Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/156834

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Al-Saigh RJ, Aldorkee SY, Rahi FA, Al-Humadi AH, Kadhum SA, Al-Humadi HW. Assessment of the activity of posaconazole against azole-resistant Aspergillus species studied in an in vitro pharmacokinetic/pharmacodynamic model [published online as ahead of print on March 7, 2023]. Adv Clin Exp Med. 2023. doi:10.17219/acem/156834

Assessment of the activity of posaconazole against azole-resistant Aspergillus species studied in an in vitro pharmacokinetic/pharmacodynamic model

Rafal Jalil Al-Saigh1,A,B,C,D,F, Suad Yousif Aldorkee2,C,D,E,F, Firas Aziz Rahi3,B,C,D,E,F, Ahmed H. Al-Humadi4,B,C,D,E,F, Samah Ahmed Kadhum1,B,C,D,E,F, Hussam W. Al-Humadi5,A,B,C,D,E,F

1 Department of Clinical Laboratory Sciences, Faculty of Pharmacy, University of Babylon, Iraq

2 Department of Pharmacy, Al-Kitab University, Kirkuk, Iraq

3 Department of Pharmacy, Al-Nisour University College, Baghdad, Iraq

4 Medical School, National and Kapodistrian University of Athens, Athens, Greece

5 Pharmacy College, University of Babylon, Iraq

Abstract

Background. Invasive pulmonary aspergillosis (IPA) with azole resistance is associated with a high death rate. Posaconazole is used for IPA as preventive and salvage therapy, and exhibits considerable efficacy against the majority of Aspergillus strains.
Objectives. An in vitro pharmacokinetic-pharmacodynamic (PK-PD) model was used to examine the potential use of posaconazole in a primary therapy against azole-resistant IPA.
Material and Methods. In an in vitro PK-PD model simulating human pharmacokinetics (PKs), 4 clinical isolates of A. fumigatus with Clinical and Laboratory Standards Institute (CLSI) minimum inhibitory concentrations (MICs) ranging from 0.030 mg/L to 16 mg/L were examined. A bioassay was used to determine drug levels, and galactomannan production was used to evaluate fungal growth. The CLSI/European Committee on Antimicrobial Susceptibility Testing (EUCAST) 48-hour values, gradient concentration strip methodologies (MTS) 24-hour values, in vitro PK-PD relationships, and the Monte Carlo method were used to estimate the simulation of the human dosing regimens of oral 400 mg twice-daily and intravenous (i.v.) 300 mg onceand twice-daily using susceptibility breakpoints.
Results. With 1 or 2 daily dosage regimes, the area under the curve (AUC)/MIC associated with 50% of the maximum antifungal activity was 160 and 22.3, respectively. For CLSI/EUCAST, the susceptibility/intermediate/resistant breakpoints were 0.125/0.25–0.5/1 mg/L. For therapeutic drug monitoring (TDM), a trough/MIC ratio of 2.6 was calculated. Therapeutic drug monitoring is not necessary for isolates with MICs of 0.06 mg/L with oral 400 mg twice-daily regimens. However, it is important to obtain MICs of 0.125 mg/L and unavoidable when MICs of 0.25–0.5 mg/L are needed. For non-wild type isolates with MICs of 1–2 mg/L, only i.v. 300 mg twice-daily regimen was effective.
Conclusion. Oral therapy with posaconazole can be considered in A. fumigatus isolates with low MIC values without TDM, whereas i.v. therapy should be considered with higher MIC values and may be important in the primary treatment of azole-resistant IPA.

Key words

posaconazole, therapeutic drug monitoring, azole-resistant Aspergillus fumigatus, invasive pulmonary aspergillosis, in vitro pharmacokinetic-pharmacodynamic model

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