Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study

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Abstract

Purpose

Although dozens of studies have associated vancomycin + piperacillin–tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion.

Methods

We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin–tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates.

Results

The study included 739 patients (vancomycin + piperacillin–tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin–tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin–tazobactam was not associated with change in alternative biomarkers: cystatin C: − 5.63% (95% CI − 18.19, 8.86); BUN: − 4.51% (95% CI − 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41).

Conclusions

Vancomycin + piperacillin–tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin–tazobactam effects on creatinine represent pseudotoxicity.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00134-022-06811-0.

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Most cited references 50

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Estimating glomerular filtration rate from serum creatinine and cystatin C.

Lesley A. Inker, Christopher H. Schmid, Hocine Tighiouart … (2012)

Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P 30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

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Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research

Peter C Austin (2009)

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2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

Mitchell Levy, Mitchell P Fink, John C Marshall … (2003)

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference. This document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.

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Author and article information

Contributors

Todd A. Miano:

ORCID: http://orcid.org/0000-0002-3832-6212

tmiano81@gmail.com

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 14 July 2022

Publication date PMC-release: 14 July 2022

Publication date (Print): 2022

Volume: 48

Issue: 9

Pages: 1144-1155

Affiliations

[1 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Biostatistics, Epidemiology, and Informatics, , Perelman School of Medicine at the University of Pennsylvania, Philadelphia, ; 423 Guardian Drive, 809 Blockley Hall, Philadelphia, PA 19104 USA

[2 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Center for Pharmacoepidemiology Research and Training, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA

[3 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Center for Clinical Epidemiology and Biostatistics, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA

[4 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Pulmonary, Allergy, and Critical Care Division, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA

[5 ]GRID grid.47100.32, ISNI 0000000419368710, Section of Nephrology and Clinical and Translational Research Accelerator, Department of Internal Medicine, , Yale School of Medicine, ; New Haven, CT USA

[6 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Medicine, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA

Author information

Todd A. Miano http://orcid.org/0000-0002-3832-6212

Article

Publisher ID: 6811

DOI: 10.1007/s00134-022-06811-0

PMC ID: 9463324

PubMed ID: 35833959

SO-VID: 33cd8af9-d5d4-4ce0-bff9-e5978d4bcb93

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 29 March 2022

Date accepted : 28 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: K08DK124658

Award ID: R01DK111638

Award ID: R01DK113191

Award ID: P30DK079310

Award Recipient : Todd A. Miano F. Perry Wilson Michael G. S. Shashaty

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: R01HL137006

Award ID: R01HL137915

Award ID: K24HL155804

Award ID: R01HL155159

Award Recipient : John P. Reilly Nuala J. Meyer

Funded by: FundRef http://dx.doi.org/10.13039/100000133, Agency for Healthcare Research and Quality;

Award ID: R01HS027626

Award Recipient : F. Perry Wilson

Funded by: National Institutes of Health (US)

Award ID: S10OD025172

Award Recipient : Nuala J. Meyer

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: vancomycin,piperacillin–tazobactam,acute kidney injury,cystatin c,nephrotoxicity,sepsis

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: vancomycin, piperacillin–tazobactam, acute kidney injury, cystatin c, nephrotoxicity, sepsis

Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study

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Karger: Nephrology

Most cited references 50

Estimating glomerular filtration rate from serum creatinine and cystatin C.

Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

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