Triazole antifungals used for prophylaxis and treatment of invasive fungal disease in adult haematology patients: Trough serum concentrations in relation to outcome

Abstract

Triazole antifungal drugs are widely used for the prophylaxis and treatment of invasive fungal disease (IFD). Efficacy may depend on attaining minimum effective plasma concentrations. The aim of this study was to ascertain the proportion of samples in which the recommended concentrations were achieved in patients given these drugs in relation to outcome. In-patients prescribed standard doses of fluconazole, itraconazole solution, posaconazole suspension, or oral voriconazole for at least one week were studied. Pre-dose serum triazole concentrations were measured using validated methods. There were 359 samples from 90 patients. The median (range) number of samples per patient was 3 (1-13), and the median (range) fluconazole, itraconazole, posaconazole (prophylaxis), posaconazole (treatment), and voriconazole serum concentrations were 5.64 (0.11-18), 0.57 (0-5.3), 0.31 (0.02-2.5), 0.65 (0.02-2.5), and 0.95 (0.10-5.4) mg/l, respectively. The number of samples in which the recommended pre-dose concentrations were achieved was 98 (54%), 9 (20%), 2 (18%), and 29 (49%) for itraconazole, posaconazole (>0.7 mg/l prophylaxis), posaconazole (treatment), and voriconazole, respectively. No significant differences were detected in the median triazole trough concentrations between patients with proven/probable IFD compared to those with no evidence of IFD. However, itraconazole was not detected in 10 samples (7 patients). The small number of patients who achieved the recommended trough posaconazole concentrations may explain the high rate of break-through IFD observed in patients prescribed this drug. Except for fluconazole, the number of patients prescribed standard doses of triazoles who achieved recommended trough triazole concentrations was low. The prospective use of serum triazole measurements assay may have improved outcomes with itraconazole, posaconazole, and with voriconazole.

Diagnosis of invasive fungal diseases in haematology and oncology: 2018 update of the recommendations of the infectious diseases working party of the German society for hematology and medical oncology (AGIHO)

“…When CT of the lungs is non‐conclusive for IFD and biomarkers in blood and/or BAL are negative, mould active prophylaxis may be continued without starting targeted antifungal therapy with a different antifungal agent. Therapeutic drug monitoring is recommended for azoles such as itraconazole, posaconazole or voriconazole to exclude insufficient serum levels of the particular drug . Breakthrough IFD may occur under mould‐active prophylaxis caused by azole‐resistant fungal pathogens .…”

Treatment of invasive fungal diseases in cancer patients—Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

“…These breakthrough IFDs may either due to resistant fungal pathogens (eg Mucor spp.) and/ or low through serum concentration of the triazole 103,110 . A definition for breakthrough IFD has been recently proposed by the Mycoses Study Group Education and Research Consortium (MSG) and the European Confederation of Medical Mycology (ECMM) 111 .…”

Therapeutic Drug Monitoring of Antifungal Drugs: Another Tool to Improve Patient Outcome?

“…Our analysis also showed a positive correlation between serum albumin concentrations and fluconazole and echinocandin exposures. Nguyen et al [16][17][18][19][20][21][22][23][24][25][26] reported that low serum albumin concentrations in the surgical ICU patients were correlated with low caspofungin exposures. We believe that patients with hypoalbuminemia should be considered a ''high-risk group'' of low antifungal serum exposure who could especially benefit from systematic monitorization of the antifungal concentration.…”

“…Nevertheless, systematic therapeutic drug monitoring (TDM) of antifungals is not considered routinely necessary [6], mainly because of the belief that an adequate antifungal serum concentration is usually achieved by prescribing fixed doses according to international guidelines [11]. Unfortunately, evidence supporting this assumption is scarce and mainly related to specific groups of patients [12][13][14][15] or antifungal class [16][17][18][19][20][21][22][23][24][25][26].…”