Abstract
Voriconazole is commonly used for the treatment of invasive pulmonary aspergillosis. Recent guidelines strongly advise routine therapeutic drug monitoring for patients receiving voriconazole. We present a case with subtherapeutic voriconazole serum levels caused by drug interactions and genetic polymorphisms.

Introduction
Voriconazole is commonly used for the treatment of invasive pulmonary aspergillosis (IPA).[1] Recent guidelines strongly advise routine therapeutic drug monitoring (TDM) for patients being treated with voriconazole.[2] We present a case where voriconazole was used in a setting of near-drowning and suspicion of subsequent IPA. The voriconazole serum levels were strongly divergent, underlining the importance of routine TDM for voriconazole, aiming at serum concentrations between 1.5-2 and 6 mg/l.

Case
A 29-year-old homeless patient known with alcohol and drug abuse was admitted to our intensive care unit (ICU) after a cardiac arrest. The patient had been found in a pond and had nearly drowned. During resuscitation, orotracheal intubation was performed and because of his decreased consciousness after return of spontaneous circulation, invasive mechanical ventilation was started. Initial computed tomography imaging of the lungs showed bilateral ground glass opacities, most probably due to pulmonary oedema, signs of aspiration, in particular in the left lower lobe, and bronchiectasis affecting the right upper lobe.

Because of the submersion in combination with the imaging results, a bronchoscopy was performed, showing food scraps on both sides which were removed successfully. Bronchoscopy showed no signs of fresh water aspiration.

The patient was treated according to the targeted temperature management protocol for attenuation of postanoxic encephalopathy, but after stopping sedatives myoclonic seizures were seen. The patient was treated with high doses of antiseizure drugs (propofol, midazolam, levetiracetam, phenytoin, clobazam and ultimately thiopental), but after cessation of thiopental, generalised myoclonus returned.
Since the patient had been found in a pond in a setting of near-drowning and ingestion of contaminated water has been associated with IPA,[3] the patient was treated with intravenous voriconazole (two loading doses of 6 mg/kg followed by 4 mg/kg bid), even though the EORTC criteria[2] of proven or probable IPA were not fulfilled (due to a lack of host factors and clinical criteria). A galactomannan test (Platelia Aspergillus Antigen Assay, Bio-Rad, Hercules, United States) on bronchoalveolar lavage (BAL) fluid was positive (optical density index of 4.5). Fungal cultures of BAL fluid remained negative and consequently, antifungal susceptibility testing was not possible. When voriconazole was started, the patient was also receiving levetiracetam, midazolam, norepinephrine, paracetamol, piperacillin/tazobactam, propofol, sufentanil (all intravenously), ascorbic acid, thiamine and vitamin B complex (all orally), nadroparin prophylaxis and standard decontamination of the digestive tract.
Serum voriconazole concentrations were measured during treatment and are shown in table 1 and figure 1. The first concentration measurement was performed after five administrations of voriconazole, including two loading doses of 6 mg/kg. Because of two subtherapeutic concentrations on day 8 and 10, the voriconazole dose was increased from 4 mg/kg bid to 6 mg/kg bid, but concentrations remained low on day 13. On day 14, the voriconazole treatment was discontinued because of low clinical suspicion of IPA.
TDM was also performed for valproate, phenytoin and clobazam (table 1). Because of consistently low serum concentrations of all the drugs measured, the patient’s DNA coding for CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was analysed for mutations. Ultra-rapid metabolism for CYP2D6 (*1/*2xN), increased metabolism for CYP2C19 (*1/*17) and normal metabolism for CYP2C9 (*1/*1) and CYP3A4 (*1/*1) were found.