Study design and patients
This prospective study was conducted at the Department of Respiratory and Intensive Care Unit, the Second Xiang-ya Hospital of Central South University, between January and December 2019. The Ethics Committee of our hospital approved the study (number 2019-005) that was registered as a China Clinical Trial (ChiCTR1900020672).
Patients treated with meropenem and admitted to the Department of Respiratory and Critical Care Medicine were eligible. Written informed consent was obtained from all participants. Inclusion criteria were as follows: (i) severe lung infection; (ii) clear indications for the use of meropenem; (iii) the time of continuous medication exceeded two days; (iv) at least one steady-state plasma concentration could be obtained; (v) age > 18 years, and (vi) gram-negative bacilli were isolated from specimen culture. Exclusion criteria were as follows: (i) pregnancy and lactation; (ii) allergy to carbapenems; (iii) concomitant uses of sodium valproate; (iv) isolation of gram-positive cocci, viruses, or fungi before enrollment; and (v) incomplete dosing information or clinical data.
Based on the standard recommendations for meropenem use, the conventional dosage regimen was 500 mg/8 h or 1000 mg/8 h, two times/8 h, and continuous infusion for 30 min, 1 h or 2 h. From the electronic medical record information system, we recorded demographic information, clinical data, and laboratory test results using a standardized data collection form on the day of serum sampling. The endogenous creatinine clearance rate was calculated using the Cockcroft-Gault formula[25, 26].
According to the MICs of bacteria to meropenem in our hospital, various meropenem MICs (1, 2, 4, and 8 mg/L) were evaluated using the following PK/PD targets: 40% fT MIC, 100% fT MIC, and 100% fT 4MIC [23, 24].
Sampling and assays
Meropenem serum concentrations were measured using automatic two-dimensional high-performance liquid chromatography (Demeter Instrument Co., Ltd., Hunan, China). The first-dimensional chromatographic column was an Aston SNCB (4.6 × 50 mm, 5 µm), and the second-dimensional chromatographic column was an Aston SBN (4.6 × 200 mm, 5 µm) [27, 28]. There was an excellent linear relationship between peak area and the concentration range of 0.78 to 58.52 μg/mL. The lower limit of detection and the lower limit of quantification were 0.04 μg/mL and 0.1 μg/mL, respectively. The intra-day precision, inter-day precision, and accuracy were 1.21%–2.58%, 0.83%–1.80%, and 100.51%–101.69%, respectively. The extraction recovery of the high, medium, and low concentrations were 99.47%, 97.77%, and 97.23%, respectively.
The PK model of meropenem in critically ill patients was developed using Phoenix NLME software (Version 8.1, Pharsight, A Certara Company, USA). Serum meropenem concentrations were fitted to a two-compartment model using the logarithmic additive residual. The first-order conditional estimation-extended least-squares method was used to estimate model parameters. The goodness of fit and visual predictive check (VPC) were used to evaluate the model. Objective function values (OFV) were used to compare the model fit. Covariates were retained in the model if the additional covariates were significant at a P-value of 0.01 (△OFV > 6.635). VPC was used to evaluate the goodness of fit [12, 29-32].
Probability of target attainment.
We use Monte Carlo simulations (n = 3,000) to determine the probability of target attainment (PTA) with different significant covariates. Meropenem doses of 500 mg, 1,000 mg, and 2,000 mg given intravenously every 8 h (q8h) with a duration of 0.5 h, 2 h, and 4h were simulated at different levels of selected covariates. The PTA was calculated after three days of therapy. The MIC at which PTA was equal to 90% was derived to enable a numeric comparison among the regimens [16, 18, 33]. MIC values were selected for the most common value of pathogenic bacterias such as Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii obtained from our hospital. PTA was calculated for single doses of 500 mg,1000 mg, and 2000 mg. The therapeutic target adopted the effect of 40% fT > MIC, 100% fT > MIC, and 100% fT > 4MIC [19, 23, 24].
Continuous variables are expressed as means (standard deviations [SD]) or medians (interquartile ranges) depending on the normality of distribution. Enumeration data were expressed as absolute numbers and relative frequencies. The Kolmogorov–Smirnov, and Shapiro–Wilk tests were used to test for normality. A two-sided P-value of < 0.05 was considered statistically significant. One-way analysis of variance was used to test the differences in selected significant covariate groups. All analyses were performed using IBM SPSS Statistics version 25 (IBM, New York, NY). Figures were generated using Phoenix NLME and Graphpad Prism version 8 (San Diego, CA, USA).