Visceral leishmaniasis or Kala-azar is a vector-borne disease caused by an intracellular parasite of the genus leishmania. In India, Amphotericin B (AmB) is a first-line medication for treating leishmaniasis. After a large-scale resistance to pentavalent antimony therapy developed in Bihar state, it was rediscovered as an effective treatment for Leishmania donovani infection. AmB which binds to the ergosterol of protozoan cells causes a change in membrane integrity resulting in ions leakage, and ultimately leading to cell death. The treatment effect of liposomal AmB can be seen more quickly than deoxycholate AmB because, it has some toxic effects, but liposomal AmB is significantly less toxic. Evidence from studies suggested that ABLC (Abelcet) and ABCD (Amphotec) are as effective as l-AmB but Liposomal form (Ambisome) is a more widely accepted treatment option than conventional ones. Nevertheless, the world needs some way more efficient antileishmanial drugs that are less toxic and less expensive for people living with parasitic infections caused by Leishmania. So, academics, researchers, and sponsors need to focus on finding such drugs. This review provides a summary of the chemical, pharmacokinetic, drug-target interactions, stability, dose efficacy, and many other characteristics of the AmB and their various formulations. We have also highlighted the clinically significant aspects of PKDL and VL co-infection with HIV/TB.

In India, COVID-19 has led to a surge in cases of a potentially fatal fungal infection called mucormycosis, popularly known as "black fungus." Intravenous amphotericin B is the only available drug for salvage therapy. Efforts to improve its therapeutic efficacy and decrease its nephrotoxicity have focussed on the reformulation of AmB in three new lipid formulations such amphotericin B lipid complex (Abelcet), amphotericin B colloidal dispersion (Amphotec), and liposomal amphotericin B (AmBisome). The aim of this study is (1) to evaluate the adverse drug reaction of various formulations of amphotericin B used for the treatment of rhinooculocerebralmucormycosis in Indian population. (2) to evaluate the adverse drug reaction of injectable form of posaconazole. This prospective observational study was done on a random sample of 110 patients who got admitted for the management of rhinooculocerebral mucormycosis in a tertiary care centre of middle india… The patients were assessed for the adverse reactions following the administration of various antifungal medication and the findings were analysed. All the 110 patients had received two forms of Amphotericin B (liposomal Amphotericin B and Amphotericin B lipid complex) and Posaconazole injection. 60 patients had received all three forms of Amphotericin B. Out of the 110 patients who received Liposomal amphotericin B, only 2 patients developed adverse drug reaction while in 110 patients who received Amphotericin B Lipid complex, 7 patients had adverse drug effects. Lyophilised amphotericin B had been administered to 60 patients in which 51 patients developed adverse drug reaction and in them one patient went to congestive cardiac failure. Injection posaconazole had been administered to 110 patients in which 72 patients developed drug reaction. In spite of its proven track record of Amphotericin B, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. Lipid formulations of AmB are better tolerated than AmB deoxycholate but infusional drug reactions have been reported in lipid formulation too. So improved strategies for the management of infusion related adverse events are required.

Although no information exists on the milk excretion of amphotericin B, it is highly protein bound, has a large molecular weight, is virtually unabsorbed orally and has been use directly in the mouths of infants;[1] therefore, most reviewers consider it acceptable to use in nursing mothers.[2,3]

Langmuir surface pressure, small-angle neutron scattering (SANS), and neutron reflectivity (NR) studies have been performed to determine how formulation of the antifungal drug amphotericin B (AmB), with sodium cholesteryl sulfate (SCS)-as in Amphotec-affects its interactions with ergosterol-containing (model fungal cell) and cholesterol-containing (model mammalian cell) membranes. The effects of mixing AmB in 1:1 molar ratio with cholesteryl sulfate (yielding AmB-SCS micelles) are compared against those of free AmB, using monolayers and bilayers formed from palmitoyloleoylphosphatidylcholine (POPC) in the absence and presence of 30 mol % ergosterol or cholesterol, in all cases employing a 1:0.05 molar ratio of lipid:AmB. Analyses of the (bilayer) SANS and (monolayer) NR data indicate that the equilibrium changes in membrane structure induced in sterol-free and sterol-containing membranes are the same for free AmB and AmB-SCS. Stopped-flow SANS experiments, however, reveal that the structural changes to vesicle membranes occur far more rapidly following exposure to AmB-SCS vs free drug, with the kinetics of these changes varying with membrane composition. With POPC vesicles, the structural changes induced by AmB-SCS become apparent only after several minutes, and equilibrium is reached after ∼30 min. The corresponding onset of changes in POPC-ergosterol and POPC-cholesterol vesicles, however, occurs within ∼5 s, with equilibrium reached after 10 and 120 s, respectively. The rate of insertion of AmB into POPC-sterol membranes is thus increased through formulation as AmB-SCS. Moreover, the differences in monolayer surface pressure and SANS structure-change equilibration times suggest significant rearrangement of AmB within these membranes following insertion. The reduced times to equilibrium for the POPC-ergosterol vs POPC-cholesterol systems are consistent with the known differences in affinity of AmB for these two sterols, and the reduced time to equilibrium for AmB-SCS interaction with POPC-ergosterol membranes vs that for free AmB is consistent with the reduced host toxicity of Amphotec.

Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome, Abelcet, and Amphotec) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations.

New lipid formulations of amphotericin B--AmBisome, Amphotec, and Abelcet--have dramatically decreased the toxicity associated with amphotericin B and have made this group of agents the treatment of choice for visceral leishmaniasis. An agent of a completely different chemical class, the aminoglycoside aminosidine, was 97% curative in India. This agent too may be used for visceral leishmaniasis.

We report two cases of cutaneous cryptococcosis in male patients without underlying disease. Case 1 had a granulomatous mass on his right neck, gradually enlarging for 3 months. After the mass was debrided surgically in a hospital, the incision wound gradually developed into a severe ulceration. Mycological examination revealed Cryptococcus neoformans infection. It was significant that histopathology of both pre-surgery granuloma and post-surgery ulceration revealed thick-walled spores with thick capsule. Chest X-ray revealed a shadow in the left lower lung. After treatment with amphotec for 21 days, the lesion healed. Case 2 had an approximately 2 x 2 cm solitary dull nodule on his right thigh, which had been present for 8 months. Mycological examination confirmed that the lesion was caused by C. neoformans. The patient's ratio of peripheral blood CD4(+) cell was slightly reduced. After 14 days of treatment with oral fluconazole, followed by oral itraconazole for 2 months, mycological and clinical cure were achieved. The two isolates were identified as C. neoformans var. gattii serotype C and C. neoformans var. grubii serotype A.

Amphotericin B(AmB) formulations, Fungizone, and Amphotec caused substantially greater proinflammatory cytokine release than AmBisome (L-AMB) and Abelcet in TPA differentiated THP-1 macrophages as determined by antibody based protein arrays. Lipopolysaccharide but not AmB induced significant pro-inflammatory cytokines in human endothelial cells.

The standard treatment of visceral leishmaniasis is pentavalent antimony (meglumine antimoniate or sodium stibogluconate), but toxicity is frequent with this drug. Moreover, antimony unresponsiveness is increasing, both in immunocompetent and in immunosuppressed patients. Amphotericin B is a polyene macrolide antibiotic that binds to sterols in cell membranes. It is the most active antileishmanial agent in use. Its infusion-related and renal toxicity may be reduced by lipid-based delivery. Liposomal amphotericin B (Ambisome) seems to be less toxic than other amphotericin B lipid formulations (Amphocil, Amphotec). Optimal drug regimens of Ambisome vary from one geographical area to another. In the Mediterranean Basin, a total dose of 18 to 24 mg/kg is safe and effective. Shortening the duration of treatment without decreasing the total dose (i.e., 10 mg/kg/day for 2 days) seems promising to reduce the global cost of the therapy.

We compared various amphotericin B formulations (no treatment or 0.8 mg of Fungizone [conventional deoxycholate amphotericin B] per kg of body weight, or 0.8, 4, or 8 mg of Amphocil, AmBisome, or Abelcet per kg of body weight) for treatment of systemic murine aspergillosis. In two studies, all formulations prolonged survival, with the results for AmBisome nearly equivalent to those for Fungizone; Amphocil and Abelcet were less effective or equivalent depending on the severity of infection. No survivors were cured in both kidneys and brain, but each formulation showed efficacy, especially in the kidneys. Although higher doses could be given, no lipid-based formulation showed consistent superiority over Fungizone or over each other.

Cytokine antibody arrays were used to establish the profiles of cytokine release from THP-1 monocytes exposed to different amphotericin B (AMB) drug delivery systems. Fungizone (FZ) and Amphotec (ABCD) caused the release of significantly more inflammatory molecules and the release of inflammatory molecules at higher levels than either AmBisome (L-AMB) or Abelcet (ABLC) after 6 h of treatment. Specifically, tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), GRO-(alphabetagamma), monocyte chemoattractant protein-1 (MCP-1), RANTES, IL-10, and IL-6 were detected and semiquantified with a chemiluminscence imaging system. TNF-alpha, IL-8, and MCP-1 were the most predominant; however, little if any TNF-alpha was present in ABLC- or L-AMB-treated cultures. The TNF- alpha and IL-8 levels determined by quantitative enzyme-linked immunosorbent assay correlated with the relative cytokine levels measured by using the antibody arrays. Although the viabilities of THP-l monocytes in all AMB-treated cultures were similar by trypan blue exclusion, the amount of lactic dehydrogenase released was significantly larger in FZ- and ABCD-treated cultures than in L-AMB- and ABLC-treated cultures, indicating more membrane perturbations with those formulations. Membrane cation channel formation was also measured in model cholesterol-containing large unilamellar vesicles to directly assess the ion channel formation ability of the system. Only FZ and ABCD induced significant ion currents at concentrations less than 1.5 x 10(-5) M. These results may help provide rationales for the immediate cytokine-mediated side effects observed with FZ and ABCD and the reduced side effects observed with L-AMB and ABLC.

The leishmaniases are protozoan diseases caused by Leishmania parasites. The first-line treatment of its visceral forms is pentavalent antimony (meglumine antimoniate or sodium stibogluconate), but toxicity is frequent with this drug. Moreover antimony unresponsiveness is increasing in Leishmania infantum and L. donovani foci, both in immunocompetent and in immunosuppressed patients. Amphotericin B is a polyene macrolide antibiotic that binds to sterols in cell membranes. It is the most active antileishmanial agent in use. Its infusion-related and renal toxicity may be reduced by lipid-based delivery. Liposomal amphotericin B (AmBisome); Gilead Science, Paris, France) seems to be less toxic than other amphotericin B lipid formulations (Amphocil); Liposome Technology Inc., Menlo Park, CA, USA, Amphotec); Ben Venue Laboratories Inc., Bedford, OH, USA). Optimal drug regimens of AmBisome) vary from one geographical area to another. In the Mediterranean Basin, a total dose of 18 mg/kg (3 mg/kg on days 1-5 and 3 mg/kg on day 10) could be used as first-line treatment of visceral leishmaniasis in immunocompetent patients. In immunocompromised patients, especially those co-infected with HIV, relapses are frequent with AmBisome), as with other drugs.

We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P<.001) in patients treated with ABCD. Rates of drug-related toxicity in patients receiving ABCD and AmB, respectively, were 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia) and 22% versus 24% (toxicity requiring study drug discontinuation). ABCD appears to have equivalent efficacy and superior renal safety, compared with AmB, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more frequently in patients receiving ABCD than in those receiving AmB.

Amphotericin B is widely used for severe life threatening fungal infections. Its use is limited by a dose-dependent nephrotoxicity manifested by a reduction in glomerular filtration rate and tubular dysfunction. An elevated creatinine associated with amphotericin B is not only a marker for renal dysfunction but is also linked to a substantial risk for the use of hemodialysis and a higher mortality rate; therefore amphotericin B nephrotoxicity is not a benign complication and its prevention is essential. Several manipulations have been proposed to try and minimize amphotericin B induced nephrotoxicity. Systematic hydration is crucial to minimize amphotericin B. Mannitol or intralipids administration were once suggested as protective based on anecdotal observational reports. Small prospective and randomized trials, however did not support a protective effect. Three new formulations have been developed in an attempts to improse both efficacy and tolerability: amphotericin B in lipid complex (ABLC, Abelcet). Colloidal dispersion (ABCD, Amphotec and amphotericin B liposome (Ambisome). Three prospectives randomized studies have clearly shown that Ambisome is less nephrotoxic than amphotericin B. Unfortunately the only randomized trial comparing Abelcet with amphotericin B is an open-label treatment of invasive candidiasis which was presented 5 years ago but never published as a full paper. Furthermore in a recent multicenter double-blind study it has been shown that Ambisome has a better safety profile than Abelcet with less chills/rigors and less nephrotocixity.