Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia

Abstract

Background and objective: Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP).

Methods: Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [C_ss] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (C_ss/MIC = 1-4) and sub-optimal (C_ss/MIC < 1) and the magnitude of C-RP production inhibition over time.

Results: A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10).

Conclusion: Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Fig. 1

Representative continuous indirect response pharmacokinetic/pharmacodynamic model, based on a one-compartment pharmacokinetic model and meropenem effect described by inhibition of C-reactive protein (C-RP) production. CL meropenem clearance, C(t) meropenem concentration, k_in C-RP production rate, k_out C-RP degradation rate

Fig. 2

Flow chart of patient inclusion and exclusion criteria and of classification into treatment groups according to the presence and type of co-administered antimicrobial. HAP hospital-acquired pneumonia, PD pharmacodynamics, PK pharmacokinetics, VAP ventilator-associated pneumonia

Fig. 3

Diagnostic plots for the population pharmacokinetic (left panels) and pharmacodynamic (right panels) models. Shown are observed versus individual-predicted concentrations (A) and individual weighted residuals (IWRES) versus individual-predicted concentrations (C) for meropenem in plasma, and observed versus individual-predicted concentrations (B) and individual weighted residuals (IWRES) versus individual-predicted concentrations (D) for C-reactive protein (C-RP) in plasma. The dashed blue line represents the line of regression

Fig. 4

Visual predictive check (VPC) for the population pharmacokinetic (A) and pharmacodynamic (B) models. Blue lines represent the median, 10th and 90th percentiles of the observed values; shaded areas are the prediction intervals for the median (red central area) and 10th and 90th percentiles (light blue bottom and top areas). C-RP C-reactive protein

Fig. 5

Simulated median C-RP relative reductions from baseline according to different C_ss/MIC ratios in patients treated with meropenem monotherapy (A) and in those treated with meropenem plus an empirical anti-MRSA agent (B). C-RP C-reactive protein, C_ss steady-state meropenem concentration, MIC minimum inhibitory concentration, MRSA methicillin-resistant Staphylococcus aureus