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Background <p>Carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) are a critical public health threat with high mortality rates. In Thailand, limited access to novel antimicrobial agents restricts first-line therapeutic options, especially for NDM-producing CRE. While tigecycline (TGC) retains in vitro activity against all carbapenemase classes, its large volume of distribution compromises serum concentrations, making its efficacy in bacteremia highly controversial. Therefore, the objective of this study was to identify the optimal pharmacokinetic/pharmacodynamic (PK/PD) targets of high-dose tigecycline (HD-TGC) that are predictive of favorable clinical and microbiological outcomes in patients with CRE BSIs.</p> Methods <p>We conducted a prospective study at a tertiary-care teaching hospital between May 2023 and May 2025, enrolling patients receiving HD-TGC for the treatment of CRE BSIs. For the non-compartmental pharmacokinetic analysis, TGC plasma concentrations were collected at five time points from each patient following at least 36&#xa0;h of HD-TGC administration. The steady-state 24-hour area under the concentration-time curve (AUCss, 0–24&#xa0;h) was calculated using Phoenix WinNonlin software. In vitro susceptibility was determined by the broth microdilution method. Patients completing a minimum of 48&#xa0;h of therapy were evaluated for clinical and microbiological outcomes, and the relationships between the steady-state area under the curve to the minimum inhibitory concentration (AUCss, 0–24&#xa0;h/MIC) and these outcomes were examined.</p> Results <p>Clinical outcomes were evaluated in 30 patients; all-cause mortality rates were 16.7% at day 7, 50.0% at day 14, and 80.0% at day 30. Pharmacokinetic analysis of 137 plasma concentrations from 28 patients revealed a median AUCss, 0–24&#xa0;h of 14.81&#xa0;mg·h/L. A PK/PD target of AUCss, 0–24&#xa0;h/MIC <b>≥</b> 9.90 was identified as significantly associated with decrease in CRE-attributable mortality and increase in the microbiological eradication rate. The causative CRE isolates demonstrated MIC50 and MIC90 values of 0.5&#xa0;mg/L and 1&#xa0;mg/L, respectively.</p> Conclusions <p>This study proposes an exploratory, hypothesis-generating AUCss, 0–24&#xa0;h/MIC target of <b>≥</b> 9.90, which is associated with favorable clinical and microbiological outcomes in CRE BSIs treated with HD-TGC. To achieve this target, our data suggest that HD-TGC is most likely to be effective against <i>Klebsiella pneumoniae</i> with a TGC MIC ≤ 1&#xa0;mg/L.</p> Clinical trial number <p>Not applicable.</p>

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The pharmacokinetics/pharmacodynamics index of high-dose tigecycline in patients with carbapenem-resistant Enterobacterales bloodstream infection: a prospective study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Sirapat Somsirikarnjanakoon,
  • Worapong Nasomsong,
  • Jatapat Hemapanpairoa,
  • Piraporn Juntanawiwat,
  • Wichai Santimaleeworagun

摘要

Background

Carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) are a critical public health threat with high mortality rates. In Thailand, limited access to novel antimicrobial agents restricts first-line therapeutic options, especially for NDM-producing CRE. While tigecycline (TGC) retains in vitro activity against all carbapenemase classes, its large volume of distribution compromises serum concentrations, making its efficacy in bacteremia highly controversial. Therefore, the objective of this study was to identify the optimal pharmacokinetic/pharmacodynamic (PK/PD) targets of high-dose tigecycline (HD-TGC) that are predictive of favorable clinical and microbiological outcomes in patients with CRE BSIs.

Methods

We conducted a prospective study at a tertiary-care teaching hospital between May 2023 and May 2025, enrolling patients receiving HD-TGC for the treatment of CRE BSIs. For the non-compartmental pharmacokinetic analysis, TGC plasma concentrations were collected at five time points from each patient following at least 36 h of HD-TGC administration. The steady-state 24-hour area under the concentration-time curve (AUCss, 0–24 h) was calculated using Phoenix WinNonlin software. In vitro susceptibility was determined by the broth microdilution method. Patients completing a minimum of 48 h of therapy were evaluated for clinical and microbiological outcomes, and the relationships between the steady-state area under the curve to the minimum inhibitory concentration (AUCss, 0–24 h/MIC) and these outcomes were examined.

Results

Clinical outcomes were evaluated in 30 patients; all-cause mortality rates were 16.7% at day 7, 50.0% at day 14, and 80.0% at day 30. Pharmacokinetic analysis of 137 plasma concentrations from 28 patients revealed a median AUCss, 0–24 h of 14.81 mg·h/L. A PK/PD target of AUCss, 0–24 h/MIC ≥ 9.90 was identified as significantly associated with decrease in CRE-attributable mortality and increase in the microbiological eradication rate. The causative CRE isolates demonstrated MIC50 and MIC90 values of 0.5 mg/L and 1 mg/L, respectively.

Conclusions

This study proposes an exploratory, hypothesis-generating AUCss, 0–24 h/MIC target of ≥ 9.90, which is associated with favorable clinical and microbiological outcomes in CRE BSIs treated with HD-TGC. To achieve this target, our data suggest that HD-TGC is most likely to be effective against Klebsiella pneumoniae with a TGC MIC ≤ 1 mg/L.

Clinical trial number

Not applicable.