Efficacy Of Liposomal Amphotericin Research Articles

Application of CL Detect™ rapid test for diagnosis and liposomal amphotericin B for treatment of cutaneous leishmaniasis: A retrospective analysis from a tertiary care centre in a non-endemic area in India.

Background Increasing urbanisation has led to the occurrence of cutaneous leishmaniasis (CL) in new areas, which was otherwise localised to endemic areas. Healthcare workers should be made aware of this entity to ensure clinical suspicion of CL and investigations needed to confirm CL. The article describes patients seen at a tertiary hospital in Delhi. Aims To establish the utility of the CL Detect Rapid test as a diagnostic tool and the efficacy of Liposomal Amphotericin B (LAmB) for the complete cure of CL patients. Methods Data of patients of CL (n = 16) was retrospectively analysed concerning diagnosis and treatment. Diagnosis rested on histopathology, real-time PCR, and CL Detect Rapid Test. Speciation of the parasite was based on the Internal transcribed spacer-I gene. Patients were treated with LAmB (i.v., 5 mg/kg up to three doses, five days apart). Results A positivity of 81.3% (95%CI, 54.4-96) was observed for CL Detect Rapid test in comparison with 100% (95%CI, 79.4-100.0) for real-time PCR and 43.8% (95%CI, 19.8-70.1) for microscopy/histopathological examination. L. tropica was the infective species in all cases. All the patients treated with LAmB responded to treatment, and 9/10 patients demonstrated complete regression of lesions, while one was lost to follow-up. Limitations It is a retrospective study, and the data includes only confirmed cases of CL at a single centre. Conclusion This study highlights the utility of CL Detect as a promising diagnostic tool and the efficacy of LAmB for the complete cure of CL.

180 - Feasibility, Safety, and Efficacy of Liposomal Amphotericin B Followed By Micafungin Prophylaxis of Invasive Fungal Infections in Pediatric Allogeneic Stem Cell Transplantation Recipients with Hematological Malignancies

180 - Feasibility, Safety, and Efficacy of Liposomal Amphotericin B Followed By Micafungin Prophylaxis of Invasive Fungal Infections in Pediatric Allogeneic Stem Cell Transplantation Recipients with Hematological Malignancies

Liposomal Amphotericin B Fosters the Corticosteroids' Anti-inflammatory Effect on Murine Allergic Bronchopulmonary Aspergillosis Model Airways.

Fungus is an antigen for bronchial asthma causing allergic bronchopulmonary mycosis (ABPM). As a therapy other than corticosteroids, itraconazole (ITCZ) is known to suppress the allergic inflammation induced by Aspergillus fumigatus (Af). However, the efficacy of liposomal amphotericin B (LAMB) with/without corticosteroid on ABPM is unknown. Mice sensitized to Dermatophagoides farinae (Df) allergen were intranasally infected with Af (DfAf group). After the infection, corticosteroid (dexamethasone (Dex)) was administered for 5days (DfAf/Dex group). The effects of ITCZ or LAMB with/without Dex were also evaluated. Pathologically, Dex and LAMB combination treatment decreased the allergic inflammation evidently. The bronchoalveolar lavage fluid (BALF) concentrations of IL-5, IL-13, and MIP-2 were significantly elevated in DfAf mice compared with control mice (p < 0.05, each). In DfAf mice, ITCZ and LAMB significantly decreased the elevation of MIP-2 (p < 0.05 vs the DfAf group). The addition of both Dex and LAMB suppressed the MIP-2 elevation in DfAf mice (p < 0.05 vs the Df/Af/Dex/LAMB group), but the addition of Dex and ITCZ did not (DfAf/Dex/ITCZ group). None of Dex, ITCZ, or LAMB decreased pulmonary IL-13 concentration. It was suggested that combination of antifungal drugs and corticosteroid enhanced the suppressing effect of airway inflammations. This finding will give a hope for the treatment of severe fungus-related asthma.

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Efficacy of Liposomal Amphotericin B.

Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound’s safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.

Efficacy of liposomal amphotericin B and anidulafungin using an antifungal lock technique (ALT) for catheter-related Candida albicans and Candida glabrata infections in an experimental model.

ObjectiveThe aims of this study were as follows. First, we sought to compare the in vitro susceptibility of liposomal amphotericin B (LAmB) and anidulafungin on Candida albicans and Candida glabrata biofilms growing on silicone discs. Second, we sought to compare the activity of LAmB versus anidulafungin for the treatment of experimental catheter-related C. albicans and C. glabrata infections with the antifungal lock technique in a rabbit model.MethodsTwo C. albicans and two C. glabrata clinical strains were used. The minimum biofilm eradication concentration for 90% eradication (MBEC90) values were determined after 48h of treatment with LAmB and anidulafungin. Confocal microscopy was used to visualize the morphology and viability of yeasts growing in biofilms. Central venous catheters were inserted into New Zealand rabbits, which were inoculated of each strain of C. albicans and C. glabrata. Then, catheters were treated for 48h with saline or with antifungal lock technique using either LAmB (5mg/mL) or anidulafungin (3.33mg/mL).ResultsIn vitro: anidulafungin showed greater activity than LAmB against C. albicans and C. glabrata strains. For C. albicans: MBEC90 of anidulafungin versus LAmB: CA176, 0.03 vs. 128 mg/L; CA180, 0.5 vs. 64 mg/L. For C. glabrata: MBEC90 of anidulafungin versus LAmB: CG171, 0.5 vs. 64 mg/L; CG334, 2 vs. 32 mg/L. In vivo: for C. albicans species, LAmB and anidulafungin achieved significant reductions relative to growth control of log10 cfu recovered from the catheter tips (CA176: 3.6±0.3 log10 CFU, p≤0.0001; CA180: 3.8±0.1 log10 CFU, p≤0.01). For C. glabrata, anidulafungin lock therapy achieved significant reductions relative to the other treatments (CG171: 4.8 log10 CFU, p≤0.0001; CG334: 5.1 log10 CFU, p≤0.0001)ConclusionsFor the C. albicans strains, both LAmB and anidulafungin may be promising antifungal lock technique for long-term catheter-related infections; however, anidulafungin showed significantly higher activity than LAmB against the C. glabrata strains.

Lack of correlation of ECV and outcome in an in vivo murine model of systemic fusariosis

The efficacy of liposomal amphotericin B and voriconazole was evaluated against the systemic infection by Fusarium oxysporum species complex or Fusarium keratoplasticum. Although MIC values were within the epidemiological cutoff values (ECVs) recently stablished for Fusarium spp., no efficacy was obtained, indicating that ECVs for Fusarium are not relevant for in vivo efficacy.

Comprehensive drug utilization review in neonates: liposomal amphotericin B.

This drug utilization evaluation aims to review current evidence on safety and efficacy of using liposomal amphotericin B (LAMB) in newborns with candidiasis, and compare it to the conventional preparation. Conventional amphotericin B deoxycholate (DAMB) is more commonly used in newborns, but dose-limiting adverse effects may compromise its efficacy. This review will examine the advantages and disadvantages of liposomal amphotericin B and define its place in current practice. The terms 'AmBisome' or 'liposomal amphotericin B' and 'neonatal candidiasis' were entered in both PubMed and Ovid; studies included focused on safety and efficacy of liposomal amphotericin B in newborns with candidiasis, as well as studies comparing the conventional and the liposomal formulations in newborns as monotherapy. Pertinent references obtained from this search were also included. Additionally, pharmacokinetic studies were reviewed to include available data on dosing. Single case reports were not included in the review due to the limited conclusions that can be drawn from such sample sizes and quality of data. Although liposomal amphotericin B may be better tolerated and as efficacious as the conventional formulation based on the published literature, the weakness of the studies available on the subject cannot be overlooked. Additional randomized controlled trials are needed to determine the true benefits of this medication.

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis.

Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866-1871, 2013, https://doi.org/10.1128/AAC.02226-12). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

237 - Safety & Efficacy of Liposomal Amphotericin B Followed By Micafungin to Prevent Invasive Fungal Infection in Pediatric Allogeneic Stem Cell Transplantation Recipients

237 - Safety & Efficacy of Liposomal Amphotericin B Followed By Micafungin to Prevent Invasive Fungal Infection in Pediatric Allogeneic Stem Cell Transplantation Recipients

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

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

Efficacy of liposomal amphotericin B and posaconazole in intratracheal models of murine mucormycosis.

Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections.

Evaluation of the safety and efficacy of liposomal amphotericin B (L-AMB) in children

A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects(52.9%). Of 12 febrile neutropenia cases, improvement in clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most commonad verse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation.In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3%(82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients.

Safety and efficacy of liposomal amphotericin B for the empirical therapy of invasive fungal infections in immunocompromised patients

Liposomal amphotericin B is a “true” liposomal formulation of amphotericin B with greatly reduced nephrotoxicity and minimal infusion-related toxicity. This broad spectrum polyene is well tolerated and effective against most invasive fungal infections. In view of the current limitations on diagnostic capability of invasive fungal infections, most clinicians are often compelled to use antifungal drugs in an empiric manner; liposomal amphotericin B continues to play an important role in the empiric management of invasive fungal infections, despite the recent availability of several other drugs in the azole and echinocandin classes.

A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India

In patients with persistent fever and netropenia, amphotericin B is administered empirically for early treatment and prevention of systemic fungal infections. Despite this treatment, there are chances of breakthrough fungal infections and drug is also toxic. A multicentric, randomized, controlled clinical trial was conducted to compare liposomal amphotericin B two doses with conventional amphotericin B as empirical antifungal therapy. The average body weight of patients was 26.4 ± 14.8 (n=22), 32.9 ± 19.4 (n=23) and 37.9 ± 20.0 (n=20) kg in 1 mg, 3 mg Fungisome (liposomal amphotericin B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2 ± 13.4, 16.0 ± 10.9 and 22.7 ± 16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively. The average duration of treatment with 1 mg and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B was 17 ± 9.8, 16.2 ± 8.3, and 14.7 ± 10.7 days, respectively. The time to resolve fever was 13.3 ± 10.2, 10.9 ± 7.1, 10.1 ± 6.7 days, and for absolute neutrophil count (ANC) to be above 500 cells per microliter, it took 13.4 ± 9.6, 10.6 ± 7.6 and 7.3 ± 3.4 days, respectively. Liposomal formulations were well-tolerated compared to conventional amphotericin B. This small randomized study showed that the indigenous liposomal formulation Fungisome appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome.

Optimizing Amphotericin B Therapy for Cryptococcal Meningitis

JavalyK,BarkerDE,andAmBisomeCryptococcalMeningitis Study Group: Comparison of 2 doses of liposomal amphotericin b and conventional amphotericin b deoxy- cholate for treatment of AIDS-associated acute cryptococ- cal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis 2010, 51:225-232. Rating: Of importance. Introduction: Although the introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of cryptococcal meningitis associated with AIDS in many countries, it is still common, especially among populations with limited access to medical care (1). Using a regimen of amphotericin B deoxycholate (0.7-1.0 mg/kg per day), with or without flucytosine, mortality rates associated with the treatment of cryptococcal meningitis have been reported to be 5% to 11% and cerebrospinal fluid (CSF) sterilization rates were reported to be 60% to 75% (2, 3). Lipid-based formulations have been widely used for the treatment ofavariety offungalinfections, withsimilar clinical efficacy and fewer adverse effects than amphotericin B deoxycholate. Interestingly, no large-scale clinical trial has been conducted to examine the comparative efficacy of liposomal amphotericin B with amphotericin B deoxycholate for the treatment of cryptococcalmeningitis. Furthermore, itis generally recognized that amphotericin B exhibits concentration-dependent fungicidal activity, and clinical data regarding the use of high-dose dose liposomal amphotericin B for the treatment of cryptococcal meningitis unfortunately are lacking (4). Aims: The purpose of this trial was compare the safety, tolerability, and efficacy of two doses of liposomal ampho- tericin B and a standard dose of amphotericin B deoxycho- late for patients with AIDS-associated acute cryptococcal meningitis.

Treatment of murine Fusarium verticillioides infection with liposomal amphotericin B plus terbinafine

Using a murine model of disseminated infection by Fusarium verticillioides, the efficacy of liposomal amphotericin (L-AmB) B at 10 mg/kg body weight once daily and terbinafine (TRB) at 150 mg/kg body weight twice daily, alone and in combination, was evaluated. The combination of L-AmB with TRB was the only treatment able to prolong survival and to reduce fungal loads in the spleen and kidneys of mice infected with either strain of F. verticillioides used. The results suggest that this combination may have a role in the treatment of F. verticillioides infection.

Safety, tolerance and outcome of treatment with liposomal amphotericin B in paediatric patients with cancer or undergoing haematopoietic stem cell transplantation

To assess safety, tolerance and efficacy of liposomal amphotericin B (LAMB) in a large unselected series of paediatric cancer/haematopoietic stem cell transplantation (HSCT) patients requiring LAMB therapy. The study included 84 children and adolescents (median age: 11 years) who received 141 consecutive courses of LAMB for prophylaxis (32), empirical therapy (83), possible (19) or probable/proven (7) invasive infections. LAMB was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician. Fifty-nine courses were post-HSCT (42%, 49 allogeneic), and 92 courses were started during granulocytopenia (65%). The median duration of LAMB therapy was 13 days (range 1-79), and the median maximum dosage was 2.8 mg/kg (range 0.93-5.10). Mild-to-moderate adverse events were noted during 109 courses (77%; hepatic, 58.8%; electrolyte wasting, 52.5%; renal, 31.9%; infusion-related reactions, 8.5%); adverse events necessitating discontinuation of LAMB occurred in 6 courses (4.3%; renal, 3; anaphylaxis, 2; hepatic, 1). While median hepatic transaminase, alkaline phosphatase and blood urea nitrogen values were slightly (P < 0.01) higher at end of treatment (EOT), bilirubin and creatinine values were not different from baseline. Complete or partial responses were observed in 16/19 and 2/7 courses for possible and probable/proven invasive infections. Thirty-two of 33 courses of prophylaxis and 74 of 83 courses of empirical therapy were completed with success. Overall survival was 90.8% at 3 months post-EOT. LAMB had acceptable safety and tolerance and was useful in prevention and treatment in unselected, mostly granulocytopenic paediatric patients undergoing treatment for cancer or HSCT.

Comparative Study on the Efficacy of Liposomal Amphotericin B and Voriconazole in a Murine Pulmonary Aspergillosis Model

Background:No clinical studies have compared the efficacy of liposomal formulation AMB (L-AMB) and voriconazole (VRC) in the treatment of pulmonary aspergillosis. The aim of this study was to compare the efficacy of L-AMB and VRC in murine pulmonary aspergillosis.Methods: Leucopenic mice were infected intratracheally with Aspergillus fumigatus and treated intravenously with L-AMB (once a day) or VRC (twice a day). Results: L-AMB and VRC at a dose of ≥5 and ≥20 mg/kg, respectively, significantly prolonged the survival time of infected mice and reduced the pulmonary fungal burden in comparison with the control group. At the maximum recommended dose for clinical use, 5 mg/kg of L-AMB exhibited greater efficacy than 10 mg/kg of VRC, which achieved an area under the concentration-time curve level equivalent to that of 6 mg/kg (loading dose) in humans, in terms of increasing survival and reducing the fungal burden. Conclusion: The in vivo efficacy of L-AMB was superior to that of VRC at the maximum recommended dose in a murine pulmonary aspergillosis model.

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients--authors' response

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients--authors' response

Standardization of an Experimental Murine Model of Invasive Pulmonary Aspergillosis

Evaluating new therapeutic agents for invasive aspergillosis requires animal models that are reproducible among different laboratories. We therefore evaluated a murine model of aerosol infection in two independent laboratories and found a high level of both intra- and interlaboratory reproducibility of survival, fungal burden over time, and the efficacy of liposomal amphotericin B.