Amphotericin infusion rate

Amphotericin B nephrotoxicity can be reduced by slowing the infusion rate to 24 hours or, in at-risk patients, substituting liposomal amphotericin B. 

Ellis ME, al-Hokail A A, Clink HM, Padmos MA, Ernst P, Spence DG, Tharpe WN, Hillier VF. Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 1992 36(l) 172-9. 

Nephrotoxicity associated with amphotericin B administration in humans is dose related and it may be severe and result in acute renal failure. The incidence of acute renal failure may be as high as 49 to 65%. It is accompanied by an increase in serum creatinine. Mortality may be high and is increased by the co-administration of other nephrotoxic drugs. Risk factors include cumulative dose, abnormal baseline renal function, concomitant nephrotoxic drugs such as cyclosporin, and infusion rates. However, rapid infusion rates are also associated with severe hyperkalaemia and potentially fatal arrhythmias. " In one case, a woman given 5mg/kgbw/day amphotericin B instead of the... 

Amphotericin B iipid compiex (Abeicet) - The recommended dose is 5 mg/kg/day prepared as a 1 mg/mL infusion and delivered at a rate of 2.5 mg/kg/hr. For pediatric patients and patients with cardiovascular disease, the drug may be diluted to a final concentration of 2 mg/mL. If the infusion exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours. Do not use an in-line filter. 

Amphotericin is highly effective in the treatment of visceral leishmaniasis (18). In a prospective study of 938 patients from Bihar, India, who received the drug in a dosage of 1 mg/kg/day infused over 2 hours for 20 days, serum creatinine values over 177 pmol/l were noted in 6.3%, and acute renal insufficiency developed in three patients. Two patients died, possibly related to amphotericin, one with renal insufficiency and one with hypokalemia and cardiac arrest. Infnsion-related chills occurred in 92% and fever in 40% of patients. The parasitological cure rate (no relapse within 6 months) exceeded 99%. 

Mucormycosis has an exceedingly high mortality rate in immunocompromised patients. In five phase I and phase II studies of ABCD, 21 patients were given ABCD (mean dose 4.8 mg/kg per infusion for a mean duration of 37 days) on the basis of pre-existing renal insufficiency, nephrotoxicity during amphotericin B therapy, or refractory infections (24). Of 20 evaluable patients, 12 responded to ABCD, and there was no renal or hepatic toxicity. However, a previous randomized, comparative trial showed an at least similar if not increased frequency... 

In an open, sequential phase II clinical study of three different regimens of liposomal amphotericin for visceral leishmaniasis (2 mg/kg on days 1-6 and on day 10 2 mg/ kg on days 1-4 and on day 10 2 mg/kg on days 1, 5, and 10) in Indian and Kenyan patients in three developing countries, there were few infusion-associated adverse effects (40). Of 32 Brazilian patients (15 of whom received 2 mg/kg on days 1-10 because of poor responses to the first regimen, 37% had a fever with one or more infusions, 9% had chills, and 6% had back pain in addition, three patients had respiratory distress and/or cardiac dysrhythmias. There were different response rates to the three regimens in the different countries, leading to the recommendation of 2 mg/kg on days 1-4 and day 10 in India and Kenya, and 2 mg/kg on days 1-10 in Brazil. 

Liposomal amphotericin and ABLC have been compared in an open randomized study in 75 adults with leukemia and 82 episodes of suspected or documented mycosis (48). The median durations of treatment and dosages were 15 days at 4 mg/kg/day for liposomal amphotericin and 10 days at 3 mg/kg/day for ABLC. Acute but not dose-limiting infusion-related adverse events occurred in 36 versus 70%. Bilirubin increased to over 1.5 times baseline in 59 versus 38%. There was no difference in the effects of either agent on renal function and drug-related withdrawals. The overall response rate to therapy in documented fungal infections (29 and 30% respectively) was not different between the two drugs. 

In 6 of 90 children given intravenous amphotericin there was a significant fall in heart rate, and monitoring of heart rate was recommended in children with underlying heart disease (69). These immediate reactions follow intravenous administration and occur particularly with excessively rapid infusion of DAMB. 

Liposomal amphotericin (3 mg/kg/day) has been compared with conventional amphotericin (0.7 mg/kg/day) for induction therapy of moderate to severe disseminated histoplasmosis in a randomized, double-blind, multicenter trial in 81 patients with AIDS (119). The duration of induction was 2 weeks, to be followed by 10 weeks of itraconazole in the case of a response. Clinical success was achieved in 14 of 22 patients treated with conventional amphotericin compared with 45 of 51 patients who received liposomal amphotericin (difference, 24% 95% Cl = 1%, 52%). Culture conversion rates were similar. Three patients treated with conventional amphotericin and one treated with liposomal amphotericin died during induction. Infusion-related adverse effects were more common with conventional amphotericin (63%) than with liposomal amphotericin (25%). Nephrotoxicity occurred in 37% of patients treated with conventional amphotericin and 9% of patients treated with liposomal amphotericin. The results of this study suggest that liposomal amphotericin is less toxic than conventional amphotericin and is associated with improved survival. 

A large, randomized, multicenter trial that compared voriconazole with hposomal amphotericin B for empirical antifungal therapy showed comparable composite success rates however, voriconazole did not fulfill the protocol-defined criteria for noninferiority to liposomal amphotericin. Voriconazole was superior in reducing documented breakthrough infections, infusion-related toxicity, and nephrotoxicity. However, patients who received voriconazole had more frequent... 

Observational studies In clinical trials, in the absence of premedication, the rates of infusion-related reactions have been higher with amphotericin B colloidal dispersion (ABCD) than with other forms of amphotericin B, including amphotericin B deoxy-cholate [7 ]. Data on pre-medication practices and infusion-related reactions in 170 patients (median age 37 years 52% men) who received 1230 infusions of ABCD (mean dose 2.8 mg/kg/day) have been captured in a multicenter, worldwide, observational registry [8 ]. Treatment was according to the site s standard treatment practice. Common pre-medications included glucocorticoids, antihistamines, paracetamol (acetaminophen), and metamizole. The overall rate of infusion-related reactions... 

Management of adverse reactions Administration of amphotericin B lipid complex (ABLC) may be associated with infusion-related reactions, such as fever, rigors, and chills. Premedication with hydrocortisone may reduce the incidence of these reactions, but there are currently limited confirmatory data from clinical practice [7 ]. In a prospective 18-month study, patients with cancers were given intravenous hydrocortisone 100 mg 15-30 minutes before each infusion of ABLC (275 cycles mean dose per cycle 931 mg) [14. There were 44 infusion-related reactions (16%), most of which followed the first infusion of a cycle (15% subsequent infusions 2.9%). The most common reactions were rigors (15%) and fever (13). There was no significant difference in the rates or types of reactions between ABLC-naive and previously treated patients. The dose of ABLC had no effect on the rate of reactions, but female sex, neutropenia, and being younger were predictive. 

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