scholarly journals Variation in target attainment of β‐lactam antibiotic dosing between international pediatric formularies

2021 ◽  
Author(s):  
Silke Gastine ◽  
Yingfen Hsia ◽  
Michelle Clements ◽  
Charlotte IS Barker ◽  
Julia Bielicki ◽  
...  
Keyword(s):  
Target Attainment ◽  
International Pediatric ◽  
Lactam Antibiotic ◽  
Antibiotic Dosing

scholarly journals Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Maria Goul Andersen ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Anders N. Kristoffersson ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Free Drug ◽  
Free Drug Concentration ◽  
Total Clearance ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Content Type ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Antibiotic Dosing

ABSTRACTSufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR(>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50%fTMIC) and 0.125 mg/liter (100%fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

scholarly journals Pharmacodynamic Target Attainment for Cefepime, Meropenem, and Piperacillin-Tazobactam Using a Pharmacokinetic/Pharmacodynamic-Based Dosing Calculator in Critically Ill Patients

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Emily L. Heil ◽  
David P. Nicolau ◽  
Andras Farkas ◽  
Jason A. Roberts ◽  
Kerri A. Thom
Keyword(s):  
Prospective Study ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Package Insert ◽  
Beta Lactam ◽  
Target Attainment ◽  
A Prospective Study ◽  
Antibiotic Dosing

ABSTRACT This was a prospective study to determine if pharmacokinetic/pharmacodynamic (PK/PD)-based antibiotic dosing software aids in achieving concentration targets in critically ill patients receiving cefepime (n = 10), meropenem (n = 20), or piperacillin-tazobactam (n = 19). Antibiotic calculator doses targeting a >90% probability of target attainment (PTA) differed from package insert doses for 22.4% (11/49) of patients. Target attainment was achieved for 98% of patients (48/49). A PK/PD-based antibiotic dosing calculator provides beta-lactam doses with a high PTA in critically ill patients.

scholarly journals Pharmacodynamic Target Attainment for Meropenem and Piperacillin/Tazobactam Using a PK/PD-based Dosing Calculator in Critically Ill Patients

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S27-S27 ◽  
Author(s):  
Emily Heil ◽  
David P Nicolau ◽  
Gwen Robinson ◽  
Andras Farkas ◽  
Kerri Thom
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Future Research ◽  
Target Attainment ◽  
Research Support ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Culture Positive ◽  
Antibiotic Dosing

Abstract Background Unbound plasma concentrations of β-lactam antibiotics vary widely and attainment of PK/PD targets is highly variable in critically ill patients, which may affect microbiologic cure or contribute to toxicity. PK/PD-based antibiotic dosing programs may provide more accurate doses that achieve predicted targets for a cultured organism. Methods This was a single center, prospective study of critically ill patients with culture positive gram-negative infections treated with meropenem (MEM) or piperacillin/tazobactam (TZP). A PK/PD-based antibiotic dosing app was used to select doses that had a probability of target attainment (PTA) of 90% or greater for time above MIC (fT>MIC) of at least 40% for MEM and 50% for TZP. Total meropenem, piperacillin and tazobactam mid-point and trough concentrations were obtained at steady-state and adjusted for protein binding, to assess target attainment. Results Thirty-six patients were enrolled; 20 received MEM and 16 TZP. Antibiotic concentrations varied widely amongst patients, particularly with TZP. MEM and TZP concentrations are displayed in Table 1 and Figure 1. Doses evaluated for >90% probability of target attainment in the dosing calculator differed from standard package labeled doses for 25% (5/20) of MEM and 18.8% (3/16) of TZP patients. All (20/20) MEM and 94% (15/16) TZP patients maintained fT>MIC for the entire dosing interval. Conclusion A PK/PD based antibiotic dosing calculator that provides individualized β-lactam doses can lead to altered doses that may increase probability of target attainment in critically ill patients. Future research is needed to review the relevance of PK/PD-based dose adjustments on clinical outcomes. Disclosures D. P. Nicolau, Shionogi & Co.: Research Contractor, Research support; A. Farkas, Optimum Dosing Strategies: Employee, Salary.

scholarly journals Right Dose Right Now: bedside data-driven personalized antibiotic dosing in severe sepsis and septic shock — rationale and design of a multicenter randomized controlled superiority trial

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Luca F. Roggeveen ◽  
Lucas M. Fleuren ◽  
Tingjie Guo ◽  
Patrick Thoral ◽  
Harm Jan de Grooth ◽  
...  
Keyword(s):  
Septic Shock ◽  
Severe Sepsis ◽  
Data Driven ◽  
Control Group ◽  
Target Attainment ◽  
Clinical Endpoints ◽  
Randomized Controlled ◽  
Superiority Trial ◽  
Sepsis And Septic Shock ◽  
Antibiotic Dosing

Abstract Background Antibiotic exposure is often inadequate in critically ill patients with severe sepsis or septic shock and this is associated with worse outcomes. Despite markedly altered and rapidly changing pharmacokinetics in these patients, guidelines and clinicians continue to rely on standard dosing schemes. To address this challenge, we developed AutoKinetics, a clinical decision support system for antibiotic dosing. By feeding large amounts of electronic health record patient data into pharmacokinetic models, patient-specific predicted future plasma concentrations are displayed graphically. In addition, a tailored dosing advice is provided at the bedside in real time. To evaluate the effect of AutoKinetics on pharmacometric and clinical endpoints, we are conducting the Right Dose Right Now multicenter, randomized controlled, two-arm, parallel-group, non-blinded, superiority trial. Methods All adult intensive care patients with a suspected or proven infection and having either lactatemia or receiving vasopressor support are eligible for inclusion. Randomization to the AutoKinetics or control group is initiated at the bedside when prescribing at least one of four commonly administered antibiotics: ceftriaxone, ciprofloxacin, meropenem and vancomycin. Dosing advice is available for patients in the AutoKinetics group, whereas patients in the control group receive standard dosing. The primary outcome of the study is pharmacometric target attainment during the first 24 h. Power analysis revealed the need for inclusion of 42 patients per group per antibiotic. Thus, a total of 336 patients will be included, 168 in each group. Secondary pharmacometric endpoints include time to target attainment and fraction of target attainment during an entire antibiotic course. Secondary clinical endpoints include mortality, clinical cure and days free from organ support. Several other exploratory and subgroup analyses are planned. Discussion This is the first randomized controlled trial to assess the effectiveness and safety of bedside data-driven automated antibiotic dosing advice. This is important as adequate antibiotic exposure may be crucial to treat severe sepsis and septic shock. In addition, the trial could prove to be a significant contribution to clinical pharmacometrics and serve as a stepping stone for the use of big data and artificial intelligence in the field. Trial registration Netherlands Trial Register (NTR), NL6501/NTR6689. Registered on 25 August 2017. European Clinical Trials Database (EudraCT), 2017-002478-37. Registered on 6 November 2017.

scholarly journals Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Alan Abdulla ◽  
Annemieke Dijkstra ◽  
Nicole G. M. Hunfeld ◽  
Henrik Endeman ◽  
Soma Bahmany ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Outcomes ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Male Gender ◽  
Beta Lactam ◽  
Target Attainment ◽  
Dosing Interval ◽  
Beta Lactam Antibiotics ◽  
Antibiotic Dosing

Abstract Background Early 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. Methods This 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. Results A 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. Conclusions Traditional 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 registration Netherlands Trial Registry (EXPAT trial), NTR 5632. Registered on 7 December 2015.

Effect of piperacillin on morphology and viability of gram-negative bacteria

1984 ◽  
Vol 42 ◽  
pp. 218-219
Author(s):  
R. H. Liss
Keyword(s):  
Inhibitory Concentration ◽  
Cytoplasmic Membrane ◽  
Drug Binding ◽  
Gram Negative Bacteria ◽  
Bacterial Cells ◽  
Drug Induced ◽  
Penicillin Binding Proteins ◽  
Lactam Antibiotic ◽  
Drug Free ◽  
Tube Dilution

Piperacillip (PIP) is b-[D(-)-α-(4-ethy1-2,3-dioxo-l-piperzinylcar-bonylamino)-α-phenylacetamido]-penicillanate. The broad spectrum semisynthetic β-lactam antibiotic is believed to effect bactericidal activity through its affinity for penicillin-binding proteins (PBPs), enzymes on the bacterial cytoplasmic membrane that control elongation and septation during cell growth and division. The purpose of this study was to correlate penetration and binding of 14C-PIP in bacterial cells with drug-induced lethal changes assessed by microscopic, microbiologic and biochemical methods.The bacteria used were clinical isolates of Escherichia coli and Pseudomonas aeruginosa (Figure 1). Sensitivity to the drug was determined by serial tube dilution in Trypticase Soy Broth (BBL) at an inoculum of 104 organisms/ml; the minimum inhibitory concentration of piperacillin for both bacteria was 1 μg/ml. To assess drug binding to PBPs, the bacteria were incubated with 14C-PIP (5 μg/0.09 μCi/ml); controls, in drug-free medium.

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