g/10.30574/wjbphs.2025.24.1.0882
Abs ac
An i ungal esis ance (AFR) has become a p essing global heal h h ea , pa icula ly among immunocomp omised
popula ions, leading o ising mo bidi y, mo ali y, and heal hca e cos s. This e iew explo es he mul i ac o ial d i e s
o AFR, including clinical o e use, ag icul u al ungicide applica ion, and en i onmen al selec ion p essu es. Majo
esis an pa hogens such as Candida au is and Aspe gillus umiga us exempli y he g owing clinical challenge.
Mechanis ic insigh s highligh gene ic mu a ions, e lux pump o e exp ession, bio ilm o ma ion, and al e a ions in
s e ol biosyn hesis as key con ibu o s o esis ance. The limi ed an i ungal pipeline, coupled wi h oxici y and
he apeu ic gaps in exis ing agen s, u he exace ba es ea men limi a ions. Eme ging s a egies—no el he apeu ics
like ib exa unge p and olo o im, nano echnology-based deli e y, immuno he apies, and apid diagnos ics—show
p omise in comba ing esis ance. A One Heal h app oach, global su eillance, and obus an i ungal s ewa dship a e
essen ial o mi iga e his escala ing c isis. Coo dina ed in e disciplina y ac ion is c i ical o sa egua d public heal h and
ensu e e ec i e managemen o esis an ungal in ec ions.
Keywo ds: An i ungal; Resis ance; Mo ali y; Mo bidi y; Mu a ions; Toxici y
1. In oduc ion
An i ungal esis ance (AFR) has eme ged as a signi ican global heal h conce n (1)(2)(3)(4)(5), pa icula ly a ec ing
immunocomp omised indi iduals such as cance pa ien s, o gan ansplan ecipien s, and people li ing wi h HIV/AIDS
(1)(2)(6). The inc easing use o an i ungal agen s and a g owing a - isk popula ion ha e con ibu ed o he ise o
esis an ungal pa hogens, especially Candida and Aspe gillus species (7)(8). Resis an in ec ions a e associa ed wi h
ele a ed mo bidi y, mo ali y, p olonged hospi al s ays, and inc eased heal hca e cos s (7)(8)(9).
This e iew aims o p o ide a comp ehensi e analysis o AFR by assessing global p e alence and esis ance pa e ns,
iden i ying majo isk ac o s such as an i ungal o e use in clinical and ag icul u al se ings, and elucida ing molecula
mechanisms o esis ance including a ge si e mu a ions, e lux pump o e exp ession, and bio ilm o ma ion
(2)(9)(10). I also examines clinical consequences and he apeu ic limi a ions.
The a icle unde sco es he u gen need o imp o ed diagnos ic ools, an i ungal s ewa dship p og ams, and no el
an i ungal he apies (2)(9)(10). I highligh s gaps in su eillance and calls o ha monized global da a collec ion and
in e disciplina y collabo a ion (11)(12)(13). By c i ically e iewing cu en li e a u e, he a icle aims o suppo
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
58
heal hca e p o essionals, esea che s, and policymake s in add essing AFR and guiding u u e s a egies o e ec i e
managemen and con ol.
2. Global Impac o An i ungal Resis ance
Fungal in ec ions ep esen a signi ican ye o en o e looked global heal h bu den, causing an es ima ed 1.5 o 1.7
million dea hs annually and a ec ing o e 1 billion indi iduals wo ldwide (14,15). Among hese, o e 150 million cases
a e classi ied as se e e o li e- h ea ening, wi h incidence a es con inuing o ise due o e ol ing medical and socie al
ac o s (15). Fungal in ec ions equen ly complica e condi ions such as as hma, HIV/AIDS, cance , o gan
ansplan a ion, and co icos e oid he apy, making imely diagnosis and ea men c i ical (14). Howe e , limi ed
diagnos ic access and delays in an i ungal he apy con ibu e subs an ially o mo bidi y, mo ali y, and complica ions
such as blindness (14). Despi e ungal- ela ed dea hs i aling ube culosis and exceeding hose om mala ia, ungal
diseases emain unde -p io i ized in global heal h agendas (15).
Long- e m an i ungal use, especially among immunocomp omised pa ien s, has accele a ed he eme gence o d ug-
esis an ungal s ains like Candida au is and mul id ug- esis an Aspe gillus umiga us, signi ican ly complica ing
ea men and educing su i al (15). Cu en global es ima es show a g owing bu den o condi ions such as ch onic
pulmona y aspe gillosis (3 million), c yp ococcal meningi is (223,100), in asi e candidiasis (700,000), ungal as hma,
and ke a i is (14), ein o cing he u gen need o imp o ed diagnos ic ools, su eillance sys ems, and b oade
an i ungal access.
The socioeconomic impac o an i ungal esis ance is se e e, wi h inc easing mo ali y, longe hospi al s ays, and highe
heal hca e cos s. E ec i e an i ungal s ewa dship, clinical awa eness, and enhanced diagnos ic capaci ies a e c ucial o
mi iga e his escala ing c isis (15).
2.1. WHO P io i y Pa hogens and Eme ging Th ea s
In esponse o he ising h ea o an i ungal esis ance, he WHO eleased a ungal p io i y pa hogen lis , ca ego izing
19 ungi in o c i ical, high, and medium p io i y g oups based on global bu den and esis ance p o iles (24).
2.1.1. C i ical P io i y Pa hogens include
• C yp ococcus neo o mans: Causes ~194,000 annual cases o c yp ococcal meningi is, wi h ~147,000 dea hs,
p edominan ly among HIV pa ien s (18,29,21).
• Candida albicans: The leading cause o candidemia, esul ing in ~995,000 dea hs annually due o bio ilm-
associa ed d ug esis ance (25,18).
• Aspe gillus umiga us: Causes ~1.83 million annual cases, pa icula ly pulmona y aspe gillosis, wi h 340,000
dea hs and ising azole esis ance (19,18).
• Candida au is: A mul id ug- esis an yeas linked o nosocomial ou b eaks in o e 50 coun ies, wi h mo ali y
eaching up o 72% (30,22,16).
2.1.2. High P io i y Pa hogens
• Candida glab a a, C. pa apsilosis, and C. opicalis: Majo causes o in asi e candidiasis, o en esis an o
mul iple d ugs (17,26).
• Fusa ium and His oplasma species: Cause in asi e disease in immunocomp omised pa ien s, pa icula ly in
opical egions (31,32,23).
• Muco ales: Cause agg essi e muco mycosis wi h mo ali y up o 80% (28).
• Eumyce oma: Caused by ungi such as Madu ella spp., o en leading o ampu a ion and ch onic mo bidi y in
poo popula ions (31,28).
2.1.3. Medium P io i y Pa hogens
• Candida k usei: Associa ed wi h mucosal and bloods eam in ec ions, especially in c i ical ca e se ings (17).
• Coccidioides species: Soil-bo ne ungi causing sys emic in ec ions, wi h g ea e isk in immunocomp omised
pa ien s and high- isk egions (28).
• C yp ococcus ga ii: Causes meningi is in immunocompe en indi iduals, p edominan ly in opical clima es
(28).
• Lomen ospo a p oli icans and Scedospo ium species: Cause se e e in ec ions wi h high mo ali y a es,
especially in cance and ansplan pa ien s (28).
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
59
• Pa acoccidioides species: Endemic o Sou h Ame ica, causes sys emic in ec ion h ough inhala ion o skin
con ac (28).
• Pneumocys is ji o ecii: A common oppo unis ic pa hogen in AIDS pa ien s, sp ead ia espi a o y d ople s
(33,27).
• Tala omyces ma ne ei: Endemic in Sou heas Asia, causes se e e sys emic in ec ions in immunocomp omised
indi iduals (24).
2.1.4. Economic Impac : Escala ing Heal hca e Cos s and Resou ce Bu den
Limi a ions in an i ungal he apeu ics and diagnos ics signi ican ly bu den heal hca e sys ems and indi iduals.
P olonged hospi al s ays, in ensi e moni o ing, and in a enous he apies o in asi e ungal in ec ions d i e up di ec
medical cos s (34). Toxici ies and d ug in e ac ions u he equi e suppo i e ca e, while he eliance on cos ly second-
o hi d-line agen s inc eases expenses (34). Diagnos ic delays lead o inapp op ia e ea men s and longe admissions.
In LMICs, e e al o e ia y cen e s and high ou -o -pocke spending compound he bu den (34). Addi ionally, he lack
o pedia ic o mula ions complica es ca e. WHO emphasizes in es ing in an i ungal d ug de elopmen , diagnos ics, and
wo k o ce aining as an economic necessi y (34).
Clinical esis ance occu s when pa ien s ail o espond o s anda d an i ungal he apy despi e app op ia e dosing. This
esis ance a ises om hos ac o s—such as immune s a us—and mic obial ac o s (35). Fungis a ic d ugs ely on he
immune sys em o clea in ec ion; immunocomp omised pa ien s a e he e o e mo e ulne able o ea men ailu e
(36). Medical de ices like ca he e s and p os he ic al es acili a e pa hogen a achmen and bio ilm o ma ion, u he
p o ec ing mic obes om an i ungal agen s (37)(38)(39). E ec i e he apy equi es adequa e d ug concen a ion a
in ec ion si es, bu d ug pene a ion is o en insu icien , enabling mic obes o pe sis and o m ese oi s ha
con ibu e o ecu en in ec ions. This en i onmen selec s o esis an s ains, including p ima y (in insically
esis an ) and seconda y (acqui ed esis ance a e d ug exposu e). The molecula mechanisms a e o en sha ed
be ween hese g oups (35).
2.1.5. Mechanisms o An i ungal Resis ance
Resis ance is ca ego ized as in insic (p ima y), gene ically encoded and independen o d ug exposu e, o acqui ed
(seconda y), esul ing om exposu e o an i ungals o hei analogues (40). Resis ance o one d ug o en ex ends o i s
en i e class, limi ing ea men op ions. The ise in in asi e ungal in ec ions pa ly s ems om inc easing esis ance
and he sca ci y o new an i ungals. Al hough ungal esis ance elemen s like plasmids a e a e, ex ensi e an i ungal use
globally, especially in high-income coun ies, has inc eased esis ance isk (41). Long- e m ea men complica es
disease managemen and p omo es non-adhe ence, inc easing esis ance isk. Fungi adap apidly ia mu a ion and
en i onmen al p essu e, o en aising minimum inhibi o y concen a ions (MICs) du ing he apy. Candida species pose
a majo h ea ; Candida au is has eme ged globally wi h 30-50% luconazole esis ance and some echinocandin
esis ance (42)(43)(44). Mu a ions in ERG11 and TAC1B genes ela e o azole esis ance, while FKS gene mu a ions
cause echinocandin esis ance (34).
2.1.6. ERG11 Mu a ions and Azole Resis ance
Mu a ions in ERG11, encoding lanos e ol 14α-deme hylase— he azole a ge — educe d ug binding, leading o
esis ance. Flowe s e al. (2015) iden i ied 26 unique amino acid subs i u ions in 63 luconazole- esis an isola es;
mu a ions like Y132F, K143R, and G464S ma kedly inc eased azole MICs. Combined mu a ions, such as Y132F+K143R,
had syne gis ic e ec s. Mos mu a ions clus e nea he enzyme’s ac i e o heme-binding si es, al e ing azole
in e ac ion. Some mu a ions, like E266D, we e neu al. This de ailed mapping aids esis ance moni o ing (45).
2.1.7. Genes D i ing Resis ance in Candida albicans
Resis ance in ol es o e exp ession o e lux pump genes—CDR1, CDR2 (ABC anspo e s), and MDR1 (MFS
anspo e )—which pump azoles ou o cells, lowe ing in acellula d ug le els. Mu a ions in ERG11 and ERG3 al e
enzyme s uc u e and memb ane s e ol composi ion, diminishing d ug suscep ibili y. These gene ic adap a ions c ea e
complex esis ance mechanisms equi ing con inuous su eillance and no el he apies (46).
2.1.8. E lux Pump O e exp ession
E lux pump o e exp ession is a majo esis ance mechanism in C. albicans, pa icula ly agains azoles (47)(48)(49).
Key pumps include Cd 1, Cd 2 (ABC amily), and Md 1 (MFS amily). Thei up egula ion educes in acellula azole
concen a ions. Regula o y ac o s like M 1p and Upc2p con ol e lux gene exp ession, wi h azole exposu e inducing
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
60
apid inc eases in ERG11 ansc ip s, acili a ing ole ance. Mu a ions in ERG11 u he educe d ug binding, e.g., F72S,
F145I, G227D, enhancing esis ance (47)(48)(49).
2.1.9. Bio ilm Fo ma ion
Candida albicans bio ilms o m p o ec i e ex acellula ma ices ha impede an i ungal pene a ion and e icacy
(50)(51)(52)(53)(54). Bio ilms de elop h ough adhesion, p oli e a ion, and ma u a ion s ages. Cells wi hin bio ilms
exhibi ole ance o an i ungals a concen a ions a abo e plank onic MICs. This ole ance a ises om physical
ba ie s, al e ed me abolism, pe sis e cells, and speci ic esis ance gene exp ession. Bio ilms hus complica e ea men
and os e pe sis en in ec ions, demanding he apies ha dis up bio ilm in eg i y and a ge esis an subpopula ions
(50)(51)(52)(53)(54).
2.1.10. Al e a ions in Memb ane S e ol Composi ion
Mu a ions a ec ing s e ol biosyn hesis genes like ERG3 al e memb ane s e ol p o iles, enabling azole and polyene
esis ance (50)(51)(52)(53)(54). ERG3 mu a ions lead o accumula ion o al e na i e s e ols ha main ain memb ane
unc ion despi e d ug ac ion. Dele ion o TLO genes also in luences e gos e ol syn hesis and mi ochond ial unc ion,
inc easing luconazole ole ance. These s e ol changes educe an i ungal binding and e icacy, unde sco ing he need
o s a egies a ge ing compensa o y pa hways (50)(51)(52)(53)(54).
2.1.11. Impac o An i ungal Agen s on Lipid Biosyn hesis and Memb anes
An i ungals dis up lipid biosyn hesis and memb ane in eg i y, essen ial o ungal iabili y. Geo gopapadakou e al.
(1987) showed imidazole’s inhibi s e ol biosyn hesis, causing e gos e ol deple ion and accumula ion o oxic
in e media es, comp omising memb ane luidi y and pe meabili y. Polyenes bind e gos e ol, o ming memb ane po es
leading o ion leakage and cell dea h. Changes in memb ane lipid composi ion in luence d ug suscep ibili y and
esis ance de elopmen , highligh ing memb ane- a ge ing as a key he apeu ic a enue (55).
3. Limi ed A senal o An i ungal D ugs and Thei Modes o Ac ion
The he apeu ic landscape o an i ungal agen s emains c i ically unde de eloped. Acco ding o he WHO epo on
an i ungal d ugs, only ou new an i ungal medicines ha e been app o ed in he pas decade in majo ma ke s like he
US, EU, and China, a a e o inno a ion ha is insu icien gi en he ising incidence and se e i y o ungal in ec ions
wo ldwide (66).
Cu en ly, only nine an i ungal d ugs a ge ing he mos h ea ening ungal pa hogens on he WHO’s Fungal P io i y
Pa hogens Lis (FPPL) a e in clinical de elopmen . O hese, me ely h ee ha e ad anced o Phase 3 clinical ials— he
inal s age be o e app o al—indica ing ew new d ugs will each he ma ke in he nea u u e. Addi ionally, 22
candida es emain in p eclinical de elopmen . Conside ing he high a i ion a es in ea ly phases and he cos and isk
o an i ungal d ug de elopmen , his pipeline is inadequa e o sus ainable he apeu ic p og ess (66).
Cu en an i ungal ea men s also p esen se e al limi a ions, including se e e ad e se e ec s, equen d ug-d ug
in e ac ions, na ow dosing op ions, and o en p olonged ea men du a ions equi ing hospi aliza ion. Some d ugs
necessi a e con inuous he apeu ic d ug moni o ing, bu dening heal hca e sys ems u he . The e is an u gen need o
new an i ungals ha a e sa e , mo e e ec i e, and ha e b oade ac i i y agains di e se ungal pa hogens (66).
Child en a e especially ulne able due o a lack o pedia ic clinical ials and app op ia e o mula ions, exposing c i ical
gaps in an i ungal d ug de elopmen . Mo eo e , many heal hca e p o ide s lack su icien aining and awa eness abou
ungal in ec ions and an i ungal esis ance, impeding imely diagnosis and managemen (66).
The WHO s esses he impo ance o global su eillance, incen i es o d ug de elopmen , esea ch in o no el ungal
a ge s, and he apies enhancing hos immuni y. Ye , he apeu ic ad ances mus be ma ched by imp o ed diagnos ics.
Al hough es s o ungal-p io i y pa hogens exis , hey o en equi e ad anced labs and ained pe sonnel, limi ing
accessibili y in low- and middle-income coun ies (LMICs). Cu en diagnos ic ools a e es ic ed in pa hogen ange,
accu acy, and speed, o en unsui able o esou ce-limi ed se ings (66).
3.1. Toxici y o Exis ing An i ungal Agen s: Neph o oxici y and Hypokalemia wi h Ampho e icin B
Ampho e icin B deoxychola e (AMBD), despi e being a highly e ec i e b oad-spec um an i ungal, is associa ed wi h
signi ican oxici y, pa icula ly neph o oxici y and hypokalemia. These side e ec s limi i s use, especially in esou ce-
poo se ings whe e sa e lipid-based o mula ions a e una ailable.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
61
A ecen s udy on AMBD-induced neph o oxici y ound no signi ican demog aphic, clinical, o ea men - ela ed
p edic o s, implying ha enal oxici y may occu unp edic ably and ein o cing he need o ou ine enal moni o ing
in all pa ien s ecei ing AMBD (67).
Ano he s udy analyzing hypokalemia du ing AMBD ea men epo ed ha 33.3% o pa ien s de eloped hypokalemia,
wi h emale gende and younge age showing signi ican co ela ions (p = 0.013 and p = 0.041). Female gende eme ged
as an independen isk ac o (p = 0.01). While concu en colis in adminis a ion and highe cumula i e AMBD doses
we e associa ed wi h hypokalemia, hese we e no independen p edic o s a e mul i a iable adjus men (68).
Clinically, elec oly e and enal unc ion moni o ing is c i ical du ing AMBD he apy. Hypokalemia can wo sen
neph o oxici y and clinical ou comes, especially when combined wi h o he neph o oxic d ugs (68). The na ow
he apeu ic index, po en ial o se ious oxici y, and lack o eliable p edic o s unde sco e he u gen need o sa e
an i ungals and s a egies o educe AMBD- ela ed ad e se e ec s (67,68).
3.2. Mul id ug-Resis an Candida au is: Challenges and T ea men Implica ions
The eme gence o Candida au is as a mul id ug- esis an ungal pa hogen poses a se ious global heal h challenge.
Resis an o azoles, echinocandins, and polyenes, C. au is complica es ea men and equi es inno a i e he apeu ic
s a egies. Hospi al ou b eaks lead o p olonged s ays, highe cos s, and ele a ed mo ali y among c i ically ill pa ien s
(70).
Con ol e o s a e hampe ed by C. au is’ abili y o pe sis on su aces and esis common disin ec an s. Misiden i ica ion
in clinical labs delays diagnosis and ea men ini ia ion. Ad anced diagnos ics such as PCR assays and MALDI-TOF mass
spec ome y a e c ucial o accu a e iden i ica ion and imely in e en ion (71,72).
Resea ch in o esis ance mechanisms, including gene ic adap a ions, highligh s he u gen need o new an i ungal
agen s and op imized ea men p o ocols (70,73). Heal hca e sys ems emphasize s ic in ec ion con ol measu es—
igo ous hygiene and pa ien isola ion— o cu b sp ead. Global su eillance and in es men s in d ug de elopmen a e
i al o add ess his pa hogen’s public heal h h ea . Collabo a ion among heal hca e p o ide s, mic obiologis s, and
esea che s is essen ial o imp o e ou comes (73,74).
4. Eme ging S a egies and Inno a ions
4.1. En i onmen al and Ag icul u al Fac o s P omo ing An i ungal Resis ance
The ise o an i ungal esis ance is inc easingly d i en by en i onmen al and ag icul u al p ac ices, no ably he
widesp ead use o azole ungicides in c op p o ec ion. These p ac ices exe selec i e p essu e a o ing esis an ungal
s ains, posing signi ican public heal h challenges (75)(76).
Azole ungicides ex ensi ely used in ag icul u e ha e been linked o azole- esis an Aspe gillus umiga us s ains.
Mu a ions in he cyp51A gene iden i ied in isola es om ag icul u al en i onmen s con e esis ance o medical azoles.
These esis an s ains can sp ead en i onmen ally and in ec humans, pa icula ly immunocomp omised pa ien s,
leading o di icul - o- ea in ec ions (75)(76).
Pe sis en en i onmen al exposu e o sub-le hal azole concen a ions p omo es esis ance mechanisms such as e lux
pump o e exp ession and d ug a ge al e a ions, unde mining bo h ag icul u al and clinical an i ungal e icacy
(75)(76).
The in e connec edness o human, animal, and en i onmen al heal h necessi a es a One Heal h app oach o comba
an i ungal esis ance. Resis an s ains o igina ing in ag icul u e can ansmi o humans and animals, unde sco ing he
need o in eg a ed su eillance and managemen s a egies (75)(76).
Mi iga ion equi es s ewa dship p og ams o p uden ungicide use, enhanced en i onmen al esis ance su eillance,
and collabo a ion be ween ag icul u al and heal hca e sec o s o p ese e an i ungal e ec i eness and p o ec public
heal h (75)(76).
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
62
4.2. Eme ging An i ungal The apeu ics
The challenge o an i ungal esis ance has spu ed de elopmen o no el agen s wi h unique mechanisms. Among hese,
ib exa unge p and olo o im a e p omising candida es (75)(76)(77)(78)(79)(80).
Ib exa unge p, a i e penoid glucan syn hase inhibi o , a ge s β-(1,3)-D-glucan syn hase c i ical o ungal cell wall
syn hesis. Unlike echinocandins, i is o ally bioa ailable and e ec i e agains a b oad ange o Candida species, including
azole- and echinocandin- esis an s ains and mul id ug- esis an Candida au is. I s a o able sa e y p o ile suppo s
clinical u ili y (75)(76)(77)(78)(79)(80).
Olo o im belongs o he o o omide class, inhibi ing dihyd oo o a e dehyd ogenase (DHODH) in py imidine
biosyn hesis—a mechanism dis inc om exis ing an i ungals, educing c oss- esis ance isk. I shows po en ac i i y
agains Aspe gillus spp., including azole- esis an s ains, wi h o al bioa ailabili y and p omising pha macokine ics o
in asi e ungal in ec ion ea men (75)(76)(77)(78)(79).
O he in es iga ional s a egies include agen s a ge ing ungal i ulence ac o s like bio ilm o ma ion and hyphal
g ow h, mi ochond ial unc ion, and cell wall in eg i y. E o s o de elop an i ungal accines and immuno he apies aim
o enhance hos de enses. These inno a ions collec i ely p omise o expand an i ungal op ions and imp o e ou comes
(78)(79).
4.3. Nano echnology o An i ungal D ug Deli e y
Nano echnology o e s a no el app oach o o e coming esis ance by imp o ing d ug solubili y, s abili y, and a ge ed
deli e y, hus bypassing esis ance mechanisms such as e lux pumps, poo memb ane pene a ion, and bio ilm
ba ie s. Nanoca ie s—liposomes, solid lipid nanopa icles (SLNs), polyme ic nanopa icles, and dend ime s—ha e
enhanced pha macokine ics and bioa ailabili y o agen s like ampho e icin B and o iconazole (80)(81)(82).
Nano o mula ions enable sus ained d ug elease, concen a ing an i ungals a in ec ion si es while educing sys emic
oxici y. SLNs and liposomes enhance pene a ion in o bio ilms, which a e esis an o s anda d he apies. Polyme ic
nanopa icles imp o e ungal cell d ug accumula ion by ci cum en ing e lux anspo e s, c ucial in azole esis ance
(80)(81)(82).
Encapsula ion also p o ec s d ugs om enzyma ic deg ada ion and enhances pene a ion ac oss biological ba ie s
such as skin and mucosa. Vo iconazole-loaded nanopa icles ha e demons a ed supe io e icacy in pulmona y and
ocula deli e y models (80)(81)(82).
O e all, nano echnology-based deli e y sys ems p o ide a mul i ace ed app oach o comba esis ance, o e ing be e
d ug e en ion, bio ilm dis up ion, dose educ ion, and oxici y minimiza ion—a i al ad ancemen in an i ungal
he apy (80)(81)(82).
4.4. Immuno he apy and Monoclonal An ibodies
Immuno he apies and monoclonal an ibodies (mAbs) ha e eme ged as adjunc s o adi ional an i ungals, aiming o
enhance hos immuni y, neu alize ungal i ulence ac o s, o inhibi ungal g ow h, he eby o e coming d ug
esis ance (83)(84)(85)(86).
mAbs a ge ing ungal an igens like hea shock p o ein 90 (Hsp90) and β-glucans ha e shown p o ec i e e ec s agains
Candida and Aspe gillus in expe imen al models by educing ungal bu den and imp o ing su i al. mAbs can also
neu alize oxins, block adhesion, and modula e immune signaling (83)(84)(85)(86).
Cy okine he apies (e.g., in e e on-γ, GM-CSF) boos inna e immuni y in immunocomp omised pa ien s, demons a ing
bene i s in in asi e ungal in ec ions. Immune checkpoin inhibi o s a ge ing PD-1/PD-L1 pa hways a e unde
explo a ion o es o e T-cell unc ion (83)(84)(85)(86).
Ad anced app oaches include dend i ic cell accines and CAR-T cells enginee ed o a ge ungal an igens, hough hese
emain ea ly-s age. Chime ic mAbs like Mycog ab, an an i-Hsp90 agmen , show syne gy wi h ampho e icin B agains
Candida albicans, hough u he clinical alida ion is needed (83)(84)(85)(86).
Challenges such as cos , immunogenici y, oxici y, and limi ed clinical da a es ic widesp ead use. None heless,
p og ess in molecula a ge ing and ungal an igen disco e y con inues o d i e his ield o wa d (83)(84)(85)(86).
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
63
4.5. Rapid Diagnos ic Tools o Resis ance De ec ion
The ise o an i ungal esis ance necessi a es apid, accu a e diagnos ics o guide ea men . T adi ional cul u e
me hods a e slow and inadequa e o esis ance de ec ion. Poin -o -ca e (POC) es s and genomic sequencing
echnologies o e ans o ma i e solu ions (87)(88)(89)(90).
POC diagnos ics—la e al low assays, biosenso s, mic o luidics—enable eal- ime iden i ica ion o pa hogens and
esis ance ma ke s wi hou complex labs, imp o ing de ec ion o Candida and Aspe gillus wi h high sensi i i y and
speci ici y (87)(88)(89)(90).
Genomic ools like whole genome sequencing (WGS) and nex -gene a ion sequencing (NGS) comp ehensi ely p o ile
esis ance genes (e.g., ERG11, FKS1, e lux pump mu a ions), e ealing bo h known and no el mechanisms
(87)(88)(89)(90).
Eme ging CRISPR-based diagnos ics and po able sequencing de ices p omise ul a- apid esis ance de ec ion wi h
minimal in as uc u e, ideal o low- esou ce se ings and ou b eak esponse (87)(88)(89)(90).
In eg a ion o ad anced POC and genomic diagnos ics is e olu ionizing an i ungal esis ance managemen , enabling
ea ly in e en ion, su eillance, and in o med s ewa dship amid escala ing mul id ug esis ance (87)(88)(89)(90).
5. The Role o An i ungal S ewa dship
An i ungal esis ance poses a c i ical global heal h h ea , d i en la gely by misuse and o e use o an i ungal agen s in
clinical and ag icul u al se ings (91, 92, 93). Pa hogens like Candida au is and Aspe gillus umiga us demons a e ising
esis ance, causing ea men ailu es and inc eased mo ali y (91, 93). An i ungal s ewa dship (AFS) p og ams aim o
p omo e a ional an i ungal use, imp o e pa ien ou comes, and p ese e exis ing he apies (92, 93).
5.1. Key S ewa dship S a egies
5.1.1. Op imized Dosing Regimens
Tailo ing he apy ia he apeu ic d ug moni o ing (TDM) ensu es an i ungals such as o iconazole and posaconazole
main ain he apeu ic le els while educing oxici y. TDM imp o es ou comes and sa e y, wi h pha macis -led
in e en ions p o ing e ec i e in op imizing p esc ip ions and minimizing unnecessa y an i ungal use (91, 92).
5.1.2. Reduced Ag icul u al Use o An i ungals
Ex ensi e azole use in ag icul u e con ibu es o en i onmen al eme gence o esis an A. umiga us. Regula o y policies
limi ing ungicide use, such as hose in he Ne he lands, ha e led o measu able declines in esis an ungal s ains (93).
5.1.3. Educa ion and Awa eness P og ams
Educa ing heal hca e p o essionals and he public on app op ia e an i ungal use, ea ly diagnosis, and guideline
adhe ence is i al. Pha macis -led educa ional ini ia i es in coun ies like Pakis an ha e imp o ed p esc ibing p ac ices
and dec eased ad e se d ug eac ions (92, 94).
5.1.4. Imp o ed Diagnos ic In as uc u e
S eng hening diagnos ic capaci y enables ea ly de ec ion and managemen o ungal in ec ions. Fo ins ance, India’s
Indian Council o Medical Resea ch (ICMR) has es ablished a ne wo k o ad anced mycology cen e s o add ess
diagnos ic limi a ions and ising esis ance (94).
5.2. Regional Success S o ies
• Uni ed S a es: The Mycoses S udy G oup Educa ion and Resea ch Conso ium de eloped AFS co e
ecommenda ions emphasizing diagnos ics, TDM, and mul idisciplina y collabo a ion (92).
• Uni ed Kingdom: The NHS inco po a ed an i ungal s ewa dship wi hin b oade an imic obial s ewa dship,
ocusing on educing unnecessa y p esc ip ions (94).
• Ne he lands: E ec i e egula ion o azole use in ag icul u e mi iga ed esis ance eme gence.
• India: ICMR-MycoNe imp o ed access o ungal diagnos ics, acili a ing imely in e en ion (93).
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
64
• Pakis an: Pha macis -led p og ams educed inapp op ia e an i ungal p esc ip ions and ad e se ou comes
(92).
6. Fu u e Pe spec i es
The expanding h ea o an i ungal esis ance calls o coo dina ed global ac ion in ol ing go e nmen s, heal hca e
p o ide s, and esea che s. S eng hening in e na ional collabo a ion h ough in eg a ed esis ance su eillance is
pa amoun . The WHO’s GLASS ini ia i e has es ablished a amewo k, bu wide adop ion, ungal esis ance inclusion,
and in eg a ion in o na ional heal h sys ems a e c i ical. Enhanced su eillance equi es e e ence labo a o ies,
s anda dized es ing, and accessible genomic da abases o enable ea ly de ec ion and esis ance mapping (97)(98)(99).
Inc eased unding o an i ungal esea ch and de elopmen is equally u gen . The an i ungal pipeline emains limi ed
due o high RANDD cos s and low ma ke incen i es, wi h ew new d ug classes eme ging. Incen i e models—combining
push unding o ea ly-s age esea ch and pull mechanisms like ma ke en y ewa ds—a e needed o s imula e
inno a ion. Recen in es men s, such as hose suppo ing colo i ic de elopmen , demons a e he impac o inancial
backing on expanding ea men op ions (97)(98)(99).
Inco po a ing an i ungal esis ance moni o ing wi hin public heal h amewo ks is i al o imely esponse. This
includes labo a o y suppo , p o essional educa ion, and da a-sha ing pla o ms o ack egional and global esis ance
ends. Explo ing al e na i e ea men pa adigms, such as combining adi ional medicine wi h mode n an i ungals,
may o e complemen a y mechanisms, hough his emains unde explo ed. Immuno he apeu ic s a egies—including
accines, monoclonal an ibodies, and immune adju an s—show p omise as adjunc s, especially o
immunocomp omised pa ien s (97)(98)(99).
O e all, e ec i ely managing he an i ungal esis ance c isis equi es a comp ehensi e, o wa d-looking app oach:
global coope a ion, s a egic unding, obus su eillance, and openness o inno a i e and in eg a i e he apies. Such a
uni ed, mul i-p onged e o is essen ial o ensu e sus ainable p og ess agains esis an ungal in ec ions (97)(98)(99).
7. Conclusion
An i ungal esis ance ep esen s an eme ging global c isis ha h ea ens e ec i e managemen o li e- h ea ening
ungal in ec ions. The ise o mul id ug- esis an pa hogens such as Candida au is and Aspe gillus umiga us unde sco es
he u gen need o coo dina ed public heal h, clinical, and esea ch esponses. Mechanis ic insigh s e eal ha
esis ance s ems om gene ic mu a ions, e lux pump o e exp ession, and bio ilm o ma ion, all o which comp omise
cu en an i ungal he apies. Limi ed d ug a ailabili y, diagnos ic delays, and oxici y issues u he exace ba e clinical
challenges. Add essing his c isis demands an in eg a ed One Heal h app oach ha encompasses an i ungal
s ewa dship, en i onmen al egula ion o ungicide use, and in es men in no el he apeu ics and apid diagnos ics.
S eng hened global su eillance, in e disciplina y collabo a ion, and sus ained inno a ion a e impe a i e o p ese e
he e icacy o exis ing an i ungals and ensu e p epa edness agains u u e ungal h ea s.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
No con lic o in e es o be disclosed.
Re e ences
[1] Kon oyiannis DP. An i ungal Resis ance: An Eme ging Reali y and a Global Challenge. J In ec Dis.
2017;216(Suppl_3):S431–5.AND
[2] Vi iello A, Fe a a F, Boccellino M, Ponzo A, Cimmino C, Combe ia i E, e al. An i ungal D ug Resis ance: An
Eme gen Heal h Th ea . Biomedicines. 2023;11:1063.
[3] Mudenda S, Ma a wali SK, Mukosha M, Daka V, Chabalenge B, Chizimu J, e al. An i ungal Resis ance and
S ewa dship: A Knowledge, A i udes and P ac ices Su ey among Pha macy S uden s a he Uni e si y o
Zambia; Findings and Implica ions. JAC-An imic ob Resis . 2023;5:dlad141.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 057-069
65
[4] A as eh a A, Gabaldón T, Ga cia-Rubio R, Jenks JD, Hoenigl M, Salze HJF, e al. D ug-Resis an Fungi: An
Eme ging Challenge Th ea ening Ou Limi ed An i ungal A mamen a ium. An ibio ics. 2020;9:877.
[5] Be man J, K ysan DJ. D ug Resis ance and Tole ance in Fungi. Na Re Mic obiol. 2020;18:319–31.
[6] Ben-Ami R, Kon oyiannis DP. Resis ance o An i ungal D ugs. In ec Dis Clin No h Am. 2021;35:279–311.
[7] Algo i R. A One Heal h App oach o Comba ing Fungal Disease: Fo wa d-Reaching Recommenda ions o Raising
Awa eness. 2019 Sep 27.
[8] Sa i H, e al. The Lance HIV. 2023;10(11):e750–4.
[9] Nicola AM, Albuque que P, Paes HC, Fe nandes L, Cos a FF, Kioshima ES, e al. An i ungal D ugs: New Insigh s in
Resea ch AND De elopmen . Pha macol The . 2019;195:21–38.
[10] Oshe o N, Kon oyiannis DP. The An i-Aspe gillus D ug Pipeline: Is he Glass Hal Full o Emp y? Med Mycol.
2017;55:118–24.
[11] Jonas OB, I win A, Be he FCJ, Le Gall FG, Ma quez P. D ug-Resis an In ec ions: A Th ea o Ou Economic Fu u e.
Wo ld Bank Repo . 2017:1–132.
[12] O’Neill J. An imic obial Resis ance: Tackling a C isis o he Heal h and Weal h o Na ions. Re An ibio Resis .
2014.
[13] O’Neill J. Tackling D ug-Resis an In ec ions Globally: Final Repo and Recommenda ions. The Re iew on
An imic obial Resis ance. 2016.
[14] Bongomin F, Gago S, Oladele RO, Denning DW. Global and Mul i-Na ional P e alence o Fungal Diseases-Es ima e
P ecision. J Fungi (Basel). 2017;3(4):57.
[15] Kainz K, Baue MA, Madeo F, Ca mona-Gu ie ez D. Fungal in ec ions in humans: he silen c isis. Mic ob Cell.
2020;7(6):143–5.
[16] de Almeida JN J , F ancisco EC, Hagen F, B andão IB, Pe ei a FM, P es a Dias PH, e al. Eme gence o Candida au is
in B azil in a COVID-19 in ensi e ca e uni . J Fungi. 2021;7(3):1–6.
[17] Denning DW. An i ungal d ug esis ance: an upda e. Eu J Hosp Pha m. 2022;29(2):109–12.
[18] Denning DW. Global incidence and mo ali y o se e e ungal disease. Lance In ec Dis. 2024;24(7):428–38.
[19] Fishe MC, Denning DW. The WHO ungal p io i y pa hogens lis as a game-change . Na Re Mic obiol.
2023;21(4):211–2.
[20] F iedman DZ, Schwa z IS. Eme ging ungal in ec ions: new pa ien s, new pa e ns, and new pa hogens. J Fungi.
2019;5(3):1–19.
[21] McGui e CN, Wal e DJ. C yp ococcus neo o mans endoca di is in an immunocompe en pa ien : A case epo .
BMC Ca dio asc Diso d. 2022;22(1):1–6.
[22] Mo eno MV, Simian ME, Villa oel J, Fuenzalida LM, Ya ad MF, So o A, e al. P ime aislamien o de Candida au is
en Chile. Re Chil In ec ol. 2019;36(6):767–73.
[23] Pal M, Rod igues PC, da Sil a RL, Gu ama KP. His oplasmosis: An impo an mycosis o public heal h signi icance.
J Mycol Med Mycol Sci. 2021;4(2):1–4.
[24] Pa ums DV. The Wo ld Heal h O ganiza ion (WHO) ungal p io i y pa hogens lis in esponse o eme ging ungal
pa hogens du ing he COVID-19 pandemic. Med Sci Moni . 2022;28:1–3.
[25] Pa hakuma i B, Liang G, Liu W. Immune de ence o in asi e ungal in ec ions: A comp ehensi e e iew. Biomed
Pha maco he . 2020;130:110550.
[26] Tó h R, Nosek J, Mon es MHM, Gabaldon T, Bliss JM, Nosanchuk JD, e al. Candida pa apsilosis: om genes o he
bedside. Clin Mic obiol Re . 2019;32(2):11–8.
[27] Ve a C, Rueda ZV. T ansmission and coloniza ion o Pneumocys is ji o ecii. J Fungi. 2021;7(11):11–6.
[28] Wo ld Heal h O ganiza ion. WHO ungal p io i y pa hogens lis o guide esea ch, de elopmen and public heal h
ac ion. Gene a: WHO; 2022.
[29] Zhao Y, Ye L, Zhao F, Zhang L, Lu Z, Chu T, e al. C yp ococcus neo o mans, a global h ea o human heal h. In ec
Dis Po e y. 2023;12(2):1–8.
