Combination Of Liposomal Amphotericin Research Articles

Covid-Associated Mucormycosis in a Case of Wegener's Granulomatosis: A Management Challenge.

A Gentleman in his 40s presented to us with left-sided hemifacial pain and nasal discharge for the last three days. He has been on immunosuppressive therapy for Wegener's Granulomatosis for over five years. Crusting was seen in the Left middle meatus upon clinical examination. Based on the post-covid status, steroid therapy, KOH mount, and radiologic imaging, a provisional diagnosis of Sinonasal mucormycosis was considered. He was posted for emergency debridement followed by Liposomal Amphotericin B and steroid therapy. Surgical histopathological specimens were suggestive of Mucormycosis. Limited sinonasal disease with no intracranial, orbital, or palatal involvement was seen in a background of Wegener's Granulomatosis, Covid, and immunosuppressive therapy. Steroids are condemned as a predisposing factor to mucormycosis. Still, the combination of Liposomal Amphotericin B and steroids was used, opening new avenues for managing mucormycosis in patients with vasculitis. The patient is well nine months post-surgery with no signs of disease relapse.

Efficacy of combination therapy of amphotericin and posaconazole in treatment of mucormycosis

Background: Mucormycosis is an opportunistic systemic fungal infection which is debilitating caused by order Mucorales. The standard management of mucormycosis consists of aggressive debridement of the infected tissue and parenteral anti-fungal therapy with Amphotericin B. Liposomal amphotericin B is a “true” liposomal formulation of amphotericin B with greatly reduced nephrotoxicity and minimal infusion-related toxicity. Very minimal data is available on the usefulness of combining different antifungal agents for an effective outcome. Our study was undertaken at a time when there was a huge turnover of mucormycosis cases during Covid 19 pandemic with resultant shortage of important resources including liposomal amphotericin B. In effect, combination of liposomal amphotericin B with posaconzole gave a promising outcome. Objectives: To study the efficacy of combination therapy of liposomal amphotericin B and posaconazole in the treatment of mucormycosis. Methodology: It is a prospective study of 43 patients with mucormycosis who received combination therapy based on their disease severity. Results: In our study, 16 (37%) were considered as patients with mild disease, 18 (41.8%) were considered as patients with moderate disease and 9 patients (20.9%) were considered as severe. 20 (58%) patients out of 34 patients with mild to moderate disease showed improvement after combination therapy. Conclusion: A significant percentage of patients in our study showed improvement with combination therapy of liposomal amphotericin B and posaconazole in terms of survival and disease recurrence.

Mortality, morbidity and sequelae of COVID-associated mucormycosis; 18 months follow up study

Background: The second wave of the COVID-19 pandemic in India was associated with an increased incidence of rhino-orbital-cerebral mucormycosis. The objective of this paper was to prospectively explore the epidemiology, management, and results of 18 months follow-up of patients presenting with COVID associated mucormycosis at a tertiary referral centre in India. Methods: Patients presenting with symptoms suggestive of COVID-associated mucormycosis over two months were included in the study. Patients were staged based on the extent of the disease. Surgery was the primary modality of treatment except in those with intracranial spread, altered sensorium, and poor prognosis. A combination of liposomal amphotericin B and posaconazole was used as adjunct medical treatment. Patients were followed up and outcomes at one year of treatment were recorded. Results: Out of a total of 26 patients who were diagnosed with COVID associated mucormycosis, 21 patients underwent bimodality treatment (medical and surgical). The extent of surgery was based on the stage of the disease. Six eyes received retrobulbar injections of Amphotericin B to salvage vision. The overall mortality was 38.46% and 23.8% in those where the intent of treatment was curative. At the end of one year, 16 of 21 operated patients survived with mild to severe sequelae. Conclusions: Mucormycosis is a deadly fungal infection with high mortality. Early diagnosis and prompt, aggressive treatment is paramount in preventing mortality. A multidisciplinary approach is useful for effective management. Continuous follow up is paramount to identifying and treating complications.

Cryptococcal Meningitis with Inadequate Response to Antifungal Therapy or Drug-Induced Side Effects That Make It Difficult to Continue Treatment: Eleven Clinical Issues in Medical Practice

Cryptococcal meningoencephalitis is mainly caused by Cryptococcus neoformans and accounts for 90% of fungal meningitis cases in Japan. Cryptococcal meningoencephalitis is a rare disease, and similar to tuberculosis meningitis. It often exhibits subacute or chronic progression symptoms such as headache, fever, coma, personality changes, and memory disturbance. Cryptococcal meningoencephalitis often develops in immunosuppressed hosts, but can sometimes occur in healthy individuals, and the mortality rate is 10-25%, indicating a poor prognosis. For the treatment of cryptococcal meningoencephalitis, introduction therapy using a combination of liposomal amphotericin B and flucytosine is recommended. However, in practice, cryptococcal meningoencephalitis is refractory and often requires prolonged treatment; therefore, it is the most difficult to treat among the central nervous system infections. We discuss the following 11 issues: I. Sustainability of first-line treatments, II. Treatment options in case of decreased renal function, III. Association with increased intracranial pressure IV. Causes of visual impairment, V. Necessary steps when symptoms/laboratory findings worsen during antifungal treatment, VI. Cerebral infarction, VII. Difficulty in controlling underlying and comorbid diseases, VIII. Indications for lumbar and ventricular drainage (Ommaya reservoir placement), IX. Pros and cons of concomitant use of corticosteroids, X. Treatment evaluation index: usefulness of head MRI, and XI. Determining the end of treatment and the need for preventive medication.

Dexamethasone Induced Sino-Orbital Mucormycosis In a Patient Infected With COVID-19.

Background:The most common causes of immunodeficiency are iatrogenic and the result of the widespread use of therapies which modulates the immune system, whether they are planned or haphazardly. Mucormycosis is an invasive fungal disease which is usually secondary to immunosuppression, diabetic ketoacidosis, and long-term use of antibiotics, corticosteroids, and cytotoxic drugs. There are researches which show patients with coronavirus disease 2019 (COVID-19), especially severely ill or immunocompromised, are more likely to suffer from invasive fungal infections. Patients with diabetes are at a higher risk for severe COVID-19 outcomes. However, there has been no clear evidence on the relationship between pre-diabetes state and mucormycosis as a complication of SARS-CoV-2 infection so far.Case Presentation:Here, we report a case of sino-orbital mucormycosis in a pre-diabetic 54-year-old female without any underlying diseases. The patient suffered from COVID-19 pneumonia. She received 8 mg dexamethasone for 12 days. Afterwards, she returned three days after her discharge with a complaint of pre-orbital cellulitis, unilateral facial numbness and decreased visual acuity. Therefore, after primary diagnostic imaging, she was regarded as a candidate for invasive surgical intervention and was consequently treated with a combination of liposomal amphotericin B, radical recurrent surgery and posaconazole.Conclusion:It is very important to consider patients who are in the pre-diabetic state or possibly immunocompromised before prescribing steroids. The patients should be examined for invasive fungal infections in post-discharge period.

“Mucormycosis” the Emerging Global Threat; Overview and Treatment Outcome Among Pediatric Cancer Patients in Egypt

Background: Mucormycosis is a serious emerging fungal infection. Unlike invasive aspergillosis, the prognosis and outcome of hematologic malignancy patients who develop invasive Mucormycosis have not significantly improved over the past decade.The aim of the study was to evaluate clinical characteristics and treatment outcome in pediatric oncology patients with Mucormycosis in children cancer hospital 57357, Cairo, Egypt. Patients and Methods: A retrospective study during the period from 2007 to 2016. Data collected included patients' demographics, diagnosis, risk factors, diagnostic work up, antifungal treatment given and treatment outcome. Diagnosis was made according to the EORTC/MSG modified criteria (2008). Results: During the study period, 45 patients developed proven Mucormycosis. Mean age was 8 years (range 2-17). Male to female ratio 1:1. Diagnosis of Mucormycosis was highest among patients with hematological malignancies (90%). Twenty-two cases of acute myeloid leukemia (49%), 17 cases acute lymphoblastic leukemia (37%), and 1 case of CML post-transplant. The other 10% were having solid malignancies. Sinus involvement has been documented in (55.5%) representing the sole localization in 16 cases. The other 9 patients had secondary localizations; 2 central nervous system (Rhino-cerebral) and 7 lung (Sino-pulmonary) cases. Other primary sites of infection were: Pulmonary, Cutaneous and Gastrointestinal in (13.3%), (8.8%) and (11%) respectively. Disseminated disease was seen in 5 cases (11%). All patients had infection documented by histopathology or/and culture. Diagnosis was reported by histopathology in 38 patients (84%), blood culture in 2 patients (4 %) and both culture and histopathology in 5 patients (12%). At time of diagnosis, 15 patients (33%) were on Voriconazole prophylaxis (n =13) or Micafungin (n= 2). Liposomal Amphotercin -B 5mg/kg/day was the mainstay of treatment with duration ranging from 3 to 4 weeks. Posaconazole was used as secondary prophylaxis in 35 % of cases mainly for patients with hematological malignancies. Combination of liposomal amphotericin B with caspofungin was used in 3 cases with progressive Mucormycosis. Surgical intervention was achievable in 50 % of cases; sinus debridement in 11 cases, lung lobectomy in 3 cases, intestinal resection anastomosis in 5 cases and debridement of necrotic lesion in 4 cases. Therapy was successful in 30 patients (66%). Co-Morbidities related to Mucormycosis was seen in 5 cases with disfigurement, and perforated hard palate. Chemotherapy delay with subsequent relapse of primary malignancy was reported in 1 case. Mucormycosis was the primary cause of death in 15 cases (34%). Gastrointestinal and disseminated Mucormycosis was independent risk factors for mortality. Conclusion: Early diagnosis of Mucormycosis infection, with rapid initiation of appropriate antifungal therapy and surgical intervention, whenever feasible, are the back bone of decreasing Mucormycosis-related mortality and morbidity among pediatric cancer patients. Disseminated and gastrointestinal Mucormycosis had higher risk for mortality. DisclosuresNo relevant conflicts of interest to declare.

Successful Treatment of Rhinocerebral Mucormycosis with Combination of Liposomal Amphotericin B and Caspofungin (LAmB-C): An Anecdotal Clinical Experience that Deserves Further Investigations

Successful Treatment of Rhinocerebral Mucormycosis with Combination of Liposomal Amphotericin B and Caspofungin (LAmB-C): An Anecdotal Clinical Experience that Deserves Further Investigations

Dusky violaceous necrotic plaques of the chest

Dusky violaceous necrotic plaques of the chest

An unusual case of tropical pyomyositis: cryptococcal pyomyositis

The more common manifestations of cryptococcal infections are restricted to the central nervous system and lungs. A young man, suffering from idiopathic dilated cardiomyopathy with a left ventricular ejection fraction of 20%, presented with subacute, painful tender swelling in both legs initially attributed to congestive cardiac failure. No response to diuretics was achieved. Metabolically active lesions in the muscles of both lower limbs suggestive of muscle abscesses were found. A diagnosis of tropical pyomyositis was therefore made, but aspiration surprisingly revealed gram-positive yeast cells, staining of which on India ink and culture confirmed Cryptococcus. A good response to a combination of liposomal amphotericin B and flucytosine was obtained, but nevertheless the patient died from heart failure after induction of antifungal therapy.

An Uncommon Infection in Common Variable Immunodeficiency

Cryptococcus neoformanscan cause life-threatening disease in both immunocompromised and healthy patients. We report a case of cryptococcal meningoencephalitis in a 68 year old patient with a history of common variable immunodeficiency due to a NFKB1 gene mutation and indeterminate colitis. Our patient was admitted following a fall where he fractured his left humerus. During his admission, a persistent fever was noted despite broad spectrum antibiotic therapy. His neurological condition deteriorated over four weeks, with impaired cognition progressing to aphasia and obtundation. Following initial concerns over an ischaemic stroke, he was found to be serum cryptococcal antigen positive, and subsequent cerebrospinal fluid analysis confirmed CNS cryptococcosis by culture. His neurological condition improved with combination of liposomal amphotericin and flucytosine and he is currently undergoing rehabilitation. The NFKB1 mutation is associated with common variable immunodeficiency and hypogammaglobulinaemia. Our patient was on weekly subcutaneous immunoglobulin replacement, but also required long term glucocorticoids (prednisolone 20mg daily) to control his colitis. To our knowledge, this is the first description of cryptococcal meningoencephalitis in a patient with the NFKB1 mutation. Cryptococcal disease is an important differential diagnosis in immunosuppressed patients with fever and neurological symptoms and full recovery is possible with prompt recognition and treatment.

Combination Antifungal Treatment for Sino-Orbito-Cerebral Mucormycosis: A Case Report

Introduction: Invasive mucormycosis is an opportunistic fungal infection in patients with predisposing factors. Case Presentation: We report a case of sino-orbito-cerebral mucormycosis in a diabetic patient successfully treated with combination of liposomal amphotericin B (L-AMB) and posaconazole. Conclusions: Clinicians should be alert of the clinical presentation of this fulminant fungal infection and notice that prompt diagnosis can be life-saving. Moreover, combination regimens may be considered as an option of treatment failure.

Assessment of Efficacy of Antifungals against Aspergillus fumigatus: Value of Real-Time Bioluminescence Imaging

Aspergillus fumigatus causes life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despite in vitro efficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy under in vitro and in vivo conditions. In vitro assays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable. In vivo studies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 × 10(5) and 2.5 × 10(5) conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enables in vivo monitoring of drug efficacy in different organs during therapy of invasive aspergillosis.

The Deferasirox–AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial

Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted. Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy. Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2). Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.

Combination Antifungal Therapy and Surgery for the Treatment of Invasive Pulmonary Aspergillosis After Hematopoietic Stem Cell Transplantation

An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.

The reversed halo sign as the initial radiographic sign of pulmonary zygomycosis

Zygomycosis is an emerging fungal infection that is associated with high mortality in hematological patients and stem cell transplantation (SCT) recipients. Radiology--computed tomography (CT) imaging in particular--facilitates the detection of lung involvement at an early stage of the infection. The reversed halo sign (RHS) has previously been reported in cryptogenetic organizing pneumonia and, more recently, as a manifestation of pulmonary zygomycosis. Here we describe a case of histologically proven zygomycosis due to Rhizopus microsporus in a SCT recipient. A chest CT scan performed on day +6 due to persistent fever unresponsive to antibiotics revealed the presence of the RHS, i.e., a focal ground-glass opacity mass surrounded by a solid ring of consolidation. The patient was treated with a combination of liposomal amphotericin B, caspofungin, and deferasirox, but subsequently developed a large pneumothorax and died on day +49 due to progressive infection. This case supports earlier observations that RHS may be an early radiological sign of zygomycosis, facilitating an aggressive diagnostic strategy.

Prevention of invasive Mold infection Post Allogeneic Stem Cell Transplantation (AlloSCT) in Pediatric Recipients Using the Sequential Combination of Liposomal Amphotericin B (Ambisome®) Followed by Micafungin (Mycamine®)

Prevention of invasive Mold infection Post Allogeneic Stem Cell Transplantation (AlloSCT) in Pediatric Recipients Using the Sequential Combination of Liposomal Amphotericin B (Ambisome®) Followed by Micafungin (Mycamine®)

Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent

BackgroundVisceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost-effective alternative compared to monotherapies.Methods and FindingsWe assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost-effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range.ConclusionsCombination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available.

Successful resolution of cardiac mycetomas by combined liposomal Amphotericin B with Fluconazole treatment in premature neonates

This manuscript reports on two very low birth weight premature infants with respiratory distress, receiving parenteral nutrition and broad-spectrum antibiotics for about 3 weeks, who developed Candida albicans sepsis associated with fungal mycoses and endocarditis, despite treatment with Amphotericin B and Caspofungin. On days 40 and 47, respectively, antifungal therapy was modified to liposomal Amphotericin B combined with Fluconazole 6 mg/kg/day for 4 weeks, resulting in complete resolution of the mycetomas. Our observations suggest that the combination of liposomal Amphotericin B with Fluconazole is able to result in complete resolution of cardiac mycetomas in preterm infants.

Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies

Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds. Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily). Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively. The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study.

Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach

The aim of this study was to assess the cost-effectiveness of a targeted treatment model of antifungal treatment strategies for adult haematopoietic stem cell transplant (HSCT) recipients in the Netherlands from a hospital perspective, using a decision analytic modelling approach. The economic evaluation of desoxycholate amphotericin B, liposomal amphotericin B, voriconazole and caspofungin was undertaken. These drugs could be used alone, in various combinations or sequentially. In our model, first-line therapy consisted of either voriconazole or liposomal amphotericin B. If necessary, treatment was switched to a second-line treatment, including combination antifungal therapy. The theoretical population in this model consisted of adult HSCT recipients with proven or probable invasive aspergillosis (IA). Long-term survival was extrapolated from survival after 12 weeks of treatment and life expectancy. First-line antifungal treatment strategies with voriconazole were both more effective and less costly over first-line strategies employing liposomal amphotericin B at a dosage of 4 mg/kg/day. The strategy of voriconazole followed by caspofungin (voriconazole/caspofungin) was dominant over the strategies of voriconazole followed by liposomal amphotericin B (voriconazole/liposomal amphotericin B) or desoxycholate amphotericin B (voriconazole/desoxycholate amphotericin B). However, the voriconazole followed by the combination of liposomal amphotericin B and caspofungin strategy (voriconazole/liposomal amphotericin B+caspofungin) was more effective though more expensive than the voriconazole/caspofungin strategy resulting in an incremental cost-effectiveness ratio (ICER) of about euro107,000 for a life-year saved. At a dosage of 1 mg/kg/day of liposomal amphotericin B, the voriconazole/caspofungin strategy was more effective but more costly than the voriconazole/desoxycholate amphotericin B strategy with an ICER of euro10,000 for each extra life-year saved. Between the voriconazole/liposomal amphotericin B+caspofungin and the voriconazole/caspofungin strategies, the ICER was euro40,000. Probabilistic analyses on net monetary benefit showed that the voriconazole/caspofungin strategy had the highest probability of being the most cost-effective strategy.