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Duration of Exposure to Antipseudomonal ?-Lactam Antibiotics in the Critically Ill and Development of New Resistance.

ABSTRACT: STUDY OBJECTIVE:Minimizing the duration of broad-spectrum antimicrobial exposure in the critically ill is a commonly used strategy aimed at preventing resistance. Our objective was to correlate the duration of exposure to antipseudomonal ?-lactam antibiotics with the development of new resistance in critically ill patients. DESIGN:Single-center, retrospective cohort study. SETTING:A large, academic, tertiary care hospital. PATIENTS:A total of 7118 adults with a discharge diagnosis of severe sepsis or septic shock who received at least one dose of cefepime, meropenem, or piperacillin-tazobactam during their hospitalization between 2010 and 2015. MEASUREMENTS AND MAIN RESULTS:Cohort entry was defined as the first day of any antipseudomonal ?-lactam initiation, and exposure was defined as the cumulative days of any antipseudomonal ?-lactam exposure during the 60-day follow-up period. The primary outcome was development of new resistance to any antipseudomonal ?-lactam > 3 days after cohort entry. New resistance was defined as detection of resistance to any antipseudomonal ?-lactam not identified within 180 days before cohort entry. Patients without an outcome (i.e., did not develop new resistance) or who died by day 60 were censored. Cox proportional hazards models were performed to assess the risk of development of new resistance to any antipseudomonal ?-lactam with each additional day of exposure. Analyses of each individual antipseudomonal ?-lactam were evaluated as secondary outcomes. Each additional day of exposure to any antipseudomonal ?-lactam resulted in an adjusted hazard ratio (aHR) of 1.04 (95% confidence interval [CI] 1.04-1.05) for new resistance development. The risk of developing new resistance to cefepime, meropenem, and piperacillin-tazobactam for each additional day of exposure resulted in an aHR of 1.08 (95% CI 1.07-1.09), 1.02 (95% CI 1.01-1.03), and 1.08 (95% CI 1.06-1.09), respectively. CONCLUSION:Among critically ill patients who receive antipseudomonal ?-lactam antibiotics, each additional day of exposure to cefepime, meropenem, and piperacillin-tazobactam is associated with an increased risk of new resistance development.

SUBMITTER: Teshome BF

PROVIDER: S-EPMC6507412 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Duration of Exposure to Antipseudomonal β-Lactam Antibiotics in the Critically Ill and Development of New Resistance.

Teshome Besu F BF Vouri Scott Martin SM Hampton Nicholas N Kollef Marin H MH Micek Scott T ST

Pharmacotherapy 20190107 3

<h4>Study objective</h4>Minimizing the duration of broad-spectrum antimicrobial exposure in the critically ill is a commonly used strategy aimed at preventing resistance. Our objective was to correlate the duration of exposure to antipseudomonal β-lactam antibiotics with the development of new resistance in critically ill patients.<h4>Design</h4>Single-center, retrospective cohort study.<h4>Setting</h4>A large, academic, tertiary care hospital.<h4>Patients</h4>A total of 7118 adults with a disch ...[more]

PMID: 30506852

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Project description:BackgroundEarly and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1-4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.MethodsThis prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.ResultsA total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.ConclusionsTraditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients.Trial registrationNetherlands Trial Registry (EXPAT trial), NTR 5632 . Registered on 7 December 2015.

Project description:Beta-lactam antibiotics exhibit high interindividual variability in drug concentrations in patients with critical illness which led to an interest in the use of therapeutic drug monitoring to improve effectiveness and safety. To implement therapeutic drug monitoring, it is necessary to define the beta-lactam therapeutic range-in essence, what drug concentration would prompt a clinician to make dose adjustments up or down. This objective of this narrative review was to summarize evidence for the "floor" (for effectiveness) and "ceiling" (for toxicity) for the beta-lactam therapeutic range to be used with individualized therapeutic drug monitoring.Data sourcesResearch articles were sourced from PubMed using search term combinations of "pharmacokinetics," "pharmacodynamics," "toxicity," "neurotoxicity," "therapeutic drug monitoring," "beta-lactam," "cefepime," "meropenem," "piperacillin/tazobactam," "ICU," and "critical illness."Study selectionArticles were selected if they included preclinical, translational, or clinical data on pharmacokinetic and pharmacodynamic thresholds for effectiveness and safety for beta-lactams in critical illness.Data synthesisExperimental data indicate a beta-lactam concentration above the minimum inhibitory concentration of the organism for greater than or equal to 40-60% of the dosing interval is needed, but clinical data indicate that higher concentrations may be preferrable. In the first 48 hours of critical illness, a free beta-lactam concentration at or above the susceptibility breakpoint of the most likely pathogen for 100% of the dosing interval would be reasonable (typically based on Pseudomonas aeruginosa). After 48 hours, the lowest acceptable concentration could be tailored to 1-2× the observed minimum inhibitory concentration of the organism for 100% of the dosing interval (often a more susceptible organism). Neurotoxicity is the primary dose-dependent adverse effect of beta-lactams, but the evidence remains insufficient to link a specific drug concentration to greater risk.ConclusionsAs studies advance the understanding of beta-lactam exposure and response in critically ill patients, it is essential to clearly define the acceptable therapeutic range to guide regimen selection and adjustment.

Dataset Information

Duration of Exposure to Antipseudomonal ?-Lactam Antibiotics in the Critically Ill and Development of New Resistance.

Publications

Duration of Exposure to Antipseudomonal β-Lactam Antibiotics in the Critically Ill and Development of New Resistance.

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