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Ashraf S. Ibrahim - One of the best experts on this subject based on the ideXlab platform.
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Monotherapy or combination therapy of isavuconazole and micafungin for treating murine Mucormycosis.
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Teclegiorgis Gebremariam, John E Edwards, Nathan P Wiederhold, Abdullah Alqarihi, Priya Uppuluri, Nkechi Azie, Ashraf S. IbrahimAbstract:OBJECTIVES Previously we demonstrated the benefit of isavuconazole in treating murine Mucormycosis due to Rhizopus. We wanted to determine the efficacy of isavuconazole in treating murine Mucormycosis caused by Mucor, the second most common cause of the disease. Furthermore, because we previously determined that Rhizopus possesses the target enzyme for echinocandins and micafungin has activity against murine Mucormycosis, we compared the activity of combination therapy (isavuconazole + micafungin) with placebo, either drug alone or standard therapy of liposomal amphotericin B (LAmB) in treating pulmonary murine Mucormycosis caused by Rhizopus delemar. METHODS In vitro susceptibility to isavuconazole of Mucorales was evaluated using the CLSI M38-A2 method. Immunosuppressed mice were intratracheally infected with either Mucor circinelloides or R. delemar. Treatment with isavuconazole (orally), micafungin (intraperitoneally), a combination of both or LAmB (intravenously) was compared, with survival and tissue fungal burden serving as primary and secondary endpoints, respectively. RESULTS Isavuconazole was as effective as LAmB in prolonging survival of mice infected with M. circinelloides. Against R. delemar-induced Mucormycosis, all monotherapy treatments significantly improved survival of mice versus placebo without showing superiority over one another. However, LAmB was superior in lowering fungal burden in target organs. Although combination therapy of isavuconazole + micafungin did not enhance survival of mice over monotherapy, antagonism was not detected between the two drugs. CONCLUSION Isavuconazole is effective in treating pulmonary murine Mucormycosis due to Mucor. In addition, combination therapy of isavuconazole + micafungin does not demonstrate synergy and it is not antagonistic against Rhizopus-induced Mucormycosis.
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passive immunization with coth3 antibodies protects neutropenic mice from lethal Mucormycosis through enhancing macrophage killing mpf6p 660
Journal of Immunology, 2015Co-Authors: Lin Lin, Teclegiorgis Gebremariam, Ashraf S. IbrahimAbstract:Mucormycosis is a fatal fungal infection caused commonly by Rhizopus. We recently identified R. oryzae CotH3 as a surface protein which mediates invasion of host cells. CotH3 is present in other fungi that cause Mucormycosis. Previously, we found polyclonal anti-CotH3 antibodies (CotH3-Abs) to block host cell invasion by R. oryzae and protect diabetic ketoacidotic mice from Mucormycosis. Because neutropenic patients are also predisposed to Mucormycosis, we used a cyclophosphamide/cortisone acetate injected mice to detect if CotH3-Abs protect against Mucormycosis. Mice were infected intratracheally with R. oryzae, Mucor, Lichtheimia, Apophysomyces, Rhizomucor, or Cunninghamella prior to treating with CotH3-Abs (0.3mg, 0.1mg or 0.03mg) at different times post infection (4, 16, or 48h). All treatment doses showed enhanced survival of mice infected with R. oryzae vs. placebo-treated mice when used 16h post infection (p<0.005). The 0.03mg dose given 16h post infection demonstrated better survival outcome vs. higher doses. Protection was time dependent with higher survival of mice receiving CotH3-Abs at earlier time points post infection. Further, CotH-Abs prolonged survival of mice infected with each of the other tested organisms. Finally, CotH3-Abs reduced tissue fungal burden in target organs and dramatically enhanced mouse macrophage killing via enhancing lysosomal synthesis. Our studies warrant further development of CotH3-Abs as a novel therapy for Mucormycosis.
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coth3 mediates fungal invasion of host cells during Mucormycosis
Journal of Clinical Investigation, 2014Co-Authors: Teclegiorgis Gebremariam, John E Edwards, Mingfu Liu, Guanpingsheng Luo, Quynh T Phan, Scott G Filler, Vincent M Bruno, Alan J Waring, Michael R Yeaman, Ashraf S. IbrahimAbstract:Angioinvasion is a hallmark of Mucormycosis. Previously, we identified endothelial cell glucose-regulated protein 78 (GRP78) as a receptor for Mucorales that mediates host cell invasion. Here we determined that spore coat protein homologs (CotH) of Mucorales act as fungal ligands for GRP78. CotH proteins were widely present in Mucorales and absent from noninvasive pathogens. Heterologous expression of CotH3 and CotH2 in Saccharomyces cerevisiae conferred the ability to invade host cells via binding to GRP78. Homology modeling and computational docking studies indicated structurally compatible interactions between GRP78 and both CotH3 and CotH2. A mutant of Rhizopus oryzae, the most common cause of Mucormycosis, with reduced CotH expression was impaired for invading and damaging endothelial cells and CHO cells overexpressing GRP78. This strain also exhibited reduced virulence in a diabetic ketoacidotic (DKA) mouse model of Mucormycosis. Treatment with anti-CotH Abs abolished the ability of R. oryzae to invade host cells and protected DKA mice from Mucormycosis. The presence of CotH in Mucorales explained the specific susceptibility of DKA patients, who have increased GRP78 levels, to Mucormycosis. Together, these data indicate that CotH3 and CotH2 function as invasins that interact with host cell GRP78 to mediate pathogenic host-cell interactions and identify CotH as a promising therapeutic target for Mucormycosis.
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pathogenesis of Mucormycosis
Clinical Infectious Diseases, 2012Co-Authors: Ashraf S. Ibrahim, Thomas J. Walsh, Brad Spellberg, Dimitrios P KontoyiannisAbstract:Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat Mucormycosis are urgently needed. Understanding the pathogenesis of Mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of Mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to Mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.
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future directions in Mucormycosis research
Clinical Infectious Diseases, 2012Co-Authors: Dimitrios P Kontoyiannis, Brad Spellberg, Ashraf S. Ibrahim, Russell E Lewis, Oliver Lotholary, G Petrikkos, Emmanuel Roillides, Thomas J. WalshAbstract:Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of Mucormycosis are discussed in this article.
Dimitrios P Kontoyiannis - One of the best experts on this subject based on the ideXlab platform.
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Mucormycosis of the central nervous system
Journal of Fungi, 2019Co-Authors: Amanda Chikley, Ronen Benami, Dimitrios P KontoyiannisAbstract:Mucormycosis involves the central nervous system by direct extension from infected paranasal sinuses or hematogenous dissemination from the lungs. Incidence rates of this rare disease seem to be rising, with a shift from the rhino-orbital-cerebral syndrome typical of patients with diabetes mellitus and ketoacidosis, to disseminated disease in patients with hematological malignancies. We present our current understanding of the pathobiology, clinical features, and diagnostic and treatment strategies of cerebral Mucormycosis. Despite advances in imaging and the availability of novel drugs, cerebral Mucormycosis continues to be associated with high rates of death and disability. Emerging molecular diagnostics, advances in experimental systems and the establishment of large patient registries are key components of ongoing efforts to provide a timely diagnosis and effective treatment to patients with cerebral Mucormycosis.
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prevalence clinical and economic burden of Mucormycosis related hospitalizations in the united states a retrospective study
BMC Infectious Diseases, 2016Co-Authors: Dimitrios P Kontoyiannis, Nkechi Azie, Hongbo Yang, Jinlin Song, Sneha S Kelkar, Xi Yang, Rachel Harrington, Alan Fan, Edward Lee, James SpaldingAbstract:Mucormycosis is a rare but devastating fungal infection primarily affecting immunocompromised patients such as those with hematological malignancy, bone marrow and solid organ transplantation, and patients with diabetes, and, even more rarely, immunocompetent patients. The objective of this study was to assess the prevalence and burden, both clinical and economic, of Mucormycosis among hospitalized patients in the U.S. This is a retrospective study using the Premier PerspectiveTM Comparative Database, with more than 560 participating hospitals covering 104 million patients (January 2005-June 2014). All hospitalizations in the database were evaluated for the presence of Mucormycosis using either an ICD-9 code of 117.7 or a positive laboratory result for Mucorales. Hospitalizations were further required to have prescriptions of amphotericin B or posaconazole to be considered as Mucormycosis-related hospitalizations. The prevalence of Mucormycosis-related hospitalizations among all hospital discharges was estimated. Mortality rate at discharge, length of hospital stay, and readmission rates at 1 and 3 months were evaluated among Mucormycosis-related hospitalizations. Cost per hospital stay and average per diem cost (inflated to 2014 USD) were reported. The prevalence of Mucormycosis-related hospitalizations was estimated as 0.12 per 10,000 discharges during January 2005-June 2014. It increased to 0.16 per 10,000 discharges if the definition of Mucormycosis was relaxed to not require the use of amphotericin B or posaconazole. The median length of stay was 17 days, with 23% dead at discharge; readmission rates were high, with 30 and 37% of patients readmitted within one and three months of discharge, respectively. The average cost per hospital stay was $112,419, and the average per diem cost was $4,096. The study provides a recent estimate of the prevalence and burden of Mucormycosis among hospitalized patients. The high clinical and economic burden associated with Mucormycosis highlights the importance of establishing active surveillance and optimizing prophylactic and active treatment in susceptible patients.
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Epidemiology and Clinical Manifestations
2016Co-Authors: Of Mucormycosis, Dimitrios P KontoyiannisAbstract:Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, Mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of Mucormycosis. During the past 2 decades, Mucormycosis has emerged as an important fungal infection with high associa-ted mortality rates. Zygomycoses are uncommon, frequently fatal diseases caused by fungi of the clas
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tacrolimus enhances the potency of posaconazole against rhizopus oryzae in vitro and in an experimental model of Mucormycosis
The Journal of Infectious Diseases, 2013Co-Authors: Russell E Lewis, Thomas J. Walsh, Ronen Benami, Leyla Best, Nathaniel D Albert, Dimitrios P KontoyiannisAbstract:Background. We hypothesized that tacrolimus, an inhibitor of the calcineurin pathway, would enhance the in vivo activity of posaconazole against Rhizopus oryzae, the Mucorales species most commonly associated with Mucormycosis. Methods. We examined patterns of growth inhibition and fungicidal activity of posaconazole and tacrolimus, alone and in combination, against R. oryzae in vitro, using multiple methods (ie, hyphal metabolic and fluorescent vital dye reduction assays and measurement of chitin concentrations), and in vivo, using 2 Mucormycosis models: an invertebrate model (Drosophila) and a nonlethal murine model of cutaneous Mucormycosis. Results. Combinations of posaconazole and tacrolimus were synergistic in checkerboard assays for 4 clinical isolates of R. oryzae (48-hour fractional inhibitory concentration index, 0.187–0.281). Pharmacodynamic analysis of the combination revealed that the 90% effective concentration threshold of posaconazole activity against R. oryzae could be achieved with 2-fold lower drug concentrations (0.5–1 mg/L) when administered with tacrolimus (0.007–2 mg/L). In vivo, combination therapy was associated with improved survival in the fly model of Mucormycosis (65% vs 57% posaconazole alone) and with significant reductions in cutaneous lesions and R. oryzae fungal burden, compared with animals that received posaconazole monotherapy, in the cutaneous model of Mucormycosis. Conclusions. Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of Mucormycosis.
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epidemiology and clinical manifestations of Mucormycosis
Clinical Infectious Diseases, 2012Co-Authors: George Petrikkos, Thomas J. Walsh, Olivier Lortholary, Anna Skiada, Emmanuel Roilides, Dimitrios P KontoyiannisAbstract:Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, Mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of Mucormycosis.
Brad Spellberg - One of the best experts on this subject based on the ideXlab platform.
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gastrointestinal Mucormycosis an evolving disease
Gastroenterología y Hepatología, 2012Co-Authors: Brad SpellbergAbstract:Mucormycosis is a life-threatening infection caused by fungi of the subphylum Mucoromycotina, order Mucorales.1 Traditional risk factors for the development of invasive Mucormycosis include diabetes, defects in host phagocytes, corticosteroid use, organ or stem cell transplantation, and increased levels of available serum iron as a result of acidosis or administration of deferoxamine.2–4 In recent years, the disease has also increasingly been described in patients without traditional risk factors.2 Mucormycosis can affect any organ system, but the most common presentations involve either the nasal sinuses, orbit, and brain (rhino-orbital-cerebral) or the lung. For many years, gastrointestinal Mucormycosis was quite rare, especially in industrialized nations. However, there has been a substantial increase in the number of cases of gastric and gastrointestinal Mucormycosis indexed on PubMed over the past 2 decades, particularly over the past decade. For example, a PubMed search for the title words “gastric” or “gastrointestinal” and “Mucormycosis” or “zygomycosis” revealed 8 publications from 1959–1989 (31 years), 23 publications from 1990–1999 (10 years), and 50 publications from 2000–2011 (12 years). The stomach is the most common site of gastrointestinal Mucormycosis, followed by the colon and ileum. In the past, gastrointestinal Mucormycosis was seen primarily in premature neonates, often in association with widespread disseminated disease.5–12 For example, necrotizing enterocolitis has been described largely in premature neonates and, more rarely, in neutropenic adults.8,9,13–20 Other rare cases of gastrointestinal Mucormycosis were previously described in association with other immunocompromising conditions, including AIDS, systemic lupus erythematosus, and organ transplantation.21–26 Cases of hepatic Mucormycosis have also been associated with ingestion of herbal medications.27 Because this infection is acute and rapidly fatal, it is often diagnosed postmortem. The symptoms of gastrointestinal Mucormycosis are varied and depend on the affected site. Nonspecific abdominal pain and distention associated with nausea and vomiting are the most common symptoms. Fever and hematochezia may also occur. The patient is often thought to have an intra-abdominal abscess. The diagnosis may be made by biopsy of the suspected area during surgery or endoscopy. Recently, an iatrogenic outbreak of gastric Mucormycosis occurred due to contamination of wooden applicators that were used to mix drugs for patients with nasogastric feeding tubes.28 These patients presented with massive gastric bleeds. The diagnosis was made by culturing gastric aspirates and the wooden tongue depressors. This experience further underscores the alarming trend of increasing iatrogenic/nosocomial onset of Mucormycosis. As mentioned previously, older clinical literature (prior to 1990) primarily describes cases of Mucormycosis in neonates and premature infants.15–18 During the 1990s, cases were predominantly described in patients receiving immunosuppressant medications due to solid organ transplantation.23,24,29,30 While such cases continue to be described in the 21st century, a substantial proportion of the cases described since 2000 have occurred in more widely disparate patient populations; these patients may have risk factors such as diabetes mellitus or corticosteroid use, a gastric or peptic ulcer that apparently became infected with the fungi, or no predisposing risk factors.4,31–37 The case reported by Morton and colleagues is typical of the increasing experience with this illness in the 21st century.38 This patient had preexisting gastrointestinal mucosal ulcerations due to her underlying Crohn's disease, and she was immunosuppressed due to her corticosteroid therapy. When she presented with her perforation, there was no specific reason to suspect Mucormycosis; indeed, the disease was much less likely than more typical causes of colonic perforations in such patients. Only the appearance of the fungi on histopathology caused the diagnosis to be made and appropriate therapy to be initiated. Thus, this case highlights the need to maintain a high index of suspicion for invasive fungal infections, including Mucormycosis, in patients who are being treated with corticosteroids and who present with disease that crosses tissue planes. The need to make a rapid diagnosis is underscored by recent data from the oncology setting, in which initiation of polyene antifungal therapy within 6 days of presentation was strongly associated with improved survival.39 There have been no prospective randomized trials to define the optimal antifungal therapy for Mucormycosis. Nevertheless, primary antifungal therapy for Mucormycosis should be based on a polyene antifungal agent, as this drug class is by far the most active against the relevant pathogens. Most experts prefer to use lipid formulations of amphotericin B, which can be administered at higher doses and with less toxicity than amphotericin B deoxycholate.3 The role of combination therapy in Mucormycosis remains unclear, although data from mouse studies and concordant retrospective data in humans suggest that combining lipid polyenes with echinocandins may improve outcomes.3 Additional research is needed to confirm this hypothesis in prospective trials. Antifungal therapy alone is typically inadequate to control Mucormycosis, and surgery to debulk the fungal infection and/or resect all infected tissue is often required to effect cure. Aside from the resistance of some fungal strains to amphotericin B, several hallmark features of Mucormycosis—including angioinvasion, thrombosis, and tissue necrosis—result in poor penetration of anti-infective agents to the site of infection. Therefore, even if the causative organism is susceptible to the antifungal agent in vitro, the antifungal agent may be ineffective in vivo. In a logistic regression model, surgery was found to be an independent variable for favorable outcomes in patients with Mucormycosis.2 Furthermore, in multiple case series, patients who did not undergo surgical debridement of Mucormycosis had a far higher mortality rate than patients who underwent surgery.40–48 While there is potential selection bias in these case series—patients who did not undergo surgery likely differed in disease severity and/or comorbidities from those who did undergo surgery—these data support the concept that surgical debridement is necessary to optimize cure rates. Finally, immunosuppressive medications, particularly corticosteroids, should be dose-reduced or stopped if at all possible. Given the increasing incidence of cancer in the aging US population, an ongoing epidemic of obesity and diabetes, and the increasing population of patients receiving corticosteroid therapy for inflammatory diseases and/or solid organ or stem cell transplantation, it is not surprising that recent studies have reported alarming increases in the incidence of Mucormycosis.49–51 Clinicians will likely continue to encounter this disease more frequently in the coming years, especially in the nosocomial setting. Further research is needed regarding new diagnostic and therapeutic modalities for these devastating infections. In the meantime, improvement in patient outcomes will require a high index of suspicion and emergent diagnostic evaluation to allow early initiation of antifungal and surgical therapy.
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pathogenesis of Mucormycosis
Clinical Infectious Diseases, 2012Co-Authors: Ashraf S. Ibrahim, Thomas J. Walsh, Brad Spellberg, Dimitrios P KontoyiannisAbstract:Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat Mucormycosis are urgently needed. Understanding the pathogenesis of Mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of Mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to Mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.
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future directions in Mucormycosis research
Clinical Infectious Diseases, 2012Co-Authors: Dimitrios P Kontoyiannis, Brad Spellberg, Ashraf S. Ibrahim, Russell E Lewis, Oliver Lotholary, G Petrikkos, Emmanuel Roillides, Thomas J. WalshAbstract:Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of Mucormycosis are discussed in this article.
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combination therapy of murine Mucormycosis or aspergillosis with iron chelation polyenes and echinocandins
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Brad Spellberg, Samuel W French, John E Edwards, Teclegiorgis Gebremariam, Ashraf S. Ibrahim, Guanpingsheng LuoAbstract:Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with Mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of Mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with Mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against Mucormycosis and aspergillosis is warranted.
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recent advances in the treatment of Mucormycosis
Current Infectious Disease Reports, 2010Co-Authors: Brad Spellberg, Ashraf S. IbrahimAbstract:In recent years, substantial advances have been achieved in the treatment of Mucormycosis. It is now clear that early initiation of therapy results in substantially better outcomes, underscoring the need to maintain a high index of suspicion and aggressively biopsy potential lesions. Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for Mucormycosis. Posaconazole may be useful as salvage therapy, but cannot be recommended as primary therapy for Mucormycosis based on available data. Pre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during Mucormycosis. A definitive trial is needed to confirm these results. The use of the iron chelator, deferasirox, as adjunctive therapy also improved outcomes in animal models of Mucormycosis. However, its efficacy was not confirmed in a recent, phase 2 clinical trial. Additional study is required of the potential for abrogation of iron acquisition as adjunctive treatment of Mucormycosis. Combination polyene-posaconazole therapy was of no benefit in pre-clinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered in selected patients. Large-scale, prospective, randomized clinical trials are needed to define optimal management strategies for Mucormycosis.
John E Edwards - One of the best experts on this subject based on the ideXlab platform.
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Monotherapy or combination therapy of isavuconazole and micafungin for treating murine Mucormycosis.
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Teclegiorgis Gebremariam, John E Edwards, Nathan P Wiederhold, Abdullah Alqarihi, Priya Uppuluri, Nkechi Azie, Ashraf S. IbrahimAbstract:OBJECTIVES Previously we demonstrated the benefit of isavuconazole in treating murine Mucormycosis due to Rhizopus. We wanted to determine the efficacy of isavuconazole in treating murine Mucormycosis caused by Mucor, the second most common cause of the disease. Furthermore, because we previously determined that Rhizopus possesses the target enzyme for echinocandins and micafungin has activity against murine Mucormycosis, we compared the activity of combination therapy (isavuconazole + micafungin) with placebo, either drug alone or standard therapy of liposomal amphotericin B (LAmB) in treating pulmonary murine Mucormycosis caused by Rhizopus delemar. METHODS In vitro susceptibility to isavuconazole of Mucorales was evaluated using the CLSI M38-A2 method. Immunosuppressed mice were intratracheally infected with either Mucor circinelloides or R. delemar. Treatment with isavuconazole (orally), micafungin (intraperitoneally), a combination of both or LAmB (intravenously) was compared, with survival and tissue fungal burden serving as primary and secondary endpoints, respectively. RESULTS Isavuconazole was as effective as LAmB in prolonging survival of mice infected with M. circinelloides. Against R. delemar-induced Mucormycosis, all monotherapy treatments significantly improved survival of mice versus placebo without showing superiority over one another. However, LAmB was superior in lowering fungal burden in target organs. Although combination therapy of isavuconazole + micafungin did not enhance survival of mice over monotherapy, antagonism was not detected between the two drugs. CONCLUSION Isavuconazole is effective in treating pulmonary murine Mucormycosis due to Mucor. In addition, combination therapy of isavuconazole + micafungin does not demonstrate synergy and it is not antagonistic against Rhizopus-induced Mucormycosis.
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coth3 mediates fungal invasion of host cells during Mucormycosis
Journal of Clinical Investigation, 2014Co-Authors: Teclegiorgis Gebremariam, John E Edwards, Mingfu Liu, Guanpingsheng Luo, Quynh T Phan, Scott G Filler, Vincent M Bruno, Alan J Waring, Michael R Yeaman, Ashraf S. IbrahimAbstract:Angioinvasion is a hallmark of Mucormycosis. Previously, we identified endothelial cell glucose-regulated protein 78 (GRP78) as a receptor for Mucorales that mediates host cell invasion. Here we determined that spore coat protein homologs (CotH) of Mucorales act as fungal ligands for GRP78. CotH proteins were widely present in Mucorales and absent from noninvasive pathogens. Heterologous expression of CotH3 and CotH2 in Saccharomyces cerevisiae conferred the ability to invade host cells via binding to GRP78. Homology modeling and computational docking studies indicated structurally compatible interactions between GRP78 and both CotH3 and CotH2. A mutant of Rhizopus oryzae, the most common cause of Mucormycosis, with reduced CotH expression was impaired for invading and damaging endothelial cells and CHO cells overexpressing GRP78. This strain also exhibited reduced virulence in a diabetic ketoacidotic (DKA) mouse model of Mucormycosis. Treatment with anti-CotH Abs abolished the ability of R. oryzae to invade host cells and protected DKA mice from Mucormycosis. The presence of CotH in Mucorales explained the specific susceptibility of DKA patients, who have increased GRP78 levels, to Mucormycosis. Together, these data indicate that CotH3 and CotH2 function as invasins that interact with host cell GRP78 to mediate pathogenic host-cell interactions and identify CotH as a promising therapeutic target for Mucormycosis.
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combination therapy of murine Mucormycosis or aspergillosis with iron chelation polyenes and echinocandins
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Brad Spellberg, Samuel W French, John E Edwards, Teclegiorgis Gebremariam, Ashraf S. Ibrahim, Guanpingsheng LuoAbstract:Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with Mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of Mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with Mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against Mucormycosis and aspergillosis is warranted.
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the endothelial cell receptor grp78 is required for Mucormycosis pathogenesis in diabetic mice
Journal of Clinical Investigation, 2010Co-Authors: Mingfu Liu, Brad Spellberg, John E Edwards, Quynh T Phan, Amy S Lee, Scott G Filler, Ashraf S. IbrahimAbstract:Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of Mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause Mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to Mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to Mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from Mucormycosis. These results suggest a unique susceptibility of patients with DKA to Mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections.
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bacterial endosymbiosis is widely present among zygomycetes but does not contribute to the pathogenesis of Mucormycosis
The Journal of Infectious Diseases, 2008Co-Authors: Ashraf S. Ibrahim, Dimitrios P Kontoyiannis, John E Edwards, Christopher D Skory, Teclegiorgis Gebremariam, Mingfu Liu, Georgios Chamilos, Richard Mink, Kyung J Kwonchung, Brad SpellbergAbstract:Mucormycoses are infections caused by fungi belonging to the order Mucorales of the class Zygomycetes [1]. Rhizopus oryzae is the most common organism isolated from patients with Mucormycosis and is responsible for 60%–80% of all Mucormycosis cases [2, 3]. The standard therapy for invasive Mucormycosis includes reversal of predisposing factors (if possible), widespread surgical debridement, and antifungal therapy [2, 4, 5]. In the absence of surgical removal of the infected focus, antifungal therapy alone is rarely curative [2, 5]. Even when surgical debridement is combined with antifungal therapy, the mortality rate associated with Mucormycosis exceeds 50% [2]. In patients with prolonged neutropenia and in those with disseminated disease, mortality approaches 90%–100% [6–8]. Equally alarming are recent data demonstrating a striking increase in the incidence of Mucormycosis [7–10]. Because of its increasing incidence, unacceptably high mortality, and the extreme morbidity of highly disfiguring surgical therapy, it is imperative to look for new therapeutic modalities to treat Mucormycosis. Some Rhizopus species, especially the plant pathogen R. microsporus [11] and R. chinensis [12], are known for their ability to produce the mycotoxin rhizoxin, an antimitotic macrocyclic polyketide metabolite. Recent studies have demonstrated that rhizoxin is not biosynthesized by Rhizopus itself but rather by an intracellular, symbiotic bacterium of the genus Burkholderia [13]. This bacterium is sensitive to antibiotics belonging to the fluoroquinolone family. For example, production of rhizoxin was completely abrogated when Rhizopus was grown in medium containing 40 µg/mL ciprofloxacin [13]. This novel finding raises the possibility that Burkholderia may contribute to the pathogenesis of Mucormycosis and that fluoroquinolones might be beneficial in combination therapy of Mucormycosis. In the present study, we sought to define the role of bacterial endosymbionts in the pathogenesis of Mucormycosis. We screened for the presence of endosymbiotic bacteria in Zygomycetes isolates from patients with Mucormycosis and determined the effect of the endosymbiotic bacteria on the pathogenesis of Mucormycosis in vitro and in vivo.
Thomas J. Walsh - One of the best experts on this subject based on the ideXlab platform.
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tacrolimus enhances the potency of posaconazole against rhizopus oryzae in vitro and in an experimental model of Mucormycosis
The Journal of Infectious Diseases, 2013Co-Authors: Russell E Lewis, Thomas J. Walsh, Ronen Benami, Leyla Best, Nathaniel D Albert, Dimitrios P KontoyiannisAbstract:Background. We hypothesized that tacrolimus, an inhibitor of the calcineurin pathway, would enhance the in vivo activity of posaconazole against Rhizopus oryzae, the Mucorales species most commonly associated with Mucormycosis. Methods. We examined patterns of growth inhibition and fungicidal activity of posaconazole and tacrolimus, alone and in combination, against R. oryzae in vitro, using multiple methods (ie, hyphal metabolic and fluorescent vital dye reduction assays and measurement of chitin concentrations), and in vivo, using 2 Mucormycosis models: an invertebrate model (Drosophila) and a nonlethal murine model of cutaneous Mucormycosis. Results. Combinations of posaconazole and tacrolimus were synergistic in checkerboard assays for 4 clinical isolates of R. oryzae (48-hour fractional inhibitory concentration index, 0.187–0.281). Pharmacodynamic analysis of the combination revealed that the 90% effective concentration threshold of posaconazole activity against R. oryzae could be achieved with 2-fold lower drug concentrations (0.5–1 mg/L) when administered with tacrolimus (0.007–2 mg/L). In vivo, combination therapy was associated with improved survival in the fly model of Mucormycosis (65% vs 57% posaconazole alone) and with significant reductions in cutaneous lesions and R. oryzae fungal burden, compared with animals that received posaconazole monotherapy, in the cutaneous model of Mucormycosis. Conclusions. Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of Mucormycosis.
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Rhino-Orbital-Cerebral Mucormycosis
Current Infectious Disease Reports, 2012Co-Authors: Maria N. Gamaletsou, Emmanuel Roilides, Nikolaos V. Sipsas, Thomas J. WalshAbstract:This review focuses on sinus, sino-orbital, and rhinocerebral infection caused by the Mucorales. As the traditional term of “rhinocerebral” Mucormycosis omits the critical involvement of the eye, the more comprehensive term as rhino-orbital-cerebral Mucormycosis (ROCM) is used. The most common underlying illnesses of ROCM are diabetes mellitus, hematological malignancies, hematopoietic stem cell transplantation, and solid organ transplantation. Sporangiospores are deposited in the nasal turbinates and paranasal sinuses in immunocompromised patients. Qualitative and quantitative abnormalities of neutrophils, monocytes and macrophages increase the risk for development of Mucormycosis. Altered iron metabolism also is a critical factor in the pathogenesis of patients with diabetes mellitus who are at risk for ROCM. Angioinvasion with thrombosis and tissue necrosis is a key pathophysiological feature of human Mucorales infection. The ethmoid sinus is a critical site from which sinus Mucormycosis may extend through the lamina papyracea into the orbit, extraocular muscles, and optic nerve. The brain may be seeded by invasion of the ethmoidal and orbital veins, which drain into the cavernous sinuses. Diplopia and ophthalmoplegia may be the earliest manifestations of cavernous sinus syndrome before changes are apparent on diagnostic imaging modalities. Negative diagnostic imaging does not exclude cavernous sinus Mucormycosis. Mucormycosis of the maxillary sinus has a constellation of clinical features that are different from that of ethmoid sinus Mucormycosis. A painful black necrotic ulceration may develop on the hard palate, indicating extension from the maxillary sinus into the oral cavity. Orbital apex syndrome is an ominous complication of Mucormycosis of the orbit. Once within the orbital compartment, organisms may extend posteriorly to the optic foramen, where the ophthalmic artery, ophthalmic nerve and optic nerve are threatened by invasion, edema, inflammation and necrosis. Early diagnosis of sinus Mucormycosis is critical for prevention of extension to orbital and cerebral tissues. Optimal therapy requires a multidisciplinary approach that relies on prompt institution of appropriate antifungal therapy with amphotericin B, reversal of underlying predisposing conditions, and, where possible, surgical debridement of devitalized tissue. Outcomes are highly dependent upon the degree of immunosuppression, site and extent of infection, timeliness of therapy, and type of treatment provided. New modalities for early diagnosis and therapeutic intervention are critically needed for improved outcome of patients with ROCM.
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epidemiology and clinical manifestations of Mucormycosis
Clinical Infectious Diseases, 2012Co-Authors: George Petrikkos, Thomas J. Walsh, Olivier Lortholary, Anna Skiada, Emmanuel Roilides, Dimitrios P KontoyiannisAbstract:Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, Mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of Mucormycosis.
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pathogenesis of Mucormycosis
Clinical Infectious Diseases, 2012Co-Authors: Ashraf S. Ibrahim, Thomas J. Walsh, Brad Spellberg, Dimitrios P KontoyiannisAbstract:Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat Mucormycosis are urgently needed. Understanding the pathogenesis of Mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of Mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to Mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.
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future directions in Mucormycosis research
Clinical Infectious Diseases, 2012Co-Authors: Dimitrios P Kontoyiannis, Brad Spellberg, Ashraf S. Ibrahim, Russell E Lewis, Oliver Lotholary, G Petrikkos, Emmanuel Roillides, Thomas J. WalshAbstract:Mucormycosis has emerged as an important opportunistic infection, especially in severely immunosuppressed hosts. The evolving epidemiology, immunopathogenesis, molecular virulence studies, early diagnosis, and pitfalls in designing clinical studies of Mucormycosis are discussed in this article.
