The study, published in eClinicalMedicine, brought together 111 adults with chronic disseminated candidiasis from 19 countries, diagnosed between January 2007 and December 2025. The condition, also known as hepatosplenic candidiasis, typically strikes patients with blood cancers such as acute myeloid leukaemia as their white blood cell counts recover after prolonged chemotherapy-induced neutropenia. It produces persistent fever, abdominal pain, cholestasis and characteristic abscesses in the liver and spleen, and it can force delays in cancer treatment that may ultimately matter more than the infection itself.

Almost all patients in the cohort had an underlying haematological malignancy. Acute myeloid leukaemia accounted for 48.6 percent of cases and acute lymphoblastic leukaemia for 24.7 percent, with lymphoma making up a further 15.6 percent. Notably, 24.8 percent of patients developed the infection despite receiving systemic antifungal prophylaxis in the days before diagnosis, so-called breakthrough disease, a figure that underscores the limits of current preventive strategies in the era of widespread mould-active azole prophylaxis.

The researchers applied a sophisticated statistical approach rarely used in this field: marginal structural models with inverse probability of treatment weighting, designed to account for time-varying confounders such as neutropenia and corticosteroid exposure that shift over the course of illness and can distort simple treatment comparisons. After this adjustment, neither the class of first-line antifungal, whether echinocandins, liposomal amphotericin B or azoles, nor the choice between fluconazole and other azoles for long-term oral step-down therapy was significantly associated with treatment response or overall survival.

This is a striking result given that international guidelines currently recommend echinocandins or liposomal amphotericin B as initial therapy, followed by an oral azole. Echinocandins were indeed the most common first-line choice in the cohort, used in 58.6 percent of patients, reflecting alignment with contemporary guidance. But the new data suggest clinicians may have greater flexibility than guidelines imply, particularly for patients with prior azole exposure or resistant organisms, where alternatives to fluconazole have previously rested on thin evidence.

Perhaps the most practice-changing observation concerns treatment duration. The median total course of targeted antifungal therapy was 107 days, substantially shorter than the four to seven months reported in earlier cohorts, and no relapses were documented after treatment was stopped during a median post-discontinuation follow-up of 92 days. Because conventional CT abnormalities can persist for many months after the infection has been controlled, with resolution rates of only 30 to 34 percent at three months in prior studies, the findings support the idea that extending therapy until complete radiological resolution may be unnecessary in selected patients.

Advanced imaging may hold the key to individualising that decision. Positron emission tomography combined with CT was performed in 26.1 percent of patients, and in 12 of them, regression of PET/CT findings was explicitly cited as the reason for stopping antifungal therapy. These patients had markedly longer treatment courses than those without PET-guided decisions, a median of 219 versus 88 days. The results complement the earlier French CANHPARI pilot study, which suggested that PET/CT normalisation at three months may better reflect resolution of active inflammation than conventional imaging, and they point toward PET/CT-guided assessment as a promising tool for distinguishing residual infection from immune reconstitution inflammatory syndrome, the paradoxical worsening that occurs as neutrophils recover.

The study also documented under-recognised manifestations of the disease. Nine patients showed central nervous system involvement, with multifocal punctate or ring-enhancing lesions on neuroimaging and, in some cases, positive cerebrospinal fluid beta-D-glucan testing. Skin and soft tissue involvement occurred in nine patients, six of whom had Candida tropicalis infection, a species known for cutaneous dissemination. The authors suggest that clinicians should consider CNS imaging in patients with neurological symptoms or refractory disease, since cerebral spread may be more common than previously appreciated.

Microbiological findings carried their own geographic and therapeutic signals. Candida albicans accounted for 32.4 percent of identified isolates and C. tropicalis for 24.3 percent, with the latter clustering markedly in Taiwan and Colombia. Fluconazole resistance was found in 11 isolates and was far more frequent in C. tropicalis than in other species, affecting 29.6 percent versus 3.6 percent, and nearly two-thirds of resistant cases occurred in the context of breakthrough infection. Yet resistance did not translate into worse survival, and beta-D-glucan, a fungal cell-wall marker measured at baseline in 35 patients, was positive in 88.6 percent, suggesting it may serve as a useful diagnostic adjunct.

Ultimately, the numbers tell a story about host biology rather than pharmacology. Only 4.5 percent of deaths were attributable to the fungal infection itself, even though all-cause mortality reached 33.3 percent, and patients with breakthrough disease actually survived more often than those without, likely because their underlying cancers were in a more favourable state. The authors caution that their comparative treatment analyses were exploratory and not powered to exclude clinically meaningful differences, and they call for prospective studies incorporating immune biomarkers such as cytokine profiles and Candida-specific T-cell responses alongside PET/CT. But for a disease that has been managed largely by tradition and caution, the message is clear: immune recovery, not drug selection, may be the true engine of cure, and shorter, individually tailored treatment could spare vulnerable patients months of toxicity, cost and delayed cancer therapy.

Subject of Research: Treatment strategies and outcomes of chronic disseminated candidiasis in patients with haematological malignancies in the era of antifungal prophylaxis

Article Title: Treatment and outcome of chronic disseminated candidiasis in the era of antifungal prophylaxis: a retrospective multicentre cohort of 111 patients

Article References: Reinhold, I., Ramirez-Sanchez, I. C., Chen, P.-Y., Chen, Y.-C., Dhariwal, A., Lambourne, J., Agrawal, S., Bastida, M., Gudiol, C., Alfandari, S., Di Pilla, A., Khostelidi, S., Aguilar-Zapata, D., Barac, A., Cipriano, A., Ehrlich, S., Grothe, J., Illarramendi, J., Jennrich, S., … Zager, L. (2026). Treatment and outcome of chronic disseminated candidiasis in the era of antifungal prophylaxis: a retrospective multicentre cohort of 111 patients. eClinicalMedicine, 100, Article 104194. https://doi.org/10.1016/j.eclinm.2026.104194

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104194

Keywords: chronic disseminated candidiasis, hepatosplenic candidiasis, haematological malignancies, antifungal therapy, echinocandins, azoles, Candida tropicalis, fluconazole resistance, PET/CT imaging, immune reconstitution, neutropenia, beta-D-glucan

Candidozyma auris has earned a reputation as one of the most concerning healthcare-associated fungal pathogens of the modern era. Unlike many of its fungal relatives, it persists stubbornly in the hospital environment, colonizes surfaces and medical equipment, spreads between patients in healthcare facilities, and frequently displays resistance to the antifungal drugs clinicians rely upon most. First recognized as a human pathogen less than two decades ago, it has since been reported on multiple continents, triggering outbreaks in intensive care units and prompting public health agencies to classify it as a serious global health threat. Its ability to survive routine disinfection and to be misidentified by conventional laboratory methods has made containment exceptionally difficult, and each new clinical dataset contributes valuable intelligence about how the organism behaves in actual patient care.

The Turkish research team set out to answer a question that has divided the field: does C. auris candidemia actually kill more patients than candidemia caused by other Candida species, or does it merely appear more lethal because it disproportionately infects patients who are already gravely ill? To address this, the investigators conducted a single-center retrospective cohort study, identifying every adult patient with candidemia seen at their institution and classifying infections by species. Identification was performed using MALDI-TOF mass spectrometry, a rapid proteomic technique that has become the gold standard for distinguishing C. auris from look-alike yeasts that older biochemical panels frequently confuse with it. Accurate speciation matters enormously here, because misidentification has historically hampered both surveillance and appropriate treatment.

The clinical profiles of the two patient groups differed in telling ways. Patients with C. auris candidemia had spent significantly longer in the hospital before their bloodstream infection developed, a pattern consistent with a healthcare-associated pathogen that colonizes patients during extended stays. They also more frequently had central venous catheters, the indwelling lines that provide fungi with a direct portal into the bloodstream, and greater exposure to corticosteroids, which suppress immune defenses. These exposures are classic risk factors for invasive candidiasis in general, but their heightened frequency in the C. auris group underscores how thoroughly this organism is woven into the fabric of modern intensive medical care. The findings reinforce the picture of C. auris as an opportunist that exploits the very devices and drugs that keep critically ill patients alive.

When the researchers examined crude outcomes, the headline number was striking in its symmetry: 30-day all-cause mortality was 62.3 percent among patients with C. auris candidemia and 62.5 percent among those with non-auris Candida infections, a difference of essentially zero. On the surface, this suggests the emerging pathogen is no deadlier than its established cousins. But crude comparisons in observational data can be deeply misleading, and the investigators knew that the patients harboring C. auris arrived at their infections with a different constellation of vulnerabilities. To disentangle the effect of the organism itself from the effect of patient characteristics, they turned to more sophisticated statistical machinery.

The team employed a multivariable Firth-penalized logistic regression model, a technique designed to produce more stable estimates when outcomes are imbalanced or sample sizes are modest, and they handled missing data through multiple imputation. The model was constructed with clinical input to ensure that the variables adjusted for reflected genuine medical knowledge rather than statistical convenience. After adjustment, C. auris candidemia was associated with higher estimated odds of 30-day mortality, with an adjusted odds ratio of 1.967, meaning the odds of death were nearly doubled relative to non-auris candidemia. However, the 95 percent confidence interval ranged from 0.954 to 4.055 and included the null value of one, with a p value of 0.067, meaning the association fell just short of conventional statistical significance.

To translate the regression results into more intuitive risk terms, the researchers used g-computation to estimate standardized marginal mortality risks. Under this approach, the adjusted 30-day mortality was estimated at 69.7 percent for C. auris candidemia compared with 59.3 percent for non-auris Candida candidemia, corresponding to an adjusted risk difference of 10.4 percentage points, with a confidence interval spanning from minus 0.2 to plus 21.3 points. In other words, once patient severity was accounted for, the data hinted that C. auris infections carry a genuinely elevated mortality burden, potentially adding roughly ten deaths per hundred patients, but the uncertainty around that estimate means the true effect could range from negligible to substantial. The authors are explicit that these findings should be interpreted as associative rather than causal, and that larger prospective multicenter studies across diverse healthcare settings are needed to confirm them.

Beyond the comparison between species, the study identified the factors that independently predicted death within 30 days across the entire cohort. Older age, higher scores on the Sequential Organ Failure Assessment, or SOFA, scale, the presence of septic shock, corticosteroid use, and hemodialysis were all associated with higher adjusted odds of mortality. These determinants are familiar from the broader candidemia literature: they reflect the reality that bloodstream fungal infections are most lethal in patients whose organs are already failing and whose immune systems have been blunted by illness or medication. The consistency of these predictors with prior research lends credibility to the study’s methodology and suggests the dataset behaves as expected, strengthening confidence in the species-specific comparisons.

The antifungal susceptibility findings carry important practical implications for treatment. Among C. auris isolates, echinocandin non-wild-type phenotypes were uncommon, which is welcome news because echinocandins are the recommended first-line therapy for invasive candidiasis and are often the drug class of choice against C. auris. However, elevated minimum inhibitory concentrations for amphotericin B were observed in approximately one-third of tested isolates, a troubling signal for an older but still-used antifungal that clinicians may reach for when first-line options fail or are unavailable. Meanwhile, resistance to fluconazole was frequent among tested Candida parapsilosis isolates, a reminder that antifungal resistance is not confined to the emerging pathogen and that susceptibility testing remains essential for guiding therapy across all Candida species. Susceptibility results were interpreted using applicable EUCAST clinical breakpoints or epidemiological cut-off values, and where no interpretive criteria existed, results were reported descriptively, reflecting the ongoing challenge that interpretive standards for some antifungal-organism combinations are still evolving.

The study’s conclusions are measured but consequential. C. auris candidemia, the authors report, is characterized by a distinct profile of healthcare-associated exposures and a distinct antifungal susceptibility pattern, and while crude mortality appears similar to other candidemia, adjusted estimates point toward higher mortality that remains statistically imprecise. For clinicians, the message is twofold: patients colonized or infected with C. auris deserve vigilant attention to modifiable risk factors such as catheter management and careful stewardship of corticosteroids, and treatment decisions should be anchored in susceptibility data rather than assumptions. For public health officials, the findings add to the accumulating evidence that C. auris is not simply another Candida species but a pathogen with its own epidemiology, its own resistance landscape, and potentially its own mortality penalty. As the global footprint of this fungus continues to expand, studies like this one, grounded in real-world clinical data and rigorous statistical adjustment, will be essential for calibrating the response. The research received no specific funding, was approved by the Etlik City Hospital clinical research ethics committee, and was conducted in accordance with the Declaration of Helsinki, with the requirement for informed consent waived given its retrospective design.

Subject of Research: Comparison of clinical characteristics, antifungal susceptibility, and 30-day mortality in Candidozyma auris versus non-auris Candida candidemia

Article Title: Clinical characteristics, treatment strategies, and factors associated with 30-day mortality in Candidozyma auris versus non-auris Candida candidemia: a retrospective cohort study

Article References: Kuzi, S., Çiçek Şentürk, G., Kul, G., Haykır, A., Yılmaz, N., Korkmaz, N., Bulut, D., Aslan, M., Yapar Toros, G., Şencan, İ., & Tütüncü, E. E. (2026). Clinical characteristics, treatment strategies, and factors associated with 30-day mortality in Candidozyma auris versus non-auris Candida candidemia: a retrospective cohort study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14401-4

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14401-4

Keywords: Candidozyma auris, candidemia, antifungal resistance, 30-day mortality, bloodstream infection, echinocandins, amphotericin B, fluconazole resistance, septic shock, healthcare-associated infection, MALDI-TOF, risk factors

The research team, led by Ahmed Rezk, Heba S. Said, Sherin M. Elfeky, Mohammed El-Mowafy, and Ramadan Hassan of Mansoura University, began by surveying the local resistance landscape. They collected 64 clinical isolates of C. albicans from hospitals in Dakhlya governorate, drawn from urine samples, vaginal swabs, blood cultures, and other clinical sources between May and July 2022. Using standard disk diffusion and broth microdilution methods aligned with Clinical and Laboratory Standards Institute guidelines, they found that 16 isolates, a full 25 percent of the collection, were resistant to fluconazole. Minimum inhibitory concentrations among these resistant strains ranged from 64 to 2048 micrograms per milliliter, levels far above what fluconazole can achieve safely in patient tissue.

That resistance is not accidental. Fluconazole works by inhibiting the fungal enzyme lanosterol demethylase, encoded by the ERG11 gene, which is essential for building ergosterol, the structural backbone of the fungal cell membrane. Resistant fungi fight back in several ways: they mutate ERG11 so the drug binds poorly, they overproduce the target enzyme, and, most importantly for this study, they crank up expression of efflux pumps that simply eject the drug from the cell before it can do damage. The dominant player among these pumps is Cdr1, an ATP-binding cassette transporter embedded in the plasma membrane. Cdr1 operates like a molecular bilge pump: azole drugs drift into the cytoplasm, slip into a hydrophobic cavity in the transporter’s transmembrane domains, and are then expelled outward when ATP binding and hydrolysis at the nucleotide-binding domains drive a conformational flip from an inward-facing to an outward-facing state.

Disulfiram, chemically known as tetraethylthiuram disulfide, has a long and curious pharmacological history. Approved for aversion therapy in alcohol use disorder, it inhibits aldehyde dehydrogenase in the liver, causing acetaldehyde to accumulate and producing the flushing, nausea, and headaches that discourage drinking. But over the past two decades it has attracted attention as a repurposing candidate in oncology and infectious disease. Previous work had already hinted at antifungal potential: an earlier study showed disulfiram directly modulates Cdr1p, and a non-toxic concentration of the drug enhanced the sensitivity of yeast cells expressing the pump to fluconazole and miconazole. It has also shown activity against methicillin-resistant Staphylococcus aureus, Helicobacter pylori, and metallo-beta-lactamase enzymes.

To test whether that promise held up against real clinical resistance, the Mansoura team measured disulfiram’s own minimum inhibitory concentration against six representative fluconazole-resistant isolates, obtaining values between 10 and 20 micrograms per milliliter. They then repeated fluconazole susceptibility testing in the presence of a subinhibitory dose of disulfiram, one too low to inhibit fungal growth on its own. The results were striking: fluconazole’s MIC dropped by factors ranging from 2-fold to as much as 128-fold across the resistant isolates. In other words, a dose of disulfiram that by itself could not harm the fungus dramatically re-sensitized it to a drug it had previously shrugged off.

Checkerboard assays, in which both drugs are titrated in two dimensions across a microtiter plate, confirmed the synergy quantitatively. Using the fractional inhibitory concentration index, the team classified the combination as fully synergistic in three isolates, partially synergistic in two, and additive in one. No antagonism was observed. Under the conventional interpretation scheme, a FICI of 0.5 or below indicates synergy, meaning the drugs together accomplish more than the sum of their individual effects, a hallmark of a genuine resistance-reversing interaction rather than simple additive killing.

The molecular mechanism behind this synergy emerged from two complementary lines of evidence. First, quantitative reverse-transcription PCR on two resistant isolates, Ca15 and Ca39, showed that Cdr1 was overexpressed when the fungi were exposed to fluconazole alone, consistent with the pump being the engine of resistance. When disulfiram was added at subinhibitory concentrations, either alone or in combination with fluconazole, Cdr1 expression was downregulated relative to untreated controls. Second, molecular docking simulations using the recently solved cryo-EM structure of Cdr1 bound to fluconazole revealed that disulfiram can occupy two strategic positions on the transporter. At the hydrophobic substrate cavity in the transmembrane domain, disulfiram binds in a mode nearly identical to fluconazole, forming a hydrogen bond with Asn1240 and hydrophobic contacts with residues including Phe552, Leu555, Phe559, and Ile1237, with a calculated binding affinity of minus 6.46 kilocalories per mole, slightly stronger than fluconazole’s minus 6.07. At the ATP-binding site in the nucleotide-binding domain, disulfiram mimics ATP itself, hydrogen bonding with Thr195, Cys193, Gly190, Ser194, and Gly192, residues essential for ATP binding and hydrolysis. By competing at both sites simultaneously, disulfiram appears to jam the pump’s fuel supply and its cargo door at once, allowing fluconazole to accumulate in the cytoplasm and attack its target enzyme.

Beyond reversing resistance, disulfiram delivered a second blow to the fungus: it interfered with biofilm formation. Biofilms, the organized communities of cells encased in a protective matrix that adhere to catheters, mucosal surfaces, and medical devices, are notoriously tolerant of antifungals and a major driver of persistent infection. Using a tissue culture plate assay with crystal violet staining, the researchers showed that disulfiram reduced biofilm formation in a dose-dependent manner at sub-MIC concentrations of one-half, one-quarter, one-eighth, and one-sixteenth of its MIC. Remarkably, even at the weakest dose tested, one-sixteenth of the MIC, the drug still achieved roughly 14 to 37 percent inhibition of biofilm formation and significant eradication of mature, 24-hour-old biofilms. This dual activity, chemosensitization plus anti-biofilm action, suggests disulfiram could undermine two of the most stubborn survival strategies C. albicans deploys in the human host.

The study’s authors are careful to frame these results as a foundation rather than a finished therapy. All experiments were conducted in vitro, and the researchers explicitly call for follow-up work including site-directed mutagenesis, functional binding assays, and investigation of other resistance mechanisms such as ERG11 point mutations and the efflux genes Cdr2 and Mdr1. In vivo efficacy and pharmacodynamic studies will be essential before any clinical conclusions can be drawn. Still, the appeal of the strategy is considerable. Drug repurposing bypasses the years of safety profiling required for entirely new molecules, and combination therapy can lower effective doses of both agents, potentially reducing toxicity and slowing the further evolution of resistance. With fluconazole resistance rates in Egyptian bloodstream isolates recently reported as high as 58.3 percent, and with the researchers highlighting the infrequent use of routine antifungal susceptibility testing in the region, the need for such adjuvant approaches is urgent. If subsequent animal and clinical studies validate what the Mansoura team observed in the laboratory, a fifty-year-old sobriety drug could become an unexpected ally in preserving the usefulness of modern antifungal medicine.

Subject of Research: Reversal of fluconazole resistance in Candida albicans by disulfiram through Cdr1 efflux pump inhibition and biofilm disruption

Article Title: Disulfiram reverses fluconazole-resistance mediated by Cdr1 in Candida albicans and interferes with biofilm formation

Article References: Rezk, A., Said, H. S., Elfeky, S. M., El-Mowafy, M., & Hassan, R. (2026). Disulfiram reverses fluconazole-resistance mediated by Cdr1 in Candida albicans and interferes with biofilm formation. Applied Microbiology and Biotechnology, 110(1), Article 269. https://doi.org/10.1007/s00253-026-13977-w

Image Credits: AI Generated

DOI: 10.1007/s00253-026-13977-w

Keywords: Candida albicans, fluconazole resistance, disulfiram, Cdr1 efflux pump, drug repurposing, antifungal synergy, biofilm inhibition, ATP-binding cassette transporter, molecular docking, candidiasis, antimicrobial resistance, combination therapy