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Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

ABSTRACT: INTRODUCTION:The present study aimed to compare the pharmacokinetic/pharmacodynamic (PK/PD) parameters of imipenem administered by two-step (50% delivered in a 30-min bolus, 50% for the following 90 min) or extended (administered continuously for 2 h) infusion. METHODS:Patients with sepsis and septic shock were prospectively enrolled and randomized into four groups. Subjects in the two-step or extended groups were given two doses of imipenem (0.5 g q6h and 1.0 g q8h). The plasma imipenem concentrations were measured at given time points after the fifth dose. The PK/PD target was defined as the achievement of a fractional time above the minimal inhibitory concentration (MIC) of?>?40%. RESULTS:Thirty-five patients were eventually enrolled. No significant difference was observed in the percentage of patients achieving 40% T?>?MIC between the different infusion modes with the same dosage, although the two-step groups exhibited a significantly shorter Tmax compared with the extended groups (0.5 g q6h: 1.5?±?0.8 vs. 2.0?±?0.0 h; 1.0 g q8h: 1.0?±?0.6 vs. 2.0?±?0.0 h; both, p??MIC when MIC was 0.5-4.0 ?g/ml, but only regimens with a higher dose (1.0 g q8h) achieved target when MIC was 8 ?g/ml. CONCLUSION:The two-step and extended regimens of imipenem are comparable to the PK/PD target in the treatment of sepsis and septic shock. A higher dose (1.0 g q8h) should be considered for target achievement at an MIC of?>?8 ?g/ml. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT02616354.

SUBMITTER: Huang Y

PROVIDER: S-EPMC7223128 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

Huang Yingzi Y Xu Kang K Zhan Ying Y Zha Xian X Liu Songqiao S Xie Jianfeng J Liu Lin L Li Qing Q Shao Hua H Yang Yi Y

Advances in therapy 20200410 5

<h4>Introduction</h4>The present study aimed to compare the pharmacokinetic/pharmacodynamic (PK/PD) parameters of imipenem administered by two-step (50% delivered in a 30-min bolus, 50% for the following 90 min) or extended (administered continuously for 2 h) infusion.<h4>Methods</h4>Patients with sepsis and septic shock were prospectively enrolled and randomized into four groups. Subjects in the two-step or extended groups were given two doses of imipenem (0.5 g q6h and 1.0 g q8h). The plasma i ...[more]

PMID: 32277344

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Project description:Background: Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT?>?MIC?>?40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT?>?MIC?>?40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT?>?4?×?MIC?>?40, fT?>?MIC?=?100, and fT?>?4?×?MIC?=?100.Methods: Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used.Results: A 3-h EI of meropenem 1000 mg Q8H achieved fT?>?2 µg/mL?>?40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT?>?4 µg/mL?>?40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT?>?8 µg?>?40. Targets of fT?>?4 µg/mL?=?100 and fT?>?8 µg/mL?=?100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H).Conclusions: In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT?>?4 µg/mL?>?40) against strains susceptible to increased exposure, which requires a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT?>?8 µg/mL?>?40 require escalation of EI dose, fT?>?4 µg/mL?=?100 and fT?>?8 µg/mL?=?100 require escalation of both EI dose and frequency.

Project description:ObjectiveTo identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.DesignA consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.MethodsEach committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science.ResultsThe Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?ConclusionsWhile the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

Project description:ObjectivesSepsis and septic shock are leading causes of in-hospital mortality. Timely treatment is crucial in improving patient outcome, yet treatment delays remain common. Early prediction of those patients with sepsis who will progress to its most severe form, septic shock, can increase the actionable window for interventions. We aim to extend a time-evolving risk score, previously developed in adult patients, to predict pediatric sepsis patients who are likely to develop septic shock before its onset, and to determine whether or not these risk scores stratify into groups with distinct temporal evolution once this prediction is made.DesignRetrospective cohort study.SettingAcademic medical center from July 1, 2016, to December 11, 2020.PatientsSix-thousand one-hundred sixty-one patients under 18 admitted to the Johns Hopkins Hospital PICU.InterventionsNone.Measurements and main resultsWe trained risk models to predict impending transition into septic shock and compute time-evolving risk scores representative of a patient's probability of developing septic shock. We obtain early prediction performance of 0.90 area under the receiver operating curve, 43% overall positive predictive value, patient-specific positive predictive value as high as 62%, and an 8.9-hour median early warning time using Sepsis-3 labels based on age-adjusted Sequential Organ Failure Assessment score. Using spectral clustering, we stratified pediatric sepsis patients into two clusters differing in septic shock prevalence, mortality, and proportion of patients adequately fluid resuscitated.ConclusionsWe demonstrate the applicability of our methodology for early prediction and stratification for risk of septic shock in pediatric sepsis patients. Through analyses of risk score evolution over time, we corroborate our past finding of an abrupt transition preceding onset of septic shock in children and are able to stratify pediatric sepsis patients using their risk score trajectories into low and high-risk categories.

Project description:BackgroundWe hypothesized that the cardiovascular responses to Surviving Sepsis Guidelines (SSG)-defined resuscitation are predictable based on the cardiovascular state.MethodsFifty-five septic patients treated by SSG were studied before and after volume expansion (VE), and if needed norepinephrine (NE) and dobutamine. We measured mean arterial pressure (MAP), cardiac index (CI), and right atrial pressure (Pra) and calculated pulse pressure and stroke volume variation (PPV and SVV), dynamic arterial elastance (Eadyn), arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees), Ees/Ea (VAC), LV ejection efficiency (LVeff), mean systemic pressure analogue (Pmsa), venous return pressure gradient (Pvr), and cardiac performance (Eh), using standard formulae.ResultsAll patients were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beat min-1), with increased lactate levels (lactate = 5.0 ± 4.2 mmol L-1) with a worsened VAC. CI was variable but > 2 L min-1 M-2 in 74%. Twenty-eight-day mortality was 48% and associated with admission lactate, blood urea nitrogen (BUN), and creatinine levels but not cardiovascular state. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Fluid administration improved Pra, Pmsa, and Pvr in all patients, whereas both HR and Ea decreased after VE, thus normalizing VAC. CI increases were proportional to baseline PPV and SVV. CI increases proportionally decreased PPV and SVV. VE increased MAP > 65 mmHg in 35/55 patients. MAP responders had higher PPV, SVV, and Eadyn than non-responders. NE was given to 20/55 patients in septic shock, but increased MAP > 65 mmHg in only 12. NE increased Ea, Eadyn, Pra, Pmsa, and VAC while decreasing HR, PPV, SVV, and LVeff. MAP responders had higher pre-NE Ees and lower VAC. Dobutamine was given to 6/8 patients who remained hypotensive following NE. It increased Ees, MAP, CI, and LVeff, while decreasing HR, Pra, and VAC. At all times and all steps of the protocol, CI changes were proportional to Pvr changes independent of treatment.ConclusionsThe cardiovascular response to SSG-based resuscitation is highly heterogeneous but predictable from pre-treatment measures of cardiovascular state.

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Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

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Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

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