Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

François Danion; Vincent Jullien; Claire Rouzaud; Manal Abdel Fattah; Simona Lapusan; Romain Guéry; Naïke Bigé; Marjolaine Morgand; Nicolas Pallet; Fanny Lanternier; Olivier Lortholary

doi:10.1128/AAC.00705-18

Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00705-18. doi: 10.1128/AAC.00705-18. Print 2018 Sep.

Authors

François Danion^{1

2}, Vincent Jullien³, Claire Rouzaud¹, Manal Abdel Fattah⁴, Simona Lapusan⁵, Romain Guéry¹, Naïke Bigé⁶, Marjolaine Morgand¹, Nicolas Pallet⁷, Fanny Lanternier^#^{1

8}, Olivier Lortholary^#^{9

8}

Affiliations

¹ Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.
² Aspergillus Unit, Institut Pasteur, Paris, France.
³ Paris Descartes University, Hôpital Européen Georges Pompidou, Department of Pharmacology, AP-HP, Paris, France.
⁴ Centre Hospitalier Universitaire de Nancy, Department of Infectious Diseases and Tropical Medicine, Nancy, France.
⁵ Hôpital Saint-Antoine, Department of Hematology and Cellular Therapy, AP-HP, Paris, France.
⁶ Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Intensive Care Unit, Paris, France.
⁷ Paris Descartes University, Hôpital Européen Georges Pompidou, Department of Clinical Chemistry, AP-HP, Paris, France.
⁸ National Reference Center for Invasive Mycoses and Antifungals, Molecular Mycology Unit, Institut Pasteur, Paris, France.
⁹ Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France olivier.lortholary@aphp.fr.

^# Contributed equally.

Abstract

Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.

Keywords: CYP2C19; cerebral aspergillosis; metabolizer; pharmacogenomics; therapeutic drug monitoring; voriconazole.

Publication types

Case Reports

MeSH terms

Adult
Aged
Antifungal Agents / therapeutic use*
Aspergillosis / drug therapy*
Aspergillosis / genetics*
Central Nervous System / microbiology*
Cytochrome P-450 CYP2C19 / genetics
Drug Monitoring / methods
Female
Humans
Mutation / genetics
Pharmacogenetics / methods
Voriconazole / therapeutic use*

Substances

Antifungal Agents
Cytochrome P-450 CYP2C19
Voriconazole