Background
Severe infections remain a major issue in the intensive care unit (ICU) because of their high prevalence and high mortality rates among critically ill patients [
1]. Hence, rational antibiotic therapy is especially important in this vulnerable population. Apart from an appropriate activity spectrum and early initiation of antibiotic therapy, a dosing regimen leading to adequate therapeutic antibiotic concentrations and exposure is crucial [
2‐
5]. Adequate antibiotic exposure not only has been found to improve clinical success but also has been suggested to reduce resistance development [
6,
7]. At the same time, pathophysiological changes in critically ill patients, including organ dysfunction or altered fluid balance, might substantially influence antibiotic concentrations and increase the risk of inadequate antibiotic exposure. As a second challenge, infections in these patients are often caused by pathogens with lower susceptibility (i.e., higher minimum inhibitory concentration [MIC]) than in other clinical settings [
8‐
11].
Meropenem is a broad-spectrum carbapenem β-lactam antibiotic frequently used to treat severe bacterial infections in critically ill patients, such as those with severe pneumonia, complicated intra-abdominal infections, complicated skin and soft tissue infections, or sepsis [
12]. For these indications, the approved standard dosing regimens for adults (intact renal function [RF]) include 500 mg or 1000 mg administered as short-term infusions every 8 h; for other indications, doses up to 2000 mg are recommended [
12]. Meropenem is a hydrophilic molecule with very low plasma protein binding of approximately 2% [
13]. It is excreted primarily via the kidney, predominantly by glomerular filtration but also by active tubular secretion [
14]. Meropenem has been shown to be readily dialysable and effectively removed by haemodialysis [
15‐
17]. As a β-lactam antibiotic, meropenem shows time-dependent activity; that is, its antibacterial activity is linked to the percentage of time that meropenem concentrations exceed the MIC value of a pathogen (%T
>MIC) [
18]. The attainment of the pharmacokinetic/pharmacodynamic (PK/PD) index %T
>MIC has been associated with clinical success in patients treated with meropenem [
19‐
21]. For example, Ariano et al. demonstrated that the probability of clinical response was 80% when %T
>MIC was 76–100 in febrile neutropenic patients with bacteraemia but only 36% when %T
>MIC was between 0 and 50 [
20].
Previous studies have revealed large inter-patient variability in meropenem concentrations after standard dosing in critically ill patients [
22‐
24], which resulted in inadequate meropenem exposure in a relevant fraction of patients [
23,
25]. However, in most of these studies, only limited numbers of patients and/or rather homogeneous patient sub-groups have been investigated. Hence, the identified variability in meropenem exposure might not have adequately reflected a typically heterogeneous critically ill population. In previous analyses, RF has been shown to be a major cause of variability in meropenem exposure [
23,
24,
26‐
31] and, as a consequence, to be influential on the attainment of specific target concentrations [
25,
32,
33]. However, the impact of kidney function on target attainment has been assessed primarily for distinct RF classes but not yet in a coherent quantitative framework for a population covering the full spectrum of RF ranging from dialysis/severe renal impairment (RI) to augmented renal clearance.
The aims of this study were (1) to quantify inter- and intra-individual variability of meropenem serum concentrations in a heterogeneous critically ill population covering the full spectrum of RF classes after meropenem standard dosing, (2) to investigate the attainment of two different PK/PD targets, (3) to assess the impact of RF on meropenem exposure and consequently target attainment and (4) ultimately to develop an easy-to-use risk assessment tool allowing identification and quantification of the risk of target non-attainment for a particular patient on the basis of the patient’s RF.
Discussion
We found a strong relationship between RF and meropenem exposure and consequently PK/PD target attainment, and we developed a graphical user tool to predict the risk of target non-attainment under meropenem standard dosing based on an ICU patient’s RF.
This work was focused on the analysis of the standard dosing regimen for meropenem (1000 mg administered as 30-minute infusions every 8 h) as the approved and still most frequently used dosing regimen in ICUs [
12,
45]. To best represent the variety of different ICU patients, the analysis was based on extensively sampled data of a prospective observational study including a large number of patients with highly heterogeneous patient-specific factors from different ICUs, though at one single study centre.
We showed large inter-individual variability in meropenem exposure, which was in accordance with previous studies [
22,
23]. The larger variability in concentrations of the late phase compared with the earlier phase of the concentration-time profile (variability: C
min, C
8h > C
4h) suggested that PK variability was due to variability in drug elimination processes rather than in drug distribution. This finding is supported by population PK analyses that identified larger inter-individual variability on the PK parameter clearance than on volume of distribution [
24,
28]. The relatively long observation period of 4 days and the large number of samples collected per patient in our study additionally enabled the quantification of intra-individual variability in meropenem exposure. Its large value led to the hypothesis that meropenem exposure is influenced by certain time-varying patient-specific factors such as confirmed in the present work by longitudinally measured CLCR
CG.
Our PK/PD analysis demonstrated that meropenem standard dosing did not achieve the desired meropenem PK/PD targets 100%T
>MIC and 50%T
>4×MIC in a considerable fraction of patients. For pathogens of MIC 2 mg/L, which represents the upper limit of the susceptible range for many important bacteria [
36], meropenem exposure was inadequate in every second dosing interval monitored. In line with our work, Carlier et al. found similar results for the target 100%T
>MIC given the same MIC value (target attainment 55%) [
25]. For infections with less susceptible bacteria of MIC 8 mg/L (I/R breakpoint [
36]), which have been shown to commonly occur in ICUs [
8,
9], target non-attainment was high, with four of five dosing intervals resulting in sub-therapeutic concentrations (target 100%T
>MIC). The target attainment analysis with the two targets 100%T
>MIC and 50%T
>4×MIC revealed similar results. Of note, current knowledge on PK/PD targets for meropenem in heterogeneous ICU populations is limited, and a PK/PD target for this special patient population has not been derived yet. In relation to other PK/PD targets derived for meropenem in diverse clinical studies (e.g., 19.2%T
>MIC and 47.9%T
>MIC [
21], 54%T
>MIC [
19] and 76-100%T
>MIC [
20]), the two PK/PD targets selected for our analysis were at the upper end (i.e., stricter). The selection of the higher targets seemed reasonable, given (1) limited knowledge on an adequate PK/PD target for heterogeneous ICU populations and (2) the high severity of illness (median APACHE II
first study day 27) and the high proportion of patients with transplants (~58%) in the evaluated population. Indeed, these targets have been reported to be commonly used in clinical practice for ICU patients [
40]. However, owing to the limited knowledge of PK/PD targets in ICU patients, there is a crucial need to explore which PK/PD target is best related to clinical outcome in critically ill patients in a prospective clinical trial. Further analyses should also be aimed at investigating differences in PK/PD targets between, for example, different patient sub-groups (e.g., with vs. without transplants), different states of severity of illness or different types of infecting bacteria (gram-positive vs. gram-negative) in a sufficiently large number of patients.
In line with other studies, we identified RF determined by CLCR
CG to influence meropenem exposure [
26,
27,
29‐
31]. On the basis of the large number of longitudinally measured meropenem serum concentrations and CLCR
CG values covering the full spectrum of RF classes, we were able to quantify a hyperbolic relationship between CLCR
CG and meropenem exposure. The present study also included special patient groups such as CRRT and ECMO patients. For CRRT patients, authors of other publications identified measured CLCR determined via 24-h urine collection [
28] or residual diuresis [
46] as influencing factors on meropenem exposure, both requiring time-consuming urine collection. Although our analysis included a rather small number of CRRT patients, it revealed CLCR
CG as a potential determinant of meropenem exposure which can be assessed more easily and quickly in clinical practice than RF markers determined via 24-h urine collection. This finding requires further investigation with a larger number of patients under a well-designed protocol. For the six ECMO patients, the relationship between CLCR
CG and meropenem concentrations did not seem different from that of the remaining patients, suggesting that ECMO therapy did not have a strong impact on meropenem serum exposure. This is in line with findings reported by Donadello et al. showing no significant difference between the PK parameters of ECMO and control non-ECMO ICU patients [
47].
The impact of RF on the target attainment was overall in accordance with the results of a recent publication by Isla et al. [
33], in which the probability of attaining the target 100%T
>MIC was analysed for three specific CLCR
CG values: Target attainment was 51% for CLCR
CG 35 ml/minute (vs. 51% in our study for CLCR
CG range 30–59 ml/minute), 3% for CLCR
CG 71 ml/minute (vs. 4.6%, 60–89 ml/minute) and 0% for CLCR
CG 100 ml/minute (vs. 3.5%, 90–129 ml/minute) for an MIC 8 mg/L. Because the present study included patients covering the full spectrum of RF classes, additional investigation of target attainment in extreme RF classes (severe RI, augmented RF) was possible. For infections with bacteria of MIC 2 mg/L, augmented RF to mild RI was identified as a risk factor of target non-attainment; given bacteria of MIC 8 mg/L, moderate RI was an additional risk factor. These findings imply the need for dosing intensification in patients identified to be at risk of target non-attainment, such as by increasing the dose or prolonged up to continuous infusion, which is currently under clinical investigation; whereas some previous studies have associated continuous infusion with improved clinical cure rates [
48,
49], others have not shown a difference in clinical outcome when comparing continuous with intermittent dosing [
50]. In this PK/PD analysis, the only patient group that reliably reached the PK/PD targets was the subgroup with severe RI. Notably, these patients also received 1000 mg meropenem every 8 h as 30-minute infusions and thus received higher doses than recommended in the summary of product characteristics (half of indicated dose every 12 h for patients with CLCR
CG 10–25 ml/minute [
12]).
To enable the practical application of the quantified relationship between RF and meropenem exposure and consequently target attainment, we developed a risk assessment tool in a commonly available and known software (
see Additional file
4: MeroRisk Calculator, beta version). This easy-to-use Excel tool allows assessment of the risk of target non-attainment for non-CRRT patients displaying RF within a broad range (25–255 ml/minute) and receiving standard dosing of meropenem (1000 mg every 8 h as 30-minute infusions). We implemented the risk of target non-attainment of meropenem depending on creatinine clearance according to the Cockcroft and Gault equation (CLCR
CG [
34]) and not depending on creatinine clearance determined by 24-h urine collection (CLCR
UC [
51]), because CLCR
CG can be assessed more easily in clinical practice, and the relationship between CLCR
UC and meropenem exposure was not better than between CLCR
CG and meropenem exposure (
see Additional file
2: Figure S3). To apply the tool, the user needs to provide only the CLCR
CG or its determinants (i.e., sex, age, total body weight and the routinely determined laboratory value serum creatinine). In addition, the MIC value of a bacterium determined or suspected in the investigated patient needs to be provided. Should MIC values not be available, the user has the option to select an MIC breakpoint for important pathogens from the EUCAST database. Because only a limited number of patients with augmented RF or severe RI were included in this analysis, the uncertainty of the CLCR
CG-meropenem exposure relationship implemented in the MeroRisk Calculator is higher for the extremes of the RF spectrum. Furthermore, the user of the tool needs to keep in mind that in addition to CLCR
CG, other factors might influence meropenem exposure. To visualise the prediction uncertainty (i.e., uncertainty in the CLCR
CG-meropenem exposure relationship combined with the variability in C
8h values) of the calculated meropenem C
8h value for a patients CLCR
CG, the prediction interval around the CLCR
CG-meropenem exposure relationship is additionally provided in the risk assessment tool. Of particular note, using the MeroRisk calculator does not require the measurement of a meropenem concentration of a patient. In case of available meropenem concentrations in a patient, use of therapeutic drug monitoring is encouraged to aid therapeutic decision making [
52]. The current beta version of the MeroRisk Calculator is intended to be used in the setting of clinical research and training. As a next step, comprehensive prospective validation of the risk calculator in clinical research setting is warranted.