Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.

Measuring antibiotics in exhaled air in critically ill, non-ventilated patients: A feasibility and proof of concept study.

PURPOSE: Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative. MATERIALS AND METHODS: We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath® device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma. RESULTS: Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg/filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate. CONCLUSIONS: Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs.

Stability of generic brands of meropenem reconstituted in isotonic saline.

BACKGROUND: Meropenem is a relatively unstable compound when dissolved. Currently, all available data have been derived from tests on the original product from Astrazeneca, and it is unsure if these data can be extrapolated to the stability of other commercially available vials. The aim of this study was therefore to assess the stability of four different brands of meropenem to be used as a prolonged or continuous infusion. METHODS: Commercially available meropenem vials were reconstituted and mixed with 0.9% sodium chloride to produce solutions with concentrations of 10.20 and 40 mg/mL in polypropylene syringes, which were kept at 25 °C. Samples were taken immediately after preparation and up to 12 hours. Solutions retaining >90% of the initial concentration were considered stable. RESULTS: The stability was concentration-dependent. At 25 °C, all 10 and 20 mg/mL solutions were stable for 12 hours in 0.9% sodium chloride, while the 40 mg/mL solutions were stable for a maximum of 8 hours. Stability of the different vials of meropenem was comparable for the time period tested (related samples Friedman's two way of analysis of variance by ranks, P=0.282). CONCLUSION: All tested commercially available vials of meropenem in a concentration of 10 and 20 mg/mL were stable for 12 hours at 25 °C when diluted in 0.9% sodium chloride. The 40 mg/mL solutions were stable for a maximum of 8 hours. This report is the first to show equivalent stability between different commercially available vials of meropenem.

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study.

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial.

PURPOSE: There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. METHODS: This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100% fT>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100% fT>4MIC and 100 % fT>MIC at 72 h. RESULTS: Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100% fT>4MIC was achieved in 21% of the PTZ patients and in none of the MEM patients; 100% fT>MIC was achieved in 71% of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100% fT>4MIC and 100% fT>MIC were higher in the intervention group: 58 vs. 16%, p = 0.007 and 95 vs. 68%, p = 0.045, respectively. CONCLUSIONS: Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Interpretation of hemolysis tests following administration of a second-generation hemoglobin-based oxygen carrier.

Hemoglobin released into the circulation during hemolysis or therapy with chemically modified hemoglobins, exert oxidative and NO-scavenging toxic effects. Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) is one of the second-generation hemoglobin-based oxygen carriers (HBOCs). We wanted to investigate the metabolism of PHP with a special focus on its consequences for interpreting hemolysis-related diagnostic parameters in PHP-treated patients. Clinical samples were analyzed from 3 patients, who received PHP (as part of the PHOENIX phase III trial) for treatment of catecholamine-resistant distributive shock. In contrast to expectations, clearance of PHP by hemopexin, instead of haptoglobin was documented by increased hemolysis indices, absence of decreased haptoglobin values, presence of free PHP-hemoglobin and exhausted hemopexin concentrations. The present case report is important for both clinicians and laboratorians since it nicely illustrates that a hemolytic aspect of plasma is not necessarely synonymous with hemolysis. A hemolytic aspect of plasma or serum (high hemolysis index) in combination with normal or increased haptoglobin values should draw the attention; additional determination of lactate dehydrogenase and hemopexin may then be useful to distinguish the condition from in vitro hemolysis and to monitor the in vivo elimination of the heme compounds.

Detection of single cells of Cryptococcus neoformans in clinical samples by solid-phase cytometry.

A method based on solid-phase cytometry for the detection and enumeration of single cells of Cryptococcus neoformans in serum and cerebrospinal fluid is described. Both viable and nonviable cells are detected by using fluorescence viability labeling and immunofluorescence. This 30-min procedure has a detection limit of 3 to 6 cells per ml.