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Therapeutic drug monitoring of meropenem and pharmacokinetic-pharmacodynamic target assessment in critically ill pediatric patients from a prospective observational study
Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, ThailandCenter of Excellence for Pediatric Infectious Diseases and Vaccines, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Corresponding author: Noppadol Wacharachaisurapol, B.Sc. (Pharm), M.D., Ph.D., Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, the Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Road, Pathumwan, Bangkok, Thailand, 10330. Phone: +6622564481.
Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Therapeutic drug monitoring (TDM) was done in children prescribed with meropenem.
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Drug dosing was 20 mg/kg IV bolus (IB) or 40 mg/kg extended infusion (EI) q 8 hours.
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Meropenem should not be initiated with a 20 mg/kg by IB in critically ill children.
•
Greater drug exposure was observed by using meropenem 40 mg/kg with EI.
•
TDM of meropenem should be implemented in children to improve dose optimization.
Abstract
Objectives
To compare the unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50%fT), end-dosing intervals (Ctrough, 100%fT), and proportions of patients achieving 50%fT and 100%fT above minimum inhibitory concentration (MIC) (50%fT>MIC and 100%fT>MIC) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children.
Methods
A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 hours by either EI or IB. Meropenem Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC were compared.
Results
TDM data from 72 patients with a median age (interquartile range [IQR]) of 12 months (3−37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% confidence interval [CI]) Cmid of EI versus IB was 17.3 mg/L (13.7−21.8) versus 3.4 mg/L (1.7–6.7) (P <0.001). Geometric mean (95% CI) Ctrough of EI versus IB was 2.3 mg/L (1.6−3.4) versus 0.8 mg/L (0.4−1.5) (P=0.005). Greater proportions of patients achieving 50%fT>MIC and 100%fT>MIC were observed in the EI group.
Conclusions
A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a central nervous system infection. A dose of 40 mg/kg/dose given by EI resulted in higher Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC.
Hospital-acquired infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB), including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales, are the cause of high morbidity and mortality rate in intensive care units (
ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram-negative bacteria in hospitalized patients.
). In addition, critical illnesses such as sepsis alter the pharmacokinetics of antibiotics, including increased volume of distribution and increased drug clearance, especially in the first few days of illnesses (
). Subsequently, plasma drug levels may be subtherapeutic when given by standard-dose regimens, even in susceptible strains of Gram-negative bacteria (
Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients.
). The desired pharmacokinetic (PK)-pharmacodynamic (PD) index of meropenem is the unbound plasma meropenem concentrations above the minimum inhibitory concentration (MIC) (fT>MIC) at least 40% of the time between dosing intervals (40% fT>MIC) (
). In more severe infections, 100% fT>MIC may be required. A recently published randomized controlled trial (RCT) comparing intermittent bolus (IB) with extended infusion (EI) of piperacillin found that the EI group had better antibiotic exposure (
Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients.
). Population PKs with dose simulation studies of meropenem in both adults and children demonstrated a greater probability of target attainment (PTA) by EI administration compared with IB administration, especially for bacteria with increased MICs (
Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements.
). Furthermore, a meta-analysis in 2018 demonstrated that prolonged infusion (extended or continuous infusion) is associated with a more significant clinical improvement and lower mortality (
Clinical outcomes of prolonged infusion (extended infusion or continuous infusion) versus intermittent bolus of meropenem in severe infection: A meta-analysis.
). Therapeutic drug monitoring (TDM) has been recommended as a tool to improve the dose optimization of beta-lactams, including meropenem, in critically ill patients (
). However, TDM for beta-lactams is not routinely available at most institutions, especially for children. The best approach to maximize efficacy would be to optimize initial dosing combined with TDM. The primary objective of this study was to compare the unbound plasma meropenem concentrations at the mid-dosing intervals (Cmid, 50% fT) and end-dosing intervals (Ctrough, 100% fT) between EI and IB administration in critically ill pediatric patients. Secondary objectives were to compare the proportions of patients who achieved targeted PK-PD indices and clinical outcomes, including length of hospital stay (LOS) and 30-day mortality rate.
2. Materials and methods
2.1 Study design and settings
This prospective observational study was conducted at the King Chulalongkorn Memorial Hospital, a tertiary care university hospital in Bangkok, Thailand. Eligibility criteria for enrollment included (1) age one month to 18 years, (2) receiving ≥3 doses of meropenem intravenous injection for suspected or proven MDR-GNB infections, and (3) being available for a vascular catheter for blood collection. Patients with a bodyweight of <3 kg, having a history of meropenem allergy, receiving another medication that could potentially cause drug interaction with meropenem such as probenecid and sodium valproate, and those receiving renal replacement therapy or extracorporeal membrane oxygenation were excluded. Patient data were collected, including demographic data (age, sex, body weight, height, serum creatinine, and comorbidity), microbiology data, meropenem dosing regimen, concomitant anti-GNB antibiotics, the use of vasopressors/inotropes, potential adverse drug reaction related to high meropenem concentration (encephalopathy or seizure) (
Usefulness of therapeutic drug monitoring of piperacillin and meropenem in routine clinical practice: a prospective cohort study in critically ill patients.
), and clinical outcomes (LOS and 30-day mortality).
This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB no. 417/63). The clinical trial registry number was TCTR20200901002 (http://www.clinicaltrials.in.th). Written informed consent was obtained from parents, and written informed assent was obtained from patients aged ≥7 years if appropriate before study enrollment.
2.2 Meropenem dosing and administration
Meropenem dosing ultimately depended on primary physician judgment. However, the most frequently prescribed meropenem doses at our institution were 20 and 40 mg/kg/dose given intravenously every 8 hours by either IB (0.5 to 1-hour infusion) or EI (3-hour infusion) administration.
2.3 Blood sampling
After ≥3 doses of meropenem were given, blood samples (3 mL of whole blood/sample in an ethylenediaminetetraacetic acid tube) were collected at 4 hours (Cmid) and 8 hours (Ctrough) after starting meropenem administration. Blood samples were centrifuged at 4°C, 4500 rpm for 10 minutes within 1 hour after collection. The plasma samples were stored at -80°C until analysis.
2.4 Meropenem determination
Meropenem concentrations were measured at the Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, using validated high-performance liquid chromatography with the ultraviolet detection (HPLC-UV) method, as previously described with some modifications (
A method for determining the free (unbound) concentration of ten beta-lactam antibiotics in human plasma using high performance liquid chromatography with ultraviolet detection.
J Chromatogr B Analyt Technol Biomed Life Sci.2012; 907: 178-184
). In brief, 500 µL of plasma sample was placed into an Amicon Ultra-0.5 mL 30,000 molecular weight cutoff centrifugal filter device and centrifuged for 30 minutes at 15,600 g, 4°C. An aliquot of 200 µL ultrafiltrate was transferred to an autosampler vial and vortex mixed for 30 seconds with 10 µL of ampicillin sodium (internal standard) and 10 µL of 1.0 M 2-(N-morpholino)ethanesulfonic acid buffer (pH 6.6) before proceeding with the chromatographic analysis. The chromatographic separations were performed at ambient temperature (33°C) on a Luna 5 µL C18, liquid chromatography column 250 × 4.6 mm using a 1.3 mL/min flow rate for 11 minutes and 30 µL injection volume. The peak of interest was detected by UV absorbance at the wavelengths of 304 nm for meropenem and 250 nm for ampicillin. A linear range of 0.5–50 mg/L meropenem (lower limit of detection = 0.5 mg/L) could be quantified with appropriate accuracy and precision. Regression coefficients were > 0.999 for all analytes. The intra- and inter-day accuracy and precision for meropenem quality control samples were conducted. The results were all within the acceptable range of variation and deviation (<15%).
2.5 Definitions
PK-PD indices included 50% fT>MIC and 100% fT>MIC. A 50% fT>MIC was defined as an unbound plasma meropenem concentration maintained above the MIC at the mid-dosing interval (Cmid >MIC). A 100% fT>MIC was defined as an unbound plasma meropenem concentration maintained above the MIC at the end of a dosing interval (Ctrough >MIC) (
) were used as surrogate MICs. Empirical treatment was defined as a meropenem-prescribing indication according to the clinical syndromes and before knowing microbiological data. Targeted treatment was defined as a meropenem-prescribing indication according to the known microbiological result of MDR-GNB. MDR-GNB was defined as the Gram-negatives resistant to at least three classes of antibiotics usually used for their treatment. Clinical outcomes included LOS and 30-day mortality. LOS was defined as the number of days from the first day of meropenem initiation to the discharge date. Furthermore, 30-day mortality was defined as death from any cause occurring within 30 days after meropenem initiation. Patients who were discharged before 30 days were considered alive. Regarding the fact that there is a lack of consensus about the augmented renal clearance (ARC) definition adapted to age-specific glomerular filtration rate (GFR) reference values for pediatric patients (
), the proportion of participants in the EI and IB groups who had plasma beta-lactam concentrations that exceeded the MIC was 82% and 29%, respectively. Using 90% power for a two-sided significance level of 5% and a ratio of 3:1 regarding meropenem is more likely to be prescribed by EI in our institution; 54 participants were enrolled in the EI groups and 18 participants were enrolled in the IB groups.
Data analysis was performed using Stata version 15.1 (StataCorp, College Station, Texas). Patient demographic data were summarized using median with interquartile ranges (IQR) for continuous variables and counts with percentages for categorical variables. The primary outcomes (meropenem Cmid and Ctrough) were presented as the geometric means with 95% confidence intervals (CIs) and compared between groups using the two-sample independent t-test. Recently, (
) conducted a population PK study of meropenem in infants and found that ARC was a significant covariate on plasma meropenem concentrations. Therefore, we compared meropenem Cmid and Ctrough between patients with or without ARC in both EI and IB groups. The proportions of patients who achieved targeted PK-PD indices and 30-day mortality were compared between groups using the chi-square test or Fisher's exact test. LOS was compared between groups using the Wilcoxon rank-sum test. All P-values reported are two-sided. Statistical significance was defined as P < 0.05.
3. Results
3.1 Patient demographics
From November 2020 to September 2021, 72 pediatric patients were enrolled in this study (EI, n = 54; IB, n = 18). The median age was 12 months (IQR 3−37 months). A total of 70 (97.2%) patients had comorbidities; chronic cardiac disease was the most common (44.4%). All patients in the EI group received meropenem 40 mg/kg/dose (range 38–40) every 8 hours, and all patients in the IB group received meropenem 20 mg/kg/dose (range 20–21) every 8 hours. Meropenem was initially prescribed as empirical treatment for 69 (95.8%) patients and targeted treatment for 3 (4.2%) patients. Of the patients with meropenem empirical treatment (EI, n = 53; IB, n = 16), 24 patients (EI, n = 21; IB, n = 3) continued using meropenem as a targeted treatment after known microbiological data. Patient demographics classified according to meropenem administration methods are summarized in Table 1.
Table 1Patient demographics classified according to meropenem administration methods.
Some patients have more than one comorbidity. ARC = augmented renal clearance (eGFR ≥ 130 mL/min/1.73 m2); BMI = body mass index; CLABSI = central line-associated bloodstream infection; CRBSI = catheter-related bloodstream infection; eGFR = estimated glomerular filtration rate; GNB = Gram-negative bacteria; SD = standard deviation.
70 (97.2)
52 (96.3)
18 (100)
0.41
Chronic cardiac disease
32 (44.4)
18 (33.3)
14 (77.8)
<0.01
Receiving immunosuppressive agent
9 (12.5)
8 (14.8)
1 (5.6)
0.43
Malignancy
8 (11.1)
8 (14.8)
0
0.19
Chronic liver disease
5 (6.9)
5 (9.3)
0
0.32
Others
22 (30.6)
18 (33.3)
4 (22.2)
0.56
Received concomitant anti-GNB antibiotics
29 (40.3)
23 (42.6)
6 (33.3)
0.49
Colistin
12 (16.7)
9 (16.7)
3 (16.7)
0.99
Amikacin
11 (15.3)
9 (16.7)
2 (11.1)
0.72
Sulbactam
7 (9.7)
5 (9.3)
2 (11.1)
0.99
Ceftazidime
6 (8.3)
5 (9.3)
1 (5.6)
0.99
Others
8 (11.1)
8 (14.8)
0
0.19
Data are shown as median (IQR) or n (%).
a P-value of median test for median; Pearson's chi-square test or Fisher's exact test for proportions.
b Others included skin and soft-tissue infection, urinary tract infection, and intra-abdominal infection.
c Some patients have more than one comorbidity.ARC = augmented renal clearance (eGFR ≥ 130 mL/min/1.73 m2); BMI = body mass index; CLABSI = central line-associated bloodstream infection; CRBSI = catheter-related bloodstream infection; eGFR = estimated glomerular filtration rate; GNB = Gram-negative bacteria; SD = standard deviation.
There were 72 samples of plasma meropenem Cmid (EI, n = 54; IB = 18) and 69 samples of plasma meropenem Ctrough (EI, n = 51; IB = 18). The geometric mean of unbound plasma meropenem Cmid was significantly higher in the EI group compared with the IB group, 17.3 mg/L (95% CI, 13.7−21.8 mg/L) versus 3.4 mg/L (95% CI, 1.7−6.7 mg/L), respectively (P < 0.001). The geometric mean of unbound plasma meropenem Ctrough was significantly higher in the EI group compared with the IB group, 2.3 mg/L (95% CI, 1.6−3.4 mg/L) versus 0.8 mg/L (95% CI, 0.4−1.5 mg/L), respectively (P = 0.005) (Figure 1). Regarding ARC status, the geometric mean of unbound plasma meropenem Cmid was lower in patients with ARC than those without ARC in both EI and IB groups (Table 2) but without a statistically significant difference.
Figure 1Geometric mean of unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50% fT) and end-dosing intervals (Ctrough, 100% fT) between treatment groups.
Of the 72 included patients, Gram-negative bacteria were isolated from 27 (37.5%) (22 from the EI group and five from the IB group) patients with bloodstream infections (Enterobacterales = 8, 29.6%; other GNB = 4, 14.8%), ventilator-associated pneumonia (A. baumannii = 4, 14.8%; Enterobacterales = 4, 14.8%; P. aeruginosa = 1, 3.7%; other GNB = 2, 7.4%), and other infections (Enterobacterales = 3, 11.1%; other GNB = 1, 3.7%). Among culture-positive patients, 59.1% (13 of 22) in the EI group and 60% (3 of 5) in the IB group were repeated culture 3–7 days after meropenem initiation. The microbiological eradication rate was 53.8% (7 of 13) in the EI group versus 33.3% (1 of 3) in the IB group, P = 0.54.
and one extra MIC of 16 mg/L were used for PK-PD indices achievement evaluation. For the PK-PD index of 50% fT>MIC, the EI group had a higher proportion of patients achieving the target than the IB group in all MIC breakpoints (Figure 2A). For the PK-PD index of 100% fT>MIC, the EI group had a higher proportion of patients achieving the target than the IB group only with the MIC < 1 mg/L (71% vs 33%, P = 0.005) and MIC < 4 mg/L (41% vs 11%, P = 0.02) (Figure 2B).
Figure 2Proportions of patients achieving pharmacokinetic-pharmacodynamic indices by using surrogate MICs: (A) 50% fT>MIC; (B) 100% fT>MIC.
The median LOS was 25 days (IQR, 12–46 days) in the EI group versus 29 days (IQR, 10–56 days) in the IB group (P = 0.94). There were no patients who developed encephalopathy or seizure during the period they received meropenem in both groups. The 30-day mortality rate was 3.7% (2 of 54) in the EI group versus 16.7% (3 of 18) in the IB group (P = 0.10). One fatality case from each group was related to MDR-GNB infection.
4. Discussion
Our study explored the unbound plasma meropenem Cmid and Ctrough in pediatric patients receiving meropenem by EI or IB administration methods. The findings revealed that the EI administration method in line with a higher dose of meropenem resulted in significantly higher unbound plasma meropenem Cmid and Ctrough. Accordingly, the proportion of patients achieving PK-PD indices was also greater. Even with a MIC cutoff of ≤2 mg/L (susceptible breakpoint for P. aeruginosa and A. baumannii), using a usual dose of meropenem of 20 mg/kg given by IB administration method every 8 hours could not achieve a target of 50% fT>MIC in almost 30% of patients.
Meropenem, a carbapenem antibiotic, is a broad-spectrum antibiotic used for the treatment of nosocomial infections caused by MDR-GNB, including Enterobacterales, P. aeruginosa, and A. baumannii, especially in patients with severe or life-threatening diseases (
). Meropenem requires 40–50% fT>MIC as a PK-PD target to ensure bactericidal activity. However, a target of 100% fT>MIC may be necessary for critically ill patients to ascertain maximal bactericidal activity, minimize the emergence of antimicrobial resistance, and improve clinical outcomes (
). For MDR-GNB with meropenem MICs of ≤2 mg/L, a meropenem dose of 40 mg/kg/dose intravenously every 8 hours is recommended. For MDR-GNB with meropenem MICs of 4–8 mg/L, the 3-hour EI strategy of meropenem 40 mg/kg/dose should be applied to achieve the PK-PD target. Meropenem should also be prescribed in combination with other anti-GNB antibiotics to treat carbapenem-nonsusceptible strains (MICs breakpoint of >1 mg/L for Enterobacterales; MIC breakpoint of >2 mg/L for P. aeruginosa and A. baumannii). Meropenem might not be effective for treating MDR-GNB with meropenem MICs of >8 mg/L.
A population PK study in children showed that the PTA for achieving 50%fT>MIC was only 50% using a meropenem dose of 20 mg/kg IB every 8 hours when the meropenem MIC was 2 mg/L. However, the PTA was improved to 80% by using a meropenem dose of 40 mg/kg administered by the EI method every 8 hours (
). The current study revealed the same direction but with a higher proportion of patients achieving the PK-PD target (Figure 2A). For a stricter PK-PD target of 80% fT>MIC when meropenem MIC is 2 mg/L, the PTA of using a meropenem dose of 20 mg/kg IB every 8 hours was only 16%. The PTA was improved to 68.6% by using a meropenem dose of 40 mg/kg 4-hour infusion every 8 hours (
). The proportion of our patients achieving 100% fT>MIC when meropenem MIC is 2 mg/L was low as 28% in the IB group and 51% in the EI group (Figure 2B), similar to Cies et al. results. A higher dose of meropenem, such as 160 mg/kg/day administered by continuous infusion, should be considered to improve a PTA for 80%−100% fT>MIC, especially in severely critically ill patients (
Several pathophysiological changes occur during critical illnesses such as sepsis and septic shock. These conditions frequently result in increased volume of distribution and occurrence of ARC, especially in the first few days, and cause insufficient hydrophilic antibiotic concentrations, including meropenem (
). A population PK study in critically ill infants found that eGFR was a significant covariate that impacts the clearance of meropenem; infants with ARC had lower plasma meropenem levels (
). Our study findings also showed a similar trend. Patients with ARC had lower plasma meropenem concentrations than those without ARC, although it was not a statistically significant difference. Therefore, besides meropenem dose reduction in patients with impaired kidney function recommended in the package insert, a higher dose should be recommended in patients with ARC. However, there is a lack of consensus about ARC thresholds adapted to age-specific GFR reference values for the pediatric population (
In critically ill patients, multiple factors that may influence PK parameters are frequently present at the same time, making the prediction of appropriate antibiotic concentrations extremely difficult. Simultaneously, MDR-GNB has been developing carbapenem resistance over time. Therefore, meropenem TDM should be used to facilitate individualized patient care. In addition, the benefit of TDM-based dose adaptation of beta-lactam antibiotics was proved in adult RCT studies (
Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial.
). Therefore, meropenem TDM should also be implemented in critically ill pediatric patients.
Although many studies reported that prolonged infusion (extended or continuous infusion) of meropenem could improve the PK-PD target achievement compared with IB (
), the clinical outcomes among different administration methods remain controversial. However, some studies from both adults and children demonstrated a potential benefit of prolonged infusion on patient treatment outcomes. In adults, meta-analyses showed that prolonged infusion of beta-lactams was associated with a greater clinical improvement and lower mortality (
Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.
). In pediatric patients, one RCT explored the clinical outcomes using prolonged infusion versus IB administration of meropenem to treat neonates with Gram-negative late-onset sepsis. It was found that prolonged infusion was associated with more significant clinical improvement, microbiologic eradication, lower mortality, and shorter duration of respiratory support (
). The current study showed a lower 30-day mortality rate using a higher dose of meropenem with EI administration but without a statistically significant difference (3.7% in the EI group versus 16.7% in the IB group [P = 0.1]). This nonstatistically significant result was probably because of the lack of the necessary power to evaluate clinical outcomes as they are not the study's primary outcome.
This study had several strengths. First, a validated plasma meropenem determination method was established successfully and will soon be implemented into clinical practice. Second, the study's findings underscored that even with susceptible pathogens, plasma meropenem levels potentially be subtherapeutic. Third, the results also confirmed that critically ill pediatric patients with increased renal function were more likely to have lower plasma meropenem levels. Finally, without a TDM approach, it is possible that PK-PD indices will not be obtained.
There were a number of limitations to this study. First, data comparing plasma meropenem levels using the same dose of meropenem given by EI versus IB methods were not available. Therefore, the direct effect of the different administration methods on drug levels could not be demonstrated. Second, the individualized PK-PD indices achievement could not be made owing to the unavailable MIC data of the individuals. Performing the MIC testing in line with TDM should be encouraged to ensure adequate drug exposure. Third, the study was designed to examine meropenem levels using various administration methods in a natural clinical setting. Thus, the benefit of EI on clinical outcomes was an exploratory analysis with insufficient power to detect any difference between different administration methods. A comparative study with a larger number of study participants is required.
In conclusion, a meropenem dose of 20 mg/kg/dose given intravenously every 8 hours by IB should not be used in critically ill children even if they are not suspected of having a central nervous system infection regarding potential subtherapeutic levels. A high dose of meropenem of 40 mg/kg/dose given intravenously every 8 hours by EI could cover resistant organisms with the MICs of ≤8 mg/L. TDM should also be performed to ensure meropenem dose optimization.
Declaration of competing interests
The authors have no competing interests to declare.
Funding
This research was supported by the internal grant of the Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University.
Ethical approval
This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB no. 417/63).
Acknowledgments
The authors would like to thank pediatric infectious diseases fellows, physicians, and nurses from all pediatric wards at the King Chulalongkorn Memorial Hospital for their support.
Author Contributions
PM: conception and design of the study (led), acquisition of data (led), analysis and interpretation of the data (supported), drafting the article (led), revising the article (supported), final approval of the version to be submitted (supported).
WY: acquisition of data (supported), revising the article (supported), final approval of the version to be submitted (supported).
SA: conception and design of the study (supported), revising the article (supported), final approval of the version to be submitted (supported).
JS: analysis and interpretation of the data (led), drafting the article (supported), revising the article (supported), final approval of the version to be submitted (supported).
WT: conception and design of the study (supported), revising the article (supported), final approval of the version to be submitted (supported).
NW: conception and design of the study (led), acquisition of data (supported), analysis and interpretation of the data (supported), drafting the article (led), revising the article (led), final approval of the version to be submitted (led).
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A method for determining the free (unbound) concentration of ten beta-lactam antibiotics in human plasma using high performance liquid chromatography with ultraviolet detection.
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Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients.
Usefulness of therapeutic drug monitoring of piperacillin and meropenem in routine clinical practice: a prospective cohort study in critically ill patients.
Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial.
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