Introduction: The current efforts of intensivists focused on individual antibiotic treatment in patients suffering from sepsis has inspired us to conduct an open prospective clinical study to assess the relationship between body fluid retention (>10 L/24 hours) and the efficiency of hydrophilic time-dependent antibiotics used in critically ill patients. Polytrauma and abdominal catastrophes are the most frequent causes of systemic inflammatory response syndrome (SIRS). Consequent body liquid retention is taken for a pathophysiological covariate modifying the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrophilic time-dependent antibiotics (betalactams and carbapenems). Not only body fluid retention but also changes in renal clearance are thought to be responsible for failure in PK/PD target attainment necessary for effective antimicrobial activity. To describe the importance of the pathophysiological covariates for the individual kinetic variables of a representative antibiotic (piperacillin) is the primary goal of this kinetic observational study.
Material and methods: Three patients with polytrauma and SIRS admitted at the ICU of the Surgical Department, Teaching Hospital Hradec Králové, whose condition was characterized by cumulative body fluid retention (>10 L), were eligible for enrolment. As per standard hospital protocol, the patients were administered with 4 g of piperacillin in combination with tazobactam 0.5 g intravenously by 1-hour (h) infusion every 8 h. A series of blood samples were taken 1, 2.5, and 5 h after the termination of the infusion. Urine was collected over each dosing interval and for 24 h. Piperacillin was detected using a previously validated HPLC method. Individual pharmacokinetic variables were estimated using non-compartmental pharmacokinetic analysis. Cumulative body fluid retention was calculated as the difference between fluid intake and output. Creatinine clearance (Cl) was used for renal function evaluation. PK/PD target attainment was analysed according to Carlier (2013).
Results: In three patients with polytrauma and SIRS, great interindividual and intraindividual differences in extravascular volume expansion, i.e. cumulative body fluid retention 2030 L and changes in renal function, were recorded. In 2/3 patients these pathophysiological changes as well as the clinical interventions administered resulted in augmented piperacillin clearance and an increase in distribution volume (Vd) (>20 L) with a maximum at Day 28 after initiation of therapy. In such patients treated with a standard dose of piperacillin, only minimum PK/PD target attainment (50% Ft >MIC) was obtained. In contrast, a patient suffering from renal dysfunction attained both minimum (50% ft >MIC) and maximum PK/PD target (100% ft >MIC).
Conclusions: In three critically ill patients with polytrauma and SIRS, pathophysiological changes (covariates) had a profound effect on the key determinants of the pharmacokinetics (Cl and Vd), resulting in significant intraindividual variability in pharmacodynamic /pharmacokinetic target attainment necessary for therapeutic time-dependent antibacterial activity of piperacillin. Consequently, patients with augmented clearance of piperacillin may be at risk for treatment failure, and/or bacterial resistance without dose up-titration. A subsequent clinical study will be conducted to describe personalised kinetically guided antibiotic therapy.