Hyperbaric oxygen therapy as an adjunctive treatment for COVID-19-associated mucormycosis: a report of two cases. / Oxigenoterapia hiperbárica como tratamiento complementario en mucormicosis asociada con la COVID-19: a propósito de dos casos.

OBJECTIVE.: We present the first two cases reported in Peru of the use of adjuvant hyperbaric oxygen therapy (HBOT) in patients with COVID-19-associated mucormycosis (CAM). The first case is a 41-year-old woman, with pain in the left side of the face and palatine region with purulent rhinorrhea for a month. Only an oroantral fistula was found during physical examination. The second case is a 35-year-old male, with decreased left visual acuity and palatal pain with a fistula, draining purulent secretion for four months. Both patients have history of diabetes, had moderate COVID-19 four months prior to admission, and received corticosteroid therapy for this diagnosis. Tomographic evaluation of both patients showed involvement of the maxillary sinus and surrounding bone tissue; both received diagnostic and therapeutic nasal endoscopy for debridement. Histological analysis showed that the samples were compatible with mucormycosis. The patients underwent debridement and were treated with amphotericin B deoxycholate; however, they presented torpid evolution. Then, HBOT was added and the patients showed an evident improvement after four weeks of treatment with subsequent controls without the presence of mucormycosis. We highlight the favorable evolution of these patients while receiving HBOT as treatment for a disease with high morbimortality, which emerged during the pandemic.

Perturbations of immune landscape in COVID-19 associated mucormycosis.

BACKGROUND: A rise in secondary fungal infections during the COVID-19 pandemic necessitates a deeper understanding of the associated immunological perturbations. OBJECTIVES: To evaluate the clinical and immunological characteristics observed in patients with COVID-19 associated mucormycosis (CAM) infection. PATIENTS/ METHODS: Cases of mucormycosis with or post-COVID-19 infection were compared with cases of acute COVID-19 and convalescent COVID-19. Lymphocyte subsets, cytokines and other laboratory markers were compared between the groups. RESULTS: The frequency of proposed risk factors for CAM was diabetes mellitus (77%), recent history of steroid use (69%) and hypoxia during COVID-19 infection (52%). Iron metabolism was dysregulated in CAM patients with low TIBC and total iron. Further, CAM was accompanied with lymphopenia with drastic reduction in B cell counts; however, plasmablasts were not altered. Further, CAM patients had low immunoglobulin levels and antibodies specific to mucor peptide did not increase in CAM suggesting dysfunction in B-cell response. There was increase in activated effector cytotoxic CD8 T cells and NK cells in CAM compared with COVID-19 infection and healthy controls. Among T helper cells, Tregs were reduced and Th-1 frequency was increased in CAM compared with COVID-19 infection. A distinct cytokine signature was evident in CAM with increase in IL-1ß, IFN-γ, IL-6, IL-22, IL-17A, IL-10, IL-2, IL-8, IL-7, IL-21 and GM-CSF. CONCLUSION: This is the first study on immunophenotyping in CAM suggesting the need for long-term monitoring of B-cell function after SARS-CoV-2 in patients with dysregulated glycaemic control and the possible benefit of therapeutic supplementation with intravenous immunoglobulins in CAM.

Neem and Turmeric in the management of Covid Associated Mucormycosis (CAM) derived through network pharmacology.

Mucormycosis or 'Black Fungus' has been known to target immunocompromised individuals even before the emergence of COVID-19. Nevertheless, the present circumstances provide the best opening for Covid Associated Mucormycosis (CAM), as the global pandemic is engulfing a large part of human population making them immunocompromised. This drastic increase in Mucormycosis infections has to be addressed as early as possible. There is a growing tendency of relying upon herbal drugs that have minimal side effects and does not compromise our immune system. Recently, the concept of network pharmacology has grabbed the attention of modern science, especially advanced medical sciences. This is a new discipline that can use computational power to systematically catalogue the molecular interactions between botanical formulations and the human body. In this study, Neem and Turmeric was considered as the target plants and an attempt was made to reveal various aspects through which phytocompounds derived from them may effectively manage CAM menace. We have taken a step-by-step approach for identifying the target proteins and ligands associated with Mucormycosis treatment. Functional network analysis and Molecular docking approaches were applied to validate our findings. Quercetin derived from both Neem and Turmeric was found to be one of the main phytocompounds working against Mucormycosis. Along with that, Caffeic acid, Curcumin, Kaempferol, Tetrahydrocurcumin and Myricetin also play a pivotal role in fighting against Black-Fungus. A thorough analysis of our result suggested a triple-front attack on the fungal pathogens and the approaches are necrosis inhibition, iron chelation and immuno-boosting.Communicated by Ramaswamy H. Sarma.

Mucormycosis an added burden to Covid-19 Patients: An in-depth systematic review.

As of 25th July, 2022, global Disease burden of 575,430,244 confirmed cases and over 6,403,511 deaths have been attributed to coronavirus disease 2019 (COVID-19). Co-infections/secondary infections continue to plague patients around the world as result of the co-morbidities like diabetes mellitus, biochemical changes caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) especially significant elevation in free iron levels, immune suppression caused by SARS-CoV-2, and indiscriminate use of systemic corticosteroids for the treatment of severe COVID-19 disease. In such circumstances, opportunistic fungal infections pose significant challenge for COVID-19 disease therapy in patients with other co-morbidities. Although COVID-19-associated Mucormycosis (CAM) has been widely recognized, currently extensive research is being conducted on mucormycosis. It has been widely agreed that patients undergoing corticosteroid therapy are highly susceptible for CAM, henceforth high index of screening and intensive care and management is need of an hour in order to have favorable outcomes in these patients. Diagnosis in such cases is often delayed and eventually the disease progresses quickly which poses added burden to clinician and increases patient load in critical care units of hospitals. A vast perusal of literature indicated that patients with diabetes mellitus and those with other co-morbidities might be highly vulnerable to develop mucormycosis. In the present work, the case series of three patients presented at Chest Disease Hospital Srinagar, Jammu and Kashmir infected with CAM has been described with their epidemiological data in supplementary section. All these cases were found to be affected with co-morbidity of Diabetes Mellitus (DM) and were under corticosteroid therapy. Furthermore, given the significant death rate linked with mucormycosis and the growing understanding of the diseases significance, systematic review of the literature on CAM has been discussed and we have attempted to discuss emerging CAM and related aspects of the disease.

Mucormicosis asociada a COVID-19: revisión de la literatura para odontólogos / COVID-19 associated mucormycosis: a literature review for dentists

La mucormicosis es una infección fúngica rara, con alta morbilidad y mortalidad. Se presenta principalmente en pa- cientes con diabetes mellitus no controlada, inmunocompro- metidos, con tratamiento crónicos con esteroides, entre otros. Actualmente, se cree que la pandemia de COVID-19 y los tratamientos con corticosteroides podrían estar implicados en el aumento de casos de esta micosis. Este hongo invade el sistema vascular, ocluyendo el flujo sanguíneo arterial y generando una rápida trombosis e isque- mia, lo que provoca la necrosis de los tejidos duros y blandos, con invasión rápida a los tejidos circundantes. Hay varias formas clínicas. En la cavidad bucal se presenta la variante rino-orbito-cerebral, que afecta el paladar en forma de lesión eritematosa o grisácea que puede progresar hacia la formación de una masa necrótica o ulceración con muy escaso sangrado de mucosa. Se manifiesta con síntomas típicos de una rinosinusitis con fiebre y dolor en las piezas dentarias superiores. El tratamiento consta de tres pilares fundamentales: el diagnóstico, un manejo adecuado de las comorbilidades y la combinación de las terapias antifúngica y quirúrgica. Desde el año 2020, la mucormicosis asociada a COVID-19 pasó a ser un evento de notificación obligatoria inmediata al Sistema Nacional de Vigilancia de la Salud (SNVS2.0) me- diante el Sistema Integrado de Información Sanitaria Argen- tina (SISA). Es importante destacar que se han reportado casos de mu- cormicosis luego de extracciones dentales; lo que impulsa a afianzar los conocimientos sobre esta enfermedad, extremar las medidas preventivas e incentivar el diagnóstico precoz en la atención odontológica, debido a la rapidez en la evolución de la patología (AU))

Mucormycosis is a rare fungal infection, with high mor- bidity and mortality. It occurs mainly in patients with uncon- trolled diabetes mellitus, immunocompromised, on chronic treatment with steroids, among others. Currently, it is believed that the COVID-19 pandemic and the corticosteroid treatments could be one of the causes of increased cases. This fungus invades the vascular system, occluding arteri- al blood flow and generating rapid thrombosis and ischemia, which causes necrosis of hard and soft tissues, with rapid in- vasion to the surrounding tissues. There are several clinical forms. In the oral cavity, the rhino-orbito-cerebral variant presents itself affecting the pal- ate in the form of an erythematous or grayish lesion that can progress towards the formation of a necrotic mass or ulcera- tion with very little mucosal bleeding. It manifests itself with typical symptoms of rhinosinusitis, with fever and pain in the upper teeth. The treatment consists of three fundamental pillars: diag- nosis, proper management of comorbidities and the combina- tion of antifungal and surgical therapies. Since 2020, COVID-19 associated mucormycosis became an event of mandatory immediate notification to the National Health Surveillance System (SNVS2.0,) through the Argentina Integrated Health Information System (SISA). It is important to emphasize that mucormycosis cases had been reported following tooth extractions, which drives to strengthen knowledge about this disease, extreme preventive measures and encourage early diagnosis in dental care, due to the speed of the evolution of the pathology (AU))

Adjunctive use of saturated solution of potassium iodide (SSKI) with liposomal amphotericin B (L-AMB) in mucormycosis achieves favorable response, shortened dose and duration of amphotericin: A retrospective study from a COVID-19 tertiary care center.

PURPOSE: Second wave of COVID-19 pandemic was associated with an unprecedented rise in cases of mucormycosis, treatment of which has been challenging owing to the availability and side effects associated with amphotericin. METHODS: All patients presenting with rhino-orbital cerebral mucormycosis (ROCM) following COVID-19 infection between April 2021 to June 2021 were included in this retrospective interventional study. Primary objective was to assess the clinical response with combination of intravenous liposomal amphotericin B (4-5 mg/kg/day) and saturated solution of potassium iodide (SSKI) given orally along with surgical debridement. RESULTS: Twenty-five patients of ROCM were treated with the regimen. Mean age and fasting blood sugar levels were 53.48 years and 239.64 mg/dL respectively. All patients had history of intake of steroids with a mean daily dose of 86.39 mg of prednisolone equivalent. 88% of patients had a "proven" diagnosis of mucormycosis. Cultures were positive in 52% of patients with Rhizopus arrhizus as the predominant species. The mean daily dose of amphotericin received was 268 mg/day with a mean duration of 9.52 days. Mean daily dose of SSKI was 2.57 g. 21 patients (84%) had stabilization of disease at week 8 and achieved cure at the end of treatment whereas the mortality rate was 16%. Factors that significantly affected outcome were eye and central nervous system (CNS) involvement on presentation. CONCLUSION: SSKI, with its remarkably low cost and safety profile, makes it a potential adjuvant drug that may help achieve the twin benefits of shortened duration and dose of LAMB.

Local Infiltration Anesthesia for Orbital Exenteration in Patients With Rhino-Orbital Cerebral Mucormycosis: A Case Series.

Orbital exenteration is occasionally required for rhino-orbital cerebral mucormycosis. Multiple associated comorbidities can pose a risk for general anesthesia. There is only 1 report of exenteration being performed under trigeminal nerve block. We describe 5 patients who underwent orbital exenteration under local infiltration anesthesia with sedation. Patients and surgeons reported satisfactory conditions, with stable hemodynamics and successful day care management. Orbital exenteration under local infiltration anesthesia can be a safe and effective alternative for patients with rhino-orbital mucormycosis who are at risk with use of general anesthesia.

Antimycotic Activity of Some Medicinal Plants against Mucor circinelloides.

The in vitro antimycotic activity of the leaf extract of Catharanthus roseus, Lantana camara, Nerium indicum, Sida cordifolia, and Ziziphus mauritiana was studied against M. circinelloides. This fungal species causes mucormycosis (black fungus). Presently, mucormycosis is affecting COVID patients due to prolonged use of steroids. So, it is needed to require development of more effective and less toxic antimycotic agents for the treatment of mucormycosis. Plants and their extraction preparations have been used as medicine against infectious disease. In this research, aqueous, ethanol, and DMSO (dimethyl sulfoxide) leaf extracts were used for antimycotic activity. All leaf extracts of selected medicinal plants recorded significant activity against M. circinelloides. Ethanol leaf extract of C. roseus showed the highest antimycotic activity followed by N. indicum and L. camara. Z. mauritiana which showed moderate activity against M. circinelloides.

Anu taila, an herbal nasal drop, suppresses mucormycosis by regulating host TNF-α response and fungal ergosterol biosynthesis.

AIM: The intractable, mucormycosis, caused by Mucorales primarily targets immunocompromised individuals. The first-line therapy, intravenous liposomal amphotericin B and surgical debridement of necrotic tissue, is contraindicative in individuals with compromised kidneys. This invokes a pressing need to identify safer treatment options. METHODS AND RESULTS: The antifungal effect of the classical nasal drop, Anu taila, against Mucor spp. was investigated through microbiological, cytological, analytical chemical (HPLC and GS-MS/MS) and scanning electron microscopic (SEM) approaches. Anu taila-pretreated spores germinated late, resulting in reduced infectivity, observed as milder monocytic immune response. Conversely, Anu taila-pretreated human THP-1 cells exhibited an improved immune response against Mucor spores, through TNF-α. Repeated Anu taila application rapidly abolished fungal microarchitectures than amphotericin B, evident from swift replacement of hyphae, sporangiophores and sporangia with fused biomass, in the SEM images. HPLC analysis showed that Anu taila treatment significantly reduced overall ergosterol content in Mucor biomass. Anu taila also downregulated sterol-C5-desaturase-coding ERG3 gene, crucial for ergosterol biosynthesis and resultant structural integrity, in Mucor spp. CONCLUSION: Taken together, Anu taila was found effective against Mucor spp., with both prophylactic and curative implications, which is attributable to the phytochemical composition of this classical nasal drop. SIGNIFICANCE AND IMPACT STATEMENT: The potential remedial effects of a classical nasal drop against an obdurate and challenging fungal infection are identified.

Online Registry of COVID-19-Associated Mucormycosis Cases, India, 2021.

We established an online registry of coronavirus disease-associated mucormycosis cases in India. We analyzed data from 65 cases diagnosed during April-June 2021, when the Delta variant predominated, and found that patients frequently received antibacterial drugs and zinc supplementation. Online registries rapidly provide relevant data for emerging infections.

[Mucormycosis: Current and future management perspective]. / Mucormicosis: perspectiva de manejo actual y de futuro.

Infections caused by mucorales, with an increasing incidence after candidiasis and aspergillosis, are characterized by the fast angioinvasion of blood vessels and invasion of neighboring organs or structures. Mucorales most commonly cause rhinocerebral, pulmonary, cutaneous, digestive or disseminated infections, and their spread is favored by certain underlying diseases (diabetes, kidney failure) and risk factors (neutropenia, immunosuppression, iron overload). These infections have a high mortality rate, over 40% in many series, and the key to their cure depends on both an early diagnosis and an antifungal treatment, associated in most cases with extensive surgical debridement and other adjunctive therapies. Currently, there are international guidelines, not only local ones, for the management of mucormycosis, in which it is considered by consensus and with a strong recommendation that first-line treatment with high-dose liposomal amphotericin B is the best choice. The combined antifungal treatment of polyene agents with triazoles or candins remains in open debate.

Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus.

Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 µg/ml) and low (0.25 µg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.

Rhizopus Infection in a Preterm Infant: A Novel Use of Posaconazole.

Posaconazole is a triazole antifungal with activity against Rhizopus, but data on its use and pharmacokinetics in preterm infants are scarce. In this case, a 24 4/7-week neonate's Rhizopus infection is successfully treated with debridement and combination antifungal therapy with amphotericin B, micafungin and enteral posaconazole. This is the first reported posaconazole use in a preterm neonate with Rhizopus.

Antifungal combinations in Mucorales: A microbiological perspective.

Mucormycosis mostly affects immunocompromised patients and is associated with a high morbidity and mortality despite currently available treatments. In that context, combination therapy might be the key to a better outcome for these patients. Purpose of this review is to summarise and to discuss the current combination data obtained in vitro, in vivo in animal models of mucormycosis, and in patients. In vitro combination studies showed that most of the interactions between antifungal drugs were indifferent, even though that some synergistic interactions were achieved for the combination of echinocandins with either azoles or amphotericin B. Importantly, antagonism was never observed. Animal models of mucormycosis focused on infections caused by Rhizopus arrhizus, neglecting most other species responsible for human disease. In these experimental animal models, no strong interactions have been demonstrated, although a certain degree of synergism has been reported in some instances. Combinations of antifungals with non-antifungal drugs have also been largely explored in vitro and in animal models and yielded interesting results. In patients with ketoacidosis and rhino-orbito-cerebral infection, combination of polyene with caspofungin was effective. In contrast, despite promising experimental data, adjunctive therapy with the iron chelator deferasirox was unfavourable and was associated with a higher mortality than monotherapy with liposomal amphotericin B. More combinations have to be tested in vitro and a much larger panel of Mucorales species has to be tested in vivo to give a valuable statement if antifungal combination therapy could be an effective treatment strategy in patients with mucormycosis.

Galleria mellonella as a model system to study virulence potential of mucormycetes and evaluation of antifungal treatment.

Mucorales can cause cutaneous to deep-seated infections, mainly in the immunocompromised host, resulting in high mortality rates due to late and inefficient treatment. In this study, Galleria mellonella larvae were evaluated as a heterologous invertebrate host to study pathogenicity of clinically relevant mucormycetes (Rhizopus spp., Rhizomucor spp., Lichtheimia spp., Mucor spp.). All tested species were able to infect G. mellonella larvae. Virulence potential was species-specific and correlated to clinical relevance. Survival of infected larvae was dependent on (a) the species (growth speed and spore size), (b) the infection dose, (c) the incubation temperature, (d) oxidative stress tolerance, and (e) iron availability in the growth medium. Moreover, we exploited the G. mellonella system to determine antifungal efficacy of liposomal amphotericin B, posaconazole, isavuconazole, and nystatin-intralipid. Outcome of in vivo treatment was strongly dependent upon the drug applied and the species tested. Nystatin-intralipid exhibited best activity against Mucorales, followed by posaconazole, while limited efficacy was seen for liposomal amphotericin B and isavuconazole. Pharmacokinetic properties of the tested antifungals within this alternative host system partly explain the limited treatment efficacy. In conclusion, G. mellonella represents a useful invertebrate infection model for studying virulence of mucormycetes, while evaluation of treatment response was limited.

Isavuconazole: A new broad-spectrum azole. Part 2: pharmacokinetics and clinical activity.

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.

Multimodal Treatment of Rhinocerebral Mucormycosis in a Pediatric Patient With Relapsed Pre-B Acute Lymphoblastic Leukemia.

A 17-year-old girl developed invasive rhinocerebral mucormycosis during intensive re-induction chemotherapy for relapsed pre-B acute lymphoblastic leukemia. Due to the high case fatality rate for invasive mucormycosis in profoundly immunosuppressed patients, an aggressive treatment regimen was pursued. In addition to the standard of care treatments with intravenous amphotericin and aggressive surgical debridements, she received intraventricular amphotericin to the brain via an Ommaya reservoir, hyperbaric oxygen treatments, filgrastim, intravenous immunoglobulin and antifungal in vitro synergy testing to allow for more targeted antifungal therapy with the addition of micafungin. After a 3-month treatment course, it was determined that her mucormycosis was under appropriate control, allowing her to continue treatment for her leukemia with hematopoietic stem cell transplant with a plan for continued intravenous antifungal therapy through engraftment.

Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection.

We compared prophylactic or continuous therapy with the investigational drug VT-1161 to that with posaconazole in treating murine mucormycosis due to Rhizopus arrhizus var. arrhizus In the prophylaxis studies, only VT-1161 resulted in improved survival and lowered tissue fungal burden of immunosuppressed infected mice. In the continuous therapy, VT-1161 outperformed posaconazole in prolonging mouse survival time despite its comparable effect in lowering tissue fungal burden. These results support the further development of VT-1161 against mucormycosis.

Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis.

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.

Successful Treatment of Rhino-Orbital-Cerebral Mucormycosis in a Child With Leukemia.

Rhino-orbital-cerebral mucormycosis (ROCM) is a rare fulminant opportunistic fungal infection that despite relevant treatment has high mortality. We present a case of a 3-year-old girl with acute lymphoblastic leukemia and ROCM, who was treated successfully with excessive surgery, systemic antifungal treatment with amphotericin B (AmB), posaconazole, and terbinafine as well as hyperbaric oxygen. Surgery included, beside extracranial and intracranial removal of infected areas, endoscopic sinus and skull base surgery with local AmB installation and in addition placement of an Ommaya reservoir for 114 intrathecal administrations of AmB. In addition, we review the literature of ROCM in pediatric patients with hematological diseases.