amphotericin-b and Liver-Failure

Caspofungin, micafungin and anidulafungin are three drugs of the echinocandin class of antifungals available for intravenous treatment of invasive candidiasis and aspergillosis. They exhibit high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In various clinical studies investigating candidemia and invasive candidiasis, Candida esophagitis, and fever in neutropenia, the clinical efficacy of the echinocandin tested was similar to that of established antifungals. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that echinocandins can be used as salvage therapy in life-threatening fungal infections. There is no cross-resistance to other antifungals. Excellent safety and tolerability of treatment with caspofungin has been documented over a total of 4.3 million patient days. Echinocandins are poor substrates of the cytochrome P450 enzyme family and can be safely co-administered with most drugs without the need for dosage adaptation. No dose reduction is required in renal impairment. A reduction in the daily maintenance dose has been recommended for caspofungin, but not for micafungin and anidulafungin in patients presenting with mild to moderate hepatic failure.

Topics: Actins; Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Area Under Curve; Candidiasis; Caspofungin; Drug Resistance, Microbial; Echinocandins; Humans; Lipopeptides; Lipoproteins; Liver; Liver Failure; Micafungin; Models, Chemical; Peptides, Cyclic; Rats

To characterize the clinical and epidemiological profiles of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (LAmB) and to identify prognostic factors for death from VL in 2008-2012 in the state of Minas Gerais, Brazil.. A historical cohort study was conducted using data obtained from treatment requests forms, Brazilian Notifiable Disease Information System and the Mortality Information System. Case-fatality rates of patients with VL treated with LAmB were compared with patients treated with other therapies. Logistic regression analysis was used to identify prognostic factors for death.. The overall case-fatality rate of the 577 patients treated with LAmB was 19.4%. Prognostic factors for death from VL were age between 35 and 49 years (OR 2.7; 95% CI 1.3-5.4) and above 50 years (OR 2.6; 95% CI 1.3-4.9), jaundice (OR 2.2; 95% CI 1.2-3.7), kidney disease (OR 2.8; 95% CI 1.6-4.9), presence of other infections (OR 2.4; 95% CI 1.5-4.1), edema (OR 2.0; 95% CI 1.1-3.4), platelet count below 50.000/mm3 (OR 3.6; 95% CI 2.1-6.0), AST higher than 100 U/L (OR 2.2; 95% CI 1.3-3.8), and assistance in non-specialized institutions (OR 1.9; 95% CI 1.0-3.5).. Case-fatality rates were higher than that observed among patients with VL treated with other therapies. Identification of prognostic factors of death from VL may allow early diagnosis of patients prone to such outcome and prompt an expeditious and appropriate management of VL to reduce fatality rates.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antiprotozoal Agents; Brazil; Child; Child, Preschool; Cohort Studies; Comorbidity; Edema; Female; Heart Diseases; HIV Infections; Humans; Infant; Jaundice; Leishmaniasis, Visceral; Liver Failure; Male; Middle Aged; Prognosis; Renal Insufficiency; Risk Factors; Young Adult

Invasive aspergillosis (IA) in liver transplant recipients is associated with grave outcomes. We reviewed 116 individual cases reported in the literature from 1985 to 2013. IA was diagnosed after a median of 25 days after transplantation and involved a single organ in 51% of the cases, whereas in the remaining cases, multiple sites were involved. The most common infecting Aspergillus species were Aspergillus fumigatus (73%), Aspergillus flavus (14%), and Aspergillus terreus (8%). Amphotericin B was the drug most frequently used, and it was followed by voriconazole and itraconazole. Combination regimens were used in 51% of the cases. The overall 1-year cumulative survival probability was 35% [95% confidence interval (CI) = 24.6%-49.6%]. Survival was significantly higher for patients reported from the year 2000 and thereafter (P < 0.001), for those diagnosed with IA more than 30 days after transplantation versus those diagnosed earlier (P = 0.019), and for patients without renal failure (P = 0.020). Additionally, the use of voriconazole was significantly associated with a higher probability of survival (P < 0.001). Cox regression analysis showed that subjects with the involvement of multiple sites had a 2.52 times higher risk of a negative outcome (95% CI = 1.08-5.87) than those with the involvement of a single site. Thus, IA causes life-threatening infections in liver transplant recipients. Predictors associated with poor outcomes may help clinicians to optimize the management of this infection.

Topics: Adult; Amphotericin B; Aspergillosis; Aspergillus flavus; Aspergillus fumigatus; Cohort Studies; Female; Humans; Kaplan-Meier Estimate; Liver Failure; Liver Transplantation; Male; Middle Aged; Probability; Proportional Hazards Models; Renal Insufficiency; Transplant Recipients; Treatment Outcome; Voriconazole

Albumin dialysis (AD) is a therapeutic option in severe cholestatic liver failure. However, it can significantly enhance drug elimination. Pharmacokinetic data on antimicrobial agents--in particular on antimycotics--administered under this clinical condition are very sparse. Therefore, amphotericin B (AMB) plasma concentrations were measured in two critically ill patients who were treated with AD because of severe cholestatic liver failure and were prescribed lipid formulated AMB--either AMB colloidal dispersion (ABCD) or AMB lipid complex (ABLC)--for suspected invasive fungal infection. AD was performed with the molecular adsorbent recirculating system (MARS). Lipid-associated and liberated AMB were separately quantified on and off AD. The clearance of the liberated AMB fraction was not essentially affected (ABLC) or moderately enhanced during AD by a factor of 2.5 (ABCD). The clearance of the lipid-formulated fraction was increased by a factor of 4 during AD (ABCD) or was similar (ABLC) on and off AD. Despite the fact that there was a four-fold higher clearance of the lipid-formulated fraction of ABCD, the clinically relevant area under the concentration time curve of the liberated AMB fraction was only moderately changed (by 37% in ABCD, 70% in ABLC) during AD. Thus, the effect of AD on lipid formulated AMB appears to be moderate. A daily dose of 5 mg/kg will probably lead to adequate plasma levels in patients on AD.

Topics: Aged; Albumins; Amphotericin B; Antifungal Agents; Critical Illness; Female; Humans; Lipid Metabolism; Liver Failure; Male; Middle Aged; Mycoses; Renal Dialysis

This case report adds pharmacokinetic knowledge regarding amphotericin B. Amphotericin B is highly protein bound. Plasma exchange removes 50-75% of a substance in plasma within 1-2 h, corresponding to an elimination half-life of 30-40 min. Amphotericin B reduction ratio by plasma exchange was 40% in this patient who had both liver and renal failure.

Topics: Adult; Amphotericin B; Antifungal Agents; Half-Life; Humans; Injections, Intravenous; Liver Failure; Male; Plasma Exchange; Protein Binding; Purpura, Thrombotic Thrombocytopenic; Renal Dialysis; Renal Insufficiency

AmBisome, a liposomal formulation of amphotericin B (CAS 1397-89-3, L-AMB), shows different pharmacokinetics from the conventional formulation, amphotericin B deoxycholate (D-AMB). To characterize the clearance process of L-AMB, the form in which it exists in rat plasma, pharmacokinetics in hepatic or renal failure rats, cellular distribution in rat liver, and placental and milk transfer in rat were investigated. Furthermore, to predict the drug-drug interaction, in vitro metabolism of amphotericin B (AMB) by rat, dog and human liver S9 fraction, and effects of L-AMB on drug-metabolizing enzyme systems were investigated. L-AMB was found to exist stably as a liposomal form in rat plasma without any notable transfer to milk or fetus in rats. After administration to hepatic failure rats, the CLtot of AMB decreased to 1/4 and the Vdss decreased to 1/8 compared with the control rat case. In contrast, after administration to renal failure rats, plasma AUC of AMB did not significantly change compared with sham-operated rats. These data suggest that hepatic clearance is the main determinant of the CLtot for L-AMB. In rat liver, L-AMB was distributed mainly to non-parenchymal cells. In the in vitro metabolism study using liver S9 fraction, no metabolite peaks were observed. After repeated administration of L-AMB to rats, there was no change in parameters related to the drug-metabolising enzyme system in liver microsomes. These data demonstrate that clinically significant metabolism-based drug interaction with L-AMB should be less likely.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Dogs; Drug Carriers; Drug Interactions; Female; Half-Life; Humans; In Vitro Techniques; Liposomes; Liver; Liver Failure; Male; Microsomes, Liver; Milk; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Renal Insufficiency

Extracorporeal blood purification techniques such as hemofiltration or albumin dialysis can exert a significant, but not easily predictable influence on plasma pharmacokinetics of antimicrobial agents. The effect of albumin dialysis on the pharmacokinetics of liposomal amphotericin B (AMB) and other lipid-formulated drugs has not been investigated so far. Therefore, plasma concentrations of liberated and liposomal AMB were measured in a patient, who obtained liposomal AMB for suspected invasive mycosis and required albumin dialysis because of cholestatic liver failure caused by graft versus host disease after bone marrow transplantation. Liberated and liposomal AMB were separated by solid phase extraction and measured by high performance liquid chromatography. No excessive AMB elimination took place during albumin dialysis. Plasma levels of liposomal AMB exceeded those of liberated AMB. Pharmacokinetic data were comparable to those obtained previously in patients on hemofiltration and in critically ill patients without extracorporeal blood purification.

Topics: Adult; Albumins; Amphotericin B; Antifungal Agents; Graft vs Host Disease; Humans; Liver Failure; Male; Renal Dialysis

Topics: Adolescent; Amphotericin B; Antifungal Agents; Drug Monitoring; Fathers; Female; Humans; Liver Failure; Liver Transplantation; Living Donors; Male; Mycoses; Preoperative Care; Treatment Outcome

Although nephrotoxicity is a common and well-recognized side effect of amphotericin B, hepatotoxicity is rare. We report on a 9-year-old girl with cystic fibrosis who developed fulminant renal and hepatic dysfunction following a short course of intravenous amphotericin B for a suspected aspergillus infection, although she did not have clinical evidence of invasive aspergillosis. The toxicity became apparent after changing to liposomal amphotericin. This association of renal and hepatotoxicity with liposomal amphotericin B has not previously been reported in children.

Topics: Amebicides; Amphotericin B; Aspergillosis; Child; Cystic Fibrosis; Female; Humans; Liver Failure; Renal Insufficiency

We present a case of recovery from fulminant hepatic failure secondary to high serum levels of fluconazole precipitated by amphotericin B induced renal dysfunction. Fluconazole dose adjustment or alternative antifungal treatment should be considered in patients with impaired renal function.

Topics: Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Cryptococcosis; Female; Fluconazole; Humans; Kidney; Liver Failure; Middle Aged

Plasma and tissue concentrations of amphotericin B were determined in a patient treated with liposomal amphotericin B during liver transplant failure. A cumulative rise in amphotericin B plasma concentrations was observed accompanied by an enhanced pulmonary deposition of the drug. Failure of the liver as a major component of the reticuloendothelial system may cause elevated plasma concentrations of liposomal amphotericin B and may consequently enhance deposition of liposomes in the lungs as a substitutive clearing organ.

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Fatal Outcome; Humans; Kidney; Liposomes; Liver Failure; Liver Transplantation; Lung; Male; Middle Aged