The predictors of fungal infections after liver transplantation and the influence of fungal infections on outcomes.

The primary objective of this study was to assess the incidence, timing, risk factors of fungal infections (FIs) within 3 months after liver transplantation (LT). The secondary objective was to evaluate the impact of FIs on outcomes. Four hundred and ten patients undergoing LT from January 2015 until January 2023 in a tertiary university hospital were included in the present retrospective cohort study to investigate the risk factors of FIs and to assess the impacts of FIs on the prognosis of LT recipients using logistic regression. The incidence of FIs was 12.4% (51/410), and median time from LT to the onset of FIs was 3 days. By univariate analysis, advanced recipient age, prolonged hospital stay prior to LT, high Model for End Stage Liver Disease (MELD) score, use of broad-spectrum antibiotics, and elevated white blood cell (WBC) count, increased operating time, massive blood loss and red blood cell transfusion, elevated alanine aminotransferase on day 1 and creatinine on day 3 after LT, prolonged duration of urethral catheter, prophylactic antifungal therapy, the need for mechanical ventilation and renal replacement therapy were identified as factors of increased post-LT FIs risk. Multivariate logistic regression analysis identified that recipient age ≥ 55 years[OR = 2.669, 95%CI: 1.292-5.513, P = 0.008], MELD score at LT ≥ 22[OR = 2.747, 95%CI: 1.274-5.922, P = 0.010], pre-LT WBC count ≥ 10 × 109/L[OR = 2.522, 95%CI: 1.117-5.692, P = 0.026], intraoperative blood loss ≥ 3000 ml [OR = 2.691, 95%CI: 1.262-5.738, P = 0.010], post-LT duration of urethral catheter > 4 d [OR = 3.202, 95%CI: 1.553-6.602, P = 0.002], and post-LT renal replacement therapy [OR = 5.768, 95%CI: 1.822-18.263, P = 0.003] were independently associated with the development of post-LT FIs. Post-LT prophylactic antifungal therapy ≥ 3 days was associated with a lower risk of the development of FIs [OR = 0.157, 95%CI: 0.073-0.340, P < 0.001]. As for clinical outcomes, FIs had a negative impact on intensive care unit (ICU) length of stay ≥ 7 days than those without FIs [OR = 3.027, 95% CI: 1.558-5.878, P = 0.001] but had no impact on hospital length of stay and 1-month all-cause mortality after LT. FIs are frequent complications after LT and the interval between the onset of FIs and LT was short. Risk factors for post-LT FIs included high MELD score at LT, advanced recipient age, pre-LT WBC count, massive intraoperative blood loss, prolonged post-LT duration of urethral catheter, and the need for post-LT renal replacement therapy. However, post-LT prophylactic antifungal therapy was independently associated with the reduction in the risk of FIs. FIs had a significant negative impact on ICU length of stay.

Metagenomic Next-Generation Sequencing as an Effective Diagnostic Tool for Talaromycosis in HIV-Negative Patients.

The diagnosis of Talaromyces marneffei infection in HIV-negative patients remains challenging. There is an urgent need for rapid and convenient methods to diagnose this complicated disease. The aim of this study was to evaluate the diagnostic efficiency of metagenomic next-generation sequencing (mNGS) for talaromycosis in non-HIV-infected patients by comparing mNGS with traditional microbial culture. In total, 66 samples from 57 patients were analyzed via both mNGS and microbial culture. The ROC curve showed a sensitivity for mNGS of 97.22%, which was greater than that of microbial culture (61.11%). Samples from the respiratory tract, infectious skin lesions, and lymph nodes are recommended as routine samples for talaromycosis detection via mNGS. Furthermore, mNGS significantly reduced the diagnostic time compared to microbial culture. Overall, our study demonstrated that mNGS is a promising tool for rapid and accurate pathogenic detection in HIV-negative patients with talaromycosis.

Voriconazole successfully treats chytridiomycosis in frogs.

Chytridiomycosis is a devastating disease and is a key cause of amphibian population declines around the world. Despite active research on this amphibian disease system for over 2 decades, we still do not have treatment methods that are safe and that can be broadly used across species. Here, we show evidence that voriconazole is a successful method of treatment for 1 species of amphibian in captivity and that this treatment could offer benefits over other treatment options like heat or itraconazole, which are not able to be used for all species and life stages. We conducted 2 treatments of chytridiomycosis using voriconazole. The treatment was effective and resulted in 100% pathogen clearance, and mortality ceased. Additionally, treating frogs with voriconazole requires less handling than treatment methods like itraconazole and requires no specialized equipment, like heat treatment. We highlight that clinical treatment trials should be conducted to identify an optimum dosage and treatment time and that trials should test whether this treatment is safe and effective for tadpoles and other species.

Diagnostic accuracy of double density sign on CT scan of para-nasal sinuses for fungal sinusitis taking microbiology culture as gold standard.

Objectives: To compare double-density sign on non-contrast computed tomography scan of paranasal sinuses with fungal sinusitis on histopathology. METHODS: This prospective study was conducted at the Shifa International Hospital, Islamabad, Pakistan, from July 1, 2021, to June 30, 2023, and comprised patients of either gender aged 20-60 years who were set to undergo functional endoscopic sinus surgery. Demographic characteristics and non-contrast computed tomography scan findings were recorded preoperatively, while microbiological and histopathology results were recorded post-operatively. The microbiological finding was taken as the gold standard. Data was analysed using SPSS 23. RESULTS: Of the 201 patients, 123(61.2%) were males and 78(38.8%) were females. The overall mean age was 41.62±8.52 years. The diagnostic accuracy of a double-density sign on computed tomography scan showed sensitivity 90%, specificity 90.8%, positive predictive value 84%, and negative predictive value 94.4%. CONCLUSIONS: A higher rate of sensitivity and specificity indicated that non-contrast computed tomography scan was an effective modality that could be used for the diagnosis of fungal sinusitis.

Peritoneal dialysis-related peritonitis caused by Stephanoascus ciferrii: A Case Report.

Stephanoascus ciferrii, a conditional pathogenic fungus prevalent in nature, is more frequently encountered in patients with compromised immunity. However, the literature rarely reports infections caused by Stephanoascus ciferrii in peritoneal dialysis patients. Here, we detail the case of a 66-year-old female suffering from renal failure who experienced catheter-related infection during peritoneal dialysis. Dialysate turbidity prompted the detection of Stephanoascus ciferrii in both peritoneal dialysate and tubes through microbiological cultures. Subsequent treatment involved antifungal drugs and a transition to hemodialysis, resulting in the disappearance of peritonitis symptoms and the patient's discharge. In recent years, fungal infections, particularly dialysis-related infections, are on the rise. This marks the first reported case of catheter-related peritonitis infection caused by Stephanoascus ciferrii. Compared to bacterial infections, fungal infections pose challenges due to limited drug options, significant side effects, and prolonged treatment durations. Hence, prompt pathogen diagnosis and drug sensitivity testing are crucial for effective clinical treatment. In essence, this scientific case report underscores the uncommon occurrence of catheter-related peritonitis attributed to Stephanoascus ciferrii in a peritoneal dialysis patient with renal failure, emphasizing the distinctive management challenges and underscoring the critical significance of prompt diagnosis and suitable intervention in such instances.

Value of MRI signal intensity in evaluation of allergic fungal rhinosinusitis compared with CT Hounsfield units: Retrospective study.

"Allergic fungal sinusitis (AFS)" is typically diagnosed using radiologic images like computed tomography (CT) scans and magnetic resonance imaging (MRI), with the "Hounsfield unit (HU)" in CT scans and T2-weighted images (T2WI) in MRI serving as reliable objective parameters. However, diagnosing AFS might be difficult because of possible signal changes and densities caused by variations in the secretion concentration in the sinus. Few studies have compared the diagnostic performance of MRI and CT scans. This study aimed to investigate the value of MRI signal intensity in evaluating AFS compared with CT HUs. This retrospective study included 111 patients with pathologically confirmed AFS who underwent CT imaging followed by MRI evaluation at King Saud Medical City, Riyadh, Saudi Arabia, from January 2012 to December 2022. Radiographic densities of sinus opacities on CT scan, including the mean HU values, and MRI findings, including signal voids on T1-weighted images and T2WI, were gathered and analyzed. To determine the efficacy of these radiographic characteristics in predicting the disease and the best cutoff value, we employed receiver operator characteristic curves. The mean age was 31.9 ±â€…15.6 years, and most patients were 74 females (66.7%). The main symptom was nasal obstruction in 73 patients (65.8%). In comparison, between HU and signal void on T2WI, there was moderate predictive performance [area under the curve: 0.856, P = .001]. An ideal HU cutoff value of 69.50 HU was obtained with a sensitivity of 100% and a specificity of 44.7%. However, the receiver operator characteristic for T1-weighted images could not be plotted, as no signal was avoided to predict AFS and it was not statistically significant (area under the curve: 0.566; P = .287). The study found a CT HU of 69.5 can predict MRI T2WI signal values with a void signal, aiding in diagnostic workup and evaluation for AFS.

PILOT STUDY OF INTRACOELOMIC TERBINAFINE IMPLANTS IN GREATER SIRENS (SIREN LACERTINA).

Chytridiomycosis caused by Batrachochytrium dendrobatidis (Bd) has been documented in greater sirens (Siren lacertina) in the wild and in the pet trade. This study evaluated the use of terbinafine-impregnated implants for chytridiomycosis prophylaxis in greater sirens exposed to Bd. Implants were placed intracoelomically in both control (blank implant, n = 4) and treatment (24.5 mg of terbinafine implant, n = 4) groups. Sirens were exposed to Bd zoospores via 24-h immersion bath at 1 and 2 mon postimplant placement. Blood was collected monthly for plasma terbinafine levels, and skin swabs were collected weekly for Bd quantitative PCR. Animals with terbinafine implants had detectable concentrations of plasma terbinafine ranging from 17 to 102 ng/ml. Only one terbinafine-implanted animal had a peak concentration above the published minimum inhibitory concentration for terbinafine against Bd zoospores (63 ng/ml); however, it is unknown how plasma terbinafine concentrations relate to concentrations in the skin. There was no difference between the two treatment groups in clinical signs or Bd clearance rate, and no adverse effects from implants were observed. These findings indicate using intracoelomic drug implants for drug delivery in amphibians is safe; however, terbinafine efficacy in preventing Bd chytridiomycosis in sirens remains unclear. Further investigation of the use of intracoelomic implants and identification of effective drugs and doses in other amphibian species against Bd and other infectious diseases is warranted, as this may provide a practical method for long-term drug delivery in wildlife.

SCHIZANGIELLA INFECTIONS IN AN EASTERN RATSNAKE (PANTHEROPHIS ALLEGHANIENSIS) AND A TIMBER RATTLESNAKE (CROTALUS HORRIDUS).

This report describes Schizangiella infections in colubrid and viperid snakes. A captive eastern ratsnake (Pantherophis alleghaniensis) was presented for a large intraoral mass associated with the mandible. The mass was debulked and histologic examination revealed severe, granulomatous stomatitis with intralesional fungi exhibiting morphologic features consistent with Schizangiella serpentis. PCR and sequencing of affected tissues confirmed S. serpentis. Because of declining health, the ratsnake was euthanized and postmortem examination identified a disseminated S. serpentis infection involving the skeletal musculature, lung, kidney, mesentery, and mandible. A wild-caught timber rattlesnake (Crotalus horridus) was presented for cutaneous lesions, weakness, and lethargy and later died. Postmortem examination revealed a mass-like structure in the esophagus characterized by high numbers of Schizangiella-like fungi associated with extensive granulomatous inflammation; the snake also had cutaneous mycosis suggestive of ophidiomycosis. This is the first report to document the unique morphologic features of S. serpentis in tissues and the presentation of schizangiellosis in snakes. Schizangiellosis should be considered as a differential diagnosis for nodular lesions involving the oral cavity and/or the gastrointestinal tract of snakes.

Drug repurposing for fungal infections.

The rise of multidrug-resistant bacteria is a well-recognized threat to world health, necessitating the implementation of effective treatments. This issue has been identified as a top priority on the global agenda by the World Health Organization. Certain strains, such as Candida glabrata, Candida krusei, Candida lusitaniae, Candida auris, select cryptococcal species, and opportunistic Aspergillus or Fusarium species, have significant intrinsic resistance to numerous antifungal medicines. This inherent resistance and subsequent suboptimal clinical outcomes underscore the critical imperative for enhanced therapeutic alternatives and management protocols. The challenge of effectively treating fungal infections, compounded by the protracted timelines involved in developing novel drugs, underscores the pressing need to explore alternative therapeutic avenues. Among these, drug repurposing emerges as a particularly promising and expeditious solution, providing cost-effective solutions and safety benefits. In the fight against life-threatening resistant fungal infections, the idea of repurposing existing medications has encouraged research into both established and new compounds as a last-resort therapy. This chapter seeks to provide a comprehensive overview of contemporary antifungal drugs, as well as their key resistance mechanisms. Additionally, it seeks to provide insight into the antimicrobial properties of non-traditional drugs, thereby offering a holistic perspective on the evolving landscape of antifungal therapeutics.

Pan-drug resistance and hypervirulence in a human fungal pathogen are enabled by mutagenesis induced by mammalian body temperature.

The continuing emergence of invasive fungal pathogens poses an increasing threat to public health. Here, through the China Hospital Invasive Fungal Surveillance Net programme, we identified two independent cases of human infection with a previously undescribed invasive fungal pathogen, Rhodosporidiobolus fluvialis, from a genus in which many species are highly resistant to fluconazole and caspofungin. We demonstrate that R. fluvialis can undergo yeast-to-pseudohyphal transition and that pseudohyphal growth enhances its virulence, revealed by the development of a mouse model. Furthermore, we show that mouse infection or mammalian body temperature induces its mutagenesis, allowing the emergence of hypervirulent mutants favouring pseudohyphal growth. Temperature-induced mutagenesis can also elicit the development of pan-resistance to three of the most commonly used first-line antifungals (fluconazole, caspofungin and amphotericin B) in different Rhodosporidiobolus species. Furthermore, polymyxin B was found to exhibit potent activity against the pan-resistant Rhodosporidiobolus mutants. Collectively, by identifying and characterizing a fungal pathogen in the drug-resistant genus Rhodosporidiobolus, we provide evidence that temperature-dependent mutagenesis can enable the development of pan-drug resistance and hypervirulence in fungi, and support the idea that global warming can promote the evolution of new fungal pathogens.

Fungal Musculoskeletal Infections: Comprehensive Approach to Proper Diagnosis.

Fungal musculoskeletal infections often have subacute or indolent manifestations, making it difficult to distinguish them from other diseases and infections, given that they are relatively uncommon. Fungal infections occur by hematogenous spread, direct inoculation, or contiguous extension and may be related to different risk factors, including immunosuppression and occupational activity. The infection can manifest in isolation in the musculoskeletal system or as part of a systemic process. The fungi may be endemic to certain regions or may be found throughout the world, and this can help to narrow the diagnosis of the etiologic agent. Infections such as candidiasis, cryptococcosis, aspergillosis, and mucormycosis are often related to immunosuppression. On the other hand, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, and blastomycosis can occur in healthy patients in geographic areas where these infections are endemic. Furthermore, infections can be classified on the basis of the site of infection in the body. Some subcutaneous infections that can have osteoarticular involvement include mycetoma, sporotrichosis, and phaeohyphomycosis. Different fungi affect specific bones and joints with greater prevalence. Imaging has a critical role in the evaluation of these diseases. Imaging findings include nonspecific features such as osteomyelitis and arthritis, with bone destruction, osseous erosion, mixed lytic and sclerotic lesions, and joint space narrowing. Multifocal osteomyelitis and chronic arthritis with joint effusion and synovial thickening may also occur. Although imaging findings are often nonspecific, some fungal infections may show findings that aid in narrowing the differential diagnosis, especially when they are associated with the patient's clinical condition and history, the site of osteoarticular involvement, and the geographic location. ©RSNA, 2024.

Severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii and Penicillium oxalicum in a diabetic patient.

BACKGROUND PAECILOMYCES: and Penicillium are considered as rare opportunistic pathogens in immunocompromised hosts, and pneumonia caused by Paecilomyces and Penicillium is rare. In this study, we present first case of severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii (P. variotii) and Penicillium oxalicum (P. oxalicum) in a 66-year-old female with poorly controlled type 2 diabetes. CASE PRESENTATION: A 56-year-old woman patient presented to hospital for nausea, poor appetite, and vomiting for one day. On the second day of admission, blood culture and renal puncture fluid culture grew multidrug-resistant Escherichia coli (imipenem/cilastatin sensitive), and she received combination therapy with imipenem/cilastatin (1 g, every 8 h) and vancomycin (0.5 g, every 12 h). On the fourth day, she developed symptoms of respiratory failure. Pulmonary computed tomography (CT) showed an increase in pneumonia compared to before, with minor pleural effusion on both sides. Two fungi were isolated repeatedly from BALF culture, which were confirmed as P. variotii and P. oxalicum by Internal transcribed spacer (ITS) sequencing. Her pleural effusion was completely absorbed, pneumonia symptoms have significantly improved and discharged with receiving liposomal amphotericin B treatment for four weeks. CONCLUSIONS: It is worth noting that clinicians and laboratory personnel should not simply consider Paecilomyces and Penicillium species as contaminants, especially in immunocompromised patients. Early fungal identification and antifungal drug sensitivity are crucial for clinical drug selection and patient prognosis.

Clinical application of voriconazole in pediatric patients: a systematic review.

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.

Hotspot shelters stimulate frog resistance to chytridiomycosis.

Many threats to biodiversity cannot be eliminated; for example, invasive pathogens may be ubiquitous. Chytridiomycosis is a fungal disease that has spread worldwide, driving at least 90 amphibian species to extinction, and severely affecting hundreds of others1-4. Once the disease spreads to a new environment, it is likely to become a permanent part of that ecosystem. To enable coexistence with chytridiomycosis in the field, we devised an intervention that exploits host defences and pathogen vulnerabilities. Here we show that sunlight-heated artificial refugia attract endangered frogs and enable body temperatures high enough to clear infections, and that having recovered in this way, frogs are subsequently resistant to chytridiomycosis even under cool conditions that are optimal for fungal growth. Our results provide a simple, inexpensive and widely applicable strategy to buffer frogs against chytridiomycosis in nature. The refugia are immediately useful for the endangered species we tested and will have broader utility for amphibian species with similar ecologies. Furthermore, our concept could be applied to other wildlife diseases in which differences in host and pathogen physiologies can be exploited. The refugia are made from cheap and readily available materials and therefore could be rapidly adopted by wildlife managers and the public. In summary, habitat protection alone cannot protect species that are affected by invasive diseases, but simple manipulations to microhabitat structure could spell the difference between the extinction and the persistence of endangered amphibians.

Clinical spectrum, phenotypic and molecular characterization, and antifungal susceptibility of an emerging human pathogen, Acrophialophora, from India.

Acrophialophora is implicated in superficial and invasive infections, especially in immunosuppressed individuals. The present study was undertaken to provide clinical, microbiological, phylogenetic, and antifungal susceptibility testing (AFST) profile of Acrophialophora isolated from India. All the isolates identified as Acrophialophora species at the National Culture Collection for Pathogenic Fungi, Chandigarh, India were revived. Phenotypic and molecular characterization was performed, followed by temperature studies, scanning electron microscopy (SEM), and AFST. We also performed systematic review of all the cases of Acrophialophora species reported till date. A total of nine isolates identified as Acrophialophora species were identified by molecular method as A. fusispora (n = 8) and A. levis (n = 1), from brain abscess (n = 4), respiratory tract (n = 3), and corneal scraping (n = 2). All patients but two had predisposing factors/co-morbidities. Acrophialophora was identified as mere colonizer in one. Temperature studies and SEM divulged variation between both species. Sequencing of the internal transcribed spacer ribosomal DNA and beta-tubulin loci could distinguish species, while the LSU ribosomal DNA locus could not. AFST showed the lowest minimum inhibitory concentrations (MICs) for triazoles and the highest for echinocandins. Systematic literature review revealed 16 cases (11 studies), with ocular infections, pulmonary and central nervous system infections, and A. fusispora was common species. All the patients except three responded well. High MICs were noted for fluconazole, micafungin, and caspofungin. This is the first study delineating clinical, phenotypic, and genotypic characteristics of Acrophialophora species from India. The study highlights microscopic differences between both species and emphasizes the role of molecular methods in precise identification. Triazoles appear to be the most effective antifungals for managing patients.

We describe clinical, phenotypic, and genotypic characteristics of Acrophialophora species. This species causes mild infection to fatal infection in immunosuppressed individuals. Triazoles are effective in treating such infections.