Posaconazole concentrations in the central nervous system

Sir, Posaconazole is a new triazole approved for prophylaxis in neutropenic high-risk patients1,2 and as salvage treatment of, for example, invasive aspergillosis.3 Pharmacokinetic analyses suggest an exposure–response relationship.3 Diarrhoea, proton pump inhibitors (PPIs) and elevated gamma-glutamyl-transferase are associated with reduced plasma concentrations.4 We report the first three patients in whom posaconazole concentrations in the CNS were determined and related to their respective serum concentrations. A 46-year-old male taking prophylactic posaconazole 200 mg three times a day and prednisone 75 mg intravenously (iv) twice daily for extensive graft-versus-host disease with severe diarrhoea presented with tenderness over the right maxillary sinus accompanied by paresis of cranial nerves III, IV and VI, acute loss of visual acuity of the left eye and a C-reactive protein (CRP) increase to 253 mg/dL. Cranial MRI revealed a space-occupying lesion in the right maxillary sinus and an occluded right internal carotid. The same day, the patient underwent surgery of the maxillary sinuses. Histopathological examination revealed zygomycosis with vascular invasion. Cladosporium cladosporioides and Rhizopus oryzae were identified by culture and PCR, respectively. The patient died after 2 weeks. During the entire stay, the patient had pantoprazole 40 mg a day orally. For all posaconazole concentrations, refer to Table 1. Posaconazole measurements in serum and CSF EVD, extraventricular drainage. Posaconazole measurements in serum and CSF EVD, extraventricular drainage. A 26-year-old female patient with hereditary IgG 2/4 deficiency, and recurrent oesophageal candidiasis leading to stenosis, developed two large frontal lobe abscesses under antibacterial treatment for bronchopneumonia. She had been receiving posaconazole 400 mg orally twice daily for 2 years. Drainage revealed Streptococcus mitis. Until deterioration of her neurological status, pantoprazole 40 mg a day orally had been administered. The patient died on the day after drainage. A 14-year-old boy with bacterial meningitis, an intracranial pressure probe and bilateral external ventricular drainages (EVDs) revealed imaging signs of bilateral ventriculitis and abscess formation in the left frontal lobe. Aspergillus fumigatus was isolated from a removed EVD and CSF galactomannan index was 3.4. Voriconazole 6 mg/kg twice-daily loading dose and 4 mg/kg twice-daily iv was initiated as well as caspofungin 70 mg loading dose and 50 mg iv once daily. After 22 days, progressive neurological deterioration with concomitant progress of cerebral aspergillosis developed, and liposomal amphotericin B 3 mg/kg iv once daily and conventional amphotericin B 20 µg a day administered via the left and right EVDs were added. Repeat imaging showed further progression of cerebral aspergillosis. Posaconazole 800 mg orally four times a day was added without success, and antifungal treatment was discontinued 15 days later. The patient died within 10 days. The patient took omeprazole 5 mg orally twice daily during the period of posaconazole administration. We present three patients whose posaconazole concentrations were measured in serum or plasma and CSF or cerebral abscess fluid, respectively. Of note, no tendency towards a fixed plasma/CNS ratio could be observed. Although posaconazole was undetectable in the CSF of Patient A, concentrations in the CNS abscess fluid of Patient B equalled 41% to 47% of his serum levels. The inverse was true for Patient C, whose posaconazole CSF/serum ratio was 2.3 (Table 1). Due to the lack of information on the pharmacokinetic and pharmacodynamic properties of posaconazole in the CNS, we hypothesize on the factors that led to this variation in drug levels. In Patient A, posaconazole measurements in serum 5 days prior to the onset of symptoms were only 88 µg/L in serum and not measurable in CSF. The low serum levels can be explained by the combination of severe diarrhoea and PPI intake, both factors being associated with decreased intestinal posaconazole resorption.4 Furthermore, significant cerebral inflammatory activity with a concomitant increase in permeability of the blood–brain barrier cannot be expected at the time point when the sample was taken, accounting for the absence of posaconazole in CSF. Lumbar puncture might have served to corroborate this hypothesis, but was not carried out in this patient. In contrast, Patients B and C presented with cerebral abscesses and bilateral ventriculitis plus abscess formation, respectively. Under these circumstances, inflammatory disturbance of the blood–brain barrier might have facilitated the penetration of posaconazole into the cerebral abscess fluid in Patient B and into the CSF in Patient C. Although lumbar puncture could not be performed in Patient B, CSF was repetitively analysed in Patient C. On the day of initiation of posaconazole administration, the albumin quotient (CSF albumin/serum albumin × 100) was 4.4, a value that is consistent with a severe disturbance of the blood–brain barrier. We hypothesize that disturbance of the blood–brain barrier may facilitate passage of posaconazole into the CSF, where it can be quantified by HPLC. Based on these data, posaconazole may be an option in the treatment of cerebral fungal infections, as has been formerly suggested by the promising results from a clinical trial by Pitisuttithum et al.5 All data presented in this article were obtained during clinical routine requiring no funding. O. A. C. is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN0706). M. K. has been a consultant for Pfizer, Eli Lilly and Roche. G. F. has been a consultant for Schering Plough, Pfizer and Gilead, has served on a speaker's bureau for Schering Plough, Pfizer and Gilead and has received grant support from Pfizer. A. J. U. has received grant support from the Schering Plough Research Institute, has been a consultant for Basilea, MSD, Pfizer, Schering Plough and Astellas and has served on a speaker's bureau for Astellas, MSD, Pfizer and Schering Plough. O. A. C. has received research grants from Astellas, Basilea, Bayer, Genzyme, Gilead, Pfizer, Merck, Optimer, Schering-Plough and Vicuron, is a consultant to Astellas, Basilea, F2G, Gilead, Pfizer, Merck, Mölnlycke, Nektar, Schering-Plough and Zeneus and has served on a speaker's bureau for Astellas, Gilead, Merck, Schering-Plough, SpePharm and United Medical. The remaining authors have no conflicts of interest to declare.