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One of the major global threats is antimicrobial resistance. To prevent the development of antimicrobial resistance it is important to use anti-infectives at the right dose, at the right time and for the right duration. Every anti-infective can cause certain toxicity that can occur when the drug exposure is too high or resistance can develop when exposure is too low, both of which can affect the treatment outcome. The goal of this thesis was to investigate optimisation of anti-infective therapy in immunocompromised patients, such as transplant recipients, patients with hematological malignancies and critically ill patients. To achieve this, we explored the opportunities to improve the design of future studies; we conducted studies on therapeutic drug monitoring (TDM, measurement of drug concentrations and adjusting the dose accordingly); and we utilised data from previous clinical studies to develop population mathematic (pharmacokinetic) models to better guide drug dosing to improve drug exposure, thereby aiming to improve treatment outcome. We showed underexposure of anti-infectives in certain patient groups and designed dosing regimens that could be utilised in the clinic and further studies. Clearly, we have only just started the journey to optimise anti-infective therapy in immunocompromised patients. To further optimise outcomes, the future challenge will be to move on to patient-level personalisation using specific targets for individuals and potentially exploring drug exposure at the site of the infection.

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty-seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1-7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8-2.7) for prophylaxis and 1.76 mg/L (IQR 1.3-2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1–2.9 mg/L, range 0.1–7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5–75 mg/L, range 0–457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.