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Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan

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Abstract

Background and Objective

Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults.

Methods

A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination.

Results

Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age.

Conclusions

The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

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Author information

Author notes

  1. Marion Hemmersbach-Miller

    Present address: ICON Plc, North Wales, PA, USA

Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, Duke University Medical Center, Durham, NC, USA

    Marion Hemmersbach-Miller & Austin W. Chan

  2. Duke Clinical Research Institute, Durham, NC, USA

    Marion Hemmersbach-Miller, Stephen J. Balevic, Michael Cohen-Wolkowiez & Emmanuel B. Walter

  3. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Stephen J. Balevic, Michael Cohen-Wolkowiez & Emmanuel B. Walter

  4. Division of Rheumatology and Immunology, Department of Internal Medicine, Duke University Medical Center, Durham, NC, USA

    Stephen J. Balevic

  5. Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    Patricia L. Winokur

  6. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Cornelia B. Landersdorfer & Carl M. J. Kirkpatrick

  7. Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    Kenan Gu

  8. The EMMES Company, LLC, Rockville, MD, USA

    Thomas Conrad

  9. College of Pharmacy, University of Iowa, Iowa City, IA, USA

    Guohua An

  10. Department of Obstetrics and Gynecology, Obstetrics Clinical Research, Duke University Medical System, Durham, NC, USA

    Geeta K. Swamy

  11. Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA

    Emmanuel B. Walter

  12. Division of Geriatrics, Department of Medicine, Duke University Medical Center, Duke Box 3469, Durham, NC, 27710, USA

    Kenneth E. Schmader

  13. Geriatric Research Education and Clinical Center (GRECC), Durham Veterans Affairs Health Care System, Durham, NC, USA

    Kenneth E. Schmader

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  1. Marion Hemmersbach-Miller
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Corresponding author

Correspondence to Kenneth E. Schmader.

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Funding

This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, through Contract No. HHSN272201500002C (Emmes), and a Vaccine and Treatment Evaluation Units award under Contract No. HHSN272201300017I (Duke University) and Contract No. HHSN2722013000201 (University of Iowa). This work was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant number 5T32AI100851 to MHM). KES also received support from the National Institute on Aging, Duke Pepper Older Americans Independence Center, NIA P30AG028716. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. MCW receives support for research from the NIH [1U24-MD016258], National Institute of Allergy and Infectious Diseases [HHSN272201500006I, HHSN272201300017I, 1K24-AI143971], NICHD [HHSN275201000003I], US Food and Drug Administration [5U18-FD006298], and industry for drug development in adults and children.

Conflict of interest

SJB receives support from the National Institutes of Health, the US Food and Drug Administration, the Patient-Centered Outcomes Research Institute, the Rheumatology Research Foundation’s Scientist Development Award, the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, and consulting for UCB. The remaining authors have no relevant disclosures.

Ethics approval

The study was reviewed and approved by the institutional review board at the respective study sites.

Consent to participate

Written informed consent was obtained by patients or their legally authorized representative.

Consent to Publish

Patients signed informed consent regarding the publishing of their data.  They were informed their identity will not be revealed.

Availability of data and material

Data are to be made available as widely as possible, while safeguarding the privacy of participants, and protecting confidential and proprietary data.

Code availability

Not applicable.

Author contributions

MH-M: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. SJB: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. PLW: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. CBL: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. KG: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. AWC: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. MC-W: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. TC: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. GA: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. CMJK: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. GKS: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. EBW: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content. KES: conception and design of the analysis, acquisition, interpretation of data for the work, and revising the work critically for important intellectual content.

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Hemmersbach-Miller, M., Balevic, S.J., Winokur, P.L. et al. Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan. Clin Pharmacokinet 62, 127–139 (2023). https://doi.org/10.1007/s40262-022-01198-z

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