Mapping the path to excellence: Evaluation of the diagnostic and treatment tools for invasive fungal infections in the balkans.

BACKGROUND: In the Balkans, rising concerns about invasive fungal infections over the past decade stem from various factors. Primarily, there has been a notable uptick in immunocompromised individuals, including those with chronic illnesses like immunological and hematological diseases. Thus, it is essential to assess the region's laboratory capabilities and the availability of antifungals. This evaluation is vital for gauging the preparedness to diagnose and treat fungal infections effectively, thus minimizing their public health impact. METHODS: Data were collected via an online questionnaire targeting healthcare professionals specializing in relevant fields across diverse healthcare settings in Balkan countries. The survey covered various aspects, including diagnostic methods, imaging techniques, and available antifungal armamentarium. RESULTS: Responses were obtained from 50 institutions across the Balkans. While conventional diagnostic methods like microscopy (96 %) and culture (100 %) diagnostics were widely available, access to newer diagnostic tools such as molecular assays (61 %) were limited, often relying on outsourced services. Imaging modalities like ultrasound (100 %) and CT scans (93 %) were universally accessible. A variety of antifungal drugs were available, including amphotericin B formulations (80 %), echinocandins (79 %), and triazoles (100 %). However, access to newer agents like posaconazole (62 %) and isavuconazole (45 %) was inconsistent. Therapeutic drug monitoring (53 %) services were also limited. CONCLUSION: The study underscores the need for equitable access to diagnostic facilities and antifungal treatments across healthcare settings in the Balkan geographic region. Improving access to molecular diagnostic tools and essential antifungal drugs, as well as implementing therapeutic drug monitoring, would optimize the management of fungal infections in the region.

Oral Lipid Nanocrystal Amphotericin B (MAT2203) for the Treatment of Invasive Fungal Infections.

Amphotericin B (AmB) has broad fungicidal activity against many fungi, but the high incidence of adverse events, particularly nephrotoxicity, and the need for intravenous administration restrict its use for many patients. MAT2203, an investigational oral AmB formulation available under a compassionate use program, uses a lipid nanocrystal bilayer structure to deliver AmB with lower toxicity. We present a synopsis of clinical characteristics, treatment course, and outcomes for 5 patients who were treated with MAT2203. Outcomes were positive, with cure of infection noted in 4 patients and improvement in 1 patient who remains on therapy. MAT2203 was well tolerated with only modest gastrointestinal adverse effects. This new oral formulation might provide a safer treatment option for patients requiring extended courses of AmB.

Antifungals in Patients With Extracorporeal Membrane Oxygenation: Clinical Implications.

Extracorporeal membrane oxygenation (ECMO) is a life-saving technique used in critical care medicine for patients with severe respiratory or cardiac failure. This review examines the treatment and prophylaxis of fungal infections in ECMO patients, proposing specific regimens based on available data for different antifungals (azoles, echinocandins, amphotericin B/liposomal amphotericin B) and invasive fungal infections. Currently, isavuconazole and posaconazole have the most supported data, while modified dosages of isavuconazole are recommended in ECMO. Echinocandins are preferred for invasive candidiasis. However, choosing echinocandins is challenging due to limited and varied data on concentration loss in the ECMO circuit. Caution is likewise advised when using liposomal amphotericin B due to uncertain concentrations and potential ECMO dysfunction based on scarce data. We further conclude with the importance of further research on the impact of ECMO on antifungal drug concentrations to optimize dosing regimens in critically ill patients.

Candida albicans skin infection in diabetic patients: An updated review of pathogenesis and management.

Candida species, commensal residents of human skin, are recognized as the cause of cutaneous candidiasis across various body surfaces. Individuals with weakened immune systems, particularly those with immunosuppressive conditions, are significantly more susceptible to this infection. Diabetes mellitus, a major metabolic disorder, has emerged as a critical factor inducing immunosuppression, thereby facilitating Candida colonization and subsequent skin infections. This comprehensive review examines the prevalence of different types of Candida albicans-induced cutaneous candidiasis in diabetic patients. It explores the underlying mechanisms of pathogenicity and offers insights into recommended preventive measures and treatment strategies. Diabetes notably increases vulnerability to oral and oesophageal candidiasis. Additionally, it can precipitate vulvovaginal candidiasis in females, Candida balanitis in males, and diaper candidiasis in young children with diabetes. Diabetic individuals may also experience candidal infections on their nails, hands and feet. Notably, diabetes appears to be a risk factor for intertrigo syndrome in obese individuals and periodontal disorders in denture wearers. In conclusion, the intricate relationship between diabetes and cutaneous candidiasis necessitates a comprehensive understanding to strategize effective management planning. Further investigation and interdisciplinary collaborative efforts are crucial to address this multifaceted challenge and uncover novel approaches for the treatment, management and prevention of both health conditions, including the development of safer and more effective antifungal agents.

Clinical response to prednisone in a severe case of infant-juvenile paracoccidioidomycosis.

BACKGROUND: Paracoccidioidomycosis is a neglected tropical disease caused by fungi of the genus Paracoccidioides. A wide range of symptoms is related to the disease; however, lungs and skin are the sites predominantly affected. The disease is mostly seen in people living in rural areas in Latin America. CASE REPORT: We present a pediatric case of severe disseminated paracoccidioidomycosis that slowly responded to the antifungal treatment. Within three months, symptoms evolved into hepatosplenomegaly, necrotic cervical and abdominal lymph nodes, and splenic abscess. Clinical response to amphotericin B deoxycholate and itraconazole was slow, resulting in pleural and peritoneal cavity effusions, heart failure and shock. Amphotericin B deoxycholate was replaced by the liposomal formulation, with no response. Subsequently, prednisone was added to the treatment, which led to improvement in the clinical response. Serological Paracoccidioides antibody titers were atypical, with very low titers in the critical phase and significant increase during the convalescence phase. The infection was finally cleared up with amphotericin B deoxycholate, liposomal amphotericin B and the use of corticosteroids. Paracoccidioidomycosis serology was non-reactive two years post-discharge. CONCLUSIONS: Due to the intense inflammatory response triggered by Paracoccidioides cells, giving low-dose prednisone for a short period of time modulated the inflammatory response and supported antifungal treatment.

Antifungal Treatment Duration in Hematology Patients With Invasive Mold Infections: A Real-life Update.

Background: Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised. Methods: This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010-31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation. Results: In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5-348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1-3; range, 1-8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression. Conclusions: AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.

Chitosan and Chitooligosaccharides: Antifungal Potential and Structural Insights.

Chitosan is a cationic polysaccharide derived from chitin deacetylation. This polysaccharide and its oligosaccharides have many biological activities and can be used in several fields due to their favorable characteristics, such as biodegradability, biocompatibility, and nontoxicity. This review aims to explore the antifungal potential of chitosan and chitooligosaccharides along with the conditions used for the activity and mechanisms of action they use to kill fungal cells. The sources, chemical properties, and applications of chitosan and chitooligosaccharides are discussed in this review. It also addresses the threat fungi pose to human health and crop production and how these saccharides have proven to be effective against these microorganisms. The cellular processes triggered by chitosan and chitooligosaccharides in fungal cells, and prospects for their use as potential antifungal agents are also examined.

An immunocompetent host with blood-disseminated Aspergillus versicolor spondylitis: a case report and literature review.

Blood-disseminated Aspergillus spondylitis in immunocompetent individuals is rare. The clinical, imaging, and pathological manifestations of this condition are not specific. Therefore, this disease is prone to misdiagnosis and a missed diagnosis. Systemic antifungal therapy is the main treatment for Aspergillus spondylitis. We report a case of blood-disseminated Aspergillus versicolor spondylitis in a patient with normal immune function. The first antifungal treatment lasted for 4 months, but Aspergillus spondylitis recurred a few months later. A second antifungal treatment course was initiated for at least 1 year, and follow-up has been ongoing. Currently, there has been no recurrence.

The Cologne ECMM Excellence Center: A Two-Year Analysis of External Consultation Service for Invasive Fungal Infections.

The European Confederation of Medical Mycology (ECMM), formed due to the surge in invasive fungal infections (IFI), initiated the Excellence Centers program in 2016 to guide stakeholders to leading medical mycology sites. This report focuses on the Cologne ECMM Excellence Center, recognized with Diamond status for active global involvement in 2017. The center offers free consultation via email and phone, responding within 24 h for life-threatening IFI, collecting data on origin, pathogens, infection details, and more. Over two years, 189 requests were received globally, predominantly from Germany (85%), mainly involving Aspergillus spp., Mucorales, and Candida spp. Fungal mixed infections occurred in 4% of cases. The center's service effectively addresses IFI challenges, advocating for a comprehensive study encompassing all ECMM Excellence Centers to enhance global mycological care. Proactive expansion of consultancy platforms is crucial, with future analyses needed to assess expert advice's impact on patient outcomes.

Laryngeal Mycosis in an Immunocompetent Patient: A Case Report.

Laryngeal mycosis, a condition often overlooked in systemically immunocompetent individuals, requires heightened clinical vigilance for accurate diagnosis. The disease mimics symptoms of other laryngeal conditions such as gastroesophageal reflux, granulomatous disease, keratosis, and glottic malignancies, with risk factors including prolonged use of antibiotics, inhaled steroids, and smoking. Clinically, it presents with variable symptoms including hoarseness, and occasionally pain, dysphagia, and odynophagia. Diagnosis involves the observation of hyperkeratosis, notably when intraepithelial neutrophils are present, prompting further investigation for fungal elements through specialized staining. Effective management encompasses prolonged systemic antifungal treatment and the elimination of predisposing factors to prevent recurrence or treatment failure. Despite its potential to mimic a range of laryngeal diseases, laryngeal mycosis remains a less considered differential diagnosis. This is compounded by the commonality of risk factors in the general population, including prolonged antibiotic use, inhaled steroid therapy, and smoking habits, which may predispose individuals to fungal infections of the larynx. Furthermore, the necessity for a high index of suspicion and specialized diagnostic techniques, such as the identification of hyperkeratosis with intraepithelial neutrophils through biopsy and specialized staining for fungal elements, underscores the complexity of diagnosing this condition. The rationale for documenting this case report is multifaceted, primarily focusing on the fact that laryngeal mycosis is rare among immunocompetent patients leading to under-recognition of laryngeal mycosis in systemically immunocompetent individuals and the diagnostic challenges it presents. Additionally, the documentation seeks to emphasize the critical need for comprehensive treatment approaches, including prolonged systemic antifungal therapy and the identification and elimination of predisposing factors, to ensure effective management and prevent recurrence.

Role of source control in critically ill candidemic patients: a multicenter retrospective study.

PURPOSE: Candidemia is associated with high mortality especially in critically ill patients. Our aim was to identify predictors of mortality among critically ill patients with candidemia with a focus on early interventions that can improve prognosis. METHODS: Multicenter retrospective study. SETTING: This retrospective study was conducted in Intensive Care Units from three European university hospitals from 2015 to 2021. Adult patients with at least one positive blood culture for Candida spp. were included. Patients who did not require source control were excluded. Primary outcome was 14-day mortality. RESULTS: A total of 409 episodes of candidemia were included. Most candidemias were catheter related (173; 41%), followed by unknown origin (170; 40%). Septic shock developed in 43% episodes. Overall, 14-day mortality rate was 29%. In Cox proportional hazards regression model, septic shock (P 0.001; HR 2.20, CI 1.38-3.50), SOFA score ≥ 10 points (P 0.008; HR 1.83, CI 1.18-2.86), and prior SARS-CoV-2 infection (P 0.003; HR 1.87, CI 1.23-2.85) were associated with 14-day mortality, while combined early appropriate antifungal treatment and source control (P < 0.001; HR 0.15, CI 0.08-0.28), and early source control without appropriate antifungal treatment (P < 0.001; HR 0.23, CI 0.12-0.47) were associated with better survival compared to those without neither early appropriate antifungal treatment nor source control. CONCLUSION: Early source control was associated with better outcome among candidemic critically ill patients.

A Rare Case of Uterine Blastomycosis and Its Management: A Case Report and Literature Review.

The report delineates the rare occurrence of uterine blastomycosis, an atypical systemic presentation of Blastomyces dermatitidis infection prevalent in North America. Focused on a 51-year-old immunocompetent female displaying abdominal pain and irregular vaginal bleeding, it underscores the intricate diagnostic hurdles posed by symptoms mirroring common gynecological conditions. Despite fewer than 10 recorded cases, the rarity of uterine involvement highlights the imperative for heightened clinical suspicion. The multifaceted diagnostic strategy integrates risk factors, travel history, imaging, and histopathological examinations. Emphasizing a multidisciplinary treatment helmed by gynecologists, pathologists, and infectious disease specialists, the utilization of antifungal agents, notably itraconazole, is pivotal. Addressing the scarcity of literature and the condition's clinical resemblance to prevalent ailments, further research becomes paramount in devising tailored diagnostic and treatment protocols for uterine blastomycosis. This study enriches the existing literature by providing critical insights into a scarcely documented condition, contributing novel perspectives essential for clinical understanding and management strategies.

Specifically Targeting Metacaspases of Candida: A New Therapeutic Opportunity.

The World Health Organization (WHO) recently published a list of fungal priority pathogens, including Candida albicans and C. auris. The increased level of resistance of Candida is raising concern, considering the availability of only four classes of medicine. The WHO is seeking novel agent classes with different targets and mechanisms of action. Targeting Candida metacaspases to control intrinsic cell death could provide new therapeutic opportunities for invasive candidiasis. In this review, we provide the available evidence for Candida cell death, describe Candida metacaspases, and discuss the potential of Candida metacaspases to offer a new specific target. Targeting Candida cell death has good scientific rationale given that the fungicidal activity of many marketed antifungals is mediated, among others, by cell death triggering. But none of the available antifungals are specifically activating Candida metacaspases, making this target a new therapeutic opportunity for non-susceptible isolates. It is expected that antifungals based on the activation of fungi metacaspases will have a broad spectrum of action, as metacaspases have been described in many fungi, including filamentous fungi. Considering this original mechanism of action, it could be of great interest to combine these new antifungal candidates with existing antifungals. This approach would help to avoid the development of antifungal resistance, which is especially increasing in Candida.

Old and new strategies in therapy and diagnosis against fungal infections.

Fungal infections represent a serious global health threat. The new emerging pathogens and the spread of different forms of resistance are now hardly challenging the tools available in therapy and diagnostics. With the commonly used diagnoses, fungal identification is often slow and inaccurate, and, on the other hand, some drugs currently used as treatments are significantly affected by the decrease in susceptibility. Herein, the antifungal arsenal is critically summarized. Besides describing the old approaches and their mechanisms, advantages, and limitations, the focus is dedicated to innovative strategies which are designed, identified, and developed to take advantage of the discrepancies between fungal and host cells. Relevant pathways and their role in survival and virulence are discussed as their suitability as sources of antifungal targets. In a similar way, molecules with antifungal activity are reported as potential agents/precursors of the next generation of antimycotics. Particular attention was devoted to biotechnological entities, to their novelty and reliability, to drug repurposing and restoration, and to combinatorial applications yielding significant improvements in efficacy. KEY POINTS: • New antifungal agents and targets are needed to limit fungal morbidity and mortality. • Therapeutics and diagnostics suffer of delays in innovation and lack of targets. • Biologics, drug repurposing and combinations are the future of antifungal treatments.

Cerebral phaeohyphomycosis due to Cladophialophora bantiana: case report and systematic review of cases.

PURPOSE: Cladophialophora bantiana is a wonted melanized fungus causing brain abscess. In past many cases were reported from Asia, particularly from India. Of late, there is a rise in cases in places besides Asia and hence a review of the cases is warranted. METHODS: We present a case of fatal cerebral phaeohyphomycosis caused by C. bantiana and conduct a systematic review of culture confirmed brain abscess due to C. bantiana reported between 2015 and 2022. RESULTS: Of the 39 cases found, majority (68%) were immunocompromised. The various clinical presentations were headache (53%), hemiparesis (34%), visual disturbance (25%), altered sensorium (18%), aphasia/dysarthria (12%) and seizures (9%). Isolated lesion was observed in 18 (60%) patients. In the sequence of occurrence, the lesions were in frontal (30%), temporal (27%) and parietal (20%) region. There were five cases with coinfections such as concurrent detection of Nocardia pneumonia in two cases, toxoplasma DNA in brain abscess, coexisting pulmonary Cryptococcus neoformans infection and coexisting Candida in a case of brain abscess in one case each. Surgical intervention was performed in 84% cases. Antifungal therapy included voriconazole (80%), liposomal amphotericin B (76%), 5-fluorocytosine (30%), posaconazole (10%), and amphotericin B deoxycholate (6%). The overall mortality was 50% with lower mortality (42%) in regions outside Asia compared to Asia (63.6%) though not statistically significant. CONCLUSIONS: C. bantiana brain abscess is an emerging infection worldwide. Next generation sequencing is an upcoming promising diagnostic test. Early complete excision of the lesion with effective antifungals may improve the outcome.

Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis.

Introduction: Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy. Methods: We considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by "gender" (168 women and 251 men by biological sex defined at birth). Results: Survival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044). Conclusions: Survivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival-associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.

Challenges in the Management of Invasive Fungal Infections in the Middle East: Expert Opinion to Optimize Management Using a Multidisciplinary Approach.

Invasive fungal infection (IFI) is a significant global healthcare concern among critically ill and immunocompromised patients. In Middle Eastern countries, IFI has been steadily increasing among hospitalized patients in the past two decades. Diagnosis of IFI at an early stage is crucial for efficient management. Invasive fungal infection management is complex and requires the involvement of physicians from different specialties. There are several challenges associated with IFI management in the countries in the Middle East. This review aims to understand the key challenges associated with IFI management in the Middle East, encompassing epidemiology, diagnosis, therapeutic options, and optimizing a multidisciplinary approach. In addition, this review aims to incorporate expert opinions from multidisciplinary fields for optimizing IFI management in different Middle Eastern countries by addressing key decision points throughout the patient's journey. Lack of epidemiological data on fungal infections, slow and poorly sensitive conventional culture-based diagnostic tests, limited availability of biomarker testing, lack of awareness of clinical symptoms of the disease, limited knowledge on fungal infections, lack of local practice guidelines, and complicated disease management are the major challenges associated with IFI diagnosis and management in the Middle Eastern countries. Implementation of a multidisciplinary approach, antifungal stewardship, improved knowledge of fungal infections, the use of rapid diagnostic tests, and enhanced epidemiological research are warranted to lower the IFI burden in the Middle East.

Overcoming clinical challenges in the management of invasive fungal infections in low- and middle-income countries (LMIC).

INTRODUCTION: The management of invasive fungal infections (IFIs) in low- and middle-income countries (LMIC) is a serious challenge due to limited epidemiology studies, sub-optimal laboratory facilities, gap in antifungal management training and resources. Limited studies highlighted distinctive epidemiology of IFIs in those countries, and difficulty in distinguishing from closely related infections. To overcome the gaps for appropriate management of IFIs, innovative approaches are required. AREAS COVERED: Extensive literature search and discussion with experts have helped us to summarize the epidemiology, diagnostic and management difficulties in managing IFIs in LMIC, and recommend certain solutions to overcome the challenges. EXPERT OPINION: The strategies to overcome the challenges in diagnosis may include local epidemiology study, training of healthcare workers, association of fungal infections with already existing budgeted national programs, development and incorporation of point-of-care test (POCT) for prompt diagnosis, simplifying clinical diagnostic criteria suitable for LMIC, judicious use of available expertise, and diagnostic stewardship. For management strategies judicious use of antifungal, partnering with industry for inexpensive antifungal agents, development of LMIC specific guidelines for cost-effective management of IFIs and fungal outbreaks, improvement of infection control practices, advocacy for implementation of WHO recommended antifungal use, and integration of IFIs with public health.

Metabolites of Xenorhabdus bacteria are potent candidates for mitigating amphibian chytridiomycosis.

Chytridiomycosis, caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd), has caused extreme losses in amphibian biodiversity. Finding bacteria that produce metabolites with antifungal properties may turn out to be invaluable in the fight against this devastating disease. The entomopathogenic bacteria, Xenorhabdus szentirmaii and X. budapestensis produce secondary metabolites that are effective against a wide range of fungal plant pathogens. To assess whether they may also be effective against Bd, we extracted cell-free culture media (CFCM) from liquid cultures of X. szentirmaii and X. budapestensis and tested their ability to inhibit Bd growth in vitro. As a second step, using juvenile common toads (Bufo bufo) experimentally infected with Bd we also tested the in vivo antifungal efficacy of X. szentirmaii CFCM diluted to 2 and 10% (v/v), while also assessing possible malign side effects on amphibians. Results of the in vitro experiment documented highly effective growth inhibition by CFCMs of both Xenorhabdus species. The in vivo experiment showed that treatment with CFCM of X. szentirmaii applied at a dilution of 10% resulted in infection intensities reduced by ca. 73% compared to controls and to juvenile toads treated with CFCM applied at a dilution of 2%. At the same time, we detected no negative side effects of treatment with CFCM on toad survival and development. Our results clearly support the idea that metabolites of X. szentirmaii, and perhaps of several other Xenorhabdus species as well, may prove highly useful for the treatment of Bd infected amphibians.

The fate of fungal periprosthetic joint infection after total knee arthroplasty.

PURPOSE: To demonstrate the clinical outcomes of patients with fungal periprosthetic joint infections (PJIs) after two-stage exchange arthroplasty combined with antifungal therapy. METHODS: We retrospectively reviewed the outcomes of 41 patients with fungal PJIs after primary total knee arthroplasty (TKA) in a single centre from January 1999 to October 2017. During the first stage of resection arthroplasty, antifungal-impregnated cement spacers (AICSs) were implanted in all patients. After systemic antifungal treatment during the interval between the two surgeries, delayed reimplantation as part of a two-stage exchange protocol was performed when patients were clinically stable. We defined treatment success as a well-functioning arthroplasty without any signs of PJI after a minimum follow-up of two years without antimicrobial suppression. Successful treatment was confirmed by repeat negative cultures as well as a return of inflammatory markers to normal levels. RESULTS: The treatment success rate was 63.4% at the final follow-up. Thirty-six of 41 patients (87.8%) met the criteria for second-stage revision after confirmation of complete infection control. The mean prosthesis-free interval was 6.6 months (range, 2.0-30.0 months). During follow-up after two-stage exchange arthroplasty, ten patients (27.7% of 36 patients) unfortunately experienced recurrence or relapse of infection after an average of 31.3 months (range, 2.7-135.6 months). The rate of survivorship free from reinfection was 94.4% at six months, 84.8% at one year, and 73.6% at two years. Cox proportional hazard regression analysis demonstrated that the prosthesis-free interval (HR = 1.016, p = 0.037) and mean length of antifungal treatment (HR = 0.226, p = 0.046) were potential risk factors for failure. CONCLUSION: Fungal PJIs led to devastating clinical outcomes despite even two-stage revision arthroplasty with the use of AICSs and antifungal medications.