Comparative pharmacodynamics of echinocandins against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model that correlates with clinical response to caspofungin therapy: Is there a place for dose optimization?

Antimicrob Agents Chemother. 2021 Jan 25:AAC.01618-20. doi: 10.1128/AAC.01618-20. Online ahead of print.

ABSTRACT

Background. Echinocandins have been used as primary therapy of invasive aspergillosis (IA) with sub-optimal results at standard dosing. We explored the efficacy of dose escalation in a validated in vitro PK/PD modelMethods. Six echinocandin WT and three non-WT A. fumigatus isolates were tested in the in vitro PK/PD model simulating anidulafungin, caspofungin and micafungin exposures with fCmax 0.01-16 mg/L and t1/2=8-22h. The relationship between the fAUC0-24/MEC and % aberrant mycelia formation was analyzed. PK/PD indices associated with 50-99.99% maximal activity (EI50-EI99.99) were correlated with the clinical outcome of 50 mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin performing Monte Carlo analysis.Results. A sigmoidal PK/PD relationship was found for WT isolates with EI99 766, 8.8 and 115 fAUC0-24/CLSI MEC for anidulafungin, caspofungin and micafungin, respectively. No aberrant mycelia were observed for non-WT isolates irrespectively of their MEC and drug exposure. The EI99, EI99.9 and EI99.99 corresponded to 2, 3 and 4 log10 formation of aberrant mycelia and correlated with survival, favorable and complete response rates to caspofungin primary therapy in patients with IA. Very low PTA (<13%) was found for the standard doses of all echinocandins, whereas a PTA ≥90% was found with 100 and 150 mg/day of caspofungin and 1400 mg/day micafungin against WT isolates. For anidulafungin, the PTA for 1500 mg/day was 10%.Conclusions. Among the three echinocandins, only caspofungin at two-three times licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.

PMID:33495222 | DOI:10.1128/AAC.01618-20