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      Clinical Validation of Therapeutic Drug Monitoring of Imipenem in Spent Effluent in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Pilot Study

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          Abstract

          Objectives

          The primary objective of this pilot study was to investigate whether the therapeutic drug monitoring of imipenem could be performed with spent effluent instead of blood sampling collected from critically ill patients under continuous renal replacement therapy.

          Methods

          A prospective open-label study was conducted in a real clinical setting. Both blood and effluent samples were collected pairwise before imipenem administration and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after imipenem administration. Plasma and effluent imipenem concentrations were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic and pharmacodynamic parameters of blood and effluent samples were calculated.

          Results

          Eighty-three paired plasma and effluent samples were obtained from 10 patients. The Pearson correlation coefficient of the imipenem concentrations in plasma and effluent was 0.950 (P<0.0001). The average plasma-to-effluent imipenem concentration ratio was 1.044 (95% confidence interval, 0.975 to 1.114) with Bland-Altman analysis. No statistically significant difference was found in the pharmacokinetic and pharmacodynamic parameters tested in paired plasma and effluent samples with Wilcoxon test.

          Conclusion

          Spent effluent of continuous renal replacement therapy could be used for therapeutic drug monitoring of imipenem instead of blood sampling in critically ill patients.

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          Most cited references45

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          Pharmacokinetic issues for antibiotics in the critically ill patient.

          Jeffrey Lipman, Jason A Roberts (2009)
          To discuss the altered pharmacokinetic properties of selected antibiotics in critically ill patients and to develop basic dose adjustment principles for this patient population. PubMed, EMBASE, and the Cochrane-Controlled Trial Register. Relevant papers that reported pharmacokinetics of selected antibiotic classes in critically ill patients and antibiotic pharmacodynamic properties were reviewed. Antibiotics and/or antibiotic classes reviewed included aminoglycosides, beta-lactams (including carbapenems), glycopeptides, fluoroquinolones, tigecycline, linezolid, lincosamides, and colistin. Antibiotics can be broadly categorized according to their solubility characteristics which can, in turn, help describe possible altered pharmacokinetics that can be caused by the pathophysiological changes common to critical illness. Hydrophilic antibiotics (e.g., aminoglycosides, beta-lactams, glycopeptides, and colistin) are mostly affected with the pathphysiological changes observed in critically ill patients with increased volumes of distribution and altered drug clearance (related to changes in creatinine clearance). Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser volume of distribution alterations, but may develop altered drug clearances. Using antibiotic pharmacodynamic bacterial kill characteristics, altered dosing regimens can be devised that also account for such pharmacokinetic changes. Knowledge of antibiotic pharmacodynamic properties and the potential altered antibiotic pharmacokinetics in critically ill patients can allow the intensivist to develop individualized dosing regimens. Specifically, for renally cleared drugs, measured creatinine clearance can be used to drive many dose adjustments. Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring.
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            Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.

            Andrew Udy, Julie M Varghese, Mahdi Altukroni … (2012)
            β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.
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              Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis.

              Rogelio F Jiménez-Ortega, Ana Almodóvar, J Garmendia … (2003)
              Our primary goal was to evaluate the impact on in-hospital mortality rate of adequate empirical antibiotic therapy, after controlling for confounding variables, in a cohort of patients admitted to the intensive care unit (ICU) with sepsis. The impact of adequate empirical antibiotic therapy on early (<3 days), 28-day, and 60-day mortality rates also was assessed. We determined the risk factors for inadequate empirical antibiotic therapy. DESIGN Prospective cohort study. ICU of a tertiary hospital. All the patients meeting criteria for sepsis at admission to the ICU. None. Four hundred and six patients were included. Microbiological documentation of sepsis was obtained in 67% of the patients. At ICU admission, sepsis was present in 105 patients (25.9%), severe sepsis in 116 (28.6%), and septic shock in 185 (45.6%). By multivariate analysis, predictors of in-hospital mortality were Sepsis-related Organ Failure Assessment (SOFA) score at ICU admission (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.19-1.40), the increase in SOFA score over the first 3 days in the ICU (OR, 1.40; 95% CI, 1.19-1.65), respiratory failure within the first 24 hrs in the ICU (OR, 3.12; 95% CI, 1.54-6.33), and inadequate empirical antimicrobial therapy in patients with "nonsurgical sepsis" (OR, 8.14; 95% CI, 1.98-33.5), whereas adequate empirical antimicrobial therapy in "surgical sepsis" (OR, 0.37; 95% CI, 0.18-0.77) and urologic sepsis (OR, 0.14; 95% CI, 0.05-0.41) was a protective factor. Regarding early mortality (<3 days), factors associated with fatality were immunosuppression (OR, 4.57; 95% CI, 1.69-13.87), chronic cardiac failure (OR, 9.83; 95% CI, 1.98-48.69) renal failure within the first 24 hrs in the unit (OR, 8.63; 95% CI, 3.31-22.46), and respiratory failure within the first 24 hrs in the ICU (OR, 12.35; 95% CI, 4.50-33.85). Fungal infection (OR, 47.32; 95% CI, 5.56-200.97) and previous antibiotic therapy within the last month (OR, 2.23; 95% CI, 1.1-5.45) were independent variables related to administration of inadequate antibiotic therapy. In patients admitted to the ICU for sepsis, the adequacy of initial empirical antimicrobial treatment is crucial in terms of outcome, although early mortality rate was unaffected by the appropriateness of empirical antibiotic therapy.
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                Author and article information

                Contributors
                Patrick Paulus: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 19 April 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 4
                Electronic Location Identifier: e0153927
                Affiliations
                [1 ]Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
                [2 ]School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, China
                [3 ]Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
                Johannes Kepler University Linz, AUSTRIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: APW MLD JB. Performed the experiments: APW ZL. Analyzed the data: JXY RL. Contributed reagents/materials/analysis tools: JXY SC. Wrote the paper: APW.

                Article
                Publisher ID: PONE-D-15-49257
                DOI: 10.1371/journal.pone.0153927
                PMC ID: 4836878
                PubMed ID: 27093294
                SO-VID: 468e66be-785c-4c64-a5e0-628002fccdf0
                Copyright © © 2016 Wen et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 11 November 2015
                Date accepted : 6 April 2016
                Page count
                Figures: 3, Tables: 4, Pages: 14
                Funding
                Funded by: This study was funded by a grant from the Research Program of the Beijing Pharmaceutical Association
                Award Recipient :
                This study was funded by a grant from the Research Program of the Beijing Pharmaceutical Association.
                Categories
                Subject: Research Article
                Subject: Ecology and Environmental Sciences
                Subject: Limnology
                Subject: Effluent
                Subject: Earth Sciences
                Subject: Marine and Aquatic Sciences
                Subject: Limnology
                Subject: Effluent
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Blood
                Subject: Blood Plasma
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Pharmacokinetics
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Pharmacodynamics
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Signs and Symptoms
                Subject: Sepsis
                Subject: Severe Sepsis
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Signs and Symptoms
                Subject: Sepsis
                Subject: Severe Sepsis
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Kidneys
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Renal System
                Subject: Kidneys
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Therapeutic Drug Monitoring
                Subject: Physical Sciences
                Subject: Physics
                Subject: Classical Mechanics
                Subject: Continuum Mechanics
                Subject: Fluid Mechanics
                Subject: Fluid Dynamics
                Subject: Flow Rate
                Custom metadata
                Data Availability All relevant data are within the paper.

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                ScienceOpen disciplines: Uncategorized

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