Toward Harmonization of Voriconazole CLSI and EUCAST Breakpoints for Candida albicans Using a Validated
            <i>In Vitro</i>
            Pharmacokinetic/Pharmacodynamic Model

Beredaki, Maria-Ioanna; Georgiou, Panagiota-Christina; Siopi, Maria; Kanioura, Lamprini; Andes, David R.; Arendrup, Maiken Cavling; Mouton, Johan W.; Meletiadis, Joseph

doi:10.1128/aac.00170-20

Cited by 5 publications

(6 citation statements)

References 27 publications

(40 reference statements)

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“…In vitro PK/PD data confirmed the breakpoint at 0.03 mg/L for C. albicans based on probability of target attainment and suggested that isolates with MICs of 0.06-0.125 mg/L can only be covered provided sufficient exposure is ensured through therapeutic drug monitoring. However, isolates with MIC ≥ 0.25 mg/L would require trough levels of at least 4 mg/L and thus close to toxic levels [67]. Infections by wild-type isolates of C. parapsilosis and C. tropicalis had similar outcome data as C. albicans, despite slightly higher ECOFFs (0.06 and 0.125 mg/L, respectively) and the limited data for C. krusei suggest voriconazole efficacy despite an ECOFF of 1 mg/L [43].…”

Section: Voriconazolementioning

confidence: 99%

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints

Astvad

Arıkan-Akdağlı

Arendrup

2022

JoF

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EUCAST has established clinical breakpoints for the six most common Candida species and Cryptococcus neoformans but not for less common yeasts because sufficient evidence is lacking. Consequently, the question “How to interpret the MIC?” for other yeasts often arises. We propose a pragmatic classification for amphotericin B, anidulafungin, fluconazole, and voriconazole MICs against 30 different rare yeasts. This classification takes advantage of MIC data for more than 4000 isolates generated in the EUCAST Development Laboratory for Fungi validated by alignment to published EUCAST MIC data. The classification relies on the following two important assumptions: first, that when isolates are genetically related, pathogenicity and intrinsic susceptibility patterns may be similar; and second, that even if species are not phylogenetically related, the rare yeasts will likely respond to therapy, provided the MIC is comparable to that against wild-type isolates of more prevalent susceptible species because rare yeasts are most likely “rare” due to a lower pathogenicity. In addition, the treatment recommendations available in the current guidelines based on the in vivo efficacy data and clinical experience are taken into consideration. Needless to say, it is of utmost importance (a) to ascertain that the species identification is correct (using MALDI-TOF or sequencing), and (b) to re-test the isolate once or twice to confirm that the MIC is representative for the isolate (because of the inherent variability in MIC determinations). We hope this pragmatic guidance is helpful until evidence-based EUCAST breakpoints can be formally established.

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Section: Voriconazolementioning

confidence: 99%

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints

Astvad

Arıkan-Akdağlı

Arendrup

2022

JoF

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“…However, based on clinical data for fluconazole, an fAUC/MIC of 100 is the clinically relevant PK/PD target (19) that corresponds to a near-maximal/near-stasis activity in animal models associated with a 2-log decrease from drug-free control or a 0.5 to 1 log 10 CFU/kidney increase from initial inoculum (17). We have recently shown that an fAUC/MIC of 100 is also clinically relevant for voriconazole, which in in vitro models correspond to the EI 50 (a 1.5 log decrease from drug-free control and a 2.5-log increase from initial inoculum) (11). For posaconazole, the pharmacodynamic effects ranged from a 21 to 3 log 10 change from initial fungal burden, since killing was observed contrary to voriconazole and fluconazole where no killing was observed.…”

Section: Discussionmentioning

confidence: 96%

“…The 24-h PK/PD targets were two times lower than the 48-h PK/PD targets, as previously found for voriconazole against Candida spp. (10,11), indicating that at least 48 h are required in order to describe the pharmacodynamics against Candida spp. Based on 48-h PK/PD indices, the oral solution would not cover the wild-type population of C. albicans (#0.06 mg/liter) without therapeutic-drug monitoring (TDM) targeting trough (upper 95% CI limit) levels of .0.7 mg/liter for EUCAST/CLSI48h and .1.4 mg/liter for CLSI24h.…”

Section: Discussionmentioning

confidence: 99%

The Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections: Data from an In Vitro Pharmacokinetic-Pharmacodynamic Model

Beredaki

Arendrup

Andes

et al. 2021

Antimicrob Agents Chemother

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Background. Posaconazole is more in vitro active against Candida albicans than fluconazole and approved for the treatment of oropharyngeal candidiasis but not invasive candidiasis (IC). We explored the efficacy of posaconazole against C. albicans in an in vitro pharmacokinetic-pharmacodynamic (PK-PD) model of IC and determined the probability of pharmacodynamic target attainment for the oral solution (o.s.) and i.v./tablet formulations. Methods. Three clinical C. albicans isolates (posaconazole MICs 0.008-0.25 mg/liter) were studied in the in vitro PK-PD dilution model simulating steady state posaconazole PK. The in vitro exposure-effect relationship fAUC0-24/MIC was described and compared with in vivo outcome in animals with IC. PK-PD susceptibility breakpoints and trough levels required for optimal treatment were determined for EUCAST and CLSI24h/48h methods, using the fAUC0-24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis for o.s. (400 mg q12h) and i.v./tablet formulations (300 mg q24h). Results. The in vitro mean (95%CI) EI50 was 330 (183-597) fAUC0-24/MIC for CLSI24h and 169 (92-310) for EUCAST/CLSI48h methods, which are close to the near-stasis in vivo effect. The probability of target attainment for EI50 was estimated and for the wild-type isolates (MIC ≤ 0.06 mg/liter) it was low for the o.s. and higher than 95% for the i.v./tablet formulations for the EUCAST/CLSI48h but not for CLSI24h method. Non-wild-type isolates with EUCAST/CLSI48h MICs 0.125 and 0.25 mg/liter would require trough levels >1.2 and >2.4 mg/liter, respectively. Conclusion. Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type C. albicans isolates provided a steady state is reached fast. A PK-PD susceptibility breakpoint at the ECOFF of 0.06 mg/liter was determined.

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“…We wonder if this difference was attributable to the adaptation of the two original methods to commercial ones. All these observations lead to the conclusion that despite efforts of standardization ( Pfaller et al., 2010 ; Pfaller et al., 2014 ; Chowdhary et al., 2015 ; Beredaki et al., 2020 ), the two consortia still have to make efforts to provide criteria and protocols that are more similar to simplify AFST among all laboratories. Some may claim that differences will remain due to the difference of sampling and thus epidemiology.…”

Section: Discussionmentioning

confidence: 99%

How Yeast Antifungal Resistance Gene Analysis Is Essential to Validate Antifungal Susceptibility Testing Systems

Pellaton

Sanglard

Lamoth

et al. 2022

Front. Cell. Infect. Microbiol.

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ObjectivesThe antifungal susceptibility testing (AFST) of yeast pathogen alerts clinicians about the potential emergence of resistance. In this study, we compared two commercial microdilution AFST methods: Sensititre YeastOne read visually (YO) and MICRONAUT-AM read visually (MN) or spectrophotometrically (MNV), interpreted with Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing criteria, respectively.MethodsOverall, 97 strains from 19 yeast species were measured for nine antifungal drugs including a total of 873 observations. First, the minimal inhibitory concentration (MIC) was compared between YO and MNV, and between MNV and MN, either directly or by assigning them to five susceptibility categories. Those categories were based on the number of MIC dilutions around the breakpoint or epidemiological cut-off reference values (ECOFFs or ECVs). Second, YO and MNV methods were evaluated for their ability to detect the elevation of MICs due to mutation in antifungal resistance genes, thanks to pairs or triplets of isogenic strains isolated from a single patient along a treatment previously analyzed for antifungal resistance gene mutations. Reproducibility measurement was evaluated, thanks to three quality control (QC) strains.ResultsYO and MNV direct MIC comparisons obtained a global agreement of 67%. Performing susceptibility category comparisons, only 22% and 49% of the MICs could be assigned to categories using breakpoints and ECOFFs/ECVs, respectively, and 40% could not be assigned due to the lack of criteria in both consortia. The YO and MN susceptibility categories gave accuracies as low as 50%, revealing the difficulty to implement this method of comparison. In contrast, using the antifungal resistance gene sequences as a gold standard, we demonstrated that both methods (YO and MN) were equally able to detect the acquisition of resistance in the Candida strains, even if MN showed a global lower MIC elevation than YO. Finally, no major differences in reproducibility were observed between the three AFST methods.ConclusionThis study demonstrates the valuable use of both commercial microdilution AFST methods to detect antifungal resistance due to point mutations in antifungal resistance genes. We highlighted the difficulty to conduct conclusive analyses without antifungal gene sequence data as a gold standard. Indeed, MIC comparisons taking into account the consortia criteria of interpretation remain difficult even after the effort of harmonization.

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Toward Harmonization of Voriconazole CLSI and EUCAST Breakpoints for Candida albicans Using a Validated In Vitro Pharmacokinetic/Pharmacodynamic Model

Cited by 5 publications

References 27 publications

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints

The Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections: Data from an In Vitro Pharmacokinetic-Pharmacodynamic Model

How Yeast Antifungal Resistance Gene Analysis Is Essential to Validate Antifungal Susceptibility Testing Systems

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