Invasive Mucormycosis Research Articles

Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial.

Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176.

SIADH secondary to rhino-orbito-cerebral mucormycosis: A case report.

Invasive fungal mucormycosis and its outcome as SIADH and orbital apex syndrome is uncommon. Mucormycosis in paranasal sinuses can even lead to intracranial invasion and its treatment with the use of amphotericin B can cure improve the prognosis of the disease. Early diagnosis and prompt treatment with antifungal, endoscopic surgery, and controlling of diabetes can be beneficial. Mucormycosis is an opportunistic invasive fungal infection which is rare and fatal and can even cause intracranial invasion leading to SIADH. The infrequency with which mucormycosis with SIADH is encountered makes it a formidable diagnostic challenge. 70-year-old women uncontrolled diabetes mellitus presented with bilious vomiting and persistent headache with ptosis, proptosis, absence of extraocular movement, pupillary light reflex, and light perception of left eye. Radiographic investigation, KOH mount, and Biopsy showed mucormycosis in sinus with intracranial extension leading to SIADH. Further investigation revealed hyponatremia, decreased plasma osmolality. Then, when diabetes was controlled and hydrocortisone and amphotericin was given along with Endoscopic sinus debridement, SIADH was well controlled. This case illustrates the potential of mucormycosis in paranasal sinuses can even lead to intracranial invasion and its treatment with the use of amphotericin B can cure improve the prognosis of the disease. Prompt diagnosis through clinical history, radiological investigation, and laboratory parameters are important and its treatment is crucial for the better prognosis.

Post COVID rhino-cerebral mucormycosis at a tertiary hospital in Central India: a retrospective cohort study

BackgroundUsually non-pathogenic in immunocompetent individuals, mucormycosis is an aggressive, angio-invasive fungus. It is a rare, opportunistic infection belonging to the zygomycete family. The second wave of COVID-19 saw the emergence of a more dangerous and a potentially deadly invasive fungal sinusitis evolving in rhino-cerebral mucormycosis thus compounding and complicating the pandemic. Alarming and exponential rise in the number of cases of rhino-cerebral mucormycosis in India versus the rest of the world when the treatment protocols essentially remained the same needs to be probed scientifically along with its prompt management. Here an attempt has been made to explore this in the study of 50 cases of rhino-cerebral mucormycosis. This study aims to explore the cause and extension of the disease along with its treatment and outcome in 50 cases of post COVID rhino-cerebral mucormycosis.ResultsThis is a retrospective cohort study conducted on 50 patients with post COVID-19 invasive mucormycosis of the paranasal sinuses with extension to surrounding structure visiting Otorhinolaryngology department at Acharya Vinoba Bhave Rural Hospital, Wardha. Among 50 patients, 86% males in 4th to 7th decade with mean age of 51.08 years. Large majority had mild–moderate severity on high-resolution computed tomography thorax with 84% having uncontrolled diabetes and 18% newly diagnosed diabetic cases. Seventy-two percent had history of steroid intake for COVID-19 management. Maxillary sinus was most commonly involved sinus in 94% cases while 32% had commonest extra nasal spread hard palate. Seventy-eight percent of the post operated mucormycosis cases are alive with no recurrence, 8% are alive and had recurrence of the disease while 14% resulted in death.ConclusionEffective management and control of the infection can be achieved with the use of strong antibiotics, oral or systemic antifungal drugs, extensive surgical excision of diseased tissue, and addressing underlying risk factors can effectively manage and control the infection. This approach results in positive outcomes and reduced morbidity compared to the time prior to the COVID-19 pandemic including cases with extensive disease.

Effectiveness, Safety, and Patterns of Real-World Isavuconazole Use in Europe (2015-2019).

Real-world data from multinational observational studies are required to better understand the role and performance of isavuconazole in real-world practice in Europe. A retrospective medical record review was conducted at 16 sites in Europe (France, Germany, Italy, Spain, and the United Kingdom). Eligible records were from patients aged ≥ 18years at the time of isavuconazole initiation and received at least one dose of isavuconazole for suspected or confirmed invasive aspergillosis (IA) or invasive mucormycosis (IM) during the eligibility period (October 15, 2015 to June 30, 2019). Data were descriptively analysed. Success rates, overall survival, and times to these events were descriptively analysed. Data were abstracted from 218 patients (201, IA; 17, IM) who received isavuconazole as monotherapy (initiated as infusion, 52%; oral, 46%). Isavuconazole was initiated as primary therapy in 92 patients (42.2%) and salvage therapy in 121 patients (55.5%) (unknown for five patients). Mean (standard deviation) age was 56.8 (15.6) years, 66% were men and 62% had at least three comorbidities, most frequently haematologic malignancy (62%). Estimated clinical response rate at week 24 was 54.5% (95% confidence interval [CI], 38.2-66.5%) for primary treatment and 73.5% (95% CI, 62.7-81.1%) for salvage therapy. Overall, 45 patients (21%) experienced at least one adverse event (AE). Serious AEs were experienced by 37 patients (17%), with seven related to isavuconazole; five patients (2.3%) discontinued isavuconazole monotherapy due to the serious AE. A total of 137 patients (63%) died, with 17 deaths (12.4%) related to their invasive fungal infection, 11 of whom initiated isavuconazole as salvage therapy. This study adds to the growing body of evidence that whether used as first-line therapy or after the failure of other antifungal therapies, isavuconazole appears to have a promising clinical response and a good safety profile as an antifungal agent in patients with varied underlying conditions.

Outcomes of Invasive Fungal Infections Treated with Isavuconazole: A Retrospective Review.

Isavuconazole (ISA) has a favorable side effect profile that makes it attractive for treatment of invasive fungal infections (IFI). It carries FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data for other organisms and non-pulmonary infections. We conducted this review to investigate how ISA performed at treating IFI, with an especial interest in these non-approved indications. We retrospectively identified and reviewed 131 patients who received ISA as treatment for IFI at our institution, some of whom received ISA as their first anti-fungal therapy and others who received ISA as either step-down therapy or salvage therapy. We identified the microbiologic cause of infection as well as the anatomic site involved for each patient. We then classified patients according to their response to ISA: namely cured, partially responded, or stabilized. The majority of patients were immunocompromised (n = 76, 58%). ISA was used primarily as a secondary therapy (n = 116, 89%); either as a step-down/switching from other agents, or as salvage therapy. The most common reasons for switching to ISA were toxicities with prior agents followed by QT prolongation. Although pulmonary aspergillosis and mucormycosis were represented in more than half of the cohort, ISA was also used off-label for treatment of other organisms such as endemic fungi (n = 19, 15%) as well as central nervous system (CNS) infections (n = 15, 11%). We have described the detailed clinical characteristics of these CNS infections cases. The overall clinical response rate varied by type of infection and site involved (57-73% response rate). We demonstrated encouraging clinical responses, particularly outside the FDA-approved indications, as well as good tolerability. This report highlights the critical need for expanded scope of prospective studies to delineate the efficacy of this better-tolerated agent, especially in central nervous system infections.

Concordance of Chest Radiography and Chest Computed Tomography Findings in Patients with Hematologic Malignancy and Invasive Mucormycosis: What Are the Prognostic Implications?

Invasive pulmonary mucormycosis (IPM) is a deadly opportunistic mold infection in patients with hematological malignancies (HM). Radiologic imaging is essential for its timely diagnosis. Here, we compared IPM lesions visualized by chest computed tomography (CCT) and chest X-ray (CXR) and determined the prognostic significance of discordant imaging. Therefore, we reviewed 44 consecutive HM patients with probable/proven IPM at MD Anderson Cancer Center in 2000-2020 who had concurrent CCT and CXR studies performed. All 44 patients had abnormal CCTs and 39 (89%) had anormal CXR findings at IPM diagnosis. However, only 26 patients (59%) showed CCT-matching IPM-suspicious lesions on CXR. Acute Physiology and Chronic Health Evaluation II score > 18 at IPM diagnosis and breakthrough infection to Mucorales-active antifungals were the only independent risk factors for 42-day and/or 84-day mortality. Absence of neutropenia at IPM diagnosis, neutrophil recovery in neutropenic patients, and surgical revision of mucormycosis lesions were protective factors. Although not reaching significance on multivariable analysis, visualization of CCT-matching lesions on CXR was associated with significantly increased 84-day mortality (log-rank test, p = 0.033), possibly as a surrogate of extensive lesions and tissue necrosis. This observation supports the exploration of radiologic lesion kinetics as a prognostic staging tool in IPM patients.

Invasive fungal infections in patients with haematological malignancies at the University Hospital of Reunion Island (2018-2022): An observational study.

Invasive fungal infections are a serious complication for haematology patients. However, there is no study on this subject in Reunion Island. The aim of this study was to estimate the incidence of invasive fungal infections in patients with haematological malignancies at the University Hospital of Reunion Island. We conducted a descriptive and ambispective study. We included any patient with haematological malignancy presenting with a putative, possible, probable, or proven invasive fungal infection, defined as per the criteria of the European Organisation for Research and Treatment of Cancer/Mycoses Study Group 2019, from January 2018 to December 2022. Data were collected from medical records and identified by ICD-10 coding and laboratory data. Eighty-nine invasive fungal infections were diagnosed in 76 patients. The 5-year incidence rate of invasive fungal infections was 1.7 per 100 person-years (95% Confidence Interval (CI) 1.3-2). Invasive aspergillosis was the most common infection (35/89, 39%), followed by invasive candidiasis (33/89, 37%), mucormycosis (7/89, 8%), and pneumocystosis (7/89, 8%). Most infections occurred in patients with acute myeloid leukaemia (32/89, 36%) and lymphoma (26/89, 29%). Six-month mortality was higher for mucormycosis (71%) than for aspergillosis (34%) and invasive candidiasis (33%). The incidence and distribution of fungal infections in haematology patients were similar to European cohorts, albeit with more mucormycosis, less pneumocystis, and a high proportion of Candida parapsilosis in candidemia.

"A Rare Encounter with Gastrointestinal Mucormycosis: Diagnostic and Therapeutic Challenges"

Mucormycosis is a very rare, life-threatening infection caused by fungi. Frequently observed in those patients having underlying immunosuppression, rarely found in immunocompetent patients. The infection can cause pulmonary, rhinocerebral, skin and soft tissue, central nervous system and gastrointestinal system. Nevertheless, gastrointestinal involvement is the rarest presentation. We present a rare case of invasive intestinal mucormycosis causing Gastrointestinal bleed in an adult female and review the literature, highlighting the rare clinical presentation, the need for high index of suspicion in the timely diagnosis and management of mucormycosis.

Mucor thriving on iron in beta thalassemia major: A case of rhino-orbital mucormycosis

Mucormycosis is a dreaded condition with high mortality rates noted in immunocompromised hosts. Though iron overload is a known risk factor, children with transfusion-dependent thalassemia have been rarely reported with invasive mucormycosis. We present an 8-year-old girl with transfusion-dependent thalassemia with hypersplenism and iron overload. She had invasive rhino-sino-orbital mucormycosis with a fatal outcome despite aggressive surgical and medical management.

PERI-OPERATIVE ANAESTHETIC CONCERNS IN COVID-19 ASSOCIATED MUCORMYCOSIS

Introduction: Mucormycosis is a fulminant life-threatening fungal infection requiring emergency surgical debridement. It is associated with immune-compromised status, multi-systemic involvement, and difficult airway posing challenges to anesthetic management. We conducted this study to find the peri-operative anesthesia concerns in patients of COVID-19-associated mucormycosis Methods: This retrospective observational study included COVID-19-infected patients operated for invasive mucormycosis under general anesthesia. Cases operated under local anesthesia were excluded from the study. Results: A total of 30 patients were included in the study where the majority of the patients were ASA physical status III. ASA classification uses a grading system of l(one) through V( five), with I identifying a person in good health and V as a person with a severe, life-threatening condition. The most common co-morbidity was diabetes mellitus plus hypertension 66% (n=20), followed by only diabetes 30% (n=9). Out of all patients, 33.3% (n=10) were intubated at the first attempt using direct laryngoscope, rest 66.6% required other interventions like the use of video laryngoscope, bougie, or external laryngeal pressure. Perioperative blood transfusion was required in 40% (n=12) of the patients. Of patients who required intensive care unit (ICU) admission 40% (n=12) out of them, 10% patients (n=3) did not survive. The average hospital stay was 55.9 +/-15.8 days with a maximum of 95 days and a minimum of 15 days. Conclusion: Mucormycosis is mostly associated with uncontrolled diabetes milletus in post-COVID patients. These require utmost care peri-operatively as they are associated with a difficult airway, intraoperative complications, prolonged morbidity, and mortality.

A global perspective of the changing epidemiology of invasive fungal disease and real-world experience with the use of isavuconazole.

Global epidemiological data show that the incidence of invasive fungal disease (IFD) has increased in recent decades, with the rising frequency of infections caused by Aspergillus and Mucorales order species. The number and variety of patients at risk of IFD has also expanded, owing in part to advances in the treatment of hematologic malignancies and other serious diseases, including hematopoietic stem cell transplantation (HCT) and other therapies causing immune suppression. Isavuconazonium sulfate (active moiety: isavuconazole) is an advanced-generation triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis that has demonstrated activity against a variety of yeasts, moulds, and dimorphic fungi. While real-world clinical experience with isavuconazole is sparse in some geographic regions, it has been shown to be effective and well tolerated in diverse patient populations, including those with multiple comorbidities who may have failed to respond to prior triazole antifungal therapy. Isavuconazole may be suitable for patients with IFD receiving concurrent QTc-prolonging therapy, as well as those on venetoclax or ruxolitinib. Data from clinical trials are not available to support the use of isavuconazole prophylactically for the prevention of IFD or for the treatment of endemic IFD, such as those caused by Histoplasma spp., but real-world evidence from case studies suggests that it has clinical utility in these settings. Isavuconazole is an option for patients at risk of IFD, particularly when the use of alternative antifungal therapies is not possible because of toxicities, pharmacokinetics, or drug interactions.

Post Covid-19 Invasive Renal Mucormycosis with acute renal failure; a case report and review of literature

Abstract: The worst nightmare of twenty first century has been discoverd, The Coronavirus, has been risen the incidence of mucormycosis during the( COVID-19) pandemic. There are many case reports of rhinoorbito-cerebral and pulmonary mucormycosis. Hypertension, COVID, and mucormycosis are lethal combination associated with high mortality. This is the first case of Covid-19 associated mucormycosis (CAM) in the kidneys from Pakistan. We report the case of a 68-years old woman who presented with fever, abdominal pain and renal failure. Mucormycosis was diagnosed on renal biopsy. She was managed with Amphotericin- B and hemodialysis via tunneled vascular catheter. She refused nephrectomy. The case highlighted CAM can present as localized renal mucormycosis. In this era of Covid pandemic CAM should be in the differential diagnosis

Disseminated Mucormycosis Masquerading as Invasive Pulmonary Aspergillosis

Pulmonary mucormycosis can closely resemble invasive pulmonary aspergillosis. If the infection is not contained at its primary site, it can lead to dissemination. A middle-aged woman, initially diagnosed with acute promyelocytic leukaemia, presented with atypical non-resolving pneumonia. Despite empirical antifungal treatment targeting Candida and Aspergillus, her clinical condition continued to deteriorate, resulting in the spread of the infection. Subsequent follow-up, combined with a high index of suspicion and isolation of Mucorales from an extrapulmonary site, identified mucormycosis as the causative pathogen. Early recognition of subtle clinical and radiological cues and prompt initiation of a classical medico-surgical approach is crucial for treating invasive mucormycosis and managing the underlying immunosuppressive condition. This case underscores the importance of early suspicion of Mucorales based on clinical and radiological signs, distinguishing it from invasive aspergillosis. The atypical presentation of pulmonary, splenic, and renal mucormycosis in this patient highlights the need for vigilance and timely intervention to prevent the most severe outcomes of disseminated mucormycosis.

A rare case of invasive mucormycosis with thrombosis of cerebral vasculature in diabetic ketoacidosis

Mucormycosis is a rare fungal infection. It is an aggressive angio invasive infection hence if left untreated is always fatal. This necrotising infection commonly involves the nose, paranasal sinuses, orbits and brain. Uncontrolled diabetes, immunosuppression, transplant recipients, COVID-19 infection are the commonest risk factors. Most common form is rhino orbital cerebral involvement. Antifungal agents along with surgical debridement is the mainstay of treatment. We are reporting such a case of invasive mucormycosis in a young diabetic male to stress the importance of clinical examination and early recognition of clinical signs of this rare invasive infection and aggressive management.

Mucormycosis in Diabetes

Abstract Fungal infections are a major health challenge especially in immunocompromised patients. Mucormycosis, a severe, frequently fatal fungal infection, has a unique predisposition to infect patients with diabetes. The infection is caused by organisms belonging to the order Mucorales, among which Rhizopus species are the most common. Uncontrolled diabetes complicated by diabetic ketoacidosis is one of the major risk factors for upsurge in mucormycosis cases. The defense mechanisms, involving macrophages and neutrophils for phagocytosis, are compromised in diabetes. In 2 cases of rhino-orbital-cerebral mucormycosis with underlying diabetes, we observed a marked immune imbalance, with elevated Th17 and diminished T regulatory cells. Recovery of CD4+CD25+ T cells after treatment indicated a favorable phenotype outcome; though high circulating CD4+CD161+ can be detrimental to the patient predisposing to future relapse(s). Mucorale specific T cells contributing to human immune responses against the fungi can be investigated to identify a surrogate diagnostic marker of invasive mucormycosis.

Real-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

A rare case of invasive intestinal mucormycosis: a case report

A rare case of invasive intestinal mucormycosis: a case report

Invasive Mucormycosis (Zygomycosis) -Pre-COVID Era and COVID Era: A Comparative Retrospective Study at a Tertiary Care Centre, Chennai

Invasive Mucormycosis (Zygomycosis) -Pre-COVID Era and COVID Era: A Comparative Retrospective Study at a Tertiary Care Centre, Chennai

Isavuconazole Induces Neurodevelopment Defects and Motor Behaviour Impairment in Zebrafish Larvae.

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1mg/L of isavuconazole 6h after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level (0.25mg/L), it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, the fluorescence intensity becoming weaker, the abnormal motor behaviour, etc. At the same time, exposure of zebrafish embryos to isavuconazole downregulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but upregulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by downregulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish.

Efficacy of an oral lipid nanocrystal formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an orally administered lipid nanocrystal formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to Rhizopus arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. In R. arrhizus var. delemar-infected mice, 15 mg/kg of MAT2203 qd was as effective as 10 mg/kg of LAMB in prolonging median survival time vs placebo (13.5 and 16.5 days for MAT2203 and LAMB, respectively, vs 9 days for placebo) and enhancing overall survival vs placebo-treated mice (40% and 45% for MAT2203 and LAMB, respectively, vs 0% for placebo). A higher dose of 45 mg/kg of MAT2203 was not well tolerated by mice and showed no benefit over placebo. Similar results were obtained with mice infected with M. circinelloides. Furthermore, while both MAT2203 and LAMB treatment resulted in a significant reduction of ~1.0-2.0log and ~2.0-2.5log in Rhizopus delemar or M. circinelloides lung and brain burden vs placebo mice, respectively, LAMB significantly reduced tissue fungal burden in mice infected with R. delemar vs tissues of mice treated with MAT2203. These results support continued investigation and development of MAT2203 as a novel and oral formulation of amphotericin for the treatment of mucormycosis.