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ANTIBACTERIAL DOSING IN SPECIAL PATIENT POPULATIONS WITH SEVERE BACTERIAL INFECTIONS: A PATIENT-ORIENTED AND COVARIATE-DRIVEN APPROACH

Boek - Dissertatie

Early and appropriate antibiotic therapy are crucial determinants for successful treatment of severe bacterial infections. Suboptimal antibiotic exposure has been shown to lead to worse clinical outcome (e.g., prolonged antibiotic course, prolonged length of stay, increased mortality). Hence, antibiotic exposure should be high enough to maximize the likelihood of clinical success, but not too high to avoid unnecessary toxicity. Beta-lactams are the most commonly used antibiotics in patients with severe bacterial infections. Conventional dosing regimens of several beta-lactams have been shown to lead to suboptimal exposure in a significant proportion of selected patient populations. Although mostly studied in critically ill patients, suboptimal exposure has also been demonstrated in other patient populations such as obese patients and patients with febrile neutropenia (FN). Personalised dosing strategies are increasingly being suggested and investigated to overcome suboptimal exposure to beta-lactams. Nevertheless, it remains unclear how personalised dosing should be applied, and if such strategies eventually lead to better clinical outcome. Therefore, the general objective of this PhD thesis was to take the step towards the implementation of personalised dosing strategies for beta-lactams in patients with severe bacterial infections. The studies reported in this PhD thesis were organized in three parts, each covering several studies. In the first part of this PhD thesis, we investigated patient-related characteristics (i.e., covariates) to determine their potential as a predictor of (beta-lactam) antibiotic exposure. First, in a large multicenter retrospective registry-based study, we developed a publicly available online tool to predict the probability of augmented renal clearance (ARC) on the next day in the intensive care unit (ICU). ARC is known to be a major predictor of increased beta-lactam clearance, and thus of decreased exposure. The abovementioned tool allows a simple and reliable bedside estimation to anticipate the presence of ARC on the next day, and could thus be used to guide upfront antibiotic dosing in critically ill patients. Moreover, we provided a cut-off for ARC when no measured urinary creatinine clearance, which is the pragmatic standard to monitor renal function in critically ill patients, is available. We also investigated the predictive performance of bioelectrical impedance analysis (BIA) to quantify the volume of distribution (Vd) of hydrophilic antibiotics. BIA, albeit promising, did not seem useful to predict the Vd. The second part of this PhD thesis consisted of three prospective observational pharmacokinetic (PK) studies. The first two studies were performed in 31 and 69 critically ill patients receiving ceftriaxone or meropenem, respectively. Both studies demonstrated suboptimal PK/pharmacodynamic target (PK/PD) attainment. Based on population PK (popPK) analysis and dosing simulations, optimized dosing strategies were suggested. These strategies will subsequently be investigated in randomised controlled trials (RCTs). Such high-quality studies are urgently needed to address the question if optimized PK/PD target attainment leads to better clinical outcome. For ceftriaxone, such an RCT (i.e., the STRADA-CEF trial) has been designed and a research consortium has been gathered. For meropenem, dose optimization is probably more complex than for ceftriaxone. Considering the variability in predictive performance of previously developed popPK models, we will first assess two new popPK methods, meta-modelling and automated model averaging, for which we will gather different popPK models of meropenem to derive a valid and generalizable dose optimization strategy for critically ill patients. In both of the abovementioned prospective PK studies performed in the ICU, a subset of patients supported by extracorporeal membrane oxygenation (ECMO) was included to investigate the impact of ECMO on beta-lactam PK. In a matched cohort study including popPK analysis, ECMO had no significant impact on meropenem PK. For ceftriaxone, we reported unbound PK during ECMO for the first time. Although only two patients were included, the descriptive analysis suggests no major differences in PK when compared to non-ECMO critically ill patients. As a result, beta-lactam PK does not seem to be substantially altered by ECMO, but rather by critical illness itself. In the third prospective PK study, we tried to define a therapeutic-toxic range for cefepime from TDM results collected during 96 treatment courses in hematological cancer patients with FN. Therefore we assessed the relation between free cefepime trough concentrations and breakthrough infections or neurotoxicity probably induced by cefepime. The included patients were relatively young and showed preserved renal function. We did not observe any breakthrough infections, and neurotoxicity probably induced by cefepime was observed in 6% of the treatment courses. Hence, although TDM is frequently advocated for cefepime, it might not be routinely needed for all FN patients with preserved renal function. In the third part of this PhD thesis, we investigated a couple of practical and methodological issues relevant to PK studies in general. Issues encountered during our own PK studies were the incentive for these studies. In the first study, we showed that correct and standardized sampling are crucial to avoid carryover from the catheter or dilution errors when performing cefepime TDM via the central venous catheter. In the second study, we reported the detailed degradation profile of meropenem at -20°C. Additionally, we raised awareness about sample storage conditions. This is an issue that has been frequently overlooked by authors and reviewers. Nevertheless, not taking meropenem degradation at -20°C into account can have a significant impact on clinical conclusions, as illustrated in the discussion of this study. In conclusion, with the studies performed in this PhD thesis, we took an important step towards the implementation of personalised dosing of beta-lactams. The research findings in this PhD thesis constitute the foundations for subsequent RCTs to investigate the clinical benefit of dose optimization strategies. For ceftriaxone, we have already designed such an RCT, the STRADA-CEF trial which will start upon successful funding application. Interestingly, in the STRADA-CEF trial, we provided a pragmatic alternative to TDM-guided personalised dosing. The simple dose stratification strategy suggested for ceftriaxone increases the odds of successful implementation of this personalised dosing strategy as opposed to more complex TDM-based strategies. This RCT might serve as a proof of concept for subsequent studies investigating beta-lactam dose optimization strategies.
Jaar van publicatie:2021
Toegankelijkheid:Closed