Antifungal treatment strategies and their impact on resistance development in clinical settings

Abstract

Invasive fungal diseases, particularly among immunocompromised patients, represent a growing clinical challenge due to limited therapeutic options, diagnostic delays and escalating antifungal resistance. Fungal pathogens employ diverse resistance mechanisms, including genetic mutations of antifungal target enzymes, biofilm formation, efflux pump overexpression and reduced drug penetration, which compromise the efficacy of clinically available antifungal classes. This review explores antifungal treatment modalities and evaluates approaches to mitigate resistance development. Advanced diagnostics and therapeutic drug monitoring are pivotal for enabling timely, targeted therapies and personalizing treatment plans, thus minimizing reliance on broad-spectrum agents. New antifungal agents, such as rezafungin, olorofim and fosmanogepix, along with long-acting and advanced formulations plus combination regimens, show substantial promise for managing resistance and improving treatment outcomes. Additionally, the development of immunotherapies and antifungal vaccines offers new avenues for bolstering host defences against fungal pathogens. Addressing antifungal resistance demands a multifaceted ‘One Health’ approach that integrates robust diagnostics, antifungal stewardship (AFS), precision medicine and collaborative global efforts. By advancing drug formulations, enhancing diagnostic tools and implementing forward-thinking AFS practices, the healthcare community can better tackle the escalating burden of fungal infections and deliver improved patient outcomes.

Introduction

Only four main classes of antifungal drugs are currently used in clinical practice to treat invasive fungal diseases (IFDs): triazoles, polyenes, echinocandins and pyrimidine analogues.¹ The emergence of antifungal drug-resistant isolates in clinical settings poses a threat to this already limited arsenal of antifungal drugs and resistance to all classes of antifungal therapy is emerging, including multidrug resistance. Adding to this public health concern is the increasing prevalence of inherently drug-resistant fungi, including Candidozyma auris, Pichia kudriavzevii and Nakaseomyces glabrata (formerly referred to as Candida auris, Candida krusei and Candida glabrata, respectively), which makes these infections particularly challenging to treat.² Notably, the renaming of these fungi aligns with their respective genera (Candidozyma, Pichia and Nakaseomyces) rather than the broader Candida genus, highlighting their fluconazole nonsusceptibility, which is now a key trait of Pichia and Nakaseomyces but not inherently shared by other Candida species.²

In clinical settings, effective and timely antifungal strategies are essential for managing IFDs. Available strategies range from prophylaxis, aimed at preventing IFDs in high-risk individuals, to targeted therapies designed for confirmed cases.^3,4 In addition, a variety of dosing regimens may be utilized, including fixed-dose, continuous, intermittent (phased dosing), weight-based, high-dose and step-down regimens, each tailored to specific infections and patient needs.⁵ However, the improper use of antifungal drugs, such as overuse, prolonged exposure, subtherapeutic levels or premature discontinuation, can create selective pressures that drive resistance and facilitate the emergence of multidrug-resistant strains.^1,5

Fungal biofilms also hinder drug penetration, leading to suboptimal exposure and increased resistance,^6–8 while limited access to accurate, rapid diagnostics further complicates treatment.⁹ Reliable diagnostics are crucial for timely therapy, better outcomes and effective antifungal stewardship (AFS), yet the current diagnostic landscape, including resistance detection, remains inadequate.¹⁰

This paper provides a comprehensive review of the complexities of antifungal treatment strategies, dosing regimens and administration routes. It highlights their respective advantages and limitations while emphasizing their collective importance in combating resistance and ensuring effective treatment outcomes.

Antifungal strategies and insights into their impact on resistance development

In clinical practice, managing IFDs with antifungals typically relies on four main strategies: prophylaxis (primary and secondary), empiric treatment, pre-emptive therapy and targeted therapy, with the certainty of disease diagnosis increasing, respectively (Figure 1).

Figure 1.

Antifungal treatment strategies. BDG, β-D-glucan assays; GM, galactomannan; L-AmB, liposomal amphotericin B; PCR, polymerase chain reaction.

Prophylaxis

Antifungal prophylaxis is a key strategy to prevent fungal infections in high-risk, typically immunocompromised, individuals such as those undergoing chemotherapy for haematologic malignancies, transplant recipients or those with HIV.^11,12 It aims to prevent IFDs caused by pathogens like Aspergillus, Candida, Pneumocystis and Cryptococcus spp.³ While prophylaxis has improved clinical outcomes, it has also altered fungal epidemiology by applying selective pressures that favour the survival and proliferation of drug-resistant species such as N. glabrata, P. kudriavzevii and azole-resistant Aspergillus spp.^12–14

Targeted antifungal prophylaxis has proven to be an effective alternative to universal approaches, reducing IFDs, drug-related toxicity and costs while maintaining high safety and adherence. Studies in lung and liver transplant recipients demonstrated its feasibility, with tailored strategies significantly minimizing IFDs and unnecessary antifungal use.^15,16 For example, targeted strategies incorporating inhaled amphotericin B (AmB), short courses of micafungin and personalized oral antifungal therapy reduce the incidence of invasive aspergillosis (IA) and invasive candidiasis (IC), limiting toxicity and post-hospitalization systemic antifungal use.¹⁵ A comparison of targeted prophylaxis versus universal prophylaxis in liver transplants revealed similar efficacy, lowering overall antifungal exposure and demonstrating the cost-effectiveness and clinical utility of targeted approaches.¹⁶

Prophylaxis influences diagnostic strategies and test performance. Effective antifungal prophylaxis reduces the pretest probability of IFDs, compromising the reliability of diagnostic tests when screening asymptomatic patients.^17,18 For example, mould-active prophylaxis, such as posaconazole, can lead to false negatives or positives in serum galactomannan (GM) testing, limiting its utility in routine surveillance.¹⁸ However, GM testing remains valuable for diagnosing IFDs in patients with clinical suspicion.¹⁸ Similarly, follow-up fungal polymerase chain reaction testing on plasma and bronchoalveolar lavage (BAL) samples after an initial negative result shows low diagnostic yield, especially within the first week, suggesting a limited utility for routine testing while on prophylaxis in the absence of suspected breakthrough infection.¹⁷ When on prophylaxis, diagnostic testing is best suited to confirm infection in a patient with suspected IFD, testing samples from the focus of infection (e.g. BAL fluid for IA).

Itraconazole remains an option for prophylaxis but is associated with significant adverse effects, such as gastrointestinal disturbances and hepatotoxicity and difficulty in obtaining efficacious levels, requiring therapeutic drug monitoring (TDM), all of which limit its widespread use in high-risk populations.^19,20 However, the development of the super bioavailability itraconazole (SUBA-ita) formulation, which has demonstrated bioequivalence, better tolerability and efficacy in treating endemic fungi, offers a more favourable safety profile compared with conventional itraconazole, potentially mitigating some of these limitations.²¹ Voriconazole, with its broad-spectrum activity, is increasingly utilized but also requires caution due to notable side effects, including visual disturbances, squamous cell carcinoma and prolonged QTc interval, necessitating close clinical monitoring and TDM.^22,23 Treatment guidelines favour posaconazole delayed-release tablets as prophylaxis for patients with AML or myelodysplastic syndrome undergoing remission–induction chemotherapy, with IV posaconazole as an alternative for those unable to tolerate oral formulations.¹² Posaconazole’s pharmacokinetic (PK) advantages, broad-spectrum activity and effectiveness in reducing resistance and breakthrough infections make it a preferred choice, though TDM is recommended to address PK variability.^12,24–26 TDM is particularly critical in cases of hypoalbuminaemia, drug interactions or critical illness to ensure adequate serum levels. Despite its efficacy, posaconazole is associated with higher rates of adverse events compared with fluconazole or itraconazole.^12,26,27

Pre-emptive strategies that combine non-mould-active antifungal prophylaxis with extensive diagnostic screening are emerging as a viable approach. For example, fluconazole is commonly used for prophylaxis in neonates and other high-risk groups, with demonstrated effectiveness in reducing fungal infections and improving survival.^5,28 In a study of 196 premature infants, the incidence of nosocomial fungal infections dropped from 45.8% in the antifungal rescue group to 15.9% in the fluconazole prophylaxis group.²⁹ However, it offers no protection against moulds, and treatment failures due to azole-resistant Candida spp. are increasing.^30–33 These strategies, supported by recent findings from Maertens et al. in the adult haematological population, ensure early detection and targeted treatment, minimizing overtreatment while maintaining low rates of IFD.³⁴ This complements existing protocols and improves patient outcomes.³⁴

While widely used as prophylaxis against Candida infections and typically well tolerated, fluconazole use can drive selective pressure for the emergence of resistant Candida spp.^3,11,35  Candidozyma auris (C. auris), first identified in 2009, has emerged as a multidrug-resistant pathogen with a crude mortality rate of 30%–60%, posing a global health threat.^36,37 Resistance in C. auris has been associated with the use of antifungal agents, including prophylactic strategies in high-risk patients, though further evidence is needed to establish a definitive causal link.³⁸ Similarly, Candida parapsilosis has shown increasing fluconazole resistance, particularly in southern Europe, South Africa and Latin America, driven by ERG11p substitutions and likely exacerbated by widespread prophylactic use.³⁹ In South Africa, an exceptionally high prevalence of fluconazole resistance in C. parapsilosis strains (∼78%) has been reported, with resistance predominantly driven by Y132F amino acid substitutions in the ERG11 gene (∼68%).⁴⁰ Emerging resistance in other species, such as P. kudriavzevii and Candida tropicalis, highlights the need for careful evaluation of prophylactic antifungal practices. Rigorous monitoring and the development of novel therapeutic strategies are crucial to combat rising resistance.^41–43

Although clinical prophylaxis contributes to selective pressures that facilitate the selection of drug-resistant strains or species, it is thought not to be the primary driver of azole-resistant A. fumigatus development.^44,45 Extensive agricultural use of azole fungicides, structurally similar to medical azoles, plays a critical role by creating selective pressures in the environment, driving the evolution of resistant strains that have been associated with human infection. This highlights the interconnectedness of agricultural and clinical settings in the development of antifungal resistance.^44,45 The role of agricultural and environmental drivers in resistance evolution underscores the need for a One Health approach to address this global challenge.⁴⁶

Echinocandins, although endorsed for prophylaxis during neutropenic phases or high-risk periods in haematology patients, face emerging resistance.³² The impact is particularly severe in paediatric cancer patients, where echinocandin-resistant Candida spp. infections are associated with high mortality rates, raising concerns about treatment failures and breakthrough infections, even with prophylactic measures in place.⁴⁷ Trimethoprim/sulfamethoxazole is the preferred option for prophylaxis against Pneumocystis jirovecii pneumonia across susceptible cohorts. However, determining resistance to this therapy is limited by the lack of culture methods.³⁵

Empiric treatment

Empiric antifungal therapy involves the use of broad-spectrum antifungal medications based on concerns of fungal infection in patients with underlying risk and generic clinical signs of infection (e.g. refractory to broad-spectrum antibiotic therapy), but in the absence of (preferably while awaiting) a definitive diagnosis. Typically, it is initiated in high-risk patients with persisting clinical symptoms, such as refractory febrile neutropenia.⁴⁸ Early administration may improve outcomes in critically ill patients.^48,49 However, overuse of unnecessary antifungals driven by generic triggers without diagnostic confirmation can promote resistance, increase drug-related toxicity/interactions and lead to significant costs.⁴⁸ Additionally, clinical relapse often prompts new empiric regimens, further complicating treatment challenges.

The rise in antifungal resistance has been attributed to selective pressures from widespread empirical use.^50–52 For example, the empiric use of fluconazole since its introduction in 1990 has increasingly contributed to resistant Candida strains.⁵³ Resistance in N. glabrata bloodstream infections increased from 9% to 14% between 1992 and 2007.^1,53 Similarly, resistant species such as Diutina rugosa and Pichia norvegensis have increased 5- to 10-fold over a decade.⁵²

Pre-emptive therapy

Pre-emptive antifungal therapy is initiated based on microbiological evidence, such as positive cultures, biomarker/molecular detection (e.g. GM for Aspergillus or beta-D-glucan for Candida spp.) or radiological findings (e.g. CT scans) that are consistent with early signs of fungal infection, though not definitive on their own.³ This strategy aims to minimize unnecessary antifungal exposure, as would occur with empirical approaches, while focusing diagnostic screening in at-risk individuals to provide early evidence of infection before overt manifestations typical of IFD emerge. Its effectiveness depends on the availability and reliability of diagnostic tools, though timely access in clinical practice is often limited.³ Moreover, challenges such as false positives, variability in biomarker performance and the need for precise protocols may limit widespread adoption.⁵⁴

Studies comparing pre-emptive and empirical therapies show mixed outcomes.^34,55 A Cochrane review found no significant difference in mortality rates but noted a reduction in antifungal use and shorter treatment durations with the pre-emptive approach.⁵⁵ Importantly, the primary focus of pre-emptive therapy lies in reducing unnecessary antifungal treatments through a more targeted approach, achieving these outcomes without compromising mortality or morbidity. Interestingly, a randomized pilot study indicated that pre-emptive therapy could lead to increased antifungal use, potentially heightening the risk of resistance.⁵⁴

Despite these challenges, pre-emptive therapy has demonstrated promise in carefully selected cases. Randomized trials within specific patient cohorts, such as neutropenic patients on fluconazole prophylaxis, have demonstrated reduced antifungal use without increases in mortality or infection rates.^34,56 Notably, pre-emptive therapy is most effective when routine mould-active antifungal prophylaxis is not used.⁵⁷

Targeted therapy

Targeted antifungal therapy relies on microbiologic and susceptibility data to focus treatment in confirmed or probable fungal disease.⁴ This precision limits unnecessary drug exposure, helps preserve antifungal efficacy and aims to reduce the development of resistance. However, delays in diagnosis or its absence can compromise patient outcomes, especially for rapidly progressing IFDs, and with very few perfect tests in mycology [the exception Crypotococcal Antigen Lateral Flow Assay (CrAg LFA)], most results, whether positive or negative, require clinical interpretation.⁵⁸ Access to and the availability of mycology can be challenging, particularly for biomarker tests, with rapid turn-around necessary for administrating timely and appropriate antifungal therapy.⁵⁹ While centres in countries with high Gross Domestic Product have 90% availability of MALDI-TOF for culture identification, in African and Asian countries, this is 17.5% and 12.3%, respectively.^60–62 Similarly, susceptibility testing is available in 90% of European centres, while it is available in <50% of centres in Africa and Asia and is typically performed in centralized laboratories, irrespective of available resources.^60–62 Targeted antifungal therapy also relies on having the appropriate antifungals available. While first-line therapies such as fluconazole, caspofungin and AmB are generally available, more recently developed antifungals such as anidulafungin and posaconazole are available in <70% of countries. With a proven diagnosis of IFD limited to a few key diagnostic scenarios, much of the targeted therapy is focused on the treatment of probable infection, relying on imperfect tests and multicomponent disease classification. While some diagnostic ambiguity certainly persists, the accuracy of targeted treatment is certainly higher than an empiric approach.

Common antifungal dosing regimens used in clinical practice and their impact on resistance

Managing IFDs effectively requires a deep understanding of antifungal dosing regimens and their implications. Table 1 outlines common dosing approaches used in clinical practice for adults.

Table 1.

Examples of common antifungal dosing regimens for adults used in clinical practice

Dosing regimen	Example IFD	Antifungal treatment strategies	Advantages	Limitations	Resistance development risk	References
Fixed-dose regimens	Candidiasis (invasive)	Empirical (C. albicans, C. tropicalis: fluconazole 400–800 mg daily for 14–21 days) Prophylaxis (Candida spp.: fluconazole 200–400 mg daily in neutropenic patients)	Simple to administer; consistent plasma levels; suitable for the majority of patients	May not account for patient-specific factors (e.g. metabolism, organ dysfunction)	Risk of resistance due to prolonged exposure to subtherapeutic or static drug levels	5, 63, 64
TDM-guided dosing	Aspergillosis	Empirical (voriconazole may be used empirically in high-risk patients with suspected IA based on clinical or radiological evidence when diagnostic confirmation is delayed); alternatives may include caspofungin and/or L-AmB for broader initial mould and Candida coverage Targeted (voriconazole is the frontline treatment of IA: 6 mg/kg IV twice daily for 1 day, then 4 mg/kg IV twice daily, adjusted based on TDM)	Maintains steady plasma levels, improving drug efficacy	Requires TDM; potential for drug accumulation in cases of renal or hepatic impairment	Selection of resistant fungal strains is less likely when monitored but remains a concern with prolonged empiric use	65, 66
Intermittent (phased dosing)	Cryptococcosis (meningitis)	Induction (AmB 1 mg/kg/day + 5-FC for 14 days) Consolidation/maintenance (fluconazole 400 mg/day for maintenance therapy in immunocompromised patients)	Reduces toxicity by limiting exposure duration; ensures high peak concentrations	Requires careful monitoring during induction phase due to potential toxicity of amphotericin B and 5-FC	Resistance development is unlikely but may occur in rare cases with prolonged or suboptimal therapy	4, 67–69
Weight-based dosing	Mucormycosis	Targeted (L-AmB 5–10 mg/kg/day for 2–4 weeks, depending on infection severity; consider surgical debridement where feasible)	Personalized therapy, ensuring adequate drug exposure in diverse patient populations	Complex calculation; potential for overdose or underdose in rapidly changing weight conditions; drug penetration into necrotic areas is often limited, highlighting the importance of surgical intervention	Resistance risk is lower if properly dosed but may still develop if insufficient concentrations are achieved	27, 70, 71
High-dose dosing	C. auris infections	Targeted (micafungin 150 mg IV daily for 14 days or until clearance is confirmed; alternative dosing includes anidulafungin)	High doses may overcome innate drug resistance in some fungal species	Associated with increased toxicity (e.g. hepatotoxicity)	Resistance may still develop despite high drug pressure	72, 73
Step-Down Therapy	Mixed candidiasis infections	Targeted (start with caspofungin 70 mg loading dose, then 50 mg daily; transition to fluconazole 400 mg daily after stabilization; for N. glabrata infections, step-down to fluconazole is typically avoided due to reduced susceptibility as highlighted in multiple cohort studies, which recommend maintaining echinocandin therapy or using alternative agents)	Reduces treatment costs and toxicity after initial infection control	Requires close monitoring to avoid incomplete eradication; Switch from a cidal to static drug class	Improper or early step-down may leave subtherapeutic drug levels, enabling resistant mutant population	5,74–77

AMB, amphotericin B; 5-FC, 5-fluorocytosine; L-AmB, liposomal amphotericin B; IV, intravenous; TDM, therapeutic-dose monitoring.

Administration routes and impact on resistance

Optimal antifungal therapy hinges on selecting the most appropriate administration route to maximize efficacy while minimizing the risk of drug resistance. Table 2 summarizes the main administration routes (i.e. oral, IV, nebulized and ophthalmic), highlighting their practical applications in treating IFDs. Understanding these administration routes is critical for clinicians seeking to balance therapeutic outcomes for the management of IFD in the era of increasing resistance.

Table 2.

Examples of Antifungal Administration Routes and Their Role in Resistance Development

Route of administration	Example IFD and (antifungal agent)	Antifungal treatment strategy	Advantages	Limitations	Role in resistance development	References
Oral	Candidaemia (fluconazole)	Prophylaxis: Fluconazole (200–400 mg daily) for prevention in immunocompromised individuals Empirical: Fluconazole (400–800 mg daily for 14–21 days) to treat suspected IC Targeted: Fluconazole (400–800 mg daily for 14–21 days) for confirmed candidaemia. TDM may be required for augmented renal function or obesity to ensure therapeutic levels	Convenient for outpatient care	Variable absorption Requires patient adherence Dose adjustments may be needed for obesity	Non-adherence or prolonged use in conditions like fluconazole-resistant C. auris fosters resistance	27, 78–81
IV	Candidemia in critically ill patients (caspofungin) Mucormycosis (L-AmB)	Empirical: Caspofungin (70 mg IV loading dose, then 50 mg daily for 14 days) for suspected candidaemia Targeted therapy: L-AmB (5 mg/kg daily, increased to 10 mg/kg for severe infections, administered for at least 3–6 weeks) for mucormycosis. Dose adjustments may be required for obesity	Caspofungin: immediate therapeutic effect L-AmB: broad-spectrum fungicidal activity	Caspofungin: Requires hospitalization Costly L-AmB: Nephrotoxicity risk and infusion reactions Requires close monitoring	Prolonged or inappropriate use of caspofungin can promote resistance in Candida spp., including echinocandin-resistant strains Chronic exposure of IV L-AmB may contribute to resistance in rare moulds such as Mucorales spp.	27,71,82
Nebulized	Refractory aspergillosis (nebulized L-AmB)	Targeted: Nebulized L-AmB (10–25 mg daily) for chronic pulmonary aspergillosis or as prophylaxis in neutropenic patients. Note: Nebulized amphotericin B may be off-label (i.e. not approved for administration)	Direct localized delivery	Requires specialized equipment	Chronic use may lead to localized resistance, particularly for A. fumigatus	83–86
Ophthalmic	Fungal keratitis (natamycin)	Targeted: Natamycin (5% eye drops, every 1–2 h for 3–4 days, then 3–4 times daily for 2–3 weeks) for fungal keratitis	High drug concentration at the infection site	Requires frequent application High costs in certain markets	Incomplete or suboptimal treatment increases tolerance in pathogens like Fusarium solani	87–89

L-AmB, liposomal amphotericin B; IFD, invasive fungal disease; IV, intravenous.

Breakthrough IFDs (fungal infections occurring during antifungal treatment) must be carefully contextualized but are not always indicative of antifungal resistance.⁹⁰ Infections that occur due to subtherapeutic drug levels cannot necessarily be classified as true breakthroughs, as the patient is not effectively protected by the treatment. This was notably observed when comparing posaconazole oral suspension and tablet formulations in patients with haematological malignancies. Oral suspension was associated with lower plasma concentrations (1.631 ± 0.878 mg/L versus 0.879 ± 0.585 mg/L), with concentrations in the oral suspension group frequently falling below the suggested optimal threshold of ≥0.5 mg/L,⁹¹ and a significantly higher rate of breakthrough infections (4.5% versus 14.8%; P = 0.005). While these infections occurred during treatment, they were largely due to inadequate drug dosing rather than intrinsic pathogen resistance.⁹⁰

Comparing inpatient, OPAT and outpatient treatment in resistance development

Resistance development is shaped by the distinct characteristics of antifungal treatment strategies across inpatient, OPAT (outpatient parenteral antimicrobial therapy) and outpatient settings.^92,93 For inpatients, IV antifungals such as AmB or echinocandins are commonly used, offering controlled administration in a hospitalized setting to ensure proper dosing and adherence.^94,95 This reduces the likelihood of subtherapeutic exposure, a driver of resistance, but increases costs and potentially prolongs and complicates hospital stays.

OPAT provides an alternative by offering IV antifungal therapy to stable patients outside the hospital, with agents such as L-AmB or caspofungin commonly employed.^92,96–99 While OPAT can alleviate healthcare system burdens and enhance patient autonomy, it is associated with challenges that may indirectly contribute to resistance development. OPAT has been linked to significant hospital readmission rates,¹⁰⁰ and carries the risk of dosing errors, missed doses or improper use of infusion devices (e.g. infusion device complications, such as occlusions or handling errors). These issues can compromise drug delivery, potentially leading to suboptimal drug levels.^92,96,97,99 Although direct evidence linking OPAT to resistance development is limited, suboptimal drug levels may inadvertently create conditions that favour pathogen survival and adaptation, which could theoretically foster resistance.^92,96,97,99 Outpatient antifungal therapy is beneficial when treating infections susceptible to oral antifungal therapies in patients who do not require hospitalization and/or prolonged periods of treatment administration. However, there remains a role for outpatient treatment when addressing certain infections where oral alternatives are inadequate. In such cases, its utility is complicated by the alternative options for administration. Examples include infections caused by N. glabrata, Mucorales spp. or Lomentaspora/Scedosporium spp.^101,102 These pathogens can exhibit intrinsic or acquired resistance to many antifungals, including azoles, limiting treatment options and making systemic and/or combination treatment with IV medications like L-AmB or echinocandins necessary to achieve therapeutic efficacy.¹⁰¹ Without these IV options, patients face poor prognoses and higher mortality risks, but daily outpatient IV administration complicates management, typically necessitating OPAT. Similarly, patients who cannot tolerate azoles due to adverse reactions, liver toxicity or interactions with concomitant medications (e.g. enzyme inducers or inhibitors), require alternative IV antifungal classes.¹⁰³ Challenges in outpatient therapy arise primarily from the need to closely monitor antifungal levels to prevent subtherapeutic exposure, which can cause treatment failure and lead to resistance. For instance, immunocompromised patients, who often rely on complex polypharmacy, are especially vulnerable to azole–drug interactions, necessitating careful treatment planning and ongoing monitoring.¹⁰³

Extending the half-life of antifungals may be one option to reduce the number of hospital visits, enhance patient convenience and reduce healthcare burden.^95,104–106 For instance, rezafungin, a next-generation echinocandin, exemplifies this approach. Its differentiated PK, including low clearance and a long half-life, enable a once-weekly dosing regimen.¹⁰⁷ This results in high, front-loaded exposure that optimizes fungicidal activity for concentration-dependent drugs like echinocandins.¹⁰⁷ By reducing the frequency of dosing, this adaptation minimizes the risk of missed doses or improper administration, which are common in outpatient settings and can lead to subtherapeutic drug levels. Long-acting formulations ensure more consistent therapeutic drug levels, reducing the likelihood of these resistance-promoting scenarios.^95,104–106 Additionally, fewer dosing events lower the chances of errors in preparation or administration, further supporting effective treatment and resistance prevention.^95,104–106

Antifungal treatment strategies to mitigate the risk of resistance development

TDM and personalized dosing regimens

The primary objective of TDM is to maintain drug concentrations within a therapeutic window that maximizes efficacy while minimizing toxicity.¹⁰⁸ This is especially critical for antifungal agents like azoles, where PK variability can result from factors such as organ dysfunction, weight extremes or genetic differences.^108,109

Additionally, drug–drug interactions (DDIs) pose a significant challenge, particularly in critically ill/complex patients receiving multiple therapies. DDIs may alter the metabolism of antifungal agents or other drugs, increasing the risk of toxicity or subtherapeutic concentrations, both of which necessitate careful monitoring and intervention through TDM.¹¹⁰

Clinical interventions such as extracorporeal membrane oxygenation (ECMO) add further complexity to antifungal PK by influencing drug clearance and distribution.¹¹¹ Through TDM, clinicians can adjust dosing in real time to account for these variables, ensuring effective and safe antifungal therapy tailored to individual patient needs.

Resistance can arise due to exposure to subtherapeutic drug levels that fail to eradicate fungal pathogens, allowing them to adapt or favour strains with tolerance to an antifungal drug.¹⁰⁹ At the same time, excessively high drug concentrations can lead to toxicity without providing additional therapeutic benefits. TDM remains instrumental in monitoring antifungal therapy to determine levels and allow for dose adjustments, ensuring optimal drug exposure that reduces the risks of both resistance development and toxicity.¹⁰⁹

The use of TDM is widely advocated when administering voriconazole. A multicentre, prospective, cluster-randomized crossover trial investigated whether TDM-guided voriconazole treatment improves outcomes compared with standard dosing in adult haematological patients with IA.¹¹² The study found no significant difference in the composite primary endpoint (treatment response and discontinuation due to adverse drug reactions) between the TDM and non-TDM groups.¹¹² While TDM resulted in more trough concentrations within the therapeutic range (74% versus 64%, P < 0.001), this did not translate into better clinical outcomes.¹¹² The findings suggest that routine TDM for IA patients may be beneficial, particularly in cases of severe disease requiring rapid and effective treatment, complex patient conditions, or if prior antifungal treatment is being or has been administered.¹¹²

TDM may be particularly valuable in managing complex cases requiring the concomitant use of therapies likely to result in DDIs and/or with known genetic or clinical conditions likely to influence PK or treating vulnerable populations, such as critically ill (e.g. on ECMO) or immunocompromised patients on multiple conflicting therapies, where achieving the correct therapeutic range is critical for both safety and efficacy. Real-world evidence further highlights the importance of TDM in challenging cases. For example, one case involved a critically ill, morbidly obese patient with persistent bloodstream infections resistant to standard treatments.¹¹³ A multidisciplinary team incorporated TDM to adjust doses of fluconazole, daptomycin and ceftobiprole, achieving levels appropriate to the pathogens’ minimum inhibitory concentration (MIC).¹¹³ This intervention led to rapid clinical improvement and infection clearance.¹¹³

For paediatric patients undergoing HSCT in real-world settings, analysis of PK/pharmacodynamic (PD) modelling integrated with TDM proves essential for determining individualized voriconazole dosing.¹¹⁴ This methodology accounts for variations in CYP2C19 metabolism and body weight and MIC targets, ensuring therapeutic concentrations.¹¹⁴ Such precision theoretically reduces the risk of resistance while maintaining safety.¹¹⁴

Preventive and initial treatment strategies

While prophylaxis limits infections in high-risk patients, the effectiveness remains dependent on knowledge of the local mycological epidemiology and rates of resistance. High resistance rates can compromise standard prophylactic strategies (e.g. fluconazole or posaconazole), increasing the risk of breakthrough infections.¹¹ If breakthrough infections occur while on posaconazole, IV L-AmB is typically used as an alternative.¹¹⁵ Conversely, if the patient is not on mould-active prophylaxis, primary therapy with voriconazole or isavuconazole can be initiated, both of which are effective for invasive mould diseases.^116,117

Fluconazole prophylaxis in HSCT recipients has been shown to significantly lower the incidence of invasive Candida infections, reducing the need for empirical therapies.¹¹⁸ Similarly, posaconazole prophylaxis has proven effective for patients with prolonged neutropenia, such as individuals with AML, limiting IFD.¹¹⁹ Additionally, secondary prophylaxis with voriconazole is beneficial in preventing the recurrence of fungal infections in leukaemic patients and HSCT recipients.¹²⁰ This ensures these patients can adhere to their treatment schedules and reduces their risk of future complications. Daily IV administration also poses challenges like catheter-related issues and reduced patient mobility, highlighting the need for alternatives.¹²¹

Advanced formulations

Newer antifungals and advanced formulations are transforming antifungal therapy by improving efficacy, adherence and patient outcomes.¹²² Advanced formulations, such as extended-release antifungals, further enhance treatment adherence by reducing the frequency of dosing and maintaining consistent therapeutic drug levels, thereby lowering the risk of subtherapeutic exposure that can drive resistance.¹²³ Extended-release posaconazole, for example, has demonstrated better plasma levels and fewer breakthrough fungal infections compared with the oral suspension form, particularly in patients with prolonged neutropenia and graft-versus-host disease.^123,124 Alternative formulations in antifungal therapy are pivotal for addressing absorption challenges and improving treatment outcomes. Lipid formulations of AmB reduce nephrotoxicity and improve drug delivery, making them particularly effective for systemic infections. While AmB is not administered orally, these formulations are advantageous in patients where poor gastrointestinal absorption of other antifungal agents limits treatment options.¹²⁵ Rezafungin, for instance, offers a broad-range treatment strategy and potential to curb resistance development, making it particularly effective for high-risk patients facing heteroresistant Candida infections.^33,122

Additionally, alternative administration routes, such as nebulized antifungals, are gaining attention for their targeted delivery and reduced systemic toxicity.⁵⁰ For example, opelconazole, a nebulized triazole antifungal, has shown promise in treating IFDs by delivering high local concentrations directly to the lungs while minimizing systemic exposure.⁵⁰

Oral administration and sequential therapy

How antifungal drugs are administered can greatly influence availability. A retrospective study highlighted that switching from IV to oral therapy resulted in a considerable decline in voriconazole trough concentrations, with significant inter-patient variability.¹²⁶ Oral itraconazole capsules, for instance, achieve better bioavailability when taken with acidic beverages or food due to their reliance on gastric acidity for optimal absorption.¹²⁷ For patients with absorption issues or severe disease, IV formulations provide an effective alternative. For voriconazole, available in oral and IV formulations, IV administration provides more reliable drug levels in patients who cannot tolerate oral intake, such as those under intensive care or with severe mucositis, though levels may still be low in rapid metabolizers.¹²⁸ Similarly, IV AmB bypasses absorption issues entirely and remains a critical option for treating life-threatening fungal infections, including IA or cryptococcal meningitis.¹²⁹

Sequential therapy, transitioning patients from IV to oral antifungal drugs once stabilized, is a key AFS strategy that enhances patient compliance, reduces catheter-associated complications and significantly lowers healthcare costs in long-term systemic mycosis treatments.¹³⁰ Voriconazole, widely used for sequential therapy in IA and candidiasis due to its high oral bioavailability, offers an option for transitioning from IV to oral therapy in outpatient care. DDIs and variable metabolism, necessitate TDM, which can complicate its oral administration.¹³¹

Isavuconazole, with its availability in both oral and IV formulations, high oral bioavailability and lack of cyclodextrin in its IV preparation, is probably best suited to the role of sequential therapy. Its predictable PK and reduced DDIs make it a favourable option for transitioning patients from IV to oral therapy, particularly in IA.¹³² Similarly, fluconazole, available in both IV and oral forms, has proven effective in sequential strategies for candidemia.^133,134 However, transitions from IV to oral fluconazole must be carefully managed, as improper transition, such as switching without ensuring adequate gastrointestinal absorption, patient adherence, or TDM, can lead to subtherapeutic levels and resistance in Candida spp., but sequential therapy ensures adequate drug concentrations to prevent such outcomes.¹³³

Combination therapy

Combination therapy plays a critical role in enhancing efficacy and reducing the risk of resistance, especially in severe or refractory fungal infections.¹³⁵ This approach is exemplified by the combination of AmB and flucytosine for cryptococcal meningitis, where flucytosine enhances fungal killing while AmB disrupts fungal cell membranes.¹³⁶ Similarly, combining an echinocandin like caspofungin with an azole such as fluconazole or voriconazole has been effective in managing IC,¹³⁷ and is a strategy used to overcome azole-resistant Aspergillosis.¹³⁸ However, the use of combination therapy is not without challenges. For instance, potential antagonism between azoles and AmB has been reported, although this has not necessarily been borne out in routine clinical practice.¹³⁹ Additionally, new generation antifungals such as olorofim have shown antagonistic interactions in vitro with azoles, adding further evidence to a complex issue.¹⁴⁰

Recent evidence from a randomized, double-blind trial underscores the potential benefits of combination therapy in IA.¹⁴¹ The study compared voriconazole and anidulafungin combination therapy to voriconazole monotherapy in patients with haematologic malignancies or those undergoing haematopoietic cell transplantation. While the difference in overall 6-week mortality between the groups did not reach statistical significance, subgroup analysis revealed improved survival in patients diagnosed through radiographic findings and GM positivity.¹⁴¹ Six-week mortality in this subgroup was noticeably lower for combination therapy (15.7%) compared with monotherapy (27.3%), suggesting enhanced efficacy in specific cases.¹⁴¹

Combination therapy improves treatment outcomes by targeting fungal pathogens through multiple mechanisms potentially limiting resistance, as one drug can remain effective and sustain antifungal activity if the levels of the other drug drop to subtherapeutic concentrations, thereby minimizing treatment gaps and enhancing synergistic action.¹⁴² However, the complexity of combination therapy requires carefully designed clinical studies to prove effectiveness and that adverse effects are limited.

Step-down/de-escalation

The step-down or de-escalation strategy in antifungal therapy focuses on transitioning patients to narrower-spectrum options with the potential for an easier route of administration, targeted against the causative pathogen once identified and its susceptibility profile (if available) and/or significant clinical improvement is achieved.^143,144 IV antifungals, such as echinocandins and L-AmB, are commonly used empirically for critically ill or immunocompromised patients due to their activity against various fungal pathogens. However, prolonged usage can inadvertently promote resistance.¹⁴⁵ De-escalation particularly involves transitioning from broad-spectrum agents like echinocandins to narrower-spectrum alternatives such as fluconazole, specifically for infections caused by susceptible Candida spp., as informed by local epidemiology or prompt susceptibility testing.^143,146

De-escalation also prioritizes the use of antifungal agents with more convenient routes of administration, lower toxicity profiles and reduced costs, such as triazoles.^143,147 This provides flexibility in the management of the patient and ensures better patient safety while alleviating financial burdens. In the context of de-escalation, where the pathogen has been identified, transitioning from echinocandins to a more targeted therapy helps preserve their efficacy for critical cases in the future. It is important to note that echinocandins exhibit cidal activity against Candida spp., but their action is only static against Aspergillus spp., underscoring the need for appropriate pathogen-directed therapy.¹⁴⁸

A study evaluating antifungal de-escalation in critically ill patients demonstrated that most guideline-recommended doses of fluconazole and voriconazole achieved the required PK/PD targets for effective therapy.¹⁴⁹ Transitioning to triazoles after initial echinocandin therapy provided sufficient therapeutic activity while avoiding prolonged broad-spectrum exposure, ensuring optimal pathogen eradication and reduced resistance pressure.¹⁴⁹ The same study highlighted challenges with standard echinocandin regimens, which often failed to achieve PK/PD targets in heavier patients or with infections caused by species like C. parapsilosis, which exhibit reduced susceptibility to echinocandins. Weight-adjusted dosing of echinocandins, particularly caspofungin, has been shown to improve PK/PD target attainment compared with conventional regimens.¹⁴⁹ However, transitioning from a cidal drug like caspofungin to a static drug like fluconazole may pose a downside, as static drugs rely on the host immune system to clear the infection, which could be less effective in immunocompromised patients.¹⁵⁰

Future perspectives

Emerging antifungal treatment strategies

Innovative approaches are shaping the future of antifungal treatments, with the goal of enhancing both efficacy and safety. Lipid-based formulations and nanotechnology are improving drug bioavailability and reducing systemic toxicity by delivering higher concentrations of the drug to target tissues while minimizing side effects.^151–154 The recent availability of generic versions of L-AmB necessitates rigorous evaluation to ensure they match the efficacy of branded products.¹⁵⁵ Novel strategies, such as immobilizing L-AmB on indwelling medical devices, show promise in preventing fungal biofilm formation in clinical settings.¹⁵⁶ Additionally, the nebulized formulation of opelconazole offers unique advantages, as described above.⁵⁰

Combination therapies are also emerging as a powerful tool, pairing antifungal agents with immunomodulators or resistance inhibitors to boost antifungal activity, counteract resistance mechanisms and optimize synergistic effects.^105,157 For instance, calcineurin inhibitors like cyclosporine A have been shown to enhance the efficacy of azoles and echinocandins.^142,158 This combination not only boosts antifungal activity but also transforms fungistatic drugs into fungicidal ones, effectively counteracting resistance mechanisms.^142,158 Careful design ensures these combinations avoid antagonism.

Drug delivery systems are evolving rapidly, with new approaches such as implantable devices, inhalable formulations and inhaled L-AmB providing targeted and sustained drug release. These innovations demonstrate significant potential for treating chronic IFDs, such as pulmonary aspergillosis.^159–161 Oral AmB formulations represent another breakthrough, offering patients a more convenient yet effective treatment option.¹⁶² These developments reflect progress in making AmB-based therapies safer, more versatile and patient-centric.

Novel classes of antifungal agents

The development of novel antifungal drugs is essential to combat antifungal resistance and improve patient outcomes. A promising advancement lies in Gwt1 inhibitors like fosmanogepix, which target glycosylphosphatidylinositol biosynthesis, which is critical for fungal cell wall integrity, while sparing human host cells, thus reducing toxicity risks.¹⁶³ Other emerging agents focus on disrupting fungal-specific processes, such as chitin synthase or other fungal cell wall synthesis enzymes, offering highly targeted treatments.^164,165 Additional breakthroughs include fungal-specific immune response modulators, which enhance host defences without directly attacking fungal cells, thereby lowering the likelihood of resistance.^166–168 Olorofim, a novel dihydroorotate dehydrogenase inhibitor, represents another significant advancement.¹⁶⁹ By targeting fungal pyrimidine biosynthesis, olorofim offers a unique mechanism of action distinct from existing antifungal classes, making it particularly effective against resistant moulds like Aspergillus and Scedosporium spp.¹⁶⁹

Repurposing existing drugs for antifungal use also complements the development of novel agents.¹⁷⁰ This approach leverages the known safety and efficacy profiles of licensed drugs, reducing research and development risks and timelines. While economic challenges limit pharmaceutical interest, academic and non-profit groups have driven efforts to repurpose drugs like clindamycin, pioglitazone, sertraline and tamoxifen for fungal infections, though results have been mixed.¹⁷⁰

The dual use of clinical antifungals and agricultural fungicide classes raises concerns about the development of cross-resistance. Similar to azoles, both olorofim and fosmanogepix have agricultural counterparts already available, which could potentially drive resistance in clinical settings.¹⁷¹

Several antifungal agents currently approved and/or in clinical trials also hold significant potential (Table 3).¹⁰⁶ The recent WHO landscape document on available and pipeline antifungal agents considered the current antifungal development process to be insufficient when compared with the required targets and innovations.¹⁷⁰

Table 3.

Examples of Recent Antifungal Agents—Approved and/or in Clinical Development

Agent name	Target pathogen(s)	Mechanism of action	Substance class	Novel aspects	Typical dose	Clinical trial phase [study name (NCT number)]	Future areas of use	Special clinical settings	References
Rezafungin	Candida spp., Aspergillus spp., Pneumocystis jirovecii	Echinocandin; inhibits β-1,3-L-glucan synthase	Echinocandin	Long half-life (152 h) enabling once-weekly dosing; it avoids QTc prolongation and has low DDI risk	400 mg (IV) loading dose once weekly, followed by 200 mg weekly	Completed: Phase 3 [ReSTORE (NCT03667690)]; Phase 2 [STRIVE (NCT03667690)]. Ongoing Phase 3 [EUCTR2017-004981-85 (NCT04368559)]; Ongoing Phase 2 (NCT05835479) of pneumocystis pneumonia	Prophylaxis in transplant patients and treatment of recurrent fungal infections	Multidrug-resistant Candida, long-term outpatient therapy	10, 170, 172, 173
Olorofim	Mould pathogens, including Aspergillus spp., Scedosporium spp., Lomentospora spp.; dimorphic fungi, not Mucorales spp., variable for Fusarium spp.	DHODH inhibitor; disrupts pyrimidine biosynthesis	Orotomide	Targets novel metabolic pathway; active against azole-resistant moulds	150 mg (oral) twice daily loading dose, then 90 mg twice daily	Completed Phase 2 [EUDRA2017-001290-17 (NCT03583164)]. Ongoing: Phase 3 [OASIS (NCT05101187)]	First-line treatment for azole-resistant aspergillosis, salvage therapy for refractory infections	Refractory mould infections, CNS infections with dimorphic fungi	10, 50, 52, 170
Ibrexafungerp	Candida spp., C. auris, Aspergillus spp., Pneumocystis jirovecii, Cladosporium spp., Coccidioides spp., not Mucorales spp., not Fusarium spp.	Triterpenoid; inhibits β-1,3-D-glucan synthase	Glucan synthase	Oral formulation for invasive fungal infections; potential for lower DDIs than with azoles	750 mg (oral) twice daily on Days 1–2, then 750 mg once daily	Terminated due to slow enrolment: Phase 2 [SCYNERGIA (NCT03672292)]	Step-down therapy after IV echinocandins, long-term management of vulvovaginal candidiasis	Fluconazole-resistant vulvovaginal candidiasis; outpatient IC	10, 170, 174
Fosmanogepix	Candida spp., except C. krusei, Aspergillus spp., Scedosporium spp., Fusarium spp., Mucorales (variable activity), Crypto coccus spp.; endemic mycoses, including coccidioidomycoses	Gwt1 inositol acyltransferase inhibition; disrupts fungal cell wall	Gwt1 protein modulator	Active against multiple resistant moulds and yeasts; high oral bioavailability (>90%); limited DDIs and wide tissue distribution	1000 mg IV twice daily on Day 1, then 600 mg IV or 700 mg orally	Completed: Phase 2 (NCT0604705) [APEX (NCT04148187)]. Ongoing: Phase 3 (NCT05421858)	Treatment of C. auris, rare mould infections; co-therapy for severe immunosuppression-related IFDs	Salvage therapy for Candida auris; CNS-penetrating infections	50, 170, 175
Oteseconazole	Azole-resistant Candida spp., C. neoformans, C. gattii, dimorphic fungi (Coccidioides, Histoplasma, Blastomyces spp.)	Tetrazole; inhibits lanosterol 14α-demethylase	Tetrazole	Improved binding specificity reduces drug interactions and toxicity; tetatogenic risk	600 mg (oral) on Day 1, reduced to once weekly thereafter	Completed: Phase 3 [ultraviolet (NCT03840616)]	Long-term oral maintenance therapy for azole-resistant Candida infections; treatment of endemic fungal infections	Recurrent vulvovaginal candidiasis in non-pregnant women	10, 170, 176
Encochleated AmB	Broad-spectrum fungi, including Candida spp., Cryptococcus spp., Aspergillus spp., Mucorales	Polyene; binds ergosterol and disrupts fungal cell membrane	Polyene	Oral delivery system reduces nephrotoxicity associated with traditional AmB	200–400 mg orally twice daily	Completed: Phase 2 [EnACT2 (NCT04031833); CAMB (NCT02629419)]. Ongoing: Phase 3 [EnACT3 (NCT05541107)]	Step-down therapy from IV AmB; durable outpatient therapy	Cryptococcal meningitis maintenance, Candida biofilm-related infections	170, 177
Opelconazole	A. fumigatus, A. flavus, A. terreus, Candida spp., Cryptococcus spp.	Triazole; inhibits lanosterol 14α-demethylase	Triazole	Designed for inhaled delivery to achieve high pulmonary concentrations	14.8 mg inhaled twice daily	Completed: Phase 2 [OPERA-S (NCT05037851)]. Ongoing: Phase 3 [OPERA-T (NCT05238116)]	Pulmonary-targeted therapy for IA and ABPA	Lung transplant patients, CPA	50, 170, 178

ABPA, allergic bronchopulmonary aspergillosis; AmB, amphotericin B; CNS, central nervous system; CPA, chronic pulmonary aspergillosis; DDI, drug–drug interaction; DHODH, dihydroorotate dehydrogenase; Gwt1, glycosylphosphatidylinositol inositol acyltransferase; IA, invasive aspergillosis; IFDs, invasive fungal diseases; IV, intravenous; MIC, minimum inhibitory concentration; MSW, mutant selection window; NCT, national clinical trial (identifier number); PK, pharmacokinetics; QTc, corrected QT interval; TDM, therapeutic drug monitoring.

Emerging immunotherapies and vaccines

The field of immunotherapy continues to gain traction in antifungal treatment strategies.^179,180 Innovative approaches include antibody-based therapies, which leverage monoclonal antibodies for the precise targeting of fungal antigens, enhancing the efficacy of antifungal drugs. Chimeric antigen receptor (CAR) T-cell therapies, specifically developed for aspergillosis, offer a cutting-edge solution by reprogramming patient immune cells to combat fungal infections effectively.¹⁸¹

Recent advances in immunomodulation strategies against IFDs focus on enhancing host immune responses to combat these challenging pathogens.¹⁸² Pro-inflammatory cytokine therapies, such as granulocyte colony-stimulating factor (G-CSF),¹⁸³ GM-CSF and IFN-γ, have shown promise in animal models by boosting neutrophil function and improving fungal clearance.¹⁸² IFN-γ therapy, in particular, has demonstrated faster clearance of Cryptococcus spp. in human trials.^184–186 Novel approaches like adoptive T-cell transfer, including Aspergillus-specific T cells and CAR T cells targeting fungal antigens, have shown potential in preclinical studies.¹⁸² Additionally, monoclonal antibodies targeting fungal cell components and innovative vaccination strategies, such as glycan-conjugate vaccines, are being explored to provide targeted and durable immune responses.¹⁸²

Another powerful avenue under research involves combining antifungal therapies with antibody or pattern recognition receptor–based systems, enabling targeted action directly against fungi.¹⁸⁷

Optimizing antifungal use and resistance control

AFS is pivotal in optimizing treatments, combating resistance and preserving the utility of antifungal agents. AFS programmes focus on improving treatment guidelines, promoting appropriate use of antifungals and fostering education among clinicians.^188–190 Global surveillance networks play a critical role in determining the burden of IFD while monitoring fungal resistance patterns, identifying resistance hotspots and fostering international collaboration to inform policy decisions.^188–190 Integrating AFS into healthcare systems also requires addressing challenges like delayed diagnostics and suboptimal knowledge about existing burdens and therapies.^191,192 Enhanced education on the importance of rapid diagnostic tools, personalized medicine and stewardship practices can play a vital role in cementing long-term success in antifungal resistance control.¹⁹³

TDM has contributed significantly to the success of AFS initiatives, extending its utility beyond individual dosing adjustments. For example, a study in paediatric cancer patients showed significant reductions in azole resistance following the implementation of AFS alongside TDM.¹⁹⁴ Before AFS, 52.5% of Candida albicans isolates were resistant to fluconazole, which dropped to 1.5% post-intervention.¹⁹⁴ Improvements in caspofungin resistance were also observed, and overall antifungal drug expenditure decreased.¹⁹⁴

Improved diagnostics and precision medicine

Rapid and accurate diagnostics are vital to identifying fungal pathogens and their resistance profiles, enabling timely and targeted therapies that minimize the use of broad-spectrum agents.¹⁹⁵ Advanced molecular techniques such as next-generation sequencing (NGS) are paving the way for quicker diagnoses, improving both treatment outcomes and AFS efforts.^195,196

Personalized, precision medicine is an equally important innovation, revolutionizing the way fungal infections are managed. By leveraging genomic technologies, clinicians can tailor antifungal therapies based on individual genetic factors, infection characteristics and susceptibility data.¹⁹⁷ This approach not only enhances treatment efficacy but also reduces adverse events and resistance development. Stratifying patients by risk profiles enables early, proactive interventions that prevent severe fungal infections.

Avoidance of dual-use antifungals

The intersection of agricultural and clinical antifungal use has raised concerns about shared resistance development, underscoring the need to avoid dual-use antifungals. The development of RNA interference-based treatments offers a promising alternative by specifically targeting fungal pathogens while leaving agricultural fungi unaffected.¹⁹⁸ Such innovations could curb the emergence of resistance stemming from agricultural exposure to antifungal agents.¹⁹⁸ It is critical that a One Health strategy is employed when discussions on this critical matter commence.⁴⁶

Conclusions

The growing universal challenge of antifungal resistance demands a deliberate and multifaceted response from healthcare providers, researchers and policymakers across all domains. Indeed, a One Health approach is critical to success. The strategic approaches of prophylaxis, empiric, pre-emptive and targeted antifungal therapies are keys to managing IFDs. However, each has its limitations, from promoting resistance through broad-spectrum prophylactic overuse to the diagnostic uncertainties that complicate pre-emptive treatments. The evaluation of real-world practices has highlighted the potential of approaches such as step-down therapy and sequential oral-therapy transitions in reducing toxicity and healthcare costs while limiting selective pressures on fungi. Robust governance through AFS frameworks is pivotal in optimizing the application of these approaches.

This review highlights the urgent need for integrating AFS into routine care to optimize drug use and minimize the selection pressures driving resistance. Enhanced diagnostic and patient management tools, such as TDM and NGS, play a fundamental role in enabling timely and precise interventions, reducing reliance on broad-spectrum antifungals and supporting the evolution of precision medicine. Emerging insights into drug penetration issues, particularly in the CNS, ocular and biofilm-associated infections, further underline the necessity for advanced drug delivery systems and personalized medicine. Lipid formulations of AmB and novel agents like rezafungin demonstrate the potential to enhance treatment consistency and outcomes by addressing these complexities through improved PK profiles. Additionally, newer antifungal agents, including ibrexafungerp, fosmanogepix and olorofim, bring hope for addressing multidrug-resistant pathogens, particularly through mechanisms that target fungal-specific pathways. These innovations are complemented by advancements in immunotherapy and vaccination efforts, aiming to strengthen host resilience as an essential aspect of infection management. The incorporation of innovative delivery systems, such as nebulized or oral AmB formulations, expands the scope of patient-centric care, ensuring accessible and effective therapy.

Addressing antifungal resistance also requires global collaboration. Policymakers must foster equitable access to diagnostics, therapies and mycological expertise, while enforcing strategies to curtail the shared environmental and clinical use of antifungal agents. The One Health framework offers a comprehensive perspective that highlights the interconnectedness of human, animal and environmental health in combating zoonotic or agricultural contributions to antifungal resistance. Ultimately, a multifaceted and collaborative effort that leverages scientific advancements and refines antifungal treatment strategies will be instrumental in combating the rise of antifungal resistance and improving global health outcomes.

Funding

Financial support for medical writing and editorial assistance was provided by Mundipharma, Cambridge, UK, in compliance with international guidelines for good publication practice.

Transparency declarations

N.V.R. has previously received speaking fees from Munidpharma. P.L.W. has performed diagnostic evaluations and received meeting sponsorship from Associates of Cape Cod, Bruker, Dynamiker and Launch Diagnostics; speaker fees, expert advice fees and meeting sponsorship from Gilead and Mundipharma; speaker and expert advice fees from Pfizer and expert advice fees from F2G.