Defining Optimal Doses of Liposomal Amphotericin B Against Candida auris: Data From an In Vitro Pharmacokinetic/Pharmacodynamic Model.

BACKGROUND: Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) dilution model. METHODS: Four C. auris isolates with Clinical and Laboratory Standards Institute (CLSI) AMB MICs = 0.5-2 mg/L were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a Candida albicans isolate tested in animals. The peak concentration (Cmax)/MIC versus log10 colony-forming units (CFU)/mL reduction from the initial inoculum was analyzed with the sigmoidal model with variable slope (Emax model). Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses. RESULTS: The in vitro PK/PD relationship Cmax/MIC versus log10 CFU/mL reduction followed a sigmoidal pattern (R2 = 0.91 for C. albicans, R2 = 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤2 mg/L and C. auris isolates with MIC ≤1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L. CONCLUSIONS: L-AMB was 4-fold less active against C. auris than C. albicans. Candida auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose.

Implementation of single high-dose liposomal amphotericin B based induction therapy for treatment of HIV-associated cryptococcal meningitis in Uganda: a comparative prospective cohort study.

BACKGROUND: In 2022, the World Health Organization (WHO) recommended a single 10mg/kg dose of liposomal amphotericin B in combination with 14 days of flucytosine and fluconazole (AMBITION-cm regimen) for induction therapy of HIV-associated cryptococcal meningitis, based on the results of the multisite AMBITION-cm trial. We evaluated outcomes after real-world implementation of this novel regimen in Uganda. METHODS: We enrolled Ugandan adults with cryptococcal meningitis into an observational cohort receiving the AMBITION-cm regimen with therapeutic lumbar punctures in routine care during 2022-2023. We compared 10-week survival and CSF early fungicidal activity with the outcomes observed in the AMBITION-cm clinical trial conducted at the same sites. RESULTS: During 2022-2023, 179 adults were treated with the AMBITION-cm regimen via routine care and compared to the 171 adults randomized to the AMBITION-cm trial interventional arm in Uganda from 2018-2021. No significant difference in 10-week survival occurred between the observational cohort (68.6%; 95%CI 61.6%-76.3%) and AMBITION-cm trial participants in the intervention arm (71.7%; 95%CI 65.2%-78.8%; absolute risk difference = -3.1%; 95%CI -13.1% to 6.9%; p=.61). Early fungicidal activity did not differ (0.42 vs 0.39 log10CFU/mL/day; p=.80) between groups. Among observational cohort participants discharged alive initially and for whom follow up data were available, the incidence of re-hospitalizations due to persistently elevated intracranial pressure was 2.8% (4/144). CONCLUSION: The AMBITION-cm regimen for cryptococcal meningitis resulted in similar outcomes as observed in the AMBITION-cm clinical trial when implemented in routine care. Intracranial pressure management during hospitalization and awareness after discharge are key components of optimizing outcomes.

Comparison of early fungicidal activity and mortality between daily liposomal amphotericin B and daily amphotericin B deoxycholate among patients with HIV-associated cryptococcal meningitis.

BACKGROUND: Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet non-inferiority criteria compared to amphotericin B deoxycholate in its registrational clinical trial. We aimed to compare the quantitative antifungal activity and mortality between daily amphotericin B deoxycholate and daily liposomal amphotericin among persons with HIV-related cryptococcal meningitis receiving adjunctive flucytosine 100 mg/kg/day. METHODS: We analyzed data from three clinical studies involving participants with HIV-associated cryptococcal meningitis receiving either daily liposomal amphotericin B at 3 mg/kg/day with flucytosine (N = 94) or amphotericin B deoxycholate at 0.7-1.0 mg/kg/day with flucytosine (N = 404) as induction therapy. We compared participant baseline characteristics, CSF early fungicidal activity (EFA), and 10-week mortality. RESULTS: We included 498 participants in this analysis, of whom 201 had available EFA data (N = 46 liposomal amphotericin; N = 155 amphotericin deoxycholate). Overall, there is no statistical evidence that the antifungal activity of liposomal amphotericin B (mean EFA = 0.495 log10 CFU/mL/day; 95%CI, 0.355-0.634) differ from amphotericin B deoxycholate (mean EFA = 0.402 log10 CFU/mL; 95%CI, 0.360-0.445) (P = 0.13). Mortality at 10 weeks trended lower for liposomal amphotericin (28.2%) vs amphotericin B deoxycholate (34.6%) but was not statistically different when adjusting for baseline characteristics (adjusted Hazard Ratio = 0.74; 95%CI, 0.44-1.25; P = 0.26). CONCLUSIONS: Daily liposomal amphotericin B induction demonstrated a similar rate of CSF fungal clearance and 10-week mortality as amphotericin B deoxycholate when combined with flucytosine for the treatment of HIV-associated cryptococcal meningitis.

Comparative pharmacodynamics and dose optimization of liposomal amphotericin B against Candida species in an in vitro pharmacokinetic/pharmacodynamic model.

As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against Candida spp. are lacking, we explored L-AMB pharmacodynamics against different Candida species in an in vitro PK/PD dilution model. Eight Candida glabrata, Candida parapsilosis, and Candida krusei isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the in vitro PK/PD model simulating L-AMB Cmax = 0.25-64 mg/L and t1/2 = 9 h. The model was validated with one susceptible and one resistant Candida albicans isolate. The Cmax/MIC-log10CFU/mL reduction from the initial inoculum was analyzed with the Emax model, and Monte Carlo analysis was performed for the standard (3 mg/kg with Cmax = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with Cmax = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 log10CFU/mL reduction was found at L-AMB Cmax = 8 mg/L against C. albicans, C. parapsilosis, and C. krusei isolates (MIC 0.25-0.5 mg/L) whereas L-AMB Cmax ≥ 32 mg/L was required for C. glabrata isolates. The in vitro PK/PD relationship followed a sigmoidal pattern (R2 ≥ 0.85) with a mean Cmax/MIC required for stasis of 2.1 for C. albicans (close to the in vivo stasis), 24/17 (EUCAST/CLSI) for C. glabrata, 8 for C. parapsilosis, and 10 for C. krusei. The probability of target attainment was ≥99% for C. albicans wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non-C. albicans species than C. albicans. A standard 3-mg/kg dose is pharmacodynamically sufficient for C. albicans whereas our data suggest that 5 mg/kg may be recommendable for the included non-C. albicans species.

Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B.

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.

Efficacy of an oral lipid nanocrystal formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis.

Invasive mucormycosis (IM) is associated with high mortality and morbidity. MAT2203 is an orally administered lipid nanocrystal formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due to Rhizopus arrhizus var. delemar or Mucor circinelloides f. jenssenii DI15-131. In R. arrhizus var. delemar-infected mice, 15 mg/kg of MAT2203 qd was as effective as 10 mg/kg of LAMB in prolonging median survival time vs placebo (13.5 and 16.5 days for MAT2203 and LAMB, respectively, vs 9 days for placebo) and enhancing overall survival vs placebo-treated mice (40% and 45% for MAT2203 and LAMB, respectively, vs 0% for placebo). A higher dose of 45 mg/kg of MAT2203 was not well tolerated by mice and showed no benefit over placebo. Similar results were obtained with mice infected with M. circinelloides. Furthermore, while both MAT2203 and LAMB treatment resulted in a significant reduction of ~1.0-2.0log and ~2.0-2.5log in Rhizopus delemar or M. circinelloides lung and brain burden vs placebo mice, respectively, LAMB significantly reduced tissue fungal burden in mice infected with R. delemar vs tissues of mice treated with MAT2203. These results support continued investigation and development of MAT2203 as a novel and oral formulation of amphotericin for the treatment of mucormycosis.

Postpartum cryptococcosis in an HIV-negative patient.

PURPOSE AND METHODS: We present an unusual case of an HIV-negative patient with postpartum pulmonary cryptococcosis and cryptococcemia. RESULTS: The diagnostic methods and treatment of cryptococcosis in a postpartum patient are presented in this case report. Due to anaphylaxis to liposomal amphotericin B, desensitisation to the drug was performed. CONCLUSION: We would like to raise awareness about rare infections such as cryptococcosis in pregnancy and the postpartum period. In addition, we were able to document a successful desensitisation to liposomal amphotericin B.

Evaluation of the pharmacokinetics of liposomal amphotericin B and analysis of the relationship between pharmacokinetics, efficacy and safety in patients with hematological diseases.

INTRODUCTION: This study aimed to identify factors responsible for changes in blood concentrations of a liposomal formulation of amphotericin B (AMPH-B, L-AMB) and analyze the relationships between blood concentrations and efficacy or toxicity. METHODS: L-AMB was administered to 30 patients being treated for hematological diseases. AMPH-B plasma concentrations were determined right before the initiation (Cmin) and at the end (Cmax) of infusion on at least 1 day, beginning on Day 3 of L-AMB treatment. The relationships of Cmin divided by dose (C/D ratio) to body weight, age, hepatic function, renal function, serum albumin, C-reactive protein (CRP), response, hypokalemia, and renal impairment were evaluated. RESULTS: C/D ratio was not correlated with age, hepatic function, renal function, or serum albumin. Body weight adjusted C/D ratio was negatively correlated with CRP. Cmax and Cmin were compared between responders and non-responders, those with or without hypokalemia, and those with or without renal impairment. A higher Cmax in patients with hypokalemia was the only significant difference seen. CONCLUSIONS: The negative correlation between CRP and plasma concentrations was likely caused by higher distribution of L-AMB from the blood to infected tissue in patients with a greater degree of infection, with a resulting decrease in plasma concentrations. AMPH-B plasma concentrations were not related to response. Higher Cmax of AMPH-B were observed in patients with hypokalemia, but no relationship between plasma concentration and renal toxicity was observed, suggesting that AMPH-B plasma concentrations appear to be minimally related to PD when used as L-AMB.

Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation.

INTRODUCTION: Fungal infection after lung transplantation can lead to poor clinical outcome, for which lung transplant recipients require prophylaxis. One of the antifungal agents used after lung transplantation is nebulized amphotericin B (AMB). Nebulized AMB causes adverse events such as dyspnea and airway irritation, and long-term use leads to high economic costs. So far, prophylactic regimens employing AMB deoxycholate (AMB-d) and liposomal AMB (L-AMB) have been developed. This study compared the efficacy, safety, and cost of AMB-d and L-AMB. PATIENTS AND METHODS: Patients who underwent lung transplantation at Kyoto University Hospital from January 2021 to May 2023 were included in this study. Thirty-three patients received nebulized AMB-d, whereas 29 received nebulized L-AMB. RESULTS: Both regimens maintained comparable prophylactic efficacy regarding the development of fungal infection in the AMB-d and L-AMB groups (3.0% vs. 3.4%, P = 0.877). Patients treated with nebulized L-AMB experienced fewer respiratory-related adverse reactions than those treated with nebulized AMB-d (6.9% vs. 30.3%, P < 0.05), leading to a longer treatment duration with L-AMB than with AMB-d. Additionally, the daily cost of administering L-AMB was lower than that of administering AMB-d (3609 Japanese yen vs. 1792.3 Japanese yen, P < 0.05). DISCUSSION: These results suggest that nebulized L-AMB is safer and more cost-effective than nebulized AMB-d, with comparable efficacy.

Association between the hypokalaemia index based on area over the serum potassium concentration curve and occurrence of acute kidney injury in patients administered liposomal amphotericin B.

BACKGROUND: Acute kidney injury (AKI) and hypokalaemia are common adverse events after treatment with liposomal amphotericin B (L-AMB). OBJECTIVES: Because excess potassium (K) leakage occurs during renal tubular injury caused by L-AMB, measuring the decrease in rate of serum K concentration might be more useful to assess the renal impact of L-AMB than hypokalaemia identified from a one-point measurement. The effects of a decrease in K concentration and duration of hypokalaemia on AKI were investigated. METHODS: A ≥ 10% decrease in K concentration from the reference concentration within a 7-day timeframe was evaluated. The hypokalaemia index, which combines the duration of K concentration lower than the reference and a marked low K concentration, was calculated from the area over the concentration curve. RESULTS: Eighty-six patients were included in the study. The incidences of AKI and decrease in K concentration were 36.0% and 63.9%, respectively. Of patients who developed both adverse events, a decrease in K concentration occurred first in 22 of 26 patients, followed by AKI 7 days later. Hypokalaemia did not increase AKI risk whereas a decrease in K concentration was an independent risk factor for AKI. The hypokalaemia index in patients with AKI was significantly higher than those without AKI (5.35 vs. 2.50 points, p = 0.002), and ≥3.45 points was a significant predictor for AKI. CONCLUSION: A ≥ 10% decrease in the K concentration was a significant factor for AKI in patients receiving L-AMB therapy. In such patients, dose reduction or alternative antifungals could be considered based on the hypokalaemia index.

Liposomal amphotericin for secondary prophylaxis: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to determine the safety of liposomal amphotericin B (L-AMB) compared to other antifungal agents for secondary prophylaxis. METHOD: We conducted a comprehensive search across international databases and reference lists of articles to compile all relevant published evidence evaluating the efficacy and safety of L-AMB versus other antifungals (NLAMB) for secondary prophylaxis against invasive fungal infections. Pooled estimates were calculated after data transformation to evaluate mortality, breakthrough infections, and the frequency of adverse effects, including hypokalemia and nephrotoxicity. Comparisons of breakthrough fungal infection and mortality between the L-AMB and NLAMB groups were performed. RESULT: We identified 10 studies. The cumulative frequency of patients using L-AMB was 148, compared to 341 patients in the NLAMB group. The mortality rates in the L-AMB and NLAMB groups were 10% and 0%, respectively. However, based on the odds ratio, the mortality in the L-AMB group was lower than that in the NLAMB group. No significant difference was observed in breakthrough invasive fungal infections between the L-AMB and NLAMB groups. The frequencies of nephropathy and hypokalemia in the L-AMB group were 36% and 18%, respectively. CONCLUSION: Our findings indicate a lower incidence of mortality in the L-AMB group compared to the NLAMB group. No statistically significant difference was observed in the incidence of breakthrough infection between the two groups. L-AMB administration is associated with nephropathy and hypokalemia. However, the refusal to continue treatment due to adverse effects is not significantly high.

Treatment of mucocutaneous leishmaniasis - A systematic review.

Mucocutaneous leishmaniasis is a severe infectious disease, predominantly endemic in Central and South America and is characterized by granulomatous, destructive mucosal lesions in the oral, nasal, and pharyngeal cavities. It is caused by protozoa of the genus Leishmania spp. transmitted to humans by sandflies. Mucocutaneous leishmaniasis occurs after untreated or inadequately treated cutaneous leishmaniasis and is more common in immunocompromised patients. The aim of this systematic review is to summarize all reported treatment options for mucocutaneous leishmaniasis. This review is based on all English, German, French, Spanish and Portuguese articles published in the databases "PubMed" and "Lilacs" from 1995 to 2020. Most of the medical literature is limited to case reports, small case series, retrospective studies, and a few randomized controlled trials. Various treatment options include pentavalent antimonates such as meglumine antimonate or sodium stibogluconate, amphotericin B (liposomal, deoxycholate, lipid complex, colloidal dispersion), miltefosine, and pentamidine. Other therapeutic options include itraconazole, fluconazole, ketoconazole, aminosidine sulfate, and azithromycin. The choice of drug depends primarily on its availability in the endemic area and the patient's comorbidities.

Single High Dose of Liposomal Amphotericin B in Human Immunodeficiency Virus/AIDS-Related Disseminated Histoplasmosis: A Randomized Trial.

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

Access to Medicines for Treating People With Cryptococcal Meningitis.

Cryptococcal meningitis accounts for 1 in 5 AIDS-related deaths globally. World Health Organization guidelines strongly recommend a single high dose of liposomal amphotericin B as part of preferred treatment, but this drug remains unaffordable in most low- and middle-income countries. A proactive approach is needed from manufacturers and other stakeholders to improve access.

Critical appraisal beyond clinical guidelines for intraabdominal candidiasis.

BACKGROUND: Regardless of the available antifungals, intraabdominal candidiasis (IAC) mortality continues to be high and represents a challenge for clinicians. MAIN BODY: This opinion paper discusses alternative antifungal options for treating IAC. This clinical entity should be addressed separately from candidemia due to the peculiarity of the required penetration of antifungals into the peritoneal cavity. Intraabdominal concentrations may be further restricted in critically ill patients where pathophysiological facts alter normal drug distribution. Echinocandins are recommended as first-line treatment in guidelines for invasive candidiasis. However, considering published data, our pharmacodynamic analysis suggests the required increase of doses, postulated by some authors, to attain adequate pharmacokinetic (PK) levels in peritoneal fluid. Given the limited evidence in the literature on PK/PD-based treatments of IAC, an algorithm is proposed to guide antifungal treatment. Liposomal amphotericin B is advocated as first-line therapy in patients with sepsis/septic shock presenting candidemia or endophthalmitis, or with prior exposure to echinocandins and/or fluconazole, or with infections by Candida glabrata. Other situations and alternatives, such as new compounds or combination therapy, are also analysed. CONCLUSION: There is a critical need for more robust clinical trials, studies examining patient heterogeneity and surveillance of antifungal resistance to enhance patient care and optimise treatment outcomes. Such evidence will help refine the existing guidelines and contribute to a more personalised and effective approach to treating this serious medical condition. Meanwhile, it is suggested to broaden the consideration of other options, such as liposomal amphotericin B, as first-line treatment until the results of the fungogram are available and antifungal stewardship could be implemented to prevent the development of resistance.

Otitis externa caused by Malassezia slooffiae complicated with mastoiditis: A case report.

Herein, we report a case of otitis externa caused by Malassezia slooffiae complicated with mastoiditis. A 70-year-old male complained of fever and severe otorrhea from left external auditory canal 2 months after undergoing a craniotomy to remove a hematoma. He had right-sided paralysis and undertook bed rest. Brain computed tomography revealed continuous fluid accumulation in the left mastoid air cells and middle ear from left external auditory canal in addition to leukocytosis and increased C-reactive protein level. The tympanic membrane was severely swelling. These results indicated the presence of otitis media and mastoiditis. Otorrhea culture showed large amounts of M. slooffiae. The administration of liposomal amphotericin B (L-AMB), the irrigation of external auditory canal with normal saline, and the application of topical ketoconazole ointment were started. The administration of L-AMB for 8 weeks and voriconazole, which was switched from L-AMB, for 4 weeks ameliorated his infection and he was transferred to another hospital to receive rehabilitation. From these results and his clinical course, the diagnosis of otitis externa caused by Malassezia slooffiae complicated with mastoiditis was made. And the possibility of the contamination by M. slooffiae was very low. Clinicians should be aware that M.slooffiae can provoke otological infections since M. slooffiae is the most common Malassezia sp. in external auditory canal.

Successful treatment of proven coronavirus disease 2019-associated pulmonary aspergillosis with liposomal amphotericin B in a patient with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Factors Associated with Breakthrough Fungemia Caused by Candida, Trichosporon, or Fusarium Species in Patients with Hematological Disorders.

Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan. A total of 121 cases of breakthrough fungemia were identified. Of the 121 involved patients, 83, 11, 5, and 22 were receiving micafungin, voriconazole, itraconazole, and liposomal amphotericin B, respectively, when the breakthrough occurred. Of the 121 causative breakthrough fungal strains, 96 were Candida species, and the rest were 13 cases of Trichosporon species, 7 of Fusarium species, 2 of Rhodotorula mucilaginosa, and 1 each of Cryptococcus neoformans, Exophiala dermatitidis, and Magnusiomyces capitatus. The crude 14-day mortality rate of breakthrough fungemia was 36%. Significant independent factors associated with the crude 14-day mortality rate were age of ≥60 years (P = 0.011), chronic renal failure (P = 0.0087), septic shock (P < 0.0001), steroid administration (P = 0.0085), and liposomal amphotericin B breakthrough fungemia (P = 0.0011). An absolute neutrophil count of >500/µL was significantly more common in candidemia in the multivariate analysis (P = 0.0065), neutropenia and nonallogeneic hematopoietic stem cell transplants were significantly more common in Trichosporon fungemia (P = 0.036 and P = 0.033, respectively), and voriconazole breakthrough fungemia and neutropenia were significantly more common in Fusarium fungemia (P = 0.016 and P = 0.016, respectively). The epidemiological and clinical characteristics of breakthrough fungemia of patients with hematological disorders were demonstrated. Some useful factors to predict candidemia, Trichosporon fungemia, and Fusarium fungemia were identified.

Liposomal amphotericin B exposure in critically ill patients: a prospective pharmacokinetic study.

Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal drug. Little is known about its pharmacokinetics (PK) in critically ill patients. The aim of this study was to document the PK of L-AmB in this population. It was also explored if covariates may be identified that influence its exposure. All adult, critically ill patients (at the intensive care unit or hematology ward) treated with L-AmB between October 2016 and January 2020 were eligible for this study. The administered dose was left at the discretion of the treating clinician. Plasma samples were collected at predose and 1, 2, 4, 8, 12, 16, 20 and 24 h postdose at an early (day 2-3) and/or later (≥ day 6) treatment day. Additionally, daily trough concentrations were collected until day 14. Of 33 included patients, 31 were evaluable; their median [IQR] age and body weight was 59 [54-64] years and 68 [59-77] kg, respectively. L-AmB was administered at doses between 2.7 mg/kg and 12.3 mg/kg, with a median [IQR] trough concentration of 3.1 [2.0-4.7] mg/l. The overall median area under the 24 h concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were 169.0 [117.0-253.0] mg h/l and 23.2 [16.9-33.7] mg/l, respectively. A considerable intra- and interpatient PK variability for Cmax and AUC0-24 was observed but no explaining variables, except the administered dose, could be identified. The PK of L-AmB in critically ill patients was documented. A considerable variability in exposure was observed between and within patients; however, it was not associated with a multitude of patient-related characteristics.

L-AmB is marketed for decades to treat invasive fungal infections; however, not much is known about its exposure. We documented L-AmB exposure in 31 critically ill patients. Although median exposure was similar compared to noncritically ill patients, a considerable variability was observed.