Dataset Information

Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With Enterobacteriaceae Bloodstream Infections.

ABSTRACT: Background:Evidence on pharmacokinetic/pharmacodynamic (PK/PD) alterations and clinical outcomes in obese patients with serious infections remains limited. This study aimed to evaluate predicted PK/PD indices of efficacy and observed clinical outcomes between obese and nonobese patients receiving cefepime or piperacillin-tazobactam for Enterobacteriaceae bacteremia. Methods:This was a retrospective study of adult inpatients from 1/2012 to 9/2015 with Enterobacteriaceae bacteremia who received empiric cefepime or piperacillin-tazobactam. The primary outcome was clinical cure. First-dose free-drug exposure was estimated via predicted concentrations generated from population PK analyses and used to assess PD target attainment (>50% fT > minimum inhibitory concentration [MIC]) for the specific Enterobacteriaceae isolate. Multivariable logistic regression was utilized to identify independent predictors of clinical cure. Results:One hundred forty-two patients were included, 57 obese and 85 nonobese. Clinical cure was achieved in 68.4% of obese and 62.4% of nonobese patients (P = .458). No significant difference in outcomes was observed when evaluated by World Health Organization (WHO) obesity classes. The PK/PD target was achieved in 98.2% of obese and 91.8% of nonobese patients (P = .144). Independent predictors of clinical cure were immunosuppression and a shorter duration of bacteremia. Obesity was not identified as a significant predictor of clinical outcomes. Conclusions:Neither predicted PK/PD parameters nor clinical outcomes differed significantly between obese and nonobese patients treated with piperacillin-tazobactam or cefepime. As the majority of patients received extended-infusion piperacillin-tazobactam for bacteremia due to pathogens with low MICs, the potentially detrimental pathophysiologic derangements caused by obesity may not have been realized. Further studies are warranted to establish the optimal treatment of serious infections in obese patients.

SUBMITTER: Santibanez M

PROVIDER: S-EPMC6790397 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With <i>Enterobacteriaceae</i> Bloodstream Infections.

Santibañez Melissa M Bunnell Kristen K Harrington Amanda A Bleasdale Susan S Wenzler Eric E

Open forum infectious diseases 20190919 10

<h4>Background</h4>Evidence on pharmacokinetic/pharmacodynamic (PK/PD) alterations and clinical outcomes in obese patients with serious infections remains limited. This study aimed to evaluate predicted PK/PD indices of efficacy and observed clinical outcomes between obese and nonobese patients receiving cefepime or piperacillin-tazobactam for <i>Enterobacteriaceae</i> bacteremia.<h4>Methods</h4>This was a retrospective study of adult inpatients from 1/2012 to 9/2015 with <i>Enterobacteriaceae</ ...[more]

PMID: 31660362

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Project description:PurposeCarbapenem-resistant Enterobacteriaceae (CRE) infection has become a concerning threat, especially in hospital settings; however, its phenotypic characterization, association with rectal colonization and subsequent bloodstream infections (BSI) remain to be clarified. This study aimed to investigate the incidence and risk factors of CRE infection in rectal CRE carriers and to understand the clonality of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains and their association with subsequent BSI in these patients.Patients and methodsThis was a prospectively designed cohort study. Hospitalized patients treated at our institution from April 2019 to October 2020 with intestinal CRE carriage were screened at admission and weekly thereafter until death or discharge from the hospital. Stool and blood samples were obtained for strain growth and mass spectrometry. The colonization and clinical infection isolates were analyzed by antimicrobial susceptibility testing to identify CRE. The clonality of the CRE strains and their corresponding clinical infection strains was studied by whole-genome sequencing to explore the mechanism of drug resistance and evaluate possible transmission. CRE-associated risk factors were analyzed in combination with epidemiological data.ResultsOf the 1203 patients, 85 were colonized by CRE and 21 developed CRE infection, of whom 13 developed CRE bloodstream infection (BSI). Ninety-one CRE strains were isolated from the rectal specimens of the 85 patients. Tracheotomy and chemotherapy in the past three months were independent risk factors for CRE infection in intestinal CRE carriers. ST11-KL64 (92.3%, 24/26) was the most dominant capsule and multilocus sequence typing (MLST) type among clonal CRKP isolates. Single-nucleotide polymorphism clustering showed homology of representative colonization and infection CRKP strain pairs (n=13) in the same patient. One group of leading clones was endemic in surgical intensive care units (ICUs). Twenty-four CRKP strains carried β-lactamase K. pneumonia carbapenemase 2, and 73.1% (19 strains) of CRKP carried mucoid phenotype regulator genes A2 and iucABCD.ConclusionIn summary, intestinal CRE colonization was detectable at an elevated rate among hospitalized patients and prevalent in ICU patients, with potential rapid horizontal transmission, providing evidence that CRE BSI infection in hospitalized patients might be due to their colonized strains and indicates the correlation between intestinal colonization and BSI.

Project description:BackgroundOptimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.MethodsA prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10.ResultsA three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW.ConclusionThis is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.

Dataset Information

Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With Enterobacteriaceae Bloodstream Infections.

Publications

Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With <i>Enterobacteriaceae</i> Bloodstream Infections.

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