Available online on 15.10.2026 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2026 The   Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article                                            Review Article

Emerging Trends in Antifungal Treatment: Role of Gels, Natural Products, and Innovative Targets

Ayush Kalhansh, Sakshi Tomar *, Ram Babu Sharma

Himalayan Institute of Pharmacy Kala-Amb, Distt-Sirmour, Himachal Pradesh, India-173030

1.  Introduction 

Gels are semi-solid systems in which particle interactions or the capacity of big molecules to dissolve in the dispersed phase regulate the dispersing medium's consistency^1,2. Gels are cross-linked, much diluted systems that don't flow steadily. They are made up of a two-component, highly liquid, semi-solid system. Gels' continuous structure, which gives them solid-like qualities, is one of their main characteristics. Because of its network structure, biocompatibility, and the molecular stability of the bioactive chemicals they contain, gels are becoming more and more popular for drug delivery formulations. Improving systemic absorption or offering localised treatment are the primary objectives of drug delivery via the skin.

Intravenous injection is invasive, but it avoids gastrointestinal side effects. Topical barrier treatments, on the other hand, increase patient compliance and are frequently self-administered^3-5. The two main categories of fungus are yeasts and moulds. Yeasts are typically single, small, oval cells, whereas mould colonies are composed of fibrous strands called hyphae. Some fungi are dimorphic, which means that depending on their surroundings, such as temperature, they can live as yeasts or moulds ^4,5. Despite the fact that fungi are ubiquitous in the environment, only a few species are commonly associated with humans and have the potential to be harmful.

A few fungi that cause sickness in healthy individuals are referred to as genuine pathogens (Histoplasma and Paracoccidioides), whereas the majority of fungi that cause illness only in immunocompromised people are classified as opportunistic pathogens Candida and Cryptococcus⁶. However, it is evident that certain opportunistic fungal infections, like Cryptococcus gattii outbreaks or Candida vaginitis, can potentially infect otherwise healthy individuals ^{7, 8}. For a systemic effect, cutaneous fungal infections are typically treated intravenously or orally. (Figure 1) Among the many negative effects it might cause are gastric irritation, diarrhoea, nausea, vomiting, stomach discomfort, headache, fever, renal impairment, and anaemia.

Figure 1: Drug delivery from various dosage form

Therefore, the best method for administering medications that go through first-pass metabolism is topical drug delivery. In general, it works well against fungal infections ⁹. In order to administer medications topically to the skin, ointments, lotions, and gels are spread and rubbed directly onto an external body surface. The medication must penetrate and distribute throughout the skin in order to have a therapeutic impact ^10,11. The drug's molecular characteristics and the biologic tissue's characteristics determine the rate and degree of transport. Targeting the infection site, improving treatment efficacy, lowering the risk of systemic adverse effects, and increasing patient compliance are all benefits of topical treatment for fungal infections ¹².

Azoles, allylamines, echinocandins, griseofulvin, and flucytosine are the five main types of antifungal drugs that are commonly used in clinical settings to treat fungal infections. Azole resistance is well known, despite the fact that the path to modern treatment has not been without issues and complications, especially drug resistance, which has not significantly affected the now used antifungals with the exception of superficial Candidiasis bacterial infections ¹³.

2. Fungal Infections of the Skin and Their Causes

Fungal exposure can cause tissue necrosis of the epidermal layers as well as superficial, systemic, and subcutaneous mycosis ^14. With the exception of yeast and non-dermatophytes producing protease enzymes, dermatophytes, yeast, and non-dermatophytes all follow the same pathogenic pathway. They always affect the keratin found in human and animal skin, nails, and hair because they use keratin as a source of nutrients, which eventually causes tissue necrosis ¹⁵. Dermatophytes can be divided into three main groups based on natural epidemiology: anthropophilic, zoophillic, and geophilic (Table 1).

Table 1. Dermatophytes based on Natural habitat and infection site^16-17

3. Mechanisms of Action and Pharmacodynamics

3.1. Classes of Antifungals and Their Targets 

Important classes of antifungals include polyenes, azoles, echinocandins, allylamines like terbinafine 18, and antimetabolites like flucytosine. Polyenes such as amphotericin B (AmB), nystatin, and natamycin were discovered in the 1950s. AmB destabilises and creates pores by binding to ergosterol, an essential component of the fungal cell membrane. It comes in lipid (ABLC lipid complex, liposomal L-AmB) and conventional (deoxycholate, AmB-d) formulations. Lipid formulations have been developed to reduce the toxicity of AmB, particularly the nephrotoxicity associated with the deoxycholate formulation. A meta-analysis found that lipid formulations significantly reduced nephrotoxicity as compared to conventional formulations ¹⁹.

Azoles have been divided into two categories since their introduction in the 1960s: Imidazoles like Miconazole and Ketoconazole which are primarily used topically or have limited systemic usage, and Triazoles such as Fluconazole, Itraconazole, Voriconazole, Posaconazole, and Isavuconazole, which are widely used systemically. They stop ergosterol from being formed by blocking the cytochrome P450-dependent enzyme lanosterol 14α-demethylase. Membrane function is altered as a result of the accumulation of dangerous methylated sterols and the depletion of ergosterol. Azoles are frequently fungicidal against Aspergillus species and fungistatic against yeasts, despite their high risk of drug interactions and potential hepatotoxicity. Isavuconazole is a more contemporary triazole that has been licensed to treat mucormycosis and invasive aspergillosis. It is delivered as the pro-pharmaceutical is avuconazole sulphate. (Figure 2)

Echinocandins such as capsofungin, micafungin, and anidulafungin were introduced in the early 2000s. They function by inhibiting the production of β-(1,3)-D-glucan, an essential structural component of the fungal cell wall, by blocking the enzyme β-(1,3)-D-glucan synthase. They are generally well tolerated, have a better drug interaction profile than azoles, are fungicidal against Aspergillus species and fungistatic against Candida species, however there have been reports of potential hepatotoxicity. Echinocandins are the first-line treatment for invasive candidiasis, according to most current guidelines.²¹. 

Figure 2: Major classes of antifungal agents: mechanisms of actions, key examples, and clinical consideration

The pyrimidine analogue flucytosine (5-FC) inhibits the synthesis of DNA and RNA after being absorbed by the fungal cell and converted into 5-fluorouracil. It is virtually exclusively used in combination therapy, typically with AmB, to treat cryptococcal meningitis and severe Candida infections. However, the potential for myelotoxicity and the rapid development of resistance when taken alone limit its use²². 

By inhibiting the enzyme squalene epoxidase, allylamines like terbinafine cause squalene buildup and ergosterol depletion, which changes the function of fungal cell membranes. With a restricted role in invasive fungal infections, their usage is mostly limited to the treatment of dermatophytoses ²³.

3.2 Principles of PK/PD Applied to Antifungals 

The capacity to attain and sustain sufficient drug concentrations at the infection site long enough to produce the intended effect is just as important to the efficacy of antifungal therapy as the selection of a medication that is effective against the pathogen in vitro ²⁴.

PK/PD studies aim to identify which pharmacokinetic parameters typically evaluated in serum or plasma best correspond with clinical or microbiological outcome in relation to the pathogen's in vitro susceptibility. The lowest medication concentration that, under regulated laboratory circumstances, inhibits apparent fungal growth is known as the Minimum Inhibitory Concentration ²⁴.  (Figure 3)

Preclinical and clinical studies have identified the most relevant PK/PD indicators for a number of antifungal classes. fAUC is often taken into account because only the free part is active. The AUC/MIC ratio is usually the best indicator of azole efficacy; for fluconazole in candidiasis, a target fAUC/MIC > 25 is linked to a positive outcome ²⁵. Since azole activity is time-dependent and concentration-independent once the MIC is exceeded, cumulative exposure (AUC) is a critical consideration. The Cmax/MIC ratio is believed to be more indicative of the effectiveness of Amphotericin B (AmB), a member of the polyenes, since it shows concentration-dependent fungicidal activity. A higher chance of therapeutic response with liposomal AmB has been associated with a Cmax/MIC > 40. 25 ²⁶.

Figure 3: PK/PD principles and key pharmacokinetics/pharmacodynamics (PK/PD) indications in antifungal therapy

Additionally, echinocandins' efficacy against Candida species is concentration-dependent ²⁶. AUC/MIC and Cmax/MIC are relevant indices, and efficacy for Candida albicans is associated with an f-AUC/MIC ratio of approximately 20 (or 7 for less virulent species). MEC (Minimum Effective Concentration) is occasionally used in place of MIC because Aspergillus is fungi-static 24. AUC/MIC is linked to the efficacy of flucytosine (5-FC). Establishing clinical susceptibility breakpoints, or MIC values that distinguish curable from resistant microorganisms, and optimising dosages are made possible by an understanding of these PK/PD indicators. Tissue distribution and plasma protein binding are two pharmacokinetic factors that are essential to the effectiveness of antifungals ^{23, 24, 22}.

A comparative summary of the main characteristics of the antifungal classes is given in Table 2. 

Table 2. Antifungal classes, Targets Mechanism and resistance^25-31.

4. Clinical Applications

The treatment of invasive fungal infections especially invasive candidiasis necessitates a prompt and focused strategy based on the pathogen's identification, evaluation of its antifungal susceptibility, and the clinical features of the patient, including the infection site, immune status, comorbidities, and concurrent treatments. Antifungal selection is greatly influenced by prompt and precise diagnosis. In addition to facilitating the quick start of the right treatment, early detection of the fungal infection and its susceptibility profile lowers toxicity, minimises needless exposure to broad-spectrum medications, and aids in preventing the formation of resistance. Empirical decisions are based on host risk factors and epidemiological data in the absence of microbiological proof, but therapy can frequently be de-escalated or modified appropriately once diagnostic information is available ³².

Evidence-based recommendations for the treatment of major clinical syndromes are provided by the Infectious Diseases Society of America and other international guidelines. For most adult patients with candidaemia, echinocandins are recommended as empirical and targeted first-line therapy due to their fungicidal activity against most Candida species, including C. glabrata, which is often resistant to fluconazole, and their favourable tolerability profile. Rezafungin is a new generation echinocandin that is given once a week and was recently approved for the treatment of invasive candidiasis. It may have benefits in terms of less frequent administration and has demonstrated efficacy comparable to that of caspofungin.³⁴.

Fluconazole is the preferred medication for de-escalation once the isolate is found to be susceptible, and it continues to be a first-line treatment for clinically stable individuals who have not recently been exposed to azoles and have a low chance of infection with resistant species. Amphotericin B lipid formulations are advised for infections of the central nervous system, endocarditis, osteomyelitis, and species resistant to azole and echinocandin, as well as in situations where the other classes are ineffective or intolerable. If the isolate is susceptible, voriconazole can be used as a de-escalation treatment for some infections or for some less prevalent species. 

The frequent multiresistance of Candida auris infections makes managing them difficult. Although echinocandins are typically thought of as the first-line treatment for invasive infections, susceptibility testing is crucial due to the emergence of resistance. An alternative is amphotericin B in lipid formulations. Research is being done on combination treatments and novel medications such fosmanogepix and ibrexafungerp. Oral triterpenoid ibrexafungerp has demonstrated in vitro efficacy against isolates of C. auris that are resistant to echinocandin ³⁵. Phase 2 studies have demonstrated the therapeutic efficacy of fosmanogepix in patients with Candida auris ³⁶. In the absence of metastatic foci, the course of treatment for invasive candidiasis typically lasts two weeks following the first negative blood culture and the remission of symptoms and signs of infection. It is very advised to remove central venous catheters.

Patients with impaired immune systems, such as those undergoing transplantation or neutropenia, are more vulnerable to invasive aspergillosis (AI), which is mostly caused by Aspergillus fumigatus. Voriconazole is the first-line treatment for invasive pulmonary aspergillosis and has been shown to be effective in treating disseminated infections of the central nervous system ³⁷. Isavuconazole is a first-line substitute that has been demonstrated to be noninferior to voriconazole and may have a superior tolerability profile with fewer side effects. Another first-line approach is lipid formulations of AmB (L-AmB), particularly in environments where azole resistance or azole contraindications/intolerance are highly prevalent ³⁸. 

While echinocandins alone are not advised for the primary treatment of AI, they may be useful in combination or in some situations. For resistant strains, novel agents like fosmanogepix and olorofim show promise. Posaconazole is advised for prevention in high-risk individuals, such as those with GVHD following allogeneic transplantation or acute myeloid leukaemia induction. In certain situations, micafungin or voriconazole may also be utilised. Immunocompromised individuals or diabetics with ketoacidosis are frequently afflicted with mucormycosis, an aggressive infection brought on by fungus of the order Mucorales ³⁹.

Empirical, pre-emptive, and targeted therapies are therapeutic options for IFIs that are tailored to host variables, clinical suspicion, and diagnostic certainty. Table 3 summarises suggested first-line and alternate treatments for severe invasive fungal infections. Empiric treatment is initiated before microbiologic confirmation of fungal infection in high-risk patients, including those with persistent febrile neutropenia. Echinocandins (such caspofungin) are often used for suspected candidiasis, whereas voriconazole, isavuconazole, or liposomal amphotericin B, for example, are used for suspected aspergillosis. Research has demonstrated that in patients with persistent fever during neutropenia, empiric treatment can lower the prevalence of reported fungal infections ^{40, 41}.

Using biomarkers like galactomannan and βD-glucan in conjunction with imaging methods, pre-emptive therapy aims to detect IFI early and start treatment before microbiological confirmation. With the benefit of lowering the needless use of antifungals, this approach has demonstrated efficacy comparable to empiric therapy ⁴². Targeted therapy, which is guided by antifungal susceptibility testing and enables optimised drug selection, dose modifications, or less toxic drugs, becomes the preferred strategy once a fungal pathogen has been identified ^{43 44 45}.

Table 3. Key invasive fungal infections, suggested first-line therapy, and alternative (backup) treatments are reviewed.

5. Antifungal Agents from Natural Products

Compounds found in plants, bacteria, fungi, and other natural sources are known as natural antifungals ^46,54. These substances have developed to defend their host organisms from harmful microorganisms, such as fungus, and have demonstrated promise as treatments for fungal infections in humans. The identification of novel antifungal chemicals from nature has been made easier by recent developments in genomics, molecular biology, and natural product chemistry. Lower toxicity, less of an impact on the environment, and the ability to target numerous fungus species at once are just a few benefits of using natural antifungals. Certain chemicals have been reported to have activity against phytopathogens and amphibian pathogens, despite the fact that the majority of research in this field has concentrated on human fungal pathogens. Table 4 lists some of the possible natural antifungals' sources.

Table 4. Natural materials may be used to generate antifungal compounds with various antifungal mechanisms ^46,55.

6. Novel Therapeutic Approaches and New Antifungal Targets

6.1 The Cell Barrier as a Basis for the Development of Antifungals

6.1.1. Standard Mannosidases and Cell Wall Integrity

The fungal cell wall is a desirable target for antifungal medications since it is an essential component for preserving fungal integrity and virulence which are produced by the C. albicans mannosidases genes Dfg5 and Dcw1 and are crucial for preserving cell wall integrity and normal hyphal development. These enzymes play a role in the covalent bonding of cell wall glycoproteins and contribute to hyphal formation, a critical pathogenic feature of Candida albicans. According to recent research, faulty cell wall assembly caused by mutations in dfg5 and dcw1 makes fungal cells vulnerable to antifungal medications ⁵⁶.

6.1.2. Chitin Synthases

Chitin synthases (Chs) produce chitin, a crucial part of the fungal cell wall. The several chitin synthases (Chs1, Chs2, Chs3, and Chs8) found in Candida albicans cooperate to preserve the integrity of the cell wall. Because chitin synthases are crucial to fungal survival, they are a prospective target for antifungal research. Fungal growth is inhibited when chitin synthase inhibitors disrupt chitin production, opening the door for new antifungal drugs.⁵⁷. Nikkomycin showed some in vitro efficacy against Blastomyces dermatitidis, but its performance mostly depended on its synergistic actions with echinocandins, especially for A. fumigatus and Candida albicans. For Candida albicans, Candida immitis, and Candida neoformans, polyoxins are often ineffective or fungistatic ^58,59,60,61.

6.2 Biofilm Inhibition 

One of the main virulence factors of fungal infections, especially Candida albicans, is biofilm development. By creating protective extracellular matrices and decreasing the effectiveness of antifungal medications, biofilms provide resistance to antifungal therapies. As a result, preventing biofilm development has become a cutting-edge antifungal tactic. A unique class of diazaspiro–decane structural analogues that can prevent C. albicans biofilm formation without impairing fungal growth was discovered by Pierce et al. These substances are antivirulence agents that target the structure of biofilms and stop fungi from colonising surfaces like medical equipment. To increase the effectiveness of conventional antifungals, biofilm inhibitors can be added. For instance, using small compounds to interfere with the production of biofilms can enhance medication penetration ⁶².

6.3. Suppression of Hyphal Morphology

For Candida albicans, hyphal morphogenesis is a crucial virulence mechanism that promotes biofilm development. Romo et al. created a number of small compounds that effectively lessen the pathogenicity of Candida albicans by selectively blocking the yeast-to-hypha transition. By inhibiting fila mentation and decreasing biofilm formation, these compounds target the signalling pathways that regulate hyphal growth, such as the cAMP and MAPK pathways. N-[3-(allyloxy)-phenyl]-4-methoxybenzamide, the lead drug, showed in vivo effectiveness in invasive candidiasis models in mice ⁶³. These compounds provide a novel antifungal strategy that lessens fungal pathogenicity without encouraging treatment resistance by focusing on virulence factors including hyphal development.

6.4. Targeting Fungal Mitochondrial Function 

Mitochondria are a promising target for antifungal therapy because they are essential for the production of energy and the control of metabolism in fungal cells. Fungal bioenergetics can be disrupted and cell death can be induced by targeting mitochondrial activity. Apart from T-2307 (refer to Section 2.2), it has been demonstrated that isothiocyanates, specifically benzyl isothiocyanate (BITC), have a promising antifungal action by either disrupting the fungal mitochondrial membrane potential or inhibiting mitochondrial oxidative phosphorylation ^64,65,66. Fungal infections can be successfully treated while lowering the risk of harm in humans by focusing on mitochondrial processes unique to fungi⁶⁶. (Figure 4)

Figure 4: Targeting Fungal Mitochondria: A Promising Strategy for Antifungal Therapy

6.5. Inhibition of Heat Shock Protein (Hsp90)

A molecular chaperone called heat shock protein 90 controls antifungal resistance pathways and fungal stress reactions. Hsp90 is a good target for overcoming resistance since blocking its function makes fungal cells more susceptible to antifungal medications. It has been demonstrated that Hsp90 inhibitors increase the effectiveness of azoles and echinocandins, especially against drug-resistant strains of Aspergillus fumigatus and Candida albicans. Hsp90 inhibitors decrease fungal cell viability under drug-induced stress by interfering with fungal stress tolerance ^{67, 68.}

Conclusion 

Due to growing antifungal resistance, a lack of medication variety, and side effects from systemic treatments, managing fungal infections remains extremely difficult. This review emphasises how crucial it is to use cutting-edge tactics to improve treatment results. Gel-based formulations show promise as a topical antifungal delivery method that minimises systemic toxicity while offering localised activity, enhanced drug penetration, and increased patient adherence. Concurrently, natural products help the development of alternative or supplemental therapies by providing a rich and mostly unexplored reservoir of bioactive chemicals with distinct antifungal actions. There are new strategies to fight resistant fungal strains by focusing on unique pathways such cell wall integrity, biofilm formation, hyphal transition, mitochondrial function, and stress response systems. Programs for antifungal stewardship are also essential for maximising medication use and halting the emergence of resistance. In conclusion, a multidisciplinary strategy that incorporates cutting-edge drug delivery methods, natural product research, and novel molecular targets has great potential to enhance the effectiveness, safety, and long-term viability of antifungal treatments.

Acknowledgement: The authors sincerely acknowledge the Himalayan Institute of Pharmacy, Kala-Amb, Himachal Pradesh, for providing the necessary facilities, laboratory support, and academic environment required to carry out this research work successfully.

Conflict of Interest: The authors declare that there is no conflict of interest associated with the research, authorship, or publication of this work.

References

1. Metta S, Amir KM, Lakshmi MS, Devi P, Shruthi K, A review: pharmaceutical gels and its types with prominence role of its drug delivery systems, International Journal of Research and Analytical Reviews,2023;10 (2):686-691.

2. Paye M, Barel AO, Maibach HI. Handbook of cosmetic science and technology. 2nd ed. New York: Taylor & Francis; 2006. https://doi.org/10.1201/b14400 PMCid:PMC538828

3. Godge GR, Bharat SC, Shaikh AB, Randhawan BB, Raskar MA, Hiremath SN. Formulation perspectives in topical antifungal drug therapy, a review, Journal of Drug Delivery and Therapeutics, 2023;13(5):110-119. https://doi.org/10.22270/jddt.v13i5.6079

4. Rajasekaran A, Govindarjan A, Ramasamy A, Formulation and evaluation of topical herbal gel for the treatment of arthritis in animal model, Brazilian Journal of Pharmaceutical Sciences, 2016;52(3):493-507. https://doi.org/10.1590/s1984-82502016000300015

5. Garje KL, Salunkhe KS, Review on: anti-inflammatory herbal gel of Boswellia serrata & Vitex negundo, International Journal of Pharmacy and Biological Sciences, 2013;3(2):374-382.

6. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K, Trends in the postmortem epidemiology of invasive fungal infections at a university hospital, Journal of Infection ,1996;33(1):23-32. https://doi.org/10.1016/S0163-4453(96)92700-0 PMid:8842991

7. Denning DW, Evans EG, Kibbler CC, Richardson MD, Roberts MM, Rogers TR, Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation, British Society for Medical Mycology, European Journal of Clinical Microbiology & Infectious Diseases, 1997;16(6):424-436. https://doi.org/10.1007/BF02471906 PMid:9248745

8. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC, Hidden killers: human fungal infections, Science Translational Medicine, 2012; 4(165):165rv13. https://doi.org/10.1126/scitranslmed.3004404 PMCid:PMC3627207

9. Fidel PL Jr, Barousse M, Espinosa T, Ficarra M, Sturtevant J, Martin DH, An intravaginal live Candida challenge in humans leads to new hypotheses for the immune pathogenesis of vulvovaginal candidiasis, Infection and Immunity, 2004; 72 (5):2939-2946. https://doi.org/10.1128/IAI.72.5.2939-2946.2004 PMid:15102806 PMCid:PMC387876

10. Byrnes EJ 3rd, Li W, Lewit Y, Ma H, Voelz K, Ren P, Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States, Public Library of Science Pathogens, 2010;6(4):e1000850 https://doi.org/10.1371/journal.ppat.1000850 PMid:20421942

11. Talaviya S, Majmudar F, Recent developments in antifungal agents. International Journal of Pharmacy and Pharmaceutical Sciences, 2012;4(Suppl 4):4-10.

12. Sathyan G, Ritschel WA, Hussain AS, Transdermal delivery of tacrine ;Identification of a suitable delivery vehicle, International Journal of Pharmaceutics, 1995;114 (1):75-83. https://doi.org/10.1016/0378-5173(94)00214-P

13. Gungor S, Erdal MS, Aksu B, New formulation strategies in topical antifungal therapy. Journal of Cosmetics, Dermatological Sciences and Applications, 2013;3: 56-65. https://doi.org/10.4236/jcdsa.2013.31A009

14. Chen SC, Sorrell TC, Antifungal agents, Medical Journal of Australia, 2007; 187 (7):404-409. https://doi.org/10.5694/j.1326-5377.2007.tb01313.x PMid:17908006

15. Boddy L, Interactions with humans and other animals. In: Watkinson SC, Boddy L, Money NP, editors. The fungi. 3rd ed. Amsterdam: Academic Press; 2016. p. 293- 336. https://doi.org/10.1016/B978-0-12-382034-1.00009-8

16. Natarajan V, Nath AK, Thappa DM, Singh R, Verma SK, Coexistence of onychomycosis in psoriatic nails: a descriptive study, Indian Journal of Dermatology, Venereology and Leprology, 2010;76 (6):723. https://doi.org/10.4103/0378-6323.72468 PMid:21079333

17. Ajello LA, taxonomic review of the dermatophytes and related species. Sabouraudia, 1968; 6(2):147-159. https://doi.org/10.1080/00362176885190271 PMid:4869482

18. Sulaiman IM, Jacobs E, Simpson S, Kerdahi K, Genetic characterization of fungi isolated from the environmental swabs collected from a compounding center known to cause multistate meningitis outbreak in United States using ITS sequencing, Pathogens. 2014; 3(3):732-742. https://doi.org/10.3390/pathogens3030732 PMid:25438021 PMCid:PMC4243438

19. Robbins N, Wright GD, Cowen LE, Antifungal drugs: the current armamentarium and development of new agents, Microbiology Spectrum, 2016; 4 (5):903-922. https://doi.org/10.1128/microbiolspec.FUNK-0002-2016 PMid:27763259

20. Steimbach LM, Tonin FS, Virtuoso S, Borba HH, Sanches AC, Wiens A, Efficacy and safety of amphotericin B lipid-based formulations-a systematic review and meta-analysis, mycosis, 2017;60(3):146-154. https://doi.org/10.1111/myc.12585 PMid:27878878

21. Balcerek MI, Stewart AG, Chapman P, Lazarus S, Reducing the off-target endocrinologic adverse effects of azole antifungals-can it be done? International Journal of Antimicrobial Agents, 2022; 59(5):106587. https://doi.org/10.1016/j.ijantimicag.2022.106587 PMid:35405267

22. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky- Zeichner L, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America, Clinical Infectious Diseases, 2016;62(4):e1-e50. https://doi.org/10.1093/cid/civ933 PMid:26679628 PMCid:PMC4725385

23. Vermes A, Guchelaar HJ, Dankert J, Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions, Journal of Antimicrobial Chemotherapy, 2000;46(2):171-179. https://doi.org/10.1093/jac/46.2.171 PMid:10933638

24. Haghani I, Babaie M, Hoseinnejad A, Rezaei-Matehkolaei A, Mofarrah R, Yahyazadeh Z, High prevalence of terbinafine resistance among Trichophyton mentagrophytes/T. interdigitale species complex, a cross-sectional study from 2021 to 2022 in northern parts of Iran, Mycopathologia, 2024;189 (4):52-59. https://doi.org/10.1007/s11046-024-00855-0 PMid:38864945

25. Lepak AJ, Andes DR, Antifungal pharmacokinetics and pharmacodynamics, Cold Spring Harbor perspectives in medicine. 2015;5(5):a019653. https://doi.org/10.1101/cshperspect.a019653 PMid:25384765 PMCid:PMC4448584

26. Lewis RE, Current concepts in antifungal pharmacology, Mayo Clinic Proceedings, 2011; 86(8):805-817. https://doi.org/10.4065/mcp.2011.0247 PMid:21803962 PMCid:PMC3146381

27. Bellmann R, Smuszkiewicz P, Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients, Infection. 2017; 45(6):737-779. https://doi.org/10.1007/s15010-017-1042-z PMid:28702763 PMCid:PMC5696449

28. Balkis MM, Leidich SD, Mukherjee PK, Ghannoum MA, Mechanisms of fungal resistance: an overview. Drugs, 2002; 62 (7):1025-1040. https://doi.org/10.2165/00003495-200262070-00004 PMid:11985489

29. De Francesco M, Drug-resistant Aspergillus spp.: a literature review of its resistance mechanisms and its prevalence in Europe, Pathogens, 2023;12 (10):1305-1312. https://doi.org/10.3390/pathogens12111305 PMid:38003770 PMCid:PMC10674884

30. Szymański M, Chmielewska S, Czyżewska U, Malinowska M, Tylicki A, Echinocandins-structure, mechanism of action and use in antifungal therapy, Journal of Enzyme Inhibition and Medicinal Chemistry, 2022;37 (1):876-894. https://doi.org/10.1080/14756366.2022.2050224 PMid:35296203 PMCid:PMC8933026

31. Gupta AK, Wang T, Mann A, Piguet V, Chowdhary A, Bakotic WL, Mechanisms of resistance against allylamine and azole antifungals in Trichophyton: A renewed call for innovative molecular diagnostics in susceptibility testing, Public Library of Science pathogens, 2025;21 (2):e1012913. https://doi.org/10.1371/journal.ppat.1012913 PMid:39932950 PMCid:PMC11813129

32. Pemán J, Cantón E, Espinel-Ingroff A, Antifungal drug resistance mechanisms, Expert Review of Anti-Infective Therapy, 2009; 7(4):453-460. https://doi.org/10.1586/eri.09.18 PMid:19400764

33. Fang W, Wu J, Cheng M, Zhu X, Du M, Chen C, Diagnosis of invasive fungal infections: challenges and recent developments, Journal of Biomedical Science2023;30:42-47. https://doi.org/10.1186/s12929-023-00926-2 PMid:37337179 PMCid:PMC10278348

34. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016; 62(4): e1-50. https://doi.org/10.1093/cid/civ933 PMid:26679628 PMCid:PMC4725385

35. Fung S, Shirley M. Rezafungin: a review in invasive candidiasis. Drugs. 2025; 85: 415-423. https://doi.org/10.1007/s40265-024-02134-0 PMid:39913021

36. Ghannoum M, Arendrup MC, Chaturvedi VP, Lockhart SR, McCormick TS, Chaturvedi S, Ibrexafungerp: a novel oral triterpenoid antifungal in development for the treatment of Candida auris infections, Antibiotics (Basel). 2020;9(9):539-545. https://doi.org/10.3390/antibiotics9090539 PMid:32854252 PMCid:PMC7559578

37. Vazquez JA, Pappas PG, Boffard K, Paruk F, Bien PA, Tawadrous M, Clinical efficacy and safety of a novel antifungal, fosmanogepix, in patients with candidemia caused by Candida auris: results from a phase 2 trial, Antimicrobial Agents and Chemotherapy, 2023;67(5): e0141922. https://doi.org/10.1128/aac.01419-22 PMid:37022196 PMCid:PMC10190264

38. Karthaus M, Guideline based treatment of invasive aspergillosis. Mycoses. 2010; 53 Suppl 1:36-43. https://doi.org/10.1111/j.1439-0507.2009.01840.x PMid:20433655

39. Douglas AP, Smibert OC, Bajel A, Halliday CL, Lavee O, McMullan B, Consensus guidelines for the diagnosis and management of invasive aspergillosis, Internal Medicine Journal, 2021; 51 (2):143-176. https://doi.org/10.1111/imj.15591 PMid:34937136

40. Brunet K, Rammaert B, Mucormycosis treatment: recommendations, latest advances, and perspectives, Journal de Mycologie Médicale, 2020; 30(3):101007. https://doi.org/10.1016/j.mycmed.2020.101007 PMid:32718789

41. Jarvis JN, Lawrence DS, Meya DB, Kagimu E, Kasibante J, Mpoza E, Single-dose liposomal amphotericin B treatment for cryptococcal meningitis, The New England Journal of Medicine, 2022;386(12):1109-1120. https://doi.org/10.1056/NEJMoa2111904 PMid:35320642

42. Yoshida M. Development of a method of measuring β-D-glucan and its use in preemptive therapy for invasive fungal infections, International Journal of Molecular Sciences, 2021;22(17):9265. https://doi.org/10.3390/ijms22179265 PMid:34502174 PMCid:PMC8431658

43. Wiederhold NP, Antifungal susceptibility testing: a primer for clinicians, Open Forum Infectious Diseases. 2021; 8(11): ofab444. https://doi.org/10.1093/ofid/ofab444 PMid:34778489

44. Chakrabarti A, Mohamed N, Capparella MR, Townsend A, Sung AH, Yura R, The role of diagnostics-driven antifungal stewardship in the management of invasive fungal infections: a systematic literature review, Open Forum Infectious Diseases,2022; 9(7): ofac234 https://doi.org/10.1093/ofid/ofac234 PMid:35873300 PMCid:PMC9297315

45. Procacci C, Marras L, Maurmo L, Vivanet G, Scalone L, Bertolino G, Antifungal stewardship in invasive fungal infections, a systematic review, Advances in Experimental Medicine and Biology, 2025;1476: 49-68. https://doi.org/10.1007/5584_2024_798 PMid:38337088

46. Costa Vasconcelos Alves AM, Cruz-Martins N, Rodrigues CF, Marine compounds with anti-Candida sp. activity: a promised "land" for new antifungals, Journal of Fungi,2022; 8(7):1-10. https://doi.org/10.3390/jof8070669 PMid:35887426 PMCid:PMC9320905

47. Bharathi D, Lee J, Recent advances in marine-derived compounds as potent antibacterial and antifungal agents: a comprehensive review, Marine Drugs, 2024;22(8):1-22. https://doi.org/10.3390/md22080348 PMid:39195465 PMCid:PMC11355281

48. Hang S, Lu H, Jiang Y. Marine-derived metabolites act as promising antifungal agents. Marine Drugs, 2024;22(4):1-28. https://doi.org/10.3390/md22040180 PMid:38667797 PMCid:PMC11051449

49. Kubota T, Nakamura K, Kurimoto SI, Sakai K, Fromont J, Gonoi T, Zamamidine D, a manzamine alkaloid from an Okinawan Amphimedon sp. marine sponge, Journal of Natural Products2017;80(4):1196-1199. https://doi.org/10.1021/acs.jnatprod.6b01110 PMid:28207259

50. Youssef DTA, Shaala LA, Mohamed GA, Badr JM, Bamanie FH, Ibrahim SRM, Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei, Marine Drugs,2014;12(4):1911-1923. https://doi.org/10.3390/md12041911 PMid:24694570 PMCid:PMC4012434

51. Fan H, Shi ZM, Lei YH, Si-Tu MX, Zhou FG, Feng C, Rare carbon-bridged citrinin dimers from the starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2, Marine Drugs, 2022;20(7):1-15. https://doi.org/10.3390/md20070443 PMid:35877736 PMCid:PMC9317178

52. Xu T, Feng Q, Jacob MR, Avula B, Mask MM, Baerson SR, The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis, Antimicrobial Agents and Chemotherapy, 2011; 55 (4):1611-1621. https://doi.org/10.1128/AAC.01022-10 PMid:21300833 PMCid:PMC3067192

53. Chiba H, Agematu H, Dobashi K, Yoshioka T, Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp. II. Structure elucidation, The Journal of Antibiotics, 1999; 52(8):700-709. https://doi.org/10.7164/antibiotics.52.700 PMid:10580383

54. Gao J, Hamann MT, Chemistry and biology of kahalalides, Chemical Society Reviews, 2011; 111(5):3208-3235. https://doi.org/10.1021/cr100187n PMid:21480581 PMCid:PMC4895206

55. Yibmantasiri P, Leahy DC, Busby BP, Angermayr SA, Sorgo AG, Boeger K, Molecular basis for fungicidal action of neothyonidioside, a triterpene glycoside from the sea cucumber, Australostichopus mollis, Molecular Bio Systems, 2012;8(3):902-912. https://doi.org/10.1039/C2MB05426D PMid:22271309

56. Razmi M, Kim J, Chinnici J, Busarajan S, Vuppalapaty H, Lankipalli D, Candida albicans mannosidases, Dfg5 and Dcw1, are required for cell wall integrity and pathogenesis, Journal of Fungi, 2024;10 (8):525-532. https://doi.org/10.3390/jof10080525 PMid:39194851 PMCid:PMC11355814

57. Draelos M, Yokoyama K. Biosynthesis and mechanism of action of antifungal peptidyl nucleoside natural products. In: Liu H, Tadhg P, editors. Comprehensive natural products III. Amsterdam: Elsevier; 2020:613-641. https://doi.org/10.1016/B978-0-12-409547-2.14680-3

58. Hector RF, Zimmer BL, Pappagianis D, and Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis, Antimicrobial Agents and Chemotherapy, 1990; 34(4):587-593. https://doi.org/10.1128/AAC.34.4.587 PMid:2344165 PMCid:PMC171648

59. Cheung YY, Hui M, Effects of echinocandins in combination with nikkomycin Z against invasive Candida albicans bloodstream isolates and the fks mutants, Antimicrobial Agents and Chemotherapy ,2017;61(11):1-4. https://doi.org/10.1128/AAC.00619-17 PMid:28827418 PMCid:PMC5655089

60. Chiou CC, Mavrogiorgos N, Tillem E, Hector R, Walsh TJ. Synergy, pharmacodynamics, and time-sequenced ultrastructural changes of the interaction between nikkomycin Z and the echinocandin FK463 against Aspergillus fumigatus, Antimicrobial Agents and Chemotherapy, 2001;45(12):3310-3321. https://doi.org/10.1128/AAC.45.12.3310-3321.2001 PMid:11709302 PMCid:PMC90831

61. Hector RF, Compounds active against cell walls of medically important fungi. Clinical Microbiology Reviews, 1993; 6(1):1-21. https://doi.org/10.1128/CMR.6.1.1 PMid:8457977 PMCid:PMC358263

62. Pierce CG, Chaturvedi AK, Lazzell AL, Powell AT, Saville SP, McHardy SF, A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance, Nature Partner Journal,2015;1:15012. https://doi.org/10.1038/npjbiofilms.2015.12 PMid:26691764 PMCid:PMC4681527

63. Romo JA, Pierce CG, Chaturvedi AK, Lazzell AL, McHardy SF, Saville SP, Development of antivirulence approaches for candidiasis via a novel series of small-molecule inhibitors of Candida albicans filamentation, mBio. 2017;8(6): e01991-17. https://doi.org/10.1128/mBio.01991-17 PMid:29208749 PMCid:PMC5717394

64. Zhang T, Chen W, The Candida albicans inhibitory activity of the extract from papaya (Carica papaya L.) seed relates to mitochondria dysfunction, International Journal of Molecular Sciences,2017;18(9):1-18. https://doi.org/10.3390/ijms18091858 PMid:28841152 PMCid:PMC5618507

65. Hareyama Y, Tarao M, Toyota K, Furukawa T, Fujii Y, Kushiro M, Effects of four isothiocyanates in dissolved and gaseous states on the growth and aflatoxin production of Aspergillus flavus in vitro, Toxins (Basel). 2022; 14(11):756-764. https://doi.org/10.3390/toxins14110756 PMid:36356006 PMCid:PMC9697429

66. Yi W, Gu L, Wang Y, Lin J, Zhang L, Wang Q, Diao W, Qi Y, Chi M, Yin M, Benzyl isothiocyanate improves the prognosis of Aspergillus fumigatus keratitis by reducing fungal load and inhibiting Mincle signal pathway, Frontiers in Microbiology,2023;14: 1119568. https://doi.org/10.3389/fmicb.2023.1119568 PMid:36876115 PMCid:PMC9978348

67. Robbins N, Uppuluri P, Nett J, Rajendran R, Ramage G, Lopez-Ribot JL, Hsp90 governs dispersion and drug resistance of fungal biofilms, Public Library of Science Pathogens, 2011; 7(9): e1002257. https://doi.org/10.1371/journal.ppat.1002257 PMid:21931556 PMCid:PMC3169563

68. Yuan R, Tu J, Sheng C, Chen X, Liu N, Effects of Hsp90 inhibitor ganetespib on inhibition of azole-resistant Candida albicans, Frontiers in Microbiology, 2021;12: 680382. https://doi.org/10.3389/fmicb.2021.680382 PMid:34093502