Evaluating prophylactic post cardiac transplantation amphotericin B treatment by simulation

Author:

Camille Mane* 1, Véronique Duhalde 2, Isabelle Labadens 2, Olivier Cointault 2, Didier Concordet 1, Peggy Gandia 1;2

Author address:

1 INTHERES, Université de Toulouse, INRA, ENVT, Toulouse, France; 2
Toulouse University Hospital, Toulouse, France

Full conference title:

European Congress of Clinical Microbiology and Infectious Diseases 2020

Date: 24 June 2020

Abstract:

Background: Antifungal treatment is recommended to prevent invasive aspergillosis, a condition which occurs frequently and is associated with a poor prognosis in the first 3 months following cardiac transplantation. Current recommendations do not include a once a week administration of liposomal amphotericin B (L-AmB), despite its favorable safety profile. The objective of the current study was to simulate the efficacy of a once a week administration of L-AmB using a pharmacokinetic-pharmacodynamic (PK-PD) approach.

Materials/methods: Based on the population PK model published by Würthwein et al., 1000 plasma and tissue kinetic profiles were simulated over a 7-day period after administration of a single dose of 7.5 mg / kg of L-AmB as a 1-hour infusion. For each simulated plasma profile, the Area Under the Curve (AUC) for total concentrations over 24 hours was calculated from D1 to D7. These AUCs were compared with L-AmB PK-PD efficacy target (AUC / MIC> 167) to determine the percentage of simulated profiles achieving this target (i.e. probability of target attainment). The theoretical duration of effectiveness was determined using both the simulated tissue kinetic profiles and a concentration higher than the MIC for more than 90% of the profiles.

Results: At D1, more than 90% of the plasma profiles met the PK-PD target for Minimum Inhibitory Concentrations (MICs) ≤ 0.5 mg/L. This percentage dropped to 80.2% when the MIC was increased to 1 mg/L (i.e. Aspergillus breakpoint). At D7 and for a MIC corresponding to the breakpoint, only 3.3% of the plasma profiles achieved the PK-PD target. The treatment efficacy assessed at tissue level does not extend to 7 days regardless of the MICs tested. Indeed, efficacy is theoretically maintained during 3.2 and 1.3 day(s) for MICs of 0.25 to 0.75 mg/L. For MICs ≥ 1 mg/L, less than 90% of the simulated profiles reached tissue concentrations ≥ 1 mg/L.

Conclusions: Regardless of plasma or tissue PK-PD target, our simulations suggest that a once a week administration of L-AmB does not guarantee antifungal efficacy throughout the entire one-week period. These results need to be confirmed in clinical practice.

Presenter email address: mane.c@chu-toulouse.fr

Abstract Number: 1607

Link to conference website:

Link Conference abstract: 

ECCMID 2020

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