Abstract
BackgroundPiperacillin levels after standard dosing have been shown frequently to be subtherapeutic, especially when renal clearance was augmented. Here, we aimed to determine if piperacillin was in its therapeutic range in a typically heterogeneous intensive care unit patient group, and also to describe target attainment dependent on daily dosage, creatinine clearance, and renal replacement therapy (RRT).MethodsSixty patients with severe infections were included in this monocentric prospective observational study. Patients received 4.5 g of piperacillin-tazobactam two to three times daily by intermittent infusion depending on renal function according to clinical guidelines. Over 4 days, multiple serum samples (median per patient, 29; in total, 1627) were obtained to determine total piperacillin concentrations using ultra-high-performance liquid chromatography/tandem mass spectrometry.ResultsA high heterogeneity of patient characteristics was observed (e.g., on day 1: creatinine clearance 2–233 mL/min and ten patients on RRT). Piperacillin trough levels showed inter-individual variation from 123 to >1785-fold on different study days. Each day, approximately 50 % and 60 % of the patients had piperacillin levels below the target ranges 1 and 2, respectively [defined for the calculated unbound piperacillin fraction according to the literature as 100 % time above MIC (100 %fT > MIC) (target range 1) and ≥ 50 %fT > 4 × MIC (target range 2); MIC = 16 mg/L]. Whereas only the minority of patients who received piperacillin-tazobactam three times daily (TID) reached target 1 (38 % on day 1), most patients who received piperacillin-tazobactam only twice daily (BID) because of severely impaired renal function reached this target (100 % on day 1). Patients with RRT had significant higher percentages of fT > MIC. Zero percent, 55 % and 100 % of patients without RRT who received antibiotics TID reached target 1 when creatinine clearance was > 65 mL/min, 30–65 mL/min and < 30 mL/min, respectively. In patients with causative strains only sensitive to piperacillin-tazobactam of all antibiotics given to the patient, piperacillin levels negatively correlated with CRP concentrations of day 4 (p < 0.05).ConclusionsA dosage of 4.5 g piperacillin-tazobactam TID seems to be frequently insufficient in critically ill patients, and also in patients where renal function is mildly to moderately impaired. For these patients, prescription of 4.5 g piperacillin-tazobactam four times daily could be considered.Trial registrationClinicaltrials.gov NCT01793012. Registered 24 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1255-z) contains supplementary material, which is available to authorized users.
Highlights
Piperacillin levels after standard dosing have been shown frequently to be subtherapeutic, especially when renal clearance was augmented
The strong association between creatinine clearance and piperacillin levels has already been described in several studies of critically ill patients, this work is novel in contemporary literature, given the number of blood-sampling time points, the Patient groups, number of patientsa
Our data emphasize that the conventional dosing of 4.5 g PIP-TAZ times daily (TID) may often lead to insufficient blood levels in critically ill patients, and in patients with slightly or moderately impaired renal function
Summary
Piperacillin levels after standard dosing have been shown frequently to be subtherapeutic, especially when renal clearance was augmented. Most studies have evaluated only limited numbers of patients or defined patient subgroups, resulting in inconclusive information regarding just how substantial the inter-individual variation of PIP concentrations is in a typical heterogeneous ICU patient group. There is only one report concerning PIP concentrations over an entire 7-day antibiotic course in critically ill patients [6]; the 11 patients included in that study exhibited coefficient of variations (CV) of 20–60 % for within-patient variability (for trough levels). Because this variability was evaluated only in patients with normal renal function, it remains unclear if this result reflects the typical intra-individual variability within ICU patients
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