Conventional Amphotericin Research Articles

Preventability and manageability of adverse drug reactions in COVID-19 with mucormycosis: An observational study.

In the intricate landscape of healthcare amid the COVID-19 pandemic, the emergence of mucormycosis as a severe complication posed a significant challenge to primary healthcare. This study delved into the complexities of adverse drug reactions (ADRs) in COVID-19 patients with mucormycosis undergoing treatment with conventional amphotericin B. Ethically approved and meticulously conducted, the study scrutinized 154 ADRs in depth, shedding light on their classification, outcomes, and interventions in COVID patients with mucormycosis. A descriptive analysis was carried out to report the findings of this study. The findings revealed that a substantial proportion (85.6%) of these ADRs were manageable, emphasizing the need for vigilant monitoring and timely interventions. Notably, gender disparities surfaced, indicating potential gender-specific responses to amphotericin B. Causality assessments based on the WHO-UMC scale classified the majority of ADRs as certain, providing a robust foundation for understanding the intricate relationships between amphotericin B and the observed adverse events. This research not only categorizes ADRs as preventable and manageable but also offers practical insights into their nature and the diverse strategies employed for their management. The study's outcomes underline the importance of personalized healthcare approaches that can be adopted by primary care physicians for effective patient care.

Using single-dose liposomal amphotericin B for cryptococcal meningitis induction therapy: nurse pearls and practical perspectives.

In Uganda where the burden of HIV-associated cryptococcal meningitis is high, conventional amphotericin B deoxycholate has been standard to manage patients with cryptococcal meningitis in research settings. However, liposomal amphotericin B (AmBisome) is now available via the efforts of UNITAID. We sought to describe our nursing experience using AmBisome within a clinical trial for cryptococcal meningitis. We describe the experience of using single-dose 10mg/kg liposomal amphotericin B from the perspective of a research nurse in Uganda. Second, we described the process of preparing and administering amphotericin. Third, we assessed the nursing time required for the administration of daily amphotericin B versus single-dose liposomal amphotericin. Fourth, we discuss the major challenges faced while using liposomal amphotericin B. We provide estimates for the nursing time required for reconstituting, filtering, diluting and administering liposomal amphotericin B and a visual aid for nursing tasks. Based on five trained nurses, the process of reconstitution and filtration lasts an average of 52 minutes (Range: 40 to 60 minutes), to reconstitute a mean of 11 (range: 8 to 15) 50mg vials (median weight 55kg). Overall, less nursing time was required for single-dose administration than for daily amphotericin B dosing. From a nursing perspective, liposomal amphotericin B was preferable to amphotericin B deoxycholate due to its reduced infusion reactions and other toxicities. Single-dose liposomal amphotericin B is a better alternative to daily amphotericin B. In addition to less toxicity, nosocomial infections, reduced hospital stay, and the potential for lower hospitalisation costs, the nursing implications should not be discounted. Quality nursing care is a finite resource in low- and middle-income countries, and single-dose amphotericin B reduced the nursing time required for the care of patients with cryptococcal meningitis.

Case report: juvenile paracoccidioidomycosis with intestinal involvement

Introduction: Contact of Paracoccidioides sp. with the human organism presents in a variety of clinical forms of the disease. Intestinal clinical manifestation is found in 10 to 30% of cases, commonly in juvenile form. This case report seeks to describe a patient with juvenile paracoccidioidomycosis with atypical intestinal involvement. Case report: A 14 years old woman with an updated vaccination schedule and no reports of chronic diseases, allergies or continued use of medications, presented a diarrheal condition that was characterized by pasty stools, where episodes became gradually more intense, associated with episodes of hematochezia, retroauricular lymphadenopathy on the right, as well as shivering and fever. A colonoscopy revealed multiple polypoid formations, ulcerations and friability throughout the colon. After biopsy results, the diagnosis of Paracoccidioidomycosis with intestinal involvement was established. Due to the wasting syndrome, anemia and persistent diarrhea, the patient was hospitalized for blood transfusion and intravenous treatment with conventional Amphotericin B. Discussion: Unlike what was presented by the patient in this case, involvement of the gastrointestinal tract is uncommon in paracoccidioidomycosis. This disease presents a range of clinical manifestations, which makes diagnosis difficult. Since this type of infection is not always considered, it may result in underdiagnosed cases, especially in women and young adults. The prognosis depends on the initial severity of the disease, the presence of comorbidities and the treatment used. Conclusion: Especially for the intestinal form, earlier treatment will better the results. The disease has a good chance of effective treatment using antifungal therapy.

A Case of Extremely Premature Baby with Persistent Metabolic Acidosis, Hypoglycemia and Dyselectrolytemia Induced by Liposomal Amphotericin B

Amphotericin B is widely used in the treatment of neonatal invasive fungal disease. Liposomal amphotericin B (LAmB) is now preferred over conventional amphotericin B deoxycholate due to its lower kidney toxicity. However, it is essential to monitor the possible side effects of LAmB when treating extremely premature infants. Herein, we present a case of an extremely premature infant who exhibited persistent metabolic acidosis, hypoglycemia, and dyselectrolytemia after administration of LAmB for a suspected fungal infection.

Incidence of Antimicrobial-Associated Acute Kidney Injury in Children: A Structured Review.

Acute kidney injury (AKI) is a commonly reported adverse effect of administration of antimicrobials. While AKI can be associated with poorer outcomes, there is little information available to understand rates of AKI in children exposed to various antimicrobials. We performed a structured review using the PubMed and Embase databases. Articles were included if they provided an AKI definition in patients who were <19 years of age receiving an antimicrobial and reported the frequency of AKI. Author-defined AKI rates were calculated for each study and mean pooled estimates for each antimicrobial were derived from among all study participants. Pooled estimates were also derived for those studies that reported AKI according to pRIFLE(pediatric risk, injury, failure, loss, end stage criteria), AKIN(acute kidney injury network), or KDIGO (kidney disease improving global outcomes)creatinine criteria. A total of 122 studies evaluating 28 antimicrobials met the inclusion criteria. Vancomycin was the most commonly studied drug: 11,514 courses across 44 included studies. Among the 27,285 antimicrobial exposures, the overall AKI rate was 13.2% (range 0-42.1% by drug), but the rate of AKI varied widely across studies (range 0-68.8%). Cidofovir (42.1%) and conventional amphotericin B (37.0%) had the highest pooled rates of author-defined AKI. Eighty-one studies used pRIFLE, AKIN, or KDIGO AKI criteria and the pooled rates of AKI were similar to author-defined AKI rates. In conclusion, antimicrobial-associated AKI is reported to occur frequently in children, but the rates of AKI varies widely across studies and drugs. Most published studies examined hospitalized patients and heterogeneity in study populations and in author definitions of AKI are barriers to a comparison of nephrotoxicity risk among antimicrobials in children.

The dose of the normal saline pre-infusion and other risk factors for amphotericin B deoxycholate-associated acute kidney injury.

Conventional amphotericin B deoxycholate (AmBd) is the preferred amphotericin B formulation in countries with limited resources despite its nephrotoxicity. Normal saline pre-infusion is a recommended measure to reduce the risk of nephrotoxicity in patients receiving AmBd. To examine the effect of different normal saline solution (NSS) pre-infusion doses, and other potential risk factors, on the development of acute kidney injury (AKI) in patients with invasive fungal infection receiving AmBd. Adult patients with invasive fungal infections who received intravenous AmBd were included in this retrospective study. Doses of the normal saline pre-infusion were adjusted to the body weight (NSS/BW) and the daily dose of amphotericin B (NSS/AmBd). Kaplan-Meier survival analysis was used to estimate 14 d AKI-free survival rates, and the log-rank test was used to compare AKI-free survivals between groups. The present study included 60 patients; 31 patients developed AKI during the AmBd therapy. The overall 14 d AKI-free survival was 48.3%. NSS/AmBd, but not NSS/BW, was associated with AKI-free survival in patients receiving AmBd: the higher the NSS/AmBd, the higher the AKI-free survival. Gender, baseline blood urea nitrogen (BUN), and baseline plasma bicarbonate (Bicarb) also affected AKI-free survival. Female gender, higher BUN, and lower Bicarb were associated with higher AKI-free survival. The present study suggests that low NSS/AmBd, male gender, low BUN, and high Bicarb are risk factors for AmBd-associated AKI. Excluding gender, these risk factors are potentially modifiable and would guide tailoring appropriate preventive measures for AmBd-associated AKI.

Fusariosis in Mexico: A 10-year retrospective series.

Fusarium species represent an opportunistic fungal pathogen. The data in Mexico about Fusarium infections in humans are scarce. Here, we present a retrospective series of patients with a confirmed diagnosis of fusariosis in eight different hospitals in Mexico from January 2010 to December 2019. The diagnosis of proven fusariosis was made according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORT/MSG) criteria. A total of 49 cases were identified in our series. Most patients had burn injuries (49%), and 37% had hematological malignancies. Most patients had fire injuries (40%), followed by electric injuries (8%), febrile neutropenia (10%), and pancytopenia (6%). Patients had skin and soft tissue involvement in 49%, followed by blood culture isolation and biopsies from different sites of the body (lung, sinuses, bone tissue, and eyes). Febrile neutropenia (10%) and fungemia (8%) were the most common clinical syndromes in immunosuppressed patients. Most patients received monotherapy (67%), where voriconazole was used in 30% of the cases, followed by conventional amphotericin B (16%), and lipidic formulations of amphotericin B in 10% (either liposomal amphotericin B or amphotericin B lipid complex). Combination therapy was used in 20% of the cases, and the most common combination therapy was triazole plus any lipidic formulation of amphotericin B (10%). Mortality related to Fusarium infection occurred in 22% of patients. Fusariosis is a serious threat. Burn injuries and hematologic malignancies represent the most common causes of infection in this small series from Mexico.

Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Characteristics, Mortality, Associated Variables with Death and Therapeutic Response Among Hiv-Positive, Solid Organ Transplant (SOT), and Non-Hiv-Positive/Non-Transplant (NHNT) Patients with Cryptococcosis: First Multicenter Cohort Study in Brazil.

Cryptococcosis is traditionally associated with immunocompromised patients but is increasingly being identified in those without the human immunodeficiency virus (HIV) or other immunocompetent individuals. We aim to describe the characteristics, mortality, and associated variables with death among hospitalized patients with cryptococcosis in Brazil. This is the first multicenter retrospective cohort study conducted in seven public tertiary Brazilian hospitals. Three hundred eighty-four patients were included; the median age was 39 years and 283 (73.7%) were men. Hosts were 304 (79.2%) HIV-positive, 16 (4.2%) solid organ transplant (SOT), and 64 (16.7%) non-HIV-positive/non-transplanted (NHNT). Central nervous system (CNS) cryptococcosis had a significantly higher number across disease categories, with 313 cases (81.5%). Two hundred and seventy-one (70.6%) patients were discharged home and 113 (29.4%) died during hospitalization. In-hospital mortality among HIV-positive, SOT, and NHNT was 30.3% (92/304), 12.5% (2/16), and 29.7% (19/64), respectively. Induction therapy with conventional AMB mainly in combination with fluconazole (234; 84.2%) was the most used. Only 80 (22.3%) patients received an AMB lipid formulation: liposomal (n = 35) and lipid complex (n = 45). Patients with CNS cryptococcosis had lower mortality (83/313, 26.5%) when compared with the other categories (P = 0.017). Multivariate analysis showed that age and disseminated cryptococcosis had a higher risk of death [odds ratio (OR), 1.03; 95% Confidence Interval (CI), 1.01 to 1.05; P = 0.008 and OR, 1.84; 95% CI, 1.01 to 3.53; P = 0.048, respectively]. Understanding the epidemiology of cryptococcosis in our settings will help to recognize the burden and causes of mortality and identify strategies to improve this scenario.

Cost-effectiveness analysis and budgetary impact of anidulafungin treatment for patients with candidemia and other forms of invasive candidiasis in Brazil.

Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.

Emergence of Cerebral Mucormycosis in the Post-COVID Period: A Detailed Analysis of Risk Factors, Clinical Progression, and Management of This Opportunistic Fungal Infection.

An epidemic ofMucoraleswas reported following the second wave of COVID-19 in India, and intracranial extension of the same was one of the most dreadful complications. A total of 62 patients with cerebral mucormycosis were recruited and followed up till 12 weeksto evaluate the risk factors, incidence, clinical manifestations, management, and prognosis of cerebral mucormycosis. A median age of 51.5 yearswith male predominance (74%) was noted. The majority of subjects reported a history of COVID infection (93.5%) and diabetes mellitus (83.87%). The first symptom of mucormycosis appeared after a mean period of 17.63 ± 8.9 days following COVID. Facial swelling and ptosis were the most common symptoms. Only 55% of patients had neurological presentations, and hemiparesis was the most common neurological sign (30.6%). Radiologically, the involvement of maxillary sinus (90.32%) and ethmoid sinus (87.10%)was commonly noted. Cerebral findings included temporal lobe (50%) andparietal lobe (30.06%) involvement, cavernous sinus thrombosis (30.06%), and internal carotid artery thrombosis (22.58%). Acute cerebral infarction was notable in 37% of subjects (p-value=0.0015, significant association with the outcome). Conventional and liposomal amphotericin B were used in 91.94% and 53.23% of patients, respectively. Retrobulbar amphotericin injections used in 11.3% of subjects significantly affected the outcome (p-value=0.03, significant). Posaconazole step-downtherapy was used in72.5% of subjects (p-value=0.0005, significant). Surgical interventions were performed in53 (85.48%) subjects (p-value=0.004, significant).Functional endoscopic sinus surgery was the most common (in 64.52% of subjects), followed by maxillectomy (20.97% of subjects) and craniotomy (17.7% of subjects). At the end of 12 weeks, 33.87% of patients died and 59.68% were alive; the rest(6.45%) were lost to follow-up. The absence or late presentation of neurological symptoms led to a delayed diagnosis of cerebral mucormycosis. The presence of acute cerebral infarction indicated a worse prognosis. However, there was a significant influence of step-down posaconazole therapy, retrobulbar amphotericin injections, and surgical intervention on the prognosis of cerebral mucormycosis.

P271 A masquerading case of Cryptococcus neoformans

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PMIntroductionCryptococcal infections are commonly seen in immunocompromised hosts, especially HIV-infected patients and patients on immunosuppressive therapy. Cryptococcus shows a strong tropism for the central nervous system however cutaneous tropism is not uncommon. Here we describe an HIV-negative immunocompromised patient who developed disseminated cryptococcosis with the predominant presentation being painful thigh lesions.Case DetailsA 56-year-old lady presented with skin lesions and burning pain over both thighs for 1 month and a high-grade fever for 15 days. Her thigh lesions were initially treated elsewhere as tinea corporis. Her previous medical history was significant for poorly controlled diabetes, and chronic liver disease (secondary to autoimmune hepatitis or AIH). Her ongoing medications included prednisolone, anti-diabetics, and tenofovir. At presentation, the only significant physical findings were large irregular areas of central hypo-pigmentation with peripheral hyper-pigmentation and superficial small blisters over both thighs. These areas showed signs of inflammation. The empiric antimicrobial therapy included piperacillin-tazobactam and fluconazole (in view of prior urine culture growing Candida species). Over the next 48 h, fever continued, thigh pain worsened and the lesions on thighs blistered with violaceous discoloration. Her blood cultures sent at admission grew Candida kruzei, resistant to fluconazole, sensitive to voriconazole, amphotericin and echinocandins. Beta-D Glucan was also elevated. Fluconazole was discontinued, and anidulafungin was initiated. A repeat culture (prior to the start of anidulafungin) was still positive for C. krusei, but a subsequent blood culture (after the start of anidulafungin) was negative. Echocardiography did not show features of endocarditis. After a transient improvement, she worsened again with breakthrough fever, hypotension, and worsening of thigh lesions with eschar formation. Wound debridement was done, and antibiotics were escalated to carbapenem and polymyxins. Tissue cultures (sent during wound debridement) grew carbapenem-resistant klebsiella pneumonia. With these, the fever and her wounds were better; but the fever still persisted and she described a persisting severe burning pain over both the thigh wounds which did not respond to several analgesics.A few days later, the fever worsened, and she had hypotension and disorientation. Blood and urine cultures were repeated. Repeat Serum beta D glucan levels were elevated. CSF examination was not possible in view of severe coagulopathy. The blood and wound cultures both grew C. neoformans (confirmed on MaldiTOFF). Antibiotics and anidulafungin were discontinued; liposomal amphotericin and flucytosine were started. Patient had significant improvement in sensorium, fever, and thigh pains within the next 72 h. Later, liposomal amphotericin was switched to conventional amphotericin because of financial constraints. This was followed by acute kidney injury and a flare of AIH. Amphotericin and flucytosine were withheld for a few days; a pulse of methylprednisolone was needed for AIH. Following resolution of acute kidney injury and AIH flare, conventional amphotericin B and flucytosine were restarted (and given for cumulative 3 weeks). This was followed by fluconazole consolidation. At hospital discharge, although there were raw areas over the thighs, these were healthy and she was otherwise well. A total of 3 months later, skin grafting was successfully performed.Conclusions Cryptococcus can be a great masquerader, and can mimic a variety of conditions. A high index of suspicion is required to clinch the diagnosis.

Comparative efficacy and safety of systemic antifungal agents for candidemia: a systematic review with network meta-analysis and multicriteria acceptability analyses

Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia. A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included. Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%). Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.

Quantitative monitoring of experimental and human leishmaniasis employing amastigote-specific genes.

The gold standard for diagnosis of leishmaniasis is the microscopic detection of amastigotes/Leishman Donovan (LD) bodies, but its moderate sensitivity necessitates the development of molecular approaches. This study aimed to quantify in experimental animal models and human leishmaniasis the expression of amastigote-specific virulence genes, A2 and amastin by droplet digital polymerase chain reaction (ddPCR). Total RNA was isolated from L. donovani-infected hamsters or murine peritoneal macrophages and lesional biopsies from patients with post kala-azar dermal leishmaniasis (PKDL). Following cDNA conversion, EvaGreen-based ddPCR was performed using specific primers for A2 or amastin and parasite load expressed in copies per μL. Assay was optimized and the specificity of amastigote-specific A2 and amastin was confirmed. In hepatic and splenic tissues of L. donovani-infected hamsters and peritoneal macrophages, ddPCR demonstrated a greater abundance of A2 than amastin. Treatment of L. donovani-infected peritoneal macrophages with conventional anti-leishmanials, miltefosine and amphotericin B translated into a dose-dependent reduction in copies per μL of A2 and amastin, and the extrapolated IC50 was comparable with results obtained by counting LD bodies in Giemsa-stained macrophages. Similarly, in dermal biopsies of patients with PKDL, A2 and amastin were detected. Overall, monitoring of A2 by ddPCR can be an objective measure of parasite burden and potentially adaptable into a high throughput approach necessary for drug development and monitoring disease progression when the causative species is L. donovani.

Nebulized Amphotericin B in Mechanically Ventilated COVID-19 Patients to Prevent Invasive Pulmonary Aspergillosis: A Retrospective Cohort Study.

IMPORTANCE:Despite high mortality rates of COVID-19-associated pulmonary aspergillosis (CAPA) in the ICU, antifungal prophylaxis remains a subject of debate. We initiated nebulized conventional amphotericin B (c-AmB) as antifungal prophylaxis in COVID-19 patients on invasive mechanical ventilation (IMV).OBJECTIVES:To assess the CAPA incidence in COVID-19 patients on IMV treated with and without nebulized c-AmB as antifungal prophylaxis.DESIGN, SETTING, AND PARTICIPANTS:Retrospective cohort study of consecutive COVID-19 patients admitted to our adult 17-bed ICU in a university-affiliated general hospital in Ede, The Netherlands, between January 25, 2021, and July 9, 2021. Patients not requiring IMV or transferred from or to another ICU were excluded. From April 9, 2021, daily nebulized amphotericin B in all patients on IMV was initiated.MAIN OUTCOMES AND MEASURES:Bronchoscopy with bronchoalveolar lavage (BAL) was performed in case of positive cultures for Aspergillus from the respiratory tract and/or unexplained respiratory deterioration. Incidence of probable and proven CAPA was compared between patients treated with and without nebulized antifungal prophylaxis using Pearson chi-square test.RESULTS:A total of 39 intubated COVID-19 patients could be analyzed, of which 16 were treated with antifungal prophylaxis and 23 were not. Twenty-six patients underwent bronchoscopy with BAL. In patients treated with antifungal prophylaxis, the incidence of probable/proven CAPA was significantly lower when compared with no antifungal prophylaxis (27% vs 67%; p = 0.047). Incidence of tracheobronchial lesions and positive Aspergillus cultures and BAL-galactomannan was significantly lower in patients treated with antifungal prophylaxis (9% vs 47%; p = 0.040, 9% vs 53%; p = 0.044, and 20% vs 60%; p = 0.047, respectively). No treatment-related adverse events and no case of proven CAPA were encountered in patients receiving antifungal prophylaxis.CONCLUSIONS AND RELEVANCE:Nebulization of c-AmB in critically ill COVID-19 patients on IMV is safe and may be considered as antifungal prophylaxis to prevent CAPA. However, a randomized controlled trial to confirm this is warranted.

Synthesis and in vitro antifungal activity of selenium-containing chitin derivatives

Mild and ‘green’ ultrasound-assisted reaction of chitin with 3-(chloromethyl)[1,2,4]selenadiazolo[4,5-a]pyridin-4-ium bromide in water affords novel selenium-containing cationic chitin derivatives. The thus obtained chitin derivatives are water soluble and are characterized by high in vitro antifungal activity comparable with conventional antifungal drug Amphotericin B.

Conventional amphotericin B elicits markers of immunogenic cell death on leukemic blasts, mediates immunostimulatory effects on phagocytic cells, and synergizes with PD-L1 blockade

ABSTRACT Immunostimulatory regimens are a game changer in the fight against cancer, but still only a minority of patients achieve clinical benefit. Combination with immunomodulatory drugs and agents converting otherwise non-immunogenic forms of cell death into bona fide “immunogenic cell death” (ICD) could improve the efficacy of these novel therapies. The aim of our study was to investigate conventional Amphotericin B (AmB) as an enhancer of antitumor immune responses. In tumor cell line models, AmB induced ICD with its typical hallmarks of calreticulin (CALR) expression and release of high mobility group box 1 (HMGB1) as well as Adenosine 5’-triphosphate (ATP). Interestingly, in contrast to non-ICD inducing treatments, ICD induction led to up-regulation of PD-L1-expression by ICD experiencing cells, resulting in decreased maturation of dendritic cells (DCs). Blocking this PD-L1 expression on tumor cells could unleash full ICD effects on antigen presenting cells. Even at sub-toxic concentrations, AmB was able to enhance CALR on leukemic blasts, particularly on phagocytic monoblastic THP-1 cells, which also showed features of “M1-like” differentiation after AmB exposure. The ability of AmB to increase the immunogenicity of tumor cells was confirmed in vivo in a mouse vaccination experiment. In conclusion, we demonstrate that AmB can promote antitumor immune responses in a dose-dependent manner by ICD induction, surface translocation of CALR on leukemic blasts even at sub-toxic concentrations, and “M1-like” polarization of phagocytic cells, making it noteworthy as potential booster for cancer immunotherapy. We additionally report for the first time that PD-L1 expression may be a feature of ICD, possibly as a negative feedback mechanism regulating the maturation status of DCs and thus indirectly affecting T-cell priming.

Tolerability and epidemiology of nephrotoxicity associated with conventional amphotericin B therapy: a retrospective study in tertiary care centers in Palestine

BackgroundIn the light of recent years, an increase in the number of life-threatening infections due to various fungi has been observed, especially in tertiary care centres. With Amphotericin B labelled as the first choice in treating these infections, one of its common side effects, nephrotoxicity, along with hypokalemia, were studied to determine the epidemiology, risk factors, and protective measures.MethodologyThe study was a retrospective observational chart review study in which patients were receiving conventional Amphotericin B in two tertiary hospitals in Palestine from January 2018 to December 2020 were evaluated for the development of hypokalemia and nephrotoxicity; according to the KDIGO criteria. A total of 117 patients were included in the study. Patients who have received the drug intermittently, in fewer than two doses, through non-IV routes and patients under the age of 12 were excluded. The data collected included, but were not limited to, age, gender, comorbidities, Amphotericin B treatment details, medications, COVID-19 status, risk factors, and hypothesized protective measures.ResultsThe incidence of conventional Amphotericin B nephrotoxicity and hypokalemia was 46% and 33%, respectively. With a roughly equal representation of both genders and a median age of 52 years in a range of 13–89. No association between the variables and the development of nephrotoxicity was found. However, a 3.4 increased risk (p-value = 0.01) of developing hypokalemia in females compared to males was observed.ConclusionOur research has shown a relatively lower yet consistent, incidence of conventional amphotericin B nephrotoxicity and hypokalemia compared to literature with gender being a risk factor for developing hypokalemia.

Hypersensitivity Reactions to Liposomal Amphotericin in a Bone Marrow Transplant Patient

Introduction: Hodgkin's lymphoma is one of the treatable types of blood cancer. Autologous bone marrow transplantation is used as one way to treat this disease. Neutropenic fevers are treated with antibiotics and antifungals, including amphotericin B. Adverse effects and hypersensitivity to liposomal amphotericin, Ambisome, are very uncommon compared with conventional amphotericin. Case Report: In this case, we noticed hypersensitivity reactions to the Ambisome, represented by an increase in body temperature, a drop in blood pressure, and hypo-oxygenemia, in addition to an increase in the heart rate. Case Management: The patient was treated with injections of hydrocortisone, chlorpheniramine, and normal saline, in addition to giving oxygen; he was improved. Conclusion: In spite of the few cases that have recorded hypersensitivity reactions to the Ambisome, it is necessary to conduct an allergy test and to monitor the patient well when giving the Ambisome, especially in the first dose.

Nephrotoxicity of continuous amphotericin B in critically ill patients with abdominal sepsis: a retrospective analysis with propensity score matching.

Continuous infusion of conventional amphotericin B (CCAB) is used in ICUs for pre-emptive treatment of invasive fungal infections. Amphotericin B has previously been associated with nephrotoxicity. To investigate if CCAB with therapeutic drug monitoring (TDM) results in renal impairment over time in critically ill patients with abdominal sepsis. The study was conducted at mixed medical-surgical ICUs of two large teaching hospitals in the Netherlands. Consecutive patients who were treated on the ICUs between 2006 and 2019 for abdominal sepsis, with or without CCAB, were included. CCAB dosing was guided by TDM. Serum creatinine concentrations and renal failure scores of patients with CCAB treatment were compared with those without CCAB treatment. Excluded were: (i) patients treated with CCAB for less than 72 h; and (ii) patients with renal replacement therapy. A total of 319 patients were included (185 treated with CCAB and 134 controls). A multiple linear regression model showed that the serum creatinine concentration was independent of CCAB treatment (β = -0.023; 95% CI = -12.2 to 7.2; P = 0.615). Propensity score matching resulted in 134 pairs of CCAB-treated and non-treated patients. Again, the analysis of these pairs showed that the cumulative CCAB dose was not associated with serum creatinine concentration during intensive care treatment (β = 0.299; 95% CI = -0.38 to 0.98; P = 0.388). CCAB with TDM did not result in renal impairment over time in critically ill patients with abdominal sepsis.