Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (cPIP) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as cPIP of 32–64 mg/L (2–4× the ‘MIC breakpoint’ of Pseudomonas aeruginosa). Of the 1544 patients screened, we included 179 patients (335 serum concentrations), of whom 89% achieved the minimum therapeutic exposure of >32 mg/L and 12% achieved potentially harmful cPIP > 96 mg/L within the first 48 h. Therapeutic exposure was achieved in 40% of the patients. Subsequent TDM-guided dose adjustments significantly enhanced therapeutic exposure to 65%, and significantly reduced cPIP > 96 mg/L to 5%. Mortality in patients with cPIP > 96 mg/L (13/21; 62%) (OR 5.257, 95% CI 1.867–14.802, p = 0.001) or 64–96 mg/L (30/76; 45%) (OR 2.696, 95% CI 1.301–5.586, p = 0.007) was significantly higher compared to patients with therapeutic exposure (17/72; 24%). Given the observed variability in critically ill patients, combining the application of dosing software and consecutive TDM increases therapeutic drug exposure of piperacillin in patients with sepsis and septic shock.

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How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients?

BMC Infectious Diseases ◽

10.1186/1471-2334-14-288 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 51

Author(s):

Gloria Wong ◽

Fekade Bruck Sime ◽

Jeffrey Lipman ◽

Jason A Roberts

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Therapeutic Drug ◽

Severe Infections

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Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02019-20 ◽

2020 ◽

Vol 65 (3) ◽

Author(s):

Indy Sandaradura ◽

Jessica Wojciechowski ◽

Deborah J. E. Marriott ◽

Richard O. Day ◽

Sophie Stocker ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Drug Exposure ◽

Fungal Infections ◽

Therapeutic Drug ◽

Target Attainment ◽

Dose Selection ◽

Dose Individualization

ABSTRACT Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

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Therapeutic Drug Monitoring of Fluconazole in Critically Ill Patients

Case Medical Research ◽

10.31525/ct1-nct04252027 ◽

2020 ◽

Author(s):

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Therapeutic Drug

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β-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2012.10.002 ◽

2013 ◽

Vol 41 (2) ◽

pp. 162-166 ◽

Cited By ~ 40

Author(s):

Yoshiro Hayashi ◽

Jeffrey Lipman ◽

Andrew A. Udy ◽

Mandy Ng ◽

Brett McWhinney ◽

...

Keyword(s):

Renal Function ◽

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Drug Exposure ◽

Therapeutic Drug

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Barriers and facilitators in the clinical implementation of beta-lactam therapeutic drug monitoring in critically ill patients

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000937 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Alan Abdulla ◽

Puck van den Broek ◽

Tim M.J. Ewoldt ◽

Anouk E. Muller ◽

Henrik Endeman ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Barriers And Facilitators ◽

Therapeutic Drug ◽

Clinical Implementation ◽

Beta Lactam

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Therapeutic Drug Monitoring of Protein Unbound Ciprofloxacin Concentrations to avoid inadequate Treatment of severe Bacterial Infections in Critically ill Patients

Journal of Applied Bioanalysis ◽

10.17145/jab.18.021 ◽

2018 ◽

Vol 4 (5) ◽

pp. 166-174

Author(s):

Nora J mabelis ◽

Kimberly N. Shudofsky ◽

Joost J. van Raaij ◽

Sjoerd D. Meenks ◽

Thomas Havenith ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Bacterial Infections ◽

Therapeutic Drug

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Personalized Antibiotic Therapy for the Critically Ill: Implementation Strategies and Effects on Clinical Outcome of Piperacillin Therapeutic Drug Monitoring—A Descriptive Retrospective Analysis

Antibiotics ◽

10.3390/antibiotics10121452 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1452

Author(s):

Schrader Nikolas ◽

Riese Thorsten ◽

Kurlbaum Max ◽

Meybohm Patrick ◽

Kredel Markus ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Antibiotic Therapy ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Implementation Strategy ◽

Care Staff ◽

Therapeutic Drug ◽

Health Care Staff ◽

Standard Operating

Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians’ alertness.

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