Pharmacodynamics of Voriconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis: Implications for In Vitro Susceptibility Breakpoints

Jeans, Adam R.; Howard, Susan J.; Al-Nakeeb, Zaid; Goodwin, Jonathan; Gregson, Lea; Majithiya, Jayesh B.; Lass‐Flörl, Cornelia; Cuenca‐Estrella, Manuel; Arendrup, Maiken Cavling; Warn, Peter; Hope, William

doi:10.1093/infdis/jis372

Cited by 35 publications

(30 citation statements)

References 16 publications

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“…The relationship between the AUC (in this case, the total AUC that developed throughout the experimental period) and the final galactomannan concentration was explored. Galactomannan readings of Ͻ1 and Ͻ0.5 were used as endpoints, as previously described in this same model for voriconazole (10). Logistic regression was used to link the AUC/ MIC value for each strain and the galactomannan concentration quantified as a dichotomous outcome (i.e., success was defined as a galactomannan reading of Ͻ0.5 or 1.0, depending on the specific analysis being performed).…”

Section: Aspergillus Isolates and In Vitro Susceptibility Testing Fomentioning

confidence: 99%

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Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

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Livermore

Johnson

et al. 2016

Antimicrob Agents Chemother

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Isavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamic in vitro model of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates of Aspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

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Section: Aspergillus Isolates and In Vitro Susceptibility Testing Fomentioning

confidence: 99%

“…Here, we use a previously described and validated in vitro dynamic model of the human alveolus, which enables human-like pharmacokinetics of isavuconazole to be simulated (10). This in vitro model was used to establish the pharmacokinetics and pharmacodynamics of isavuconazole against two wild-type and two mutant strains of Aspergillus fumigatus.…”

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confidence: 99%

Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

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Livermore

Johnson

et al. 2016

Antimicrob Agents Chemother

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“…We have recently used a dynamic model of the human alveolus to demonstrate that A. fumigatus Cyp51A mutants with decreased susceptibility to voriconazole can be treated only with drug exposures that are likely to be toxic to humans (19). Our current data suggest that the addition of anidulafungin to voriconazole does not significantly alter the exposure-response relationships for isolates of A. fumigatus with these resistance mutations.…”

Section: Discussionmentioning

confidence: 75%

Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in an In Vitro Model of Invasive Pulmonary Aspergillosis

Jeans

Howard

Al-Nakeeb

et al. 2012

Antimicrob Agents Chemother

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Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.

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“…with an MIC 2 mg/L that have an area under the curve : MIC > 32.1 is 67.5%, which then quickly drops to unacceptably low levels for MICs of 4 mg/L and higher [8]. Data from multiple clinical trials suggest that Aspergillus is a good target for voriconazole [10,11].…”

Section: Research Note Mycologymentioning

confidence: 99%

EUCAST Technical Note on Voriconazole and Aspergillus spp.

Hope

Cuenca‐Estrella

Lass‐Flörl

et al. 2013

Clinical Microbiology and Infection

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The European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing (EUCAST-AFST) has determined breakpoints for voriconazole against Aspergillus spp. This Technical Note is based on the EUCAST rationale document for voriconazole (available on the EUCAST website: http://www.eucast.org). Voriconazole breakpoints are based on epidemiological cut-off values, pharmacokinetic/pharmacodynamic data and clinical experience. Breakpoints will be reviewed regularly or when new data emerge.

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Pharmacodynamics of Voriconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis: Implications for In Vitro Susceptibility Breakpoints

Abstract: This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.

Cited by 35 publications

References 16 publications

Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in an In Vitro Model of Invasive Pulmonary Aspergillosis

EUCAST Technical Note on Voriconazole and Aspergillus spp.

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