Pulmonary penetration of piperacillin and tazobactam in critically ill patients

Abstract

Pulmonary infections in critically ill patients are common and are associated with high morbidity and mortality. Piperacillin-tazobactam is a frequently used therapy in critically ill patients with pulmonary infection. Antibiotic concentrations in the lung reflect target-site antibiotic concentrations in patients with pneumonia. The aim of this study was to assess the plasma and intrapulmonary pharmacokinetics (PK) of piperacillin-tazobactam in critically ill patients administered standard piperacillin-tazobactam regimens. A population PK model was developed to describe plasma and intrapulmonary piperacillin and tazobactam concentrations. The probability of piperacillin exposures reaching pharmacodynamic end points and the impact of pulmonary permeability on piperacillin and tazobactam pulmonary penetration was explored. The median piperacillin and tazobactam pulmonary penetration ratios were 49.3 and 121.2%, respectively. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated with pulmonary permeability. Current piperacillin-tazobactam regimens may be insufficient to treat pneumonia caused by piperacillin-tazobactam-susceptible organisms in some critically ill patients.

Figure 1

External validation of the piperacillin and tazobactam population model. The panels in the top row show total plasma drug concentrations, and the lower panels show ELF drug concentrations. Each panel shows the median drug concentration (solid black line), the interquartile range (shaded gray area), and the 5th and 95th percentiles (dotted black lines). Overlying data points represent observed data from Boselli et al. ²² ELF, epithelial lining fluid.

Figure 2

concentration–time profiles for piperacillin (left) and tazobactam (right). The top panel compares total drug concentration (dotted line), unbound drug concentration (solid black line), and ELF drug concentration (solid gray line). The middle panels show unbound plasma concentration, and the lower two panels show ELF concentrations with median drug concentration (solid black line), the interquartile range (shaded gray area), and the 5th and 95th percentiles (dotted black lines). ELF, epithelial lining fluid.

Figure 3

Relationship between unbound plasma and ELF drug concentrations for piperacillin (left) and tazobactam (right) for each of the observed trial patients (black dots) and for 5,000 simulated patients (small gray dots). AUC, area under the concentration–time curve; ELF, epithelial lining fluid.

Figure 4

Comparison of the piperacillin and tazobactam exposures in the plasma (left) and ELF (center), as well as the plasma: ELF ratio (right). The dotted lines illustrate the 8:1 ratio of piperacillin to tazobactam in the administered piperacillin 4.0 g/tazobactam 0.5 g preparation. AUC, area under the concentration–time curve; ELF, epithelial lining fluid.

Figure 5

Comparison of the plasma: ELF ratio for piperacillin (left) and tazobactam (right) exposure with pulmonary permeability. AUC, area under the concentration–time curve; ELF, epithelial lining fluid.

Figure 6

Results of the Monte Carlo simulation with the probability of target attainments, for unbound (solid line) and ELF (dashed line) piperacillin, against a range of MICs. The pharmacodynamic targets are the fraction of patients whose drug concentration was about the MIC for 50% (left panel) or 100% (middle panel) of the dosing interval and the fraction of patients whose trough piperacillin concentration to MIC ratio was ≥3.4. Histogram shows MIC distribution for organisms causing hospital‐acquired and ventilator‐associated pneumonia. ²⁶ ELF, epithelial lining fluid; MIC, minimum inhibitory concentration.