Continuously infused amphotericin B deoxycholate for primary treatment of invasive fungal disease in acute myeloid leukaemia

Abstract

Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D-AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3-13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 μmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 μmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option.

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

“…The estimated overall survival probability at 5 years was 0.493 in the AmB and 0.291 in the control patients. 49 These results are consistent with an early experimental analysis that demonstrated a synergistic effect of AmB and chemotherapy against transplantable AKR leukemia in a syngeneic mice model. The addition of AmB to chemotherapy resulted in long-term survival of mice inoculated with leukemic cells in a substantial number of cases.…”

From bench to bedside: Perspectives on the utility of pharmacokinetics/pharmacodynamics in predicting the efficacy of antifungals in invasive candidiasis

“…Although they found that continuous infusion might be helpful in reducing the nephrotoxicity risk of amphotericin B, data on clinical outcome with continuous infusion of amphotericin B were inconclusive and contradictory. [35][36][37][38] It should not be overlooked that administering amphotericin B by continuous infusion is in contrast to the findings of the preclinical studies which showed that the C max /MIC ratio correlated best with efficacy. 31,32 The aim therefore should be to achieve high peak serum concentrations of amphotericin B, which is best approached by rapid infusion, and not with continuous infusion.…”

“…Some authors assessed comparatively in the clinical setting the role of administering amphotericin B by continuous infusion vs intermittent infusion. Although they found that continuous infusion might be helpful in reducing the nephrotoxicity risk of amphotericin B, data on clinical outcome with continuous infusion of amphotericin B were inconclusive and contradictory 35‐38 . It should not be overlooked that administering amphotericin B by continuous infusion is in contrast to the findings of the preclinical studies which showed that the C max /MIC ratio correlated best with efficacy 31,32 .…”

Delivery strategies of amphotericin B for invasive fungal infections

“…Besides, the emergence of drug-resistant fungi due to upregulated drug transporters, activated efflux pumps and mutations in resistant genes leads to treatment failure 14 , 15 . Moreover, drug-associated adverse effect and lack of adequate diagnostic strategies are additional factors that limit the success of IFIs treatment 16 .…”