Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

doi:10.1186/s40560-023-00699-8

. 2023 Nov 8;11(1):48.

doi: 10.1186/s40560-023-00699-8.

Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

Nozomi Takahashi^{1

2}, Yutaka Kondo³, Kenji Kubo⁴, Moritoki Egi⁵, Ken-Ichi Kano⁶, Yoshiyasu Ohshima⁷, Taka-Aki Nakada⁸

Affiliations

¹ Centre for Heart Lung Innovation, St. Paul's Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. nozomi_t1991@hotmail.com.
² Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. nozomi_t1991@hotmail.com.
³ Department of Emergency and Critical Care Medicine, Juntendo University Urayasu Hospital, Chiba, Japan.
⁴ Department of Emergency Medicine and Department of Infectious Diseases, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
⁵ Department of Anesthesia and Intensive Care, Kyoto University Hospital, Kyoto, Japan.
⁶ Department of Emergency Medicine, Fukui Prefectural Hospital, Fukui, Fukui, Japan.
⁷ Department of Pharmacy, Kobe Tokushukai Hospital, Hyogo, Japan.
⁸ Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

PMID: 37936203
PMCID: PMC10631080
DOI: 10.1186/s40560-023-00699-8

Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

Nozomi Takahashi et al. J Intensive Care. 2023.

. 2023 Nov 8;11(1):48.

doi: 10.1186/s40560-023-00699-8.

Authors

Nozomi Takahashi^{1

2}, Yutaka Kondo³, Kenji Kubo⁴, Moritoki Egi⁵, Ken-Ichi Kano⁶, Yoshiyasu Ohshima⁷, Taka-Aki Nakada⁸

Affiliations

¹ Centre for Heart Lung Innovation, St. Paul's Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. nozomi_t1991@hotmail.com.
² Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. nozomi_t1991@hotmail.com.
³ Department of Emergency and Critical Care Medicine, Juntendo University Urayasu Hospital, Chiba, Japan.
⁴ Department of Emergency Medicine and Department of Infectious Diseases, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
⁵ Department of Anesthesia and Intensive Care, Kyoto University Hospital, Kyoto, Japan.
⁶ Department of Emergency Medicine, Fukui Prefectural Hospital, Fukui, Fukui, Japan.
⁷ Department of Pharmacy, Kobe Tokushukai Hospital, Hyogo, Japan.
⁸ Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

PMID: 37936203
PMCID: PMC10631080
DOI: 10.1186/s40560-023-00699-8

Abstract

Background: The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients.

Methods: Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3.

Results: In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77-1.14; I² = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76-1.20), clinical cure (RR 1.23, 95% CI: 0.91-1.67), length of stay in the ICU (mean difference 0, 95% CI: - 2.18-2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88-1.48) and day 3 (RR 1.35, 95% CI: 0.90-2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes.

Conclusion: TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required.

Trial registration: Clinical trial registration; PROSPERO ( https://www.crd.york.ac.uk/prospero/ ), registry number: CRD 42022371959. Registered 24 November 2022.

Keywords: Antibiotics; Pharmacodynamics; Pharmacokinetics; Sepsis; TDM.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Flow diagram of the study selection

**Fig. 2**
Forest plot of TDM and control group comparing 28-day mortality (A), hospital mortality (B), ICU length of stay (C), clinical cure (D), target attainment in 24 h (E), and target attainment at day 3 (F). CI confidence interval, df degrees of freedom, *M-H* Mantel–Haenszel test, IV inverse variance, RR risk ratio, *TDM* therapeutic drug monitoring

**Fig. 3**
Summary of risk of bias for primary outcome in the included studies

See this image and copyright information in PMC

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References

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1. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146–155. doi: 10.1378/chest.118.1.146. - DOI - PubMed
1. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med. 2011;39(1):46–51. doi: 10.1097/CCM.0b013e3181fa41a7. - DOI - PubMed
1. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509. doi: 10.1016/S1473-3099(14)70036-2. - DOI - PMC - PubMed
1. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. doi: 10.1097/CCM.0000000000005337. - DOI - PubMed

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[1] Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462–474. doi: 10.1378/chest.115.2.462. - DOI - PubMed

[2] Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462–474. doi: 10.1378/chest.115.2.462. - DOI - PubMed

[3] Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146–155. doi: 10.1378/chest.118.1.146. - DOI - PubMed

[4] Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146–155. doi: 10.1378/chest.118.1.146. - DOI - PubMed

[5] Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med. 2011;39(1):46–51. doi: 10.1097/CCM.0b013e3181fa41a7. - DOI - PubMed

[6] Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med. 2011;39(1):46–51. doi: 10.1097/CCM.0b013e3181fa41a7. - DOI - PubMed

[7] Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509. doi: 10.1016/S1473-3099(14)70036-2. - DOI - PMC - PubMed

[8] Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498–509. doi: 10.1016/S1473-3099(14)70036-2. - DOI - PMC - PubMed

[9] Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. doi: 10.1097/CCM.0000000000005337. - DOI - PubMed

[10] Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. doi: 10.1097/CCM.0000000000005337. - DOI - PubMed

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Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

Affiliations

Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

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Abstract

Conflict of interest statement

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Abstract

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