Utility of Itraconazole in Combination with Liposomal Amphotericin B in Rhizopus oryzae Associated Mucormycosis-An Exploratory Study.

BACKGROUND: During the COVID-19 pandemic-associated mucor epidemic, acute antifungal drug shortage necessitated the exploration of other antifungals based on culture sensitivity. Itraconazole is a cheap, safe, and effective antifungal in sensitive cases. METHODOLOGY: We enrolled itraconazole-sensitive COVID-19-associated mucormycosis during the mucormycosis pandemic. After the intensive phase course of liposomal amphotericin B, Itraconazole was offered in susceptible cases during the maintenance phase along with standard of care. These patients were clinically and radiologically followed for 6 months. RESULTS: We enrolled 14 patients (Male: Female-11:3) of Rhino-orbito-cerebral mucormycosis (ROCM) which included 12 diabetics. All patients had facial swelling, orbital swelling, visual impairment, and headache. MRI showed involvement of bilateral sinus (10/14), orbital extension (13/14), cavernous sinus (5/14), cerebral part of the internal carotid artery (3/14), and brain infarcts (4/14). All 14 patients showed sensitivity to Itraconazole with 12 having minimum inhibitory concentration (MIC) ≤ 1 µg/ml and 2 having MIC ≤ 2 µg/ml. Follow-up at 6 months showed clinical improvement in the majority (11/14) and radiological improvement in six out of seven scanned patients. CONCLUSION: Our study shows the potential therapeutic role of oral Itraconazole in ROCM.

[Saksenaea caused invasive infection in an immunocompetent patient after trauma]. / Saksenaea-svamp gav invasiv infektion hos frisk traumapatient.

This text discusses a rare case of soft tissue infection caused by the fungus Saksenaea in a young, immunocompetent woman following an all-terrain vehicle accident abroad. Despite initial treatment, her wound worsened, necessitating multiple surgical revisions and aggressive antifungal therapy with liposomal Amphotericin B. The interdisciplinary collaboration among orthopedic surgeons, infectious disease specialists, and plastic surgeons played a vital role in her successful treatment. Prompt identification of the fungus and immediate intervention were crucial. This case emphasizes the importance of awareness among healthcare providers regarding this rare condition and underscores the significance of early diagnosis and timely surgical and medical interventions for a positive outcome.

Mucorales: A systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list (FPPL). This systematic review aimed to evaluate the epidemiology and impact of invasive fungal disease due to Mucorales. PubMed and Web of Science were searched to identify studies published between January 1, 2011 and February 23, 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 24 studies were included. Mortality rates of up to 80% were reported. Antifungal susceptibility varied across agents and species, with the minimum inhibitory concentrations lowest for amphotericin B and posaconazole. Diabetes mellitus was a common risk factor, detected in 65%-85% of patients with mucormycosis, particularly in those with rhino-orbital disease (86.9%). Break-through infection was detected in 13.6%-100% on azole or echinocandin antifungal prophylaxis. The reported prevalence rates were variable, with some studies reporting stable rates in the USA of 0.094-0.117/10 000 discharges between 2011 and 2014, whereas others reported an increase in Iran from 16.8% to 24% between 2011 and 2015. Carefully designed global surveillance studies, linking laboratory and clinical data, are required to develop clinical breakpoints to guide antifungal therapy and determine accurate estimates of complications and sequelae, annual incidence, trends, and global distribution. These data will provide robust estimates of disease burden to refine interventions and better inform future FPPL.

Mucormycosis in Liver Allograft Following Transplant for Secondary Biliary Cirrhosis.

Mucormycosis, a group of opportunistic mycoses caused by Mucorales, present a significant threat to immunocompromised patients. In this report, we present the case of a 57-year-old male patient who underwent liver transplant for secondary biliary cirrhosis following inadvertent bile duct injury. Despite initial satisfactory postoperative evolution, the patient developed fever, and imaging revealed a suspicious lesion. Preliminary culture growth suggested a filamentous fungus, leading to initiation of liposomal amphotericin B. However, the lesion progressed, and a surgical debridement was necessary. During surgery, involvement of the liver dome and diaphragm was observed, and a nonanatomical hepatectomy was performed. Despite efforts, the patient's condition deteriorated, ultimately resulting in multiple organ failure and mortality. This case emphasizes the challenging nature of mucormycosis in livertransplant recipients.

Choanephora infundibulifera Rhinosinusitis in Man with Acute Lymphoblastic Leukemia, Tennessee, USA.

Choanephora infundibulifera is a member of the Mucorales order of fungi. The species is associated with plants as a saprophyte or parasite and may be responsible for spoilage or disease but is an uncommon cause of human infection. We describe C. infundibulifera rhinosinusitis in a young man with leukemia in Tennessee, USA.

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis.

Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood-brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.

Mucormycosis: A Rare disease to Notifiable Disease.

Mucormycosis is the third most frequent invasive mycosis, following candidiasis and aspergillosis. It is frequently neglected due to its rare occurrence; but recently attend the status of notifiable disease due to its higher incidence in both developed and developing nations. India has received global notice since its estimated instances were greater than the global estimated figures. Mucormycosis has several clinical manifestations, including rhino-orbital-cerebral (ROCM), pulmonary, gastrointestinal, cutaneous, renal, and diffuse Mucormycosis. ROCM is the most frequent clinical manifestation in India, although pulmonary mucormycosis is prevalent worldwide. This review also discusses host defenses, pre disposing risk factors and fungal virulence factors that impair host's ability to prevent fungus invasion and disease establishment. The diagnosis of the disease depends on clinical interventions, histological or microbiological procedures along with molecular methods to obtain timely results. But there are still unmet challenges for rapid diagnosis of the disease. Treatment of the disease is achieved by multimodal approaches such as reversal of underlying predisposing factors, rapid administration of antifungals in optimal doses and surgical procedures to remove infected tissues. Liposomal Amphotericin B, Posaconazole and Isavuconazoles are preferred as the first line of treatment procedures. clinical trials. Different studies have improved the existing drug and under clinical trials while several studies predicted the new potential targets as CotH and Ftr1 as shown in infection and in vitro models. Therefore, current scenario demands a multidisciplinary approach is needed to investigate the prevalence, pathogenesis which is highly important for the advancement of rapid diagnosis and effective treatment.

Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B.

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.

Pulmonary mucormycosis diagnosed by ultrasound guided percutaneous biopsy: A case series.

Pulmonary mucormycosis is a rare but highly lethal fungal infection, usually affecting immunocompromised patients. Pulmonary mucormycosis was also a critical problem that complicated the later part of the clinical course of COVID-19 in India. Early diagnosis of the disease, combined with aggressive treatment, is crucial for patient survival. Fibreoptic bronchoscopy is a useful procedure for diagnosis of pulmonary mucormycosis, but image-guided percutaneous biopsy efficiently samples lesions abutting the chest wall. Biopsy is more yielding than cultures and imaging guided biopsy is required for lesions that cannot be microbiologically confirmed by fibreoptic bronchoscopy. We present a case series of four patients of pulmonary mucormycosis in whom ultrasound guided biopsy clinched the diagnosis. All the four patients were poor surgical candidates and underwent medical management with antifungal agents, and had successful clinical recovery and radiological resolution. Our case series illustrates the utility of ultrasound guided percutaneous biopsy as a diagnostic tool for sampling cavitatory disease due to pulmonary mucormycosis, when fibreoptic bronchoscopy failed to yield a diagnosis and the beneficial role antifungal agents as salvage therapy in poor surgical candidates.

Human Vγ9Vδ2 T cells exhibit antifungal activity against Aspergillus fumigatus and other filamentous fungi.

Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.

Molecular mechanisms that govern infection and antifungal resistance in Mucorales.

SUMMARYThe World Health Organization has established a fungal priority pathogens list that includes species critical or highly important to human health. Among them is the order Mucorales, a fungal group comprising at least 39 species responsible for the life-threatening infection known as mucormycosis. Despite the continuous rise in cases and the poor prognosis due to innate resistance to most antifungal drugs used in the clinic, Mucorales has received limited attention, partly because of the difficulties in performing genetic manipulations. The COVID-19 pandemic has further escalated cases, with some patients experiencing the COVID-19-associated mucormycosis, highlighting the urgent need to increase knowledge about these fungi. This review addresses significant challenges in treating the disease, including delayed and poor diagnosis, the lack of accurate global incidence estimation, and the limited treatment options. Furthermore, it focuses on the most recent discoveries regarding the mechanisms and genes involved in the development of the disease, antifungal resistance, and the host defense response. Substantial advancements have been made in identifying key fungal genes responsible for invasion and tissue damage, host receptors exploited by the fungus to invade tissues, and mechanisms of antifungal resistance. This knowledge is expected to pave the way for the development of new antifungals to combat mucormycosis. In addition, we anticipate significant progress in characterizing Mucorales biology, particularly the mechanisms involved in pathogenesis and antifungal resistance, with the possibilities offered by CRISPR-Cas9 technology for genetic manipulation of the previously intractable Mucorales species.

Genome-based solutions for managing mucormycosis.

An uncommon opportunistic fungal infection known as mucormycosis is caused by a class of molds called mucoromycetes. Currently, antifungal therapy and surgical debridement are the primary treatment options for mucormycosis. Despite the importance of comprehensive knowledge on mucormycosis, there is a lack of well-annotated databases that provide all relevant information. In this study, we have gathered and organized all available information related to mucormycosis that include disease's genome, proteins, diagnostic methods. Furthermore, using the AlphaFold2.0 prediction tool, we have predicted the tertiary structures of potential drug targets. We have categorized the information into three major sections: "genomics/proteomics," "immunotherapy," and "drugs." The genomics/proteomics module contains information on different strains responsible for mucormycosis. The immunotherapy module includes putative sequence-based therapeutics predicted using established tools. Drugs module provides information on available drugs for treating the disease. Additionally, the drugs module also offers prerequisite information for designing computationally aided drugs, such as putative targets and predicted structures. In order to provide comprehensive information over internet, we developed a web-based platform MucormyDB (https://webs.iiitd.edu.in/raghava/mucormydb/).

Pharmacological management of invasive mold infections in solid organ transplant recipients.

INTRODUCTION: Solid organ transplant (SOT) recipients face an increased susceptibility to invasive fungal infection (IFI) due to filamentous fungi. Post-transplant invasive aspergillosis (IA) and mucormycosis are related to exceedingly high mortality rates and graft loss risk, and its management involve a unique range of clinical challenges. AREAS COVERED: First, the current treatment recommendations for IA and mucormycosis among SOT recipients are critically reviewed, including the supporting evidence. Next, we discussed particular concerns in this patient population, such as drug-drug interactions (DDIs) between triazoles and post-transplant immunosuppression or treatment-related toxicity. The role for immunomodulatory and host-targeted therapies is also considered, as well as the theoretical impact of the intrinsic antifungal activity of calcineurin inhibitors. Finally, a personal opinion is made on future directions in the pharmacological approach to post-transplant IFI. EXPERT OPINION: Despite relevant advances in the treatment of mold IFIs in the SOT setting, such as the incorporation of isavuconazole (with lower incidence of DDIs and better tolerability than voriconazole), there remains a large room for improvement in areas such as the position of combination therapy or the optimal strategy for the reduction of baseline immunosuppression. Importantly, future studies should define the specific contribution of newer antifungal agents and classes.