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Continuous Infusion of Piperacillin/Tazobactam and Meropenem in ICU Patients Without Renal Dysfunction: Are Patients at Risk of Underexposure?

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Abstract

Background and Objectives

Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment.

Results

We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02–0.12) mg/l; piperacillin: 3 (1–4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = − 0.01 (95% CI − 0.02 to − 0.0; p = 0.043)] and piperacillin [β = − 0.01 (95% CI − 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = − 0.36 (95% CI − 0.61 to − 0.11; p = 0.005)].

Conclusion

Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.

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Acknowledgements

We thank the joint dedication of staff members of the departments of intensive care, infectious disease, microbiology, biochemistry and nursing staff of the Hospital Universitari de Bellvitge. Without the teamwork, it would not have been possible to carry out this project.

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Author notes

  1. Helena Colom-Codina and Ariadna Padullés-Zamora contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain

    Erika Esteve-Pitarch

  2. Farmacoteràpia, Farmacogenètica i Tecnologia Farmacèutica, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Erika Esteve-Pitarch, Sara Cobo-Sacristán, Helena Colom-Codina & Ariadna Padullés-Zamora

  3. Department of Intensive Care Medicine, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Víctor Daniel Gumucio-Sanguino, Kristel Maisterra-Santos, Joan Sabater-Riera & Xosé L. Pérez-Fernandez

  4. Department of Pharmacy, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, C/Feixa Llarga s/n., 08907, Barcelona, Spain

    Sara Cobo-Sacristán & Ariadna Padullés-Zamora

  5. Department of Infectious Diseases, Hospital Universitari de Bellvitge. Hospitalet de Llobregat, Barcelona, Spain

    Evelyn Shaw

  6. Epidemiologia de les infeccions bacterianes, Patologia Infecciosa i Transplantament, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Evelyn Shaw

  7. Spanish Network for Research in Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain

    Evelyn Shaw

  8. Department of Clinical Laboratory, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain

    Raül Rigo-Bonnin

  9. Department of Microbiology, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

    Fe Tubau-Quintano

  10. Department of Microbiology, CIBERES-Instituto de Salud Carlos III, Madrid, Spain

    Fe Tubau-Quintano

  11. Department of Infectious Diseases, Hospital Universitari de Bellvitge. Hospitalet de Llobregat, Barcelona, Spain

    Jordi Carratalà

  12. Infeccions respiratòries i en l’hoste immunocompromès, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Jordi Carratalà

  13. Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, Faculty of Barcelona, University of Barcelona, Barcelona, Spain

    Helena Colom-Codina

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  1. Erika Esteve-Pitarch
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  2. Víctor Daniel Gumucio-Sanguino
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Corresponding author

Correspondence to Ariadna Padullés-Zamora.

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Funding

Part of this study has been financed thanks to the aid for research projects granted to us by the Sociedad Española de Farmacia Hospitalaria (Convocatoria de Ayudas a Proyectos de Investigación de la SEFH 2013/2014. EPA056/14 ATB-2014-01).

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

The study was approved by the local Ethics Committee (SFB-ATB-2014-01) and conducted following the Declaration of Helsinki.

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Written informed consent was requested from the patient or the closest relative before inclusion.

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Main data will be made available on request to the corresponding author.

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Author Contributions

Conception and design: EEP, VGS, SCS, ESP, KMS, JSR, XPF, RRB, FTQ, HCC, APZ. Data collection: EEP, VGS, KMS. Analysis and interpretation: EEP, HCC, APZ. Drafting the manuscript for important intellectual content: EEP, HCC, APZ. Revision and final approval: EEP, VGS, SCS, ESP, KMS, JSR, XPF, RRB, FTQ, JC, HCC, APZ.

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Esteve-Pitarch, E., Gumucio-Sanguino, V.D., Cobo-Sacristán, S. et al. Continuous Infusion of Piperacillin/Tazobactam and Meropenem in ICU Patients Without Renal Dysfunction: Are Patients at Risk of Underexposure?. Eur J Drug Metab Pharmacokinet 46, 527–538 (2021). https://doi.org/10.1007/s13318-021-00694-0

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