Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients

doi:10.1016/S0924-8579(01)00474-5

International Journal of Antimicrobial Agents

Volume 19, Issue 2, February 2002, Pages 105-110

https://doi.org/10.1016/S0924-8579(01)00474-5 Get rights and content

Abstract

The pharmacokinetics and pharmacodynamics of meropenem were investigated in 14 critically ill patients with sepsis. Patients with creatinine clearance (CrCl) higher than 50 ml/min received 1 g meropenem three times daily (Group I) and patients with CrCl lower than 50 ml/min received 1 g meropenem twice daily (Group II). Meropenum concentrations in plasma were determined by high performance liquid chromatography with UV detection. The pharmacokinetic parameters differed between the two groups as follows, Group I, maximal concentration 56.3±19.1 μg/ml; trough concentration 3.3±2.5 μg/ml; elimination half life 2.5±1.2 h; clearance (Cl) 155.8±40.6 ml/min; MRT 2.2±0.4 h; steady state volume of distribution (V_ss) 21.7±5.7 l, and AUC_0–8 119.4±32.6 μg/ml h. Group II, maximal concentration 71.1±5.1 μg/ml; trough concentration 3.4±1.8 μg/ml; elimination half life 3.9±1.6 h; Cl 77.7±15.8 ml/min; MRT 3.5±0.6 h; V_ss, 17.1±2.1 l, and AUC_0–12 230.2±43.3 μg/ml h. The most frequently isolated bacteria from blood and wound infections were Acinetobacter baumanii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; their meropenem minimal inhibitory concentrations (MICs) ranged from 0.064 to 3.0 mg/l. In most cases the pharmacodynamic parameters, measured as T>MIC index, were higher than 75%. In both groups, patients with susceptible pathogens (MIC<1 mg/l) had meropenem plasma levels which exceeded the MIC for the whole dosing interval. When pathogens were highly resistant (A. baumanii or P. aeruginosa) the T>MIC indices were lower.

Introduction

Meropenem is a carbapenem antibiotic characterized by a broad antibacterial spectrum. There are several studies describing the pharmacokinetics of meropenem in patients with severe infections [1], [2], [3], [4], [5], [6], [7], [8], [9] including cystic fibrosis [10] and respiratory tract infections [11]. Since meropenem is partly excreted via the renal route, the elimination of this drug was studied in patients with various degrees of renal failure [12], [13], [14], [15], [16], [17], [18], [19].

The aim of the study was to determine the pharmacokinetics and pharmacodynamics of meropenem in severely ill patients with septicaemia and to determine if the recommended administered dose resulted in plasma concentrations of meropenem higher than the minimal inhibitory concentration (MIC) of the bacterial isolates. The therapeutic efficacy of the dose regimen was also noted.

Section snippets

Subjects

Fourteen patients hospitalized in intensive care unit (ICU) with severe sepsis, defined according to Bone [20], were included in the study. The demographic data are presented in Table 1.

All patients had blood or other cultures growing bacteria sensitive to meropenem. Patients were divided into two groups according to their creatinine clearance (CrCl). Patients with CrCl higher then 50 ml/min (Group I) received 1 g meropenem every 8 h (3 g daily) and patients with CrCl lower than 50 ml/min

Results

The mean plasma concentration time profiles obtained for the two groups of patients are shown in Fig. 1. The C_max was measured at the end of the IV infusion i.e. 30 min after the beginning of administration. The mean C_max values were 56.3±19.1 and 71.1±5.1 μg/ml for patients receiving 1 g meropenem three or two times daily, with respective C_min of 3.3±2.5 and 3.4±1.8 μg/ml.

Individual and mean pharmacokinetic parameters are shown in Table 2. Patients in Group I showed mean elimination half life

Discussion

Severe infections accompanied by different degrees of renal failure are often seen in critically ill patients in ICU. These patients may be ventilated and develop infections with resistant strains of A. baumanii, P. aeruginosa and K. pneumoniae. Meropenem has been suggested as the drug of choice for these patients, but the recommended daily dosage regimen which promotes maximal bactericidal activity against resistant bacteria, still has to be confirmed.

In this study, meropenem was administered

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Citation Excerpt :
The quality of most studies was fair (15/27) (Table 2). Best evidence on dose reduction of antibiotics in patients with impaired renal function was available for meropenem [19–22]. Other frequently investigated antibiotics were imipenem/cilastatin, cefepime, ceftolozane/tazobactam, ciprofloxacin and teicoplanin; however, only one good-quality study per antibiotic was identified [19–37].
There is inconsistency between many guidelines in the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function.
This systematic review summarizes the available evidence on the adequacy of the recommended dose reduction in terms of achieving sufficient antibiotic drug exposure or pharmacokinetic/pharmacodynamic target attainment after treatment with these reduced doses.
We systematically searched Ovid Medline and Embase from inception (respectively 1946 and 1947) through July 2019.
All studies reporting antibiotic drug exposure and/or pharmacokinetic/pharmacodynamic (PK/PD) target attainment after dose reduction of antibiotics in patients with impaired renal function.
Adult patients with or without infections.
Administration of reduced doses of antibiotics (orally, intravenously or intramuscularly).
The reduced dose was considered adequate when the most relevant parameters of drug exposure or PK/PD target attainment in patients with impaired renal function were within a range of 80% to 125% of that patients with adequate renal function receiving a regular dose (reference) or when PK/PD target attainment was attained in at least 90% of the patients with impaired renal function, regardless of the lack of a reference group.
Twenty-seven of the 4202 identified studies were included. The quality of 15 of 27 studies was fair, and most studies were of β-lactams (12/27). Best evidence was available for meropenem: four studies were included, of which two studies were of good quality. Drug exposure for meropenem is 158% to 286% higher in patients with impaired renal function receiving reduced doses compared to patients with adequate renal function receiving regular doses. For all other antibiotics, a maximum of one good-quality study could be identified.
No good-quality evidence on the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function is present, with the exception of meropenem.
Pharmacokinetics of meropenem in burn patients with infections caused by Gram-negative bacteria: Are we getting close to the right treatment?
2020, Journal of Global Antimicrobial Resistance
Citation Excerpt :
Of note, for TBSA ≥ 50%, only two patients had a Cmin ≥ 3.3 mg/L and only one patient had a Cmax > 28.4 mg/L, suggesting that the percentage TBSA might strongly affect the Vd and other physiological parameters, although in the current study no statistically significant correlation was found, possibly due to the small number of patients enrolled. Despite the 2-h i.v. infusion, patients in this study had lower AUC0–24 compared with data from the literature, and only nine patients (53%) achieved the target of >226 mg h/L [3,6,9–14]. Moreover, an AUC/MIC of 125 was achieved in all patients except one when the MIC was 0.5 mg/L or 1 mg/L, whereas the proportion of patients reaching this PK/PD target decreased progressively at higher MICs.
Infections caused by multidrug-resistant Gram-negative bacteria are associated with high mortality. A relevant concern is the efficacy of antibiotic therapy in burn patients in whom pathophysiological changes strongly influence pharmacokinetic (PK) parameters. This study aimed to describe the PK parameters of meropenem in a population of burn patients.
Blood samples were collected immediately before and 2 h and 5 h after the start of intravenous drug administration. Plasma meropenem concentrations were determined using an ultra-performance liquid chromatography–photodiode array method.
Seventeen burn patients were enrolled in the study. Thirteen patients (76%) were treated with meropenem for infections byPseudomonas aeruginosa or Acinetobacter baumannii isolated from blood or wounds. Mean C_max, C_min, AUC_0–24, half-life, drug clearance and volume of distribution were 28.9 mg/L, 3.7 mg/L, 280.2 mg h/L, 2.0 h, 19.0 L/h and 44.4 L, respectively. Six patients (35%) achieved a C_min ≥3.3 mg/L and seven patients (41%) achieved a C_max ≥ 28.4 mg/L, whilst nine patients (53%) achieved an AUC_0–24 of >226 mg h/L. Given a minimum inhibitory concentration (MIC) of 0.5 mg/L, all patients satisfied the target AUC/MIC of >125, but when the MIC rises to 2 mg/L (the ECOFF), only five patients reached the desired AUC/MIC. Regarding fT_>MIC at an MIC of 2 mg/L with a 2-h infusion time, 13 patients (76%) achieved the PK target (>75%).
These data suggest that a combined 2-h infusion with a higher dosage of meropenem, including a loading dose, may be successful to achieve effective PK parameters.
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The use of antibacterial drugs is very common in critically ill patients and beta-lactam agents are widely used in this context. Critically ill patients show several characteristics (e.g., sepsis, renal impairment or conversely augmented renal clearance, renal replacement therapy) that may alter beta-lactam pharmacokinetics (PK) in comparison with non-critically ill patients. This narrative literature review aims to identify recent studies quantifying the variability of beta-lactams volume of distribution and clearance and to determine its main determinants. Seventy studies published between 2000 and 2018 were retained. Data on volume of distribution and clearance variability were reported for 5 penicillins, 3 beta-lactamase inhibitors, 6 cephalosporins and 4 carbapenems. Data confirm specific changes in PK parameters and important variability of beta-lactam PK in critically ill patients. Renal function, body weight and use of renal replacement therapy are the principal factors influencing PK parameters described in this population. Few studies have directly compared beta-lactam PK in critically ill versus non-critically ill patients. Conclusions are also limited by small study size and sparse PK data in several studies. These results suggest approaches to assess this PK variability in clinical practice. Beta-lactam therapeutic drug monitoring seems to be the best way to deal with this issue.
The effect of direct hemoperfusion with polymyxin B immobilized cartridge on meropenem in critically ill patients requiring renal support
2019, Journal of Critical Care
To evaluate the effect of direct hemoperfusion with polymyxin B immobilized cartridge (DHP-PMX) on meropenem pharmacokinetics in critically ill patients with sepsis requiring continuous venovenous hemofiltration (CVVH).
After intravenous infusion of 1 g meropenem over 3 h repeated every 8 h for at least 3 doses, 2 serial blood and ultrafiltration fluid samples were collected: one over a dose interval of meropenem with DHP-PMX therapy; and the other on the following day over a dose interval of meropenem with no DHP-PMX therapy. Meropenem concentrations were measured by high performance liquid chromatography. Pharmacokinetic parameters of meropenem and extraction ratio of DHP-PMX were calculated.
Mean AUC_0–8 of meropenem on DHP-PMX day was comparable to that of the DHP-PMX free day (285.2 ± 138.2 vs 297.8 ± 130.2 mg ∗ h/L; paired t-test, p = .618). No statistical significance of peak and trough concentrations, volume of distribution, sieving coefficient, or half-life were found. Extraction ratio of DHP-PMX on meropenem was 0 [0–0.03] and clearance by DHP-PMX was 0.04 [0–0.2] L/h which was not considered clinically significant.
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Clinical Trial Registry detail: NCT registry: 02413541 (First registered March 3, 2015, last update October 16, 2017).
Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials
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The findings of randomised controlled trials (RCT), observational studies, and meta-analyses vary regarding the effectiveness of prolonged β-lactam infusion. We aimed to identify the effectiveness of prolonged versus short-term infusion of antipseudomonal β-lactams in patients with sepsis.
We did a systematic review and meta-analysis to compare prolonged versus short-term intravenous infusion of antipseudomonal β-lactams in patients with sepsis. Two authors independently searched PubMed, Scopus, and the Cochrane Library of clinical trials until November, 2016, without date or language restrictions. Any RCT comparing mortality or clinical efficacy of prolonged (continuous or ≥3 h) versus short-term (≤60 min) infusion of antipseudomonal β-lactams for the treatment of patients with sepsis was eligible. Studies were excluded if they were not RCTs, the antibiotics in the two arms were not the same, neither mortality nor clinical efficacy was reported, only pharmacokinetic or pharmacodynamic outcomes were reported, or if ten or fewer patients were enrolled or randomised. Data were extracted in prespecified forms and we then did a meta-analysis using a Mantel-Haenszel random-effects model. The primary outcome was all-cause mortality at any timepoint. This meta-analysis is registered with the PROSPERO database, number CRD42016051678, and is reported according to PRISMA guidelines.
2196 articles were identified and screened, and 22 studies (1876 patients) were included in the meta-analysis. According to the Grading of Recommendations Assessment, Development, and Evaluation tool, the quality of evidence for mortality was high. Carbapenems, penicillins, and cephalosporins were studied. Patients with variable age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis and renal function were enrolled. Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR] 0·70, 95% CI 0·56–0·87). Heterogeneity was not observed (p=0·93, I²=0%). The funnel plot and the Egger's test (p=0·44) showed no evidence of publication bias.
Prolonged infusion of antipseudomonal β-lactams for the treatment of patients with sepsis was associated with significantly lower mortality than short-term infusion. Further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction, and immunocompetence are warranted.
None.
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Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration–time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CL_Cr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0–14.1) L/h vs. 17.4 (4.3–30.3) L/h, respectively; P <0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CL_Cr was found to be the strongest determinant of appropriate dosing regimens.

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Original articlePharmacokinetics and pharmacodynamics of meropenem in critically ill patients

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Meropenem—a review of its use in intensive care

Drugs

Meropenem pharmacokinetics and pharmacodynamics in patients with ventilator associated pneumonia

J. Antimicrob. Chemother.

Continuous infusion versus intermittent administration of meropenem in critically ill patients

J. Antimicrob. Chemother.

Pharmacokinetics of meropenem in febrile neutropenic patients

Eur. J. Clin. Microbiol. Infect. Dis.

Pharmacokinetics of meropenem in patients with liver disease

Clin. Infect. Dis.

Is continuous infusion of β lactam antibiotics worthwhile?—Efficacy and pharmacokinetic considerations

J. Antimicrob. Chemother.

The pharmacokinetics of meropenem

Scand. J. Infect. Dis. Suppl.

The pharmacokinetics of meropenem in surgical patients with moderate or severe infections

J. Antimicrob. Chemother.

Pharmacokinetics of meropenem in patients with intra abdominal infections

Antimicrob. Agents Chemother.

Pharmacokinetics of meropenem in patients with cystic fibrosis

Eur. J. Clin. Microbiol. Infect. Dis.

Clinical pharmacokinetics of meropenem after the first and tenth intramuscular administration

J. Antimicrob. Chemother.

Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration

Crit. Care Med.

Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration

Clin. Pharmacol. Ther.

Single dose pharmacokinetics of meropenem during continuous venovenous hemofiltration

Antimicrob. Agents Chemother.

Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration

Antimicrob. Agents Chemother.

Original article
Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients