Relationship of blood level and susceptibility in voriconazole treatment of histoplasmosis.

Monitoring of voriconazole serum levels has been advocated by Smith et al. as a method of ensuring adequate drug exposure in treating invasive mycoses (9). Voriconazole blood levels may vary considerably between subjects as a consequence of genetic polymorphisms that dictate variable clearance and nonlinear elimination (4, 5, 7, 8, 10). Among patients taking 200 mg twice a day, trough voriconazole concentrations range from below 0.100 g/ml to nearly 10 g/ml in several studies (2, 4, 5, 6). Although clinical trial data are lacking, voriconazole is occasionally used to treat Histoplasma capsulatum infections. In this report, we determined blood levels in patients treated with voriconazole as a secondary therapy for histoplasmosis, usually because of intolerance of other antifungal therapies, mostly amphotericin B or itraconazole. Serum specimens from nine patients with disseminated histoplasmosis that had been submitted for antigen testing were later tested for serum levels of voriconazole (3). All nine patients were considered to have improved clinically during secondary oral voriconazole treatment at a dose of 200 mg twice daily. All patients had received voriconazole for at least 2 weeks before blood concentrations were determined, but the exact timing of the blood specimens obtained following the oral administration of voriconazole was not recorded. Specimens had been frozen for up to 4 years prior to the determination of serum drug levels. Our experience with a similar compound, itraconazole, showed no loss of activity after 4 years at 20°C. Furthermore, the levels observed in the patients in this study are consistent with levels obtained in realtime testing of fresh specimens. Isolates of H. capsulatum for this patient cohort were unavailable for voriconazole susceptibility testing; therefore, archived H. capsulatum isolates from AIDS patients who had either primary or relapsed histoplasmosis were employed for this testing by a modified CLSI (formerly NCCLS) method as described previously (1). A comparison of voriconazole susceptibilities (by MIC measurements) of these archived H. capsulatum isolates from patients with both primary and relapsed disease (Fig. 1) was made with the random voriconazole blood levels measured from the nine patients who were being treated with the drug for disseminated histoplasmosis (Fig. 1). Among 20 samples for the nine patients, voriconazole concentrations ranged from undetectable to 8.00 g/ml (Fig. 1). Voriconazole blood levels were highly variable and possibly inadequate in several of our patients, with two random blood levels clearly falling below the median MIC for primary (0.015 g/ml) and relapsed (0.030 g/ml) isolates. Three other levels fell below the lowest calibrator (0.125 g/ml) for serum voriconazole levels, and therefore we do not know if they were