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Open research questions in Antifungal resistance and susceptibility

68 unresolved questions extracted from the limitations and future-work sections of 896 Antifungal resistance and susceptibility papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Electronic nicotine delivery systems (ENDS), including e-cigarettes, are increasingly marketed as safer alternatives to combustible tobacco, yet their effects on oral health remain underexplored.

    The Vape, the Mouth, and the Mycobiome: A Comparative Metagenomic Analysis · 2026 · DOI

  • Our data support an association between e-cigarette use and remodeling of the oral mycobiome and microbiome, driven by enhanced polymicrobial interactions and increased functional complexity, suggesting that assumptions regarding the biological neutrality of e-cigarette aerosols warrant further investigation.

    The Vape, the Mouth, and the Mycobiome: A Comparative Metagenomic Analysis · 2026 · DOI

  • These findings highlight the potential of the HDAC6/8 inhibitor MC1568 as adjunct therapy to combat NAC infections, warranting further research to optimize antifungal efficacy while minimizing toxicity.

    Effects of the HDAC6/8 Inhibitor MC1568, Alone and in Combination With Fluconazole, in Non‐ <i>Albicans Candida</i> Species Infections · 2026 · DOI

  • In particular, the widely used clinical isolate BG2 differs from CBS138 in genome structure, adhesin regulation and macrophage survival, yet the extent to which these differences are reflected at the fungal cell surface remains unknown.

    Divergence in surface protein exposure between reference and clinical-derived Candida glabrata (Nakaseomyces glabratus) strains (CBS138 vs. BG2) – a preliminary proteomic perspective · 2026 · DOI

  • This finding supports the robustness of the diagnostic stratification pattern while also reinforcing that diagnostic uncertainty is an important limitation in retrospective real-world IPA ascertainment.

    A meta-analysis-informed diagnostic stratification tool for invasive pulmonary aspergillosis in severe fever with thrombocytopenia syndrome: systematic review, meta-analysis, and single-center cohort-based assessment · 2026 · DOI

  • substantially to AFP development, but advances in mechanistic understanding of biological systems, together with translational validation, will be essential for progress. The integration of mechanistic insight and closed-loop computational design may drive a paradigm shift in the development of rational and clinically applicable AFPs, moving beyond empirical peptide screening approaches. Despite advances in AI-powered peptide engineering, AFP development continues to face several important challenges. These challenges arise from limited fungal-specific datasets, a lack of mechanistic interpretability, and a persistent gap between computational prediction and translational validation. The discovery of AFPs has benefited substantially from recent advances in computational frameworks. Unfortunately, AFP prediction models are often adapted from antibacterial AMP datasets rather than trained on large fungalspecific datasets. Research on antibacterial peptides has generated large and diverse datasets, while AFP-related datasets remain comparatively limited, particularly with respect to quantitative antifungal activity, fungal subtype specificity, and in vivo pharmacokinetic and toxicity studies. These limitations may reduce model generalizability and, in turn, can affect the predictive performance of AFP design frameworks and computational screening systems (Mookherjee et al., 2020). Another major limitation is the lack of experimentally resolved fungal target structures. Recent improvements in AlphaFold and cryoelectron microscopy have substantially advanced structural biology. Nevertheless, high-resolution structural information is not yet available for many fungal membrane proteins, biofilm-associated targets, and cell wall synthesis complexes. As a result, important limitations remain regarding docking precision, the interpretation and accuracy of molecular interactions, and the reliability of mechanistic modeling for many AFP–fungal systems (Jumper et al., 2021). Furthermore, contemporary molecular dynamics simulations tend to rely on simplified membrane models. Consequently, accurately modeling ergosterol heterogeneity, lipid microdomains, and diffusion barriers associated with the cell wall remains important for understanding the physicochemical complexity of fungal membranes (Rodrigues, 2018). Improvements in computational prediction models may facilitate AFP optimization; however, successful translation ultimately requires experimental and clinical validation. Translational AI models increasingly incorporate antifungal activity, docking affinity and interaction dynamics with target proteins, and toxicity prediction. Clinically relevant AFP candidates are computationally predicted to exhibit favorable pharmacokinetics, proteolytic stability, immunocompatibility, formulation feasibility, and scalability for industrial production.

    Integrative computational–experimental discovery and translation of antifungal peptides for multidrug-resistant fungi · 2026 · DOI

  • In this setting, CSF tNGS may serve as a useful adjunctive etiological tool when routine microbiological studies are inconclusive, although the results should be interpreted together with the clinical and laboratory context.

    Post-endoscopic neurosurgical Candida albicans meningoencephalitis diagnosed by targeted next-generation sequencing: a case report · 2026 · DOI

  • Although the pathogenesis of fungal CNS infection has not been fully elucidated, penetration across the blood–brain bar- rier (BBB) is considered the most likely mechanism in Candida men- ingitis (2, 10).

    Post-endoscopic neurosurgical Candida albicans meningoencephalitis diagnosed by targeted next-generation sequencing: a case report · 2026 · DOI

  • auris has not been described precisely yet but one such ability of this yeast is that they can grow at an elevated temperature and fail to grow in the presence of cycloheximide and in automated approaches like VITEK 2, Matrix-assisted Laser Desorption/ionisation Timeof-flight (MALDI-TOF), Analytical Profile Index 20C AUX yeast (APIC20C-AUX) they can be misidentified as other species, which can lead to errors in the choice of antifungals.

    Standardisation of a Semi-nested PCR for Early Identification of Candida auris: A Cross-sectional Study from Southern India · 2026 · DOI

  • However, results of adhesion assays on inert surfaces and human keratinocytes found relatively modest roles of Wor2 and Scf1 in this process, suggesting that their effect on biofilm formation is complex and not limited to the adhesion step.

    Role of the transcription factor Wor2 in biofilm formation of <i>Candidozyma auris</i> · 2026 · DOI

  • Additionally, the downstream signaling pathways of STP1 and MRR2 in regulating autophagy and SAP2 expression need to be further explored, and the interac- tion between STP1 and MRR2 is also worthy of in-depth study.

    The roles of SAP2, STP1, and MRR2 on biofilm formation and itraconazole resistance through autophagy in Candida albicans · 2026 · DOI

  • The clinical and imaging manifestations of this case closely resem- ble those of pericardial tuberculosis, leading to initial diagnostic chal- lenges and a high risk of misdiagnosis. This highlights that Aspergillus udagawae infection can mimic the classic features of tuberculosis. For “tuberculosis-like” cases unresponsive to conventional antimicrobial therapy, proactive pursuit of molecular microbiological evidence (e.g., mNGS) is essential to rule out fungal infection. Additionally, the reduced susceptibility of this strain to voriconazole further compli- cates treatment, underscoring the critical value of early, precise species identification and antifungal susceptibility testing in improving prognosis. During treatment, only symptomatic therapy was adminis- tered, failing to reduce serum autoantibody titers—likely contrib- uting to disease progression. In clinical practice, patients with recurrent infections and immune dysfunction should undergo early testing for anti-interferon-γ autoantibodies. Where feasible, immunomodulators (e.g., rituximab, cyclophosphamide, glucocor- ticoids) may be considered to lower antibody titers. Tailored treat- ment plans should be developed based on individual patient characteristics, including pathogen profile, immune status, and drug tolerance. Currently, understanding of anti-interferon-γ antibody syndrome remains limited, and its rarity necessitates further research to elucidate pathogenesis and develop more effective therapies. Future efforts should focus on mechanisms of autoantibody production, improved detection methods, novel immunomodulatory regimens, and multi- disciplinary management models.

    Invasive pericardial and pulmonary aspergillosis by uncommon Aspergillus species in anti-interferon-γ autoantibody-associated immunodeficiency: a case report · 2026 · DOI

  • This case has the following limitations. Firstly, although the patient’s imaging condition deteriorated during the maintenance treatment with fluconazole, and improved significantly after switching to caspofungin, this suggests the possibility of C. tropicalis resistance to fluconazole. However, since no in vitro antifungal drug susceptibility testing (AST) was conducted on the isolated C. tropicalis strains, we cannot confirm the mechanism and spectrum of resistance at the microbiological level. Therefore, the conclusion of “azole resistance” in this article is more based on clinical eÿcacy inference rather than laboratory-confirmed “microbiological resistance.” Secondly, although we hypothesized that skin malignancy might be the potential cause of the patient’s impaired immune function, a systematic assessment of immune function (such as immune cells counts, Candida tropicalis specific IgG antibodies levels, CD4+ T-cell count, etc.) was not performed. Therefore, this assumption lacks direct immunological evidence support. Lastly, as a case report, the conclusion of this study has limited extrapolation. More cases accumulation and prospective studies are still needed to further clarify the clinical characteristics, resistance status, and host susceptibility factors of invasive pulmonary fungal disease caused by C. tropicalis.

    Misdiagnosis of invasive pulmonary fungal disease caused by drug-resistant Candida tropicalis as airway neoplasm: case report and literature review · 2026 · DOI

  • The paper identifies alterations in sterol-to-phospholipid ratios and ergosterol reorientation/masking in Candida cell membranes as drivers of polyene resistance but does not investigate whether these membrane compositional changes are stable across serial passages or reversible under different environmental conditions (pH, temperature, nutrient availability) in the feline oral cavity.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The study documents increased catalase activity as a resistance mechanism to polyene antifungals in Candida spp. but does not quantitatively measure catalase expression levels or correlate them with amphotericin B and nystatin resistance phenotypes in the feline oral isolates.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The paper establishes bidirectional Candida transmission between cats and owners but does not investigate the epidemiological chain of transmission, including whether owner-derived strains infect cats or vice versa, and what environmental or behavioral factors facilitate cross-species transfer. Longitudinal tracking of resistant strain genotypes in paired cat-owner households is required.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The study identifies pan-resistant C. glabrata isolates from cat oral mucosa but does not characterize the molecular mechanisms conferring resistance to azole and polyene antifungals in this specific niche. Genomic sequencing and targeted analysis of efflux pump expression, sterol synthesis pathway mutations, and cell wall remodeling genes in these isolates are needed.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The inverse correlation between clinical lesions and yeast isolation in cat-owner pairs suggests complex host-pathogen interactions that are not elucidated. Future research must characterize the specific immunological, microbiota composition, and local mucosal factors in cats versus humans that determine whether Candida colonization remains asymptomatic or progresses to clinical disease.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The study reports universal resistance to Nystatin and amphotericin B in C. albicans and C. glabrata from feline oral cavities, which contradicts existing literature showing susceptibility in these species from various sources. The mechanistic basis for this unusual pan-resistance phenotype in cat-derived isolates requires investigation of ergosterol quantitative and qualitative alterations specific to the feline oral environment.

    The Emergence of Pan Antifungal Resistance in Candida spp Isolated from The Oral Mucosa of Cats and Owners · 2026 · DOI

  • The association between high-intensity chemotherapy and IFI risk might be driven solely by pemetrexed-based regimens indicated for non-squamous histology, requiring further investigation.

    Influence of chemotherapy intensity on opportunistic fungal infection risk in non-small cell lung carcinoma: a retrospective study · 2026 · DOI

  • While G-CSF may mitigate some infection risk, the interaction term was not statistically significant, suggesting mechanisms beyond neutropenia are likely involved but remain incompletely characterized.

    Influence of chemotherapy intensity on opportunistic fungal infection risk in non-small cell lung carcinoma: a retrospective study · 2026 · DOI

  • While MALDI-TOF MS offers rapid identification, the need for Sanger sequencing in ambiguous or clinically significant cases highlights gaps in diagnostic standardization that future research should address.

    Antifungal susceptibility and in vitro virulence characteristics of clinical Magnusiomyces/Saprochaete isolates: a multicenter study from Türkiye · 2026 · DOI

  • The causal relationship between hypokalemia and ISA administration could not be definitively established due to concomitant medications (methylprednisolone and caspofungin) with documented hypokalemic potential, limiting conclusions about ISA's direct contribution to this adverse effect.

    Therapeutic drug monitoring-guided optimization of isavuconazole dose for ICU patients with refractory pulmonary aspergillosis: case report · 2026 · DOI

  • Previous studies have suggested that ISA may exhibit suboptimal plasma concentrations in ICU populations, but large-scale clinical trials are needed to validate the optimal timing for therapeutic drug monitoring implementation in this patient population.

    Therapeutic drug monitoring-guided optimization of isavuconazole dose for ICU patients with refractory pulmonary aspergillosis: case report · 2026 · DOI

  • As a single case report, these findings require validation through large-scale clinical trials to establish optimal dosing strategies and TDM timing for ISA in critically ill patients.

    Therapeutic drug monitoring-guided optimization of isavuconazole dose for ICU patients with refractory pulmonary aspergillosis: case report · 2026 · DOI

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68 open questions have been extracted from the limitations and future-work passages of 896 Antifungal resistance and susceptibility papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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