Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.

BACKGROUND: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. METHODS: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). RESULTS: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). CONCLUSIONS: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. CLINICAL TRIALS REGISTRATION: NCT04031833.

Safety and usefulness of nebulized liposomal amphotericin B: Systematic scoping review.

PURPOSE: Invasive fungal infections potentially result in fatal outcomes in immunocompromised hosts. Compared to intravenous administration, a nebulization therapy can achieve a high concentration of drug delivered in the respiratory tract, without a systematic absorption. We herein summarized the study findings on the safety and clinical utility of nebulized liposomal amphotericin B therapy. METHODS: According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with relevant keywords, including "inhaled liposomal amphotericin B″, "nebulized liposomal amphotericin B″, or "aerosolized liposomal amphotericin B″, from the inception of these databases to August 31, 2022. RESULTS: Of the 172 articles found, 27 articles, including 13 case reports, 11 observational studies, and 3 clinical trials, were selected. Generally, findings showed that nebulized liposomal amphotericin B treatment appeared to be safe and without severe adverse effects. We found an accumulated evidence for the safety, tolerability, and effectiveness of nebulized liposomal amphotericin B prophylaxis among lung transplantation recipients; however, a randomized controlled study has yet to be reported. Data on hemato-oncological patients are relatively scarce; however, a randomized controlled study suggested the prophylactic effect of nebulized liposomal amphotericin B on invasive pulmonary aspergillosis. Observational and randomized controlled studies to evaluate therapeutic efficacy of the nebulized liposomal amphotericin B therapy have not been performed. CONCLUSION: In conclusion, we found increasing evidence for the effectiveness of the inhalation therapy among patients after lung transplantation and with hemato-oncological diseases.

Amphotericin B colloidal dispersion: an effective drug for the treatment of mucormycosis in China.

Objective: Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but the effective drugs for the treatment are limited. Hence, the study aimed to summarize the characteristics of mucormycosis in patients with hematological malignancies, and investigate the efficacy and safety of Amphotericin B Colloidal Dispersion (ABCD) in treating mucormycosis. Methods: In this study, patients with mucormycosis complicated by hematological malignancies who received ABCD at the First Affiliated Hospital of Zhengzhou University from April 2021 to May 2022 were retrospectively enrolled. The clinical data of the enrolled patients were collected, and then, the drug response at 2 weeks, 4 weeks, and the end of treatment; the survival rate at 4, 8, and 12 weeks; and the laboratory-related indicators and adverse events (AEs) associated with ABCD were evaluated. Results: In total, 9 patients with mucormycosis complicated by hematological malignancies were enrolled. The main symptoms were fever, cough, and chest pain. In addition, reversed halo signs (RHS) were found on chest CTs. The responses to ABCD at 2 weeks, 4 weeks, and the end of treatment were 100% (9/9), 77.8% (7/9), and 77.8% (7/9), respectively. The survival rates of the patients at 4, 8, and 12 weeks were 77.8% (7/9), 66.7% (6/9), and 66.7% (6/9), respectively. Among laboratory-related indicators, white blood cell (WBC) counts were significantly increased from baseline after 1 and 2 weeks of ABCD treatment (P<0.05), whereas neutrophil counts were only increased significantly from baseline at 2 weeks post-treatment (P<0.05). The most common AEs were infusion-related AEs manifesting as fever, chills, and pruritus. Moreover, none of the patients suffered from renal injury once again. Conclusion: ABCD is a promising treatment strategy for patients with mucormycosis complicated by hematologic malignancies, showing remarkable efficacy and safety.

Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group.

BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies.

BACKGROUND: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines. METHODS: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021. RESULTS: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001). CONCLUSIONS: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.

Treatment of Cryptococcal Meningitis: How Have We Got Here and Where are We Going?

Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by adulthood, but symptomatic infection only occurs in a minority, in most cases, months or years after exposure. Disease has been described in almost all tissues, but it is the organism's tropism for the central nervous system that results in the most devastating illness. While invasive disease can occur in the immunocompetent, the greatest burden by far is in immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV), organ transplant recipients and those on glucocorticoid therapy or other immunosuppressive drugs. Clinical presentation is variable, but diagnosis is usually straightforward, with cerebrospinal fluid microscopy, culture, and antigen testing proving significantly more sensitive than diagnostic tests for other brain infections. Although disease incidence has reduced since the advent of effective HIV therapy, mortality when disease occurs remains extremely high, and has changed little in recent decades. This Therapy in Practice review is an update of a talk first given by JND at the European Congress on Clinical Microbiology and Infectious Diseases in 2019 in the Netherlands. The review contextualizes the most recently published World Health Organization (WHO) guidelines for the treatment of HIV-associated cryptococcal meningitis in terms of the data from large, randomized, controlled trials published between 1997 and 2022. We discuss the rationale for induction and maintenance therapy and the efficacy and undesirable effects of the current therapeutic armamentarium of amphotericin, flucytosine and fluconazole. We address recent research into repurposed drugs such as sertraline and tamoxifen, and potential future treatment options, including the novel antifungals fosmanogepix, efungumab and oteseconazole, and non-pharmaceutical solutions such as neurapheresis cerebrospinal fluid filtration.

Amphotericin B plus fluorocytosine combined with voriconazole for the treatment of non-HIV and non-transplant-associated cryptococcal meningitis: a retrospective study.

BACKGROUND: Our previous study explored Amphotericin B (AMB) plus 5-flucytosine (5-FC) combined with fluconazole (FLU) therapy in the induction period, which seemed to be better than the previous AMB + 5-FC antifungal therapy in non-HIV and non-transplant-associated CM. However, based on our clinical finding, the outcomes of some CM patients who received AMB plus 5-FC combined with FLU antifungal therapy were still poor. Therefore, we need to explore new antifungal methods in non-HIV and non-transplant-associated CM during the induction period. METHODS: Clinical data from 148 patients admitted to the Third Affiliated Hospital of Sun Yat Sen University from January 2011 to December 2020 were collected. These patients were stratified based on antifungal treatment methods in the induction period (group I with AMB + 5-FC + VOR, group II with AMB + 5-FC + FLU, group III with AMB + 5-FC). RESULTS: The first hospitalization time of Group I (median: 25 days, IQR: 20-34.5) was significantly shorter than that of Group II (median: 43 days, IQR: 29-62) (p < 0.001) and Group III (median: 50.5 days, IQR: 43-77.5) (p < 0.001). After 2 weeks of follow-up, Group I (26/49) had more patients reaching CSF clearance (p = 0.004) than Group II (18/71) and Group III (7/28). In multivariable analysis, Group II (OR: 3.35, 95%CI 1.43-7.82, p = 0.005) and Group III (OR: 3.8, 95%CI 1.23-11.81, p = 0.021) were associated with higher risk about CSF clearance failure at 2 weeks follow-up than Group I. After 10 weeks of follow-up, the incidence of hypokalemia in Group I was significantly lower than that in Group II (p = 0.003) and Group III (p = 0.004), and the incidence of gastrointestinal discomfort in Group I was significantly lower than that in Group II (p = 0.004). CONCLUSION: AMB plus 5-FC combined with VOR may rapidly improve clinical manifestation, decrease CSF OP and clear the cryptococci in CSF during the early phase, substantially shorten the hospitalization time, and reduce the incidences of hypokalemia and gastrointestinal discomfort.

Safety of Inhaled Amphotericin B Lipid Complex as Antifungal Prophylaxis in Lung Transplant Recipients.

Inhaled formulations of amphotericin B are the most widely used antifungal prophylactic agents in lung transplant recipients, yet there are limited data on their safety. We performed a single-center retrospective cohort study of 603 consecutive patients who underwent lung transplantation between 2012 and 2017 and received antifungal prophylaxis with inhaled amphotericin B lipid complex (iABLC) from the day of transplantation until hospital discharge. Of 603 patients, 600 (99.5%) received ≥1 dose of iABLC, and 544 (90.2%) completed the recommended prophylactic course. In total, 4,128 iABLC doses (median, 5; range, 1 to 48 per patient) were administered; 24 patients received >3 months of therapy. Only one (0.2%) patient discontinued therapy due to a drug-attributable adverse event. During the first posttransplant year, 80 (13.3%) patients died (median time to death, 171 days; interquartile range [IQR], 80 to 272 days), and 3,352 (median, 6 per patient) lung biopsies were performed; 414 (68.7%) patients developed biopsy-proven acute cellular rejection. One-year adverse events in our cohort of lung transplant recipients treated with iABLC during transplant hospitalization matched national outcomes for rejection, graft loss, and death. iABLC is a safe and well-tolerated antifungal prophylactic agent in lung transplant recipients.

[Cryptococcal Meningitis with Inadequate Response to Antifungal Therapy or Drug-Induced Side Effects That Make It Difficult to Continue Treatment: Management to Avoid Treatment Difficulties and Intracerebroventricular Antifungal Administration for Refractory Cases].

The treatment of cryptococcal encephalomyelitis is often complicated by an inadequate response to antifungal therapy and the reduction or withdrawal of antifungal agents due to adverse effects. To achieve a favorable prognosis, patients should be treated with appropriate drugs according to the latest guidelines. In addition to systemic antifungal drug administration in refractory cases, intracerebroventricular administration of amphotericin B may be considered.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

[Clinical analysis of amphotericin B cholesteryl sulfate complex for injection in the treatment of invasive fungal disease for patients with hematological malignancies in 30 cases].

Objective: To assess the safety and effectiveness of amphotericin B cholesteryl sulfate complex for injection in the context of empirical and diagnostic antifungal therapy for patients with hematological malignancies in addition to invasive fungal illness. Methods: This single-arm clinical study enrolled 30 patients who received empirical and diagnostic-driven antifungal therapy for hematological malignancies combined with invasive fungal disease. The primary endpoint was safety. Response rate, fever duration, and treatment completion rate were all considered secondary objectives. Results: 30 participants were eventually enrolled in the study, and the treatment completion rate was 80.0% . Most adverse events were in grades 1-2. Infusion response was the most frequent adverse event (24/30, 80% ) . The overall response rate was 80.0% (24/30) . In 24 patients (80.0% ) , the fever persisted for 1 day. Conclusions: Treatment of invasive fungal illness in conjunction with hematological malignancies showed good efficacy and safety with amphotericin B cholesteryl sulfate complex for injection.

Alginate-amphotericin B nanocomplexes covered by nanocrystals from bacterial cellulose: physico-chemical characterization and in vitro toxicity.

Nanocomplexes systems made up natural poylymers have pharmacotechnical advantages such as increase of water solubility and a decrease of drugs toxicity. Amphotericin B (AmB) is a drug apply as anti-leishmanial and anti-fungal, however it has low water solubility and high toxicity, limiting its therapeutic application. With this in mind, the present study aimed to produce nanocomplexes composed by alginate (Alg), a natural polymer, with AmB covered by nanocrystals from bacterial cellulose (CNC). For this reason, the nanocomplexes were produced utilizing sodium alginate, amphotericin B in a borate buffer (pH 11.0). The CNC was obtained by enzymatic hydrolysis of the bacterial cellulose. To CNC cover the nanocomplexes 1 ml of the nanocomplexes was added into 1 ml of 0.01% CNC suspension. The results showed an ionic adsorption of the CNC into the Alg-AmB nanocomplexes surface. This phenomena was confirmed by an increase in the particle size and PDI decrease. Besides, nanocomplexes samples covered by CNC showed uniformity. The amorphous inclusion of AmB complex into the polysaccharide chain network in both formulations. AmB in the nanocomplexes was in supper-aggregated form and showed good biocompatibility, being significantly less cytotoxic in vitro against kidney cells and significantly less hemolytic compared to the free-drug. The in vitro toxicity results indicated the Alg-AmB nanocomplexes can be considered a non-toxic alternative to improve the AmB therapeutic effect. All process to obtain nanocomplexes and it coat was conduce without organic solvents, can be considered a green process, and allowed to obtain water soluble particles. Furthermore, CNC covering the nanocomplexes brought additional protection to the system can contribut advancement in the pharmaceutical.

Weekly high-dose liposomal amphotericin B prevents invasive aspergillosis after heart transplantation.

BACKGROUND: Preventive strategies for invasive aspergillosis (IA) have still not been determined in heart transplant recipients whereas IA leads to a high mortality rate at 12 months posttransplantation. The use of voriconazole or echinocandins was proposed but can favor emergence of Aspergillus or Candida sp. resistant strains or promote neurological and liver disorders in some patients. OBJECTIVES: To assess whether universal prophylaxis with weekly high-dose of liposomal amphotericin-B (L-AmB) can safely prevent IA in heart transplant recipients. PATIENTS/METHODS: Retrospective before/after study that included 142 patients who received heart transplantation between 2010 and 2019 at the University Hospital of Toulouse (France). Weekly high dose of L-AmB (7.5 mg/kg/week) was used as universal prophylaxis from 2016 because of high environmental exposure to Aspergillus sp. and high incidence of IA. RESULTS: Cumulative 1-year incidence of IA decreased from 23% to 5% after introduction of L-Amb prophylaxis. Multivariate analysis (Cox model) identified L-AmB prophylaxis as a protective factor against IA (hazard ratio [HR] 0.21 [95% confidence interval 0; 0.92], p = .04), whereas postoperative renal replacement therapy was associated with IA (HR 3.6 [95% confidence interval 1.38; 9.3], p = .001), after correction for confounding effects (induction regimen, methylprednisolone pulses and history of hematological malignancy). The incidence of acute kidney injury requiring renal replacement therapy was similar in the two groups, suggesting a low risk of kidney toxicity when L-AmB is used weekly. No patient developed severe kidney electrolyte loss nor L-AmB-related anaphylaxis. CONCLUSIONS: Once-weekly high-dose L-AmB is safe and may prevent the development of IA after heart transplantation.

Efficacy of Intravenous Itraconazole Versus Liposomal Amphotericin B as Empirical Antifungal Therapy in Hematological Malignancy with Persistent Fever and Neutropenia: Study Protocol for a Multicenter, Prospective, Randomized Non-inferiority Trial.

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

Evaluation of renal effects of liposomal amphotericin B in children with malignancies with KDIGO and RIFLE criteria.

BACKGROUND: Amphotericin B is a broad-spectrum antifungal agent and is the backbone of the treatment for medically important opportunistic fungal pathogens in children. This study aimed to compare the nephrotoxicity associated with L-AmB in children with acute lymphoblastic leukemia and acute myeloid leukemia. MATERIALS AND METHODS: A total of 112 pediatric acute lymphoblastic leukemia or acute myeloid leukemia patients who received treatment with L-AmB (Ambisome®) at the University of Health Sciences Dr Behcet Uz Children's Hospital over 7 years were included. The incidence of hypokalemia, decreased estimated glomerular filtration rate and presence of acute kidney injury was recorded. RESULTS: The average L-AmB treatment duration was 17.1±15.0 days. Five patients (4.4%) of the patients had grade I acute renal injury according to KDIGO criteria and 16 patients (14.2%) had increased risk for kidney injury according to RIFLE criteria. There were no patients with eGFR decrease above 50% and no renal injury and failure were observed during L-AmB treatment. The rate of patients with hypokalemia in the pre-treatment was 17.9% and the post-L-AmB group was 50.0%. The rate of hypokalemia was higher in the post-treatment group (P=0.0015). Among the 112 patients, only two patients (1.7%) required cessation of L-AmB treatment due to resistant hypokalemia despite supplementation. CONCLUSIONS: Hypokalemia was more common compared to glomerulotoxicity and acute renal injury (according to KDIGO and RIFLE criteria) in pediatric leukemia patients treated with L-AmB. Hypokalemia developed in nearly half of the patients and the study shows the need for randomized controlled trials and strategies for hypokalemia associated with L-AmB treatment.

Ambulatory induction phase treatment of cryptococcal meningitis in HIV integrated primary care clinics, Yangon, Myanmar.

BACKGROUND: Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. METHOD: This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day). RESULTS: Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. CONCLUSION: Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.

Unusual disseminated Talaromyces marneffei infection mimicking lymphoma in a non-immunosuppressed patient in East China: a case report and review of the literature.

BACKGROUND: Talaromyces marneffei infection is an important opportunistic infection associated with acquired immune deficiency syndrome (AIDS). However, it is unusual in patients with non-AIDS and other non-immunosuppressed conditions. We report a case of delayed diagnosis of disseminated T. marneffei infection in non-AIDS, non-immunosuppressive and non-endemic conditions. CASE PRESENTATION: We describe a previously healthy 24-year-old man who complained of a 3-month history of intermittent diarrhea and a recent week of uncontrollable high fever. The HIV antibody test was negative. Enhanced abdominal computed tomography (CT) and integrated 18F-2-deoxy-2-fluoro-D-glucose position emission tomography/computed tomography (FDG PET/CT) both suspected malignant lymphoma. However, a large number of yeast-like cells were found in macrophages in cervical lymph node samples by hematoxylin and eosin stain and silver hexamine stain. Subsequent blood culture suggested T. marneffei infection. Metagenomic Next Generation Sequencing (mNGS) results suggested T. marneffei as the dominant pathogen. Unfortunately, the patient continued to develop acute liver failure and died due to adverse events associated with amphotericin B. CONCLUSIONS: Early diagnosis in HIV-negative patients who are otherwise not immunosuppressed and endemic poses a serious challenge. T. marneffei infection is an FDG-avid nonmalignant condition that may lead to false-positive FDG PET/CT scans. Nevertheless, integrated FDG PET/CT is necessary in patients with fever of unknown origin in the early period to perform earlier biopsy for histopathology and culture in highly avid sites and to avoid delays in diagnosis and treatment.

Low-dose liposomal amphotericin B for antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell transplantation.

BACKGROUND: Primary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions. OBJECTIVES: To evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients. PATIENTS AND METHODS: Retrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day -1 to 48 h before discharge) between January 2012 and December 2016. RESULTS: In total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2-11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI. CONCLUSIONS: The incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.

Non-occlusive ST-segment elevated myocardial infarction following the administration of liposomal amphotericin B in the treatment of cryptococcal meningitis.

WHAT IS KNOWN AND OBJECTIVE: Liposomal amphotericin B (L-AmB) is the cornerstone of many serious invasive fungal infections. Despite lower frequencies of commonly reported adverse events in clinical trials compared to conventional formulations, post-marketing complications continue to mount. CASE DESCRIPTION: We present a case of chest pain following the initial dose of L-AmB for cryptococcal meningitis. Electrocardiogram demonstrated no acute electrocardiogram findings. Upon rechallenge, the chest pain worsened was subsequently accompanied by ST-segment elevation. Emergent coronary angiography found no acute findings. WHAT IS NEW AND CONCLUSION: Providers should be aware of cardiac complications with L-AmB, including non-occlusive ST-segment elevation.

Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study.

PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.