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Objective <p>To validate a predictive risk score of early aggressive pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment with continuous infusion (CI) piperacillin/tazobactam or meropenem in a retrospective cohort of critically ill patients having documented Gram-negative infections.</p> Methods <p>Critically ill adult patients receiving treatment of documented Gram-negative infections with CI piperacillin-tazobactam or meropenem and undergoing first real-time beta-lactam therapeutic drug monitoring (TDM) instance within 72&#xa0;h from starting standard dosing regimens were retrospectively included. A receiving operating characteristic (ROC) curve analysis was performed by using the proposed predictive score as the test variable and early aggressive PK/PD target non-attainment as the state variable. Area under the curve (AUC) and 95% confidence interval were calculated. The identified cut-off risk values were used for stratifying patients and assessing the impact on clinical/microbiological outcome in each sub-cohort of patients receiving targeted monotherapy.</p> Results <p>Overall, 209 and 203 patients receiving CI piperacillin-tazobactam and meropenem were included, respectively. Early aggressive PK/PD target non-attainment was reported in 33 cases (15.8%) receiving piperacillin-tazobactam and in 8 (3.9%) of those treated with meropenem. A score threshold ≥ 2 points for piperacillin-tazobactam (<i>AUC</i> 0.81; 95% <i>CI</i> 0.75–0.86; <i>p</i> &lt; 0.0001) and ≥ 3 points for patients treated with meropenem (<i>AUC</i> 0.96; 95% <i>CI</i> 0.93–0.99; <i>p</i> &lt; 0.0001) were significantly associated with early aggressive PK/PD target non-attainment. Patients achieving the cut-off predictive score showed a significant higher microbiological failure rate in both piperacillin-tazobactam (56.3% vs. 28.6%, <i>p</i> = 0.044) and meropenem sub-cohorts (50.0% vs. 10.4%, <i>p</i> = 0.028).</p> Conclusions <p>Our findings suggest that the proposed predictive cut-off risk score may represent a valuable tool for identifying promptly critically ill patients at high risk of early aggressive PK/PD target non-attainment with CI piperacillin-tazobactam or meropenem for whom a more intensified CI dosing regimens should be promptly applied bedside.</p>

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Validation of a predictive risk score of aggressive PK/PD target non-attainment with continuous infusion piperacillin/tazobactam or meropenem in critically ill patients having documented Gram-negative infections

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  • 发表日期：

    2025年12月4日

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  • Milo Gatti,
  • Pierantonio Grimaldi,
  • Matteo Rinaldi,
  • Antonio Siniscalchi,
  • Tommaso Tonetti,
  • Pierluigi Viale,
  • Federico Pea

摘要

Objective

To validate a predictive risk score of early aggressive pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment with continuous infusion (CI) piperacillin/tazobactam or meropenem in a retrospective cohort of critically ill patients having documented Gram-negative infections.

Methods

Critically ill adult patients receiving treatment of documented Gram-negative infections with CI piperacillin-tazobactam or meropenem and undergoing first real-time beta-lactam therapeutic drug monitoring (TDM) instance within 72 h from starting standard dosing regimens were retrospectively included. A receiving operating characteristic (ROC) curve analysis was performed by using the proposed predictive score as the test variable and early aggressive PK/PD target non-attainment as the state variable. Area under the curve (AUC) and 95% confidence interval were calculated. The identified cut-off risk values were used for stratifying patients and assessing the impact on clinical/microbiological outcome in each sub-cohort of patients receiving targeted monotherapy.

Results

Overall, 209 and 203 patients receiving CI piperacillin-tazobactam and meropenem were included, respectively. Early aggressive PK/PD target non-attainment was reported in 33 cases (15.8%) receiving piperacillin-tazobactam and in 8 (3.9%) of those treated with meropenem. A score threshold ≥ 2 points for piperacillin-tazobactam (AUC 0.81; 95% CI 0.75–0.86; p < 0.0001) and ≥ 3 points for patients treated with meropenem (AUC 0.96; 95% CI 0.93–0.99; p < 0.0001) were significantly associated with early aggressive PK/PD target non-attainment. Patients achieving the cut-off predictive score showed a significant higher microbiological failure rate in both piperacillin-tazobactam (56.3% vs. 28.6%, p = 0.044) and meropenem sub-cohorts (50.0% vs. 10.4%, p = 0.028).

Conclusions

Our findings suggest that the proposed predictive cut-off risk score may represent a valuable tool for identifying promptly critically ill patients at high risk of early aggressive PK/PD target non-attainment with CI piperacillin-tazobactam or meropenem for whom a more intensified CI dosing regimens should be promptly applied bedside.