Meropenem pharmacokinetics and pharmacodynamics in patients with ventilator-associated pneumonia

Dear sir, Recently Thalhammer et al.1 compared the pharmacokinetics of continuous infusion with intermittent administration of meropenem. However, no data about the pharmacodynamic efficacy of meropenem were included. In a pilot study we have investigated the pharmacokinetics and pharmacodynamics of meropenem after intermittent administration. Eight male intensive care patients, diagnosed with ventilator-associated pneumonia (VAP), were included in this study: age 55 ± 8 years (mean ± s.d.), weight 73 ± 11 kg, creatinine clearence 85 (26) mL/min. A 1 g meropenem dose (7 min infusion in 20 mL NaCl 0.9%) was given every 8 h for 3–12 days. Plasma samples were taken daily just before administration (trough) and half an hour after administration (peak). On the second day, samples were taken just before and 5, 10, 15, 20, 25, 30, 40 min, 1, 2, 3, 4, 6 and 8 h after meropenem administration. Plasma concentrations were measured with a validated HPLC assay. Semi-quantitative cultures of tracheal aspirate were performed daily. The susceptibility of all isolates was tested by determining MICs of meropenem. Pharmacokinetic parameters were calculated by non-linear regression analysis using a weighted least-square simplex algorithm (MW/Pharm 3.15E; Mediware, Groningen, The Netherlands). The mean (± s.d.) pharmacokinetic and pharmacodynamic parameters were as follows: clearance (Cl), 11.0 ± 4.3 L/h; volume of distribution at steady state (VSS), 34.4 ± 15.9 L; volume of the central compartment (V1), 6.4 ± 2.9 L; half-life of the α, β and γ phase 0.049 ± 0.025, 0.374 ± 0.124 and 3.08 ± 1.7 h, respectively; area under the concentration–time curve at steady state (AUCSS0–8) 102.7 ± 42.9 mg/L•h; ratio of total AUC to MIC (AUCSS0–24/MIC), 154.1 ± 64.3 h; area under the inhibitory curve (AUICSS), 152.5 ± 66 h; time during which plasma concentrations remain above MIC (t > MIC), 90.8 ± 13.4%. For all patients a better ‘fit’ of the data was observed with a three-compartment than a two-compartment model; in five of the eight patients this better fit reached statistical significance (P < 0.05). A three-compartment model has not been reported in the literature. As could be expected with critically ill patients, Cl was lower and VSS higher than with healthy volunteers. Cl was equal and VSS even higher (34.4 L compared with 26.6 L) than found by Thalhammer et al. Mean peak and trough concentrations were 32.9 ± 11.3 mg/L, and 3.3 ± 3.5 mg/L, respectively (n = 8). For four of the five patients treated for 12 days, there was a decline of peak and trough plasma concentrations: 29.5/3.8 mg/L (day 2) and 25.8/0.7 mg/L (day 12). The following isolates were cultured as the causative agents of VAP: five isolates of Pseudomonas aeruginosa, two of Haemophilus influenzae and one of Escherichia coli. The MIC for all initial isolates was ≤2 mg/L. In subsequent isolates cultured during therapy, elevated MICs of meropenem were found in three of five patients with Pseudomonas VAP: the MIC was 4 mg/L in isolates from patient 2, 16 mg/L in isolates from patients 1 and 3. Pharmacodynamic data and peak/trough concentrations for these three patients are shown in the Table. An AUCSS/MIC of <100 is associated with development of antimicrobial resistance, while an AUIC of >125 and a t >MIC >70% are associated with effective killing.2–4 A gradual decline of plasma peak and trough concentrations during therapy was observed for two of the patients. Concentrations in one of these patients were rather high and never fell below the MIC. We were unable to find a clear association between development of bacterial resistance to meropenem and pharmacokinetic and pharmacodynamic parameters. However, for time-dependent antibiotics a target concentration of 4 × MIC has been proposed.5 Our patients performed less well in this respect: the concentration was ≥4 × MIC for 52 ± 22% of the time. With a continuous infusion (4 g/24 h), as proposed by Thalhammer et al.,1 an adequate mean steady state concentration of 11.5 mg/L and a concentration maintained at ≥4 × MIC could have been obtained for our patients.1 Further studies are needed to prove the efficacy of the latter dosage regimen. Pharmacodynamic parameters and peak/trough levels of patients infected with P. aeruginosa showing increased resistance to meropenem Pharmacodynamic parameters and peak/trough levels of patients infected with P. aeruginosa showing increased resistance to meropenem