PhD defence A. (Alan) Abdulla

Dissertation in short:

Antibiotics are among the most important and most commonly prescribed drugs in critically ill patients in the intensive care unit (ICU). Unfortunately, changes associated with critical illness can lead to variable antibiotic exposure. Traditional antibiotic dosages do not account for these changes and may result in suboptimal outcomes in ICU patients. Optimizing treatment is therefore of great importance in these patients, but at the same time challenging and requires an individualized approach. In this thesis advanced analytical methods to measure antibiotic concentrations are described, antibiotic pharmacokinetics and associated variability are characterized, the impact of patient covariates relevant to clinical practice is assessed, followed by investigating the added value of therapeutic drug monitoring (TDM) and model-based dosing strategies.

In the EXPAT study, we investigated whether standard doses of commonly used antibiotics are adequate for patients in the ICU wards of Erasmus MC and Maasstad Hospital. This study has shown that the exposure to beta-lactam antibiotics is too low in 40% of patients and even more than 70% in patients with ciprofloxacin. This can, for example, lead to treatment failure and the development of resistance to antibiotics. In addition, we found that male gender, increased renal clearance and a high body mass index (BMI) are important risk factors for low blood levels. Subsequently, we started the DOLPHIN study, a multi-center RCT investigating whether early model-based TDM of beta-lactam and fluoroquinolone antibiotics is superior to standard drug dosing on clinical outcomes in 8 ICU departments in Dutch hospitals. By using TDM and model-based dosing, under- and overdosing can be detected in time and thus contribute to an adequate antibiotic dosage. This study is unique as precision dosing studies in critically ill patients, focused on clinical outcomes and on this scale, are rarely conducted.