High-dose Liposomal Amphotericin Research Articles

Adjunctive Single-Dose Liposomal Amphotericin to Prevent Cryptococcal Meningitis in People With Human Immunodeficiency Virus (HIV)-Associated Cryptococcal Antigenemia and Low Plasma Cryptococcal Antigen (CrAg) Titers.

Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%-30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal amphotericin B to standard pre-emptive fluconazole therapy could improve meningitis-free survival. Participants with human immunodeficiency virus (HIV) and asymptomatic cryptococcal antigenemia in Uganda were randomized to liposomal amphotericin B (10 mg/kg once) with fluconazole or fluconazole alone through 24 weeks. We compared 24-week, meningitis-free survival time between treatment groups. After the second interim review, the Data Safety and Monitoring Board recommended no further enrollment of participants with low plasma CrAg lateral flow assay titers (≤1:80) due to futility. Herein, we present the results of participants with low plasma CrAg titers. 168 participants enrolled into the ACACIA trial had low plasma CrAg titers (≤1:80). During 24 weeks of follow-up, meningitis or death occurred in 14.5% (12/83) of participants randomized to liposomal amphotericin B with fluconazole versus 10.6% (9/85) assigned to fluconazole alone (hazard ratio, 1.42; 95% CI, .60-3.36; P = .431). Adverse events were more frequent in participants assigned to the intervention versus standard-of-care (28% vs 12%; P = .011). Among CrAg-positive persons with low titers (≤1:80), the addition of single-dose liposomal amphotericin B to fluconazole as pre-emptive therapy provided no additional clinical benefit. This trial provides supportive evidence that, in asymptomatic populations with low plasma CrAg titers, lumbar punctures are likely unnecessary as administration of meningitis treatment did not improve outcomes. Clinicaltrials.gov (NCT03945448).

High-dose amphotericin: yay or nay? A case series and literature review.

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium. The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies (n=260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8-62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Safety of Single High-Dose Liposomal Amphotericin B for Induction Treatment of Cryptococcal Meningitis and Histoplasmosis in People With HIV: A Systematic Review and Meta-analysis.

Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

Clinical Phenotypes of COVID-19 Associated Mucormycosis (CAM): A Comprehensive Review.

A mucormycosis surge was reported during the COVID-19 pandemic in India. A literature search until 14 July 2022, with the aim of updating COVID-19-associated mucormycosis (CAM), identified 663 studies and 88 met inclusion criteria (8727 patients). India reported 8388 patients, Egypt 208 and Europe 40. Rhino-orbito-cerebral mucormycosis (ROCM) was identified among 8082 (98.3%) patients, followed by 98 (1.2%) with pulmonary. In India, 82.6% of patients had diabetes mellitus, with 82% receiving corticosteroids. In Europe, 75% presented pulmonary CAM, 32.5% had diabetes and 40% were immunocompromised. CAM was identified at a median of 17.4 days (IQR 7.5 days) post COVID-19 diagnosis, and PCR was performed in five studies. Rhino-orbital invasion is clinically obvious, while cerebral involvement presents with cavernous sinus thrombosis, meningitis and cerebrovascular disease. Symptoms of pulmonary CAM usually overlap with severe COVID-19 pneumonia. High-dose liposomal Amphotericin B (and early surgical debridement in ROCM) are the mainstay of therapy. The median mortality rate was estimated to be 21.4% (IQR 31.9%), increased by the presence of pulmonary (80% (IQR 50%) or cerebral involvement (50% (IQR 63.9%). In summary, different CAM clinical phenotypes need to be distinguished, influenced by geographical presentation. Opportunities exist for diagnosis and therapy optimization, based on earlier high-dose antifungal therapy, early source control, strict glycemic control and restriction of steroids to COVID-19 patients with oxygen requirements.

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363) L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351) h-1, and from peripheral to central compartment 2.951 (4.070) h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Progressive skin ulceration in a febrile returning traveller

Two weeks prior to admission, while in Cape Verde, a 66-year-old man developed a fever and a necrotic ulcer on his right leg following an insect bite. He was treated with intravenous Flucloxacillin, but subsequently developed an abscess at the intravenous cannula site on his left forearm. On his return to the UK, he underwent an incision & drainage of the abscess which yielded sterile fluid. During the next ten days the incision site progressively deteriorated and became necrotic, the right leg ulcer enlarged, and fever and rigors continued despite treatment with intravenous Piperacillin/Tazobactam and Clindamycin. We suspected pyoderma gangrenosum or a systemic vasculitis. Treatment commenced with high-dose Prednisolone, Meropenem and liposomal Amphotericin. A skin biopsy from the right leg confirmed pyoderma gangrenosum; no fungi were seen. Aspergillus fumigatus was cultured from the left forearm wound. A blood film showed a leucoerythroblastic picture with 3% blasts, and a bone marrow biopsy confirmed acute myeloid leukaemia. The skin lesions progressively improved and the anti-fungal therapy was changed to Posaconazole. He received chemotherapy for acute myeloid leukaemia, before proceeding to an allogeneic bone marrow transplant. He remains well one year post-transplant. Pyoderma gangrenosum should be considered in a febrile patient who has non-healing ulcer(s) at sites of trauma. It is often associated with a systemic disease, most commonly inflammatory bowel disease, inflammatory arthritis or haematological malignancies. Because these conditions and their treatments are associated with immunocompromise, patients with pyoderma gangrenosum may also be at risk of a superimposed cutaneous fungal infection.

Combination Therapy for HIV-Associated Cryptococcal Meningitis-A Success Story.

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.

Isavuconazole and Liposomal Amphotericin B as Successful Combination Therapy of Refractory Invasive Candidiasis in a Liver Transplant Recipient: A Case Report and Literature Review

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

DISSEMINATED MULTIFOCAL MUCORMYCOSIS TREATED WITH A COMBINATION ANTIFUNGAL REGIMEN

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Rhinocerebral mucormycosis is a fatal infection in poorly controlled diabetic patients with a history of diabetic ketoacidosis (DKA). DKA blunts neutrophil chemotaxis, phagocytosis and boosts serum iron, a mucor nutrient. It spreads to the brain via the hematogenous or contiguous spread [1]. We present a case of disseminated rhinocerebral mucormycosis in a diabetic patient on treatment with a combination antifungal regimen CASE PRESENTATION: A 22-year-old poorly controlled diabetic with a hemoglobin A1c of 14.1% was admitted to an outside hospital for a week of chest pain, dyspnea, fever, and dry cough with recently diagnosed coronavirus disease 2019. She was treated for DKA. Four days later, she developed a new-onset right-sided vision loss, ptosis, areflexic pupil, eye abduction loss, and bloody nasal mucus drainage. Computed tomography (CT) of the chest was normal. CT angiogram (CTA) of the head and neck showed occlusion of the right ophthalmic artery and the superior ophthalmic vein. Magnetic resonance imaging (MRI) showed subacute right frontal infarct and chronic sinusitis. An oral exam disclosed a large hard palate necrotic area, which on biopsy culture grew Rhizopus oryzae (Figure A-B). She was transferred to our facility for further surgical debridement. On arrival, she was placed on high-dose liposomal amphotericin (LAmB) and euglycemic control. A cerebral angiogram revealed right internal carotid artery occlusion. MRI showed right cavernous sinus thrombosis, right ophthalmic artery mycotic aneurysm, paranasal sinusitis with right sphenoid fungal sinusitis extending into gyri rectus, and watershed infarcts in the right middle and anterior cerebral artery territories (Figure C1). Neurosurgery deferred surgical debridement. Later caspofungin and deferasirox were added adjunctively for two weeks with surgical debridements and a week of hyperbaric oxygen, after which MRI findings improved (Figure C2). She is clinically improving on LAmB and caspofungin DISCUSSION: Combination regimens are ineffective in neutropenic or cancer patients [2,3]. LAmB and deferasirox with or without an echinocandin/posaconazole have been effective in diabetics with intracranial lesions [2]. Combination regimen efficacy has been observed in diabetic mice and anecdotal case reports [3,4]. This is due to prompt recovery of neutrophil function and loss of glucose-regulated protein78 mediated Rhizopus angioinvasion once acidosis and hyperglycemia are corrected [5] CONCLUSIONS: To improve diabetic patient outcomes, a timely diagnosis, prompt reversal of DKA and hyperglycemia, along with surgical debridement and antifungal therapy, are of immense importance. Combination antifungal therapy may benefit cases where complete surgical debridement is not achievable REFERENCE #1: Mallis A, Mastronikolis SN, Naxakis SS, Papadas AT. Rhinocerebral mucormycosis: an update. Eur Rev Med Pharmacol Sci. 2010;14(11):987-92 DISCLOSURES: No relevant relationships by Mohammed Alnijoumi, source=Web Response No relevant relationships by Phillip Beck, source=Web Response No relevant relationships by Paragkumar Patel, source=Web Response No relevant relationships by SACHIN PATIL, source=Web Response No relevant relationships by Deepthi Rao, source=Web Response No relevant relationships by Hariharan Regunath, source=Web Response No relevant relationships by Blaine Winterton, source=Web Response

Mucormycosis, a dangerous complication of covid-19 disease: Documenting the occurrence in Iraq and a review of the literature

Background: Mucormycosis, a rare, but severe angio-invasive disease that can have a catastrophic or fatal outcome. It is an opportunistic infection that has been mostly reported in immunocompromized and diabetic patients, and it commonly begins by invading the respiratory tract. The aim of this paper is to document the emergence of mucormycosis as a dangerous complication of covid-19 in Iraq and many countries in the world.
 Materials and methods: On the first of June, 1,201,352 cases of covid-19 were reported by the Iraqi Ministry of Health, and 16375 patients died because of the disease. During, the first week of June, 2021, the death of Iraqi three patients having covid-19 disease complicated by mucormycosis was reported. At least 140 patients with covid-19 disease complicated by mucormycosis have been reported throughout the world including 100 patients from India, 18 patients from Iran, 11 patients from Turkey, 7 patients from the United States of America, 6 patients from Egypt, 2 patients from Spain, and one patient from each of the following countries, Brazil, Italy, Austria, France, Mexico, UK, and the United Kingdom. Most patients were males and the disease was documented in sixteen females.
 Results: Sino/rhino-orbital mucormycosis with or without cerebral involvement was the most commonly reported type including 87 patients. Pulmonary mucormycosis was the second most common type, and was reported in five patients. Catastrophic outcome occurred in nineteen patients including patients ending with orbital exenteration in patients (14), and patients developed irreversible loss of vision (5). Forty patients with covid-19 with mucormycosis died including, 15 patients from India, eight patients from Iran, seven from Turkey, four deaths from USA, two deaths from Egypt, on death from Brazil, one death from Austria, one death from Mexico, and one death from the United Kingdom.
 Conclusions: Mucormycosis is a rare disease that is generally associated with diagnostic difficulty and delay, high morbidity, catastrophic outcome, and mortality. Diabetes mellitus and use of corticosteroids increase the risk of the development of invasive mucormycosis which may appear during the course of the covid-19, or appear as a later complication. Hyperglycemia induced impaired chemotaxis and phagocytosis of neutrophils, steroid-induced immunosuppression, and covid-19 induced immune dysregulation associated with decreased numbers of T lymphocytes, CD8+T, and CD4+T cells were considered the important factors that led to the emergence of invasive mucormycosis as a catastrophic and fatal complication of covid-19 disease. Mucormycosis can be rapidly progressive, requiring immediate surgical and medical interventions. High index of suspicion can contribute to making an early diagnosis, and providing early aggressive management which can improve survival. Upon suspicion of mucormycosis appropriate imaging is advised to determine extent of disease. First-line treatment is generally including the use of a high-dose liposomal amphotericin B. Other antifungal drugs that have been used include isavuconazole and posaconazole.

“Mucormycosis” The Emerging Global Threat – A Complete Review

Mucormycosis is a life-threatening invasive fungal infection that affects people who are immunocompromised (haematological malignancies, solid organ transplantation, diabetes mellitus). Pulmonary, rhinocerebral, cutaneous, and disseminated infections are the most common. Controlling mucormycosis requires reversing the underlying problems. Treatment for mucormycosis also includes quick and vigorous surgery. Extensive surgical debridement of necrotic tissues is required. Finally, an antifungal treatment is required. High-dose liposomal amphotericin B (5 mg/kg/day) is the first-line treatment for mucormycosis. Antifungal chemotherapy has no set length; instead, it is determined by the remission of all related symptoms and results (usually 6-8 weeks). Posaconazole maintenance therapy/secondary prophylaxis should be recommended in patients who have a persistently weakened immune system. Keywords: Mucormycosis, Diabetes mellitus, Liposomal Amphotericin B.

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.

Safety and Efficacy of Intermittent High-Dose Liposomal Amphotericin B Antifungal Prophylaxis in Haemato-Oncology: An Eight-Year Single-Centre Experience and Review of the Literature.

Triazoles remain first-line agents for antifungal prophylaxis in high-risk haemato-oncology patients, but their use is increasingly contraindicated due to drug–drug interactions and additive toxicities with novel treatments. In this retrospective, single-centre, observational study, we present our eight-year experience of antifungal prophylaxis using intermittent high-dose liposomal Amphotericin B (L-AmB). All adults identified through our Antifungal Stewardship Programme as receiving L-AmB prophylaxis at 7.5 mg/kg once-weekly between February 2012 and January 2020 were included. Adverse reactions, including infusion reactions, electrolyte loss, and nephrotoxicity, were recorded. ‘Breakthrough’ invasive fungal infection (IFI) occurring within four weeks of L-AmB was classified using European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Moreover, 114 courses of intermittent high-dose L-AmB prophylaxis administered to 92 unique patients were analysed. Hypokalaemia was the most common grade 3–4 adverse event, with 26 (23%) courses. Grade 3 nephrotoxicity occurred in 8 (7%) and reversed in all six patients surviving to 90 days. There were two (1.8%) episodes of breakthrough IFI, one ‘probable’ and one ‘possible’. In this study, the largest evaluation of intermittent high-dose L-AmB prophylaxis conducted to date, toxicity was manageable and reversible and breakthrough IFI was rare. L-AmB prophylaxis represents a viable alternative for patients with a contraindication to triazoles.

Isolated Laryngeal Leishmaniasis: A Diagnostic Dilemma.

Isolated laryngeal Leishmaniasis is a rare entity in the Indian subcontinent. We describe a case of a 45year old male with hoarseness and noisy breathing. Patient's initial histological and serological workup was inconclusive. Final biopsy findings (suggestive of Leishmania donovani), positive rK-39 serology and his native place being Bihar (endemic for Leishmaniasis) led us to the diagnosis. He was treated with high dose liposomal Amphotericin B to which he responded well. This case report highlights the importance of remaining aware of rare infectious causes of laryngitis. Timely diagnosis and intervention are crucial.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study

IntroductionCryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes....

A Case of African Visceral Leishmaniasis (VL) Treated with a Combination of Liposomal Amphotericin-B and oral Miltefosine

A 36-year-old Nigerian man was assessed for chronic recurrent fever, generalized weakness, body aches, epistaxis and bleeding gums of 3-month duration. Despite receiving treatment for suspected malaria twice and undergoing multiple courses of antibiotics for suspected infections, his symptoms persisted. Examination revealed hepatosplenomegaly, lymphadenopathy, and severe pallor. Investigations revealed severe anemia, pancytopenia, raised globulin levels. Bone marrow biopsy revealed Leishmania Donovani (LD) bodies. He received treatment with a short duration of high-dose liposomal Amphotericin B followed by outpatient oral Miltefosine to which he responded successfully.

Pseudohypophosphatemia associated with high-dose liposomal amphotericin B therapy

BackgroundHypophosphatemia is commonly observed in critically ill patients. Inorganic phosphorus is quantified by spectrophotometric measurement of a phosphomolybdate complex, a method with multiple documented interferents. Our clinical laboratory was contacted to investigate a case of asymptomatic hypophosphatemia in a patient receiving high-dose liposomal amphotericin B therapy (L-AMB). MethodsIn vitro experiments were performed by spiking L-AMB into residual plasma specimens. Phosphate was measured on the Beckman Coulter AU and Ortho Diagnostics Vitros instruments. ResultsWhen measured on the AU, phosphate in plasma with approximately 250mcg/mL of L-AMB demonstrated a median negative bias of 3.45mg/dL relative to unspiked samples. In contrast, Vitros phosphate measurements demonstrated excellent agreement for specimens with and without L-AMB (median bias −0.2mg/dL). ConclusionsHigh L-AMB concentrations induced a significant negative bias on phosphate measured by the AU assay, but did not affect the Vitros assay. Laboratorians and clinicians should be aware of this phenomenon in patients receiving L-AMB who develop unexplained hypophosphatemia.

Weekly high-dose liposomal amphotericin B (L-AmB) in critically ill septic patients with multiple Candida colonization: The AmBiDex study.

BackgroundTo demonstrate the feasibility and safety of weekly high-dose liposomal amphotericin B (L-AmB) (as a pre-emptive antifungal treatment) for 2 weeks in patients with septic shock and Candida colonization.MethodsPilot, multicentre, open-label, prospective study conducted in seven French ICUs. Non-immunocompromised patients, receiving mechanical ventilation were eligible if they presented ICU-acquired severe sepsis requiring newly administered antibacterial agents and Candida colonization in at least two sites. Exclusion criteria included the need for antifungal therapy and creatinine > 220 μmol/L. All patients were to receive a high-dose L-AmB (10 mg/kg/week) for two weeks. A follow-up period of 21 days following the second administration of L-AmB was conducted. Treated patients were compared to 69 matched untreated controls admitted in the same ICUs before the study period.ResultsTwenty-one patients were included in the study, of which 20 received at least one infusion of high-dose L-AmB. A total of 24 adverse events were identified in 13(61%) patients. Fourteen adverse events were categorized as serious in 8(38%) patients. In four cases the adverse events were considered as potentially related to study drug administration and resulted in L-AmB discontinuation in one patient. Few patients experienced severe renal toxicity since no patient presented with severe hypokalemia. No patients required renal replacement therapy. Compared to matched controls, no significant increase in serum creatinine levels in patients receiving high-dose L-AmB was reported.ConclusionsWeekly administration of high-dose L-AmB has a manageable safety profile and is feasible in patients with ICU-acquired sepsis and multiple Candida colonization. Trials of L-AmB versus other antifungal agents used as pre-emptive antifungal therapy are warranted.Trial registrationClinicalTrials.gov NCT00697944

Aspergillus flavus Disseminated Infection in Paediatric Acute Lymphoblastic Leukaemia: A Case Report

Here we report the case of a disseminated Aspergillus flavus infection in an adolescent affected by acute lymphoblastic leukaemia at the beginning of first-line chemotherapy. Association of surgery and combination antifungal therapy (high dose liposomal amphotericin B and caspofungin) allowed infection improvement. 18-FDG PET-MRI was used for response-to therapy monitoring.

Safety and efficacy of liposomal amphotericin B for treatment of complicated visceral leishmaniasis in patients without HIV, North-West Ethiopia.

BackgroundVisceral leishmaniasis (VL) is a protozoan disease that is invariably fatal if left untreated. The disease is found in 70 countries with incidence of 0.2 – 0.4 million cases. The mainstay of treatment in resource limited countries like Ethiopia is antimonials, while use of liposomal amphotericin B is reserved for treatment of complicated VL cases. The aim of this study was to assess the safety and efficacy of liposomal amphotericin B in HIV negative VL patients diagnosed with complications.MethodsA retrospective chart review was conducted involving records of patients admitted between January 2009 and December 2014. Baseline sociodemographic, clinical, and treatment outcome data were collected. The doses of liposomal amphotericin B and adverse events related to treatment were retrieved. Categorical and continuous variables respectively were analyzed by Chi-square and Mann–Whitney U tests. A p-value of less than 0.05 was considered statistically significant.ResultsA total of 147 patients with severe VL were treated with liposomal amphotericin B in total dose ranges of 20 mg/kg to 35 mg/kg. In the overall treatment outcome analysis, initial cure (30 days after start of treatment) was observed in 128 (87.1 %), treatment failures in 10 (6.8 %), interruptions in 2(1.4 %) and deaths in 7 (4.8 %) patients. Initial cure rate at high dose (24-35 mg/kg total dose) was 96.7 % (59/61) versus 80.2 % (69/86) at lower doses (<24 mg/kg); which was significantly higher (P < 0.01), OR = 4.56: 95 %, Confidence Interval (CI) = 1.17 – 20.78). Ten cases (11.8 %) of treatment failure occurred in the low dose treatment group. The most common adverse events (AEs) were hypokalemia in 39 cases (26.5 %) and infusion related reactions in 16 (10.9 %). The frequency of hypokalemia and infusion related reactions were not significantly different between the low and high dose liposomal amphotericin B.ConclusionIn HIV negative complicated VL patients, high dose of liposomal amphotericin B was found to have high cure rate at the end of treatment. The appropriate dose for better efficacy needs to be determined. Monitoring serum potassium level during treatment with liposomal amphotericin B should be an essential component of the clinical management of VL.