Although delivery of prompt and appropriate antimicrobial therapy is of paramount importance for critically ill patients, few data exist to guide what doses of antimicrobials should be used in critically ill patients. Presently available generic guidelines are derived from healthy young adults and are unlikely to be appropriate for critically ill patients due to the major physiological changes that occur. Altered physiology can result in significant changes in antimicrobial pharmacokinetics and greatly affect dosing requirements. There is limited guidance to determine therapeutic antimicrobial doses due to only limited pharmacokinetic data being available in these patients. Additionally, there will be great variance between patients because of differences in co-morbidities, the invasiveness of procedures and the disease status. Thus, it is very unlikely that a dose found to be effective in non-critically ill patients will be optimal for the majority of critically ill patients. Since available data do not appear to suitably guide dosing in these patient subpopulations, directed pharmacokinetic studies should be considered fundamental. Therefore, the principal aims of this thesis were to evaluate the appropriateness of standard doses in achieving pharmacokinetic/pharmacodynamic targets and clinical scenarios affecting this target in critically ill patients.
Dynamic renal function is commonly seen in critically ill patients. For drugs cleared through the renal route; while decreasing renal function trigger reduced dosing, elevated renal function or augmented renal clearance should also trigger dosing increases. This is to avoid sub-therapeutic concentrations. However, due to scarce data available, this phenomenon has not been clearly described. This led to a study in this thesis, conducted in Malaysian intensive care units to describe this clinical scenario. It was found that almost half of the subjects recruited have augmented renal clearance. Significant bias and imprecision was demonstrated when comparing estimated Cockcroft-Gault creatinine clearance and measured urinary creatinine clearance with the bias being larger in augmented renal clearance patients and significant difference were found between this two methods. This study supports previous data that equation-based estimates of creatinine clearance are unreliable for use in critically ill patients.