Scholarlink

Background <p>Ceftolozane/tazobactam (TOL/TAZ) and ceftazidime-avibactam (CAZ/AVI) are increasingly used to treat pneumonia caused by multidrug-resistant Gram-negative bacilli. However, data on intrapulmonary penetration to confirm dosing adequacy are limited. Therefore, the aim of this study was to compare epithelial lining fluid (ELF) penetration and pharmacokinetic/pharmacodynamic (PK/PD) target attainment of TOL/TAZ versus CAZ/AVI administered by continuous infusion (CI) in critically ill patients with nosocomial pneumonia.</p> Methods <p>Single-center, open-label, randomized pharmacokinetic (PK) study. Thirty patients were randomized 1:1 to receive 6&#xa0;g/3&#xa0;g of TOL/TAZ or 6&#xa0;g/1.5&#xa0;g of CAZ/AVI administered by CI. A population PK model was constructed using plasma and ELF concentrations. Lung penetration was estimated based on the ratio AUC<sub>0−8ELF</sub>/AUC<sub>0−8plasma</sub>. Simulations were performed to estimate the probability of attaining predefined joint ELF PK/PD target defined as free concentration 100% fT&gt; minimum inhibitory concentration (MIC) for the β-lactam component and 100% fT&gt; concentration threshold (CT) for the β-lactamase inhibitors, among relevant MIC scenarios. Three different dosing regimens (low, standard and high) were evaluated for each combination.</p> Results <p>A total of 298 plasma and 58 ELF samples were analyzed. The median [IQR] age, body mass index, and creatinine clearance were 77 [9.8] years, 26.48 [5.5] kg/m², and 76.0 [96.0] mL/min, respectively. Median intrapulmonary penetration was 0.66 [0.32] for ceftolozane, 0.41 [0.30] for ceftazidime 0.44 [0.05] for tazobactam and 0.44 [0.46] for avibactam. Under the prespecified ELF PK/PD target, standard dosing achieved adequate target attainment for both combinations. Simulations showed that all CAZ/AVI regimens achieved high ELF target attainment under conservative inhibitor threshold assumptions (assuming ceftazidime MIC = 8&#xa0;mg/L and avibactam C<sub>T</sub> =1&#xa0;mg/L), whereas for TOL/TAZ (assuming ceftolozane MIC = 4&#xa0;mg/L and tazobactam C<sub>T</sub> 2&#xa0;mg/L) at least the standard-dose regimen was required. More aggressive target scenarios reduced the probability of target attainment, particularly for inhibitor thresholds of 4&#xa0;mg/L and for Enterobacterales-oriented joint targets.</p> Conclusions <p>In critically ill adults with nosocomial pneumonia receiving TOL/TAZ or CAZ/AVI by CI, standard doses achieved ELF exposures consistent with dual PK/PD target attainment against all susceptible isolates. Interindividual variability and the risk of plasma overexposure support individualized dosing and consideration of therapeutic drug monitoring.</p> Trial registration <p>The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT No. 2021-006908-32). Registered 10 February 2022; <a href="https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-006908-32/ES">https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-006908-32/ES</a>.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Intrapulmonary penetration of ceftolozane/tazobactam and ceftazidime/avibactam administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月13日

查看全文
  • Adela Benítez-Cano,
  • Aymara Sancho-Araiz,
  • Jesús Carazo,
  • Isabel Ramos,
  • Albert Sánchez-Font,
  • Roberto Chalela,
  • Michelle López-Palacio,
  • Francisco F. García-Prieto,
  • María Eugenia Navarrete-Rouco,
  • Ana María Juanes-Borrego,
  • Joan Gómez-Junyent,
  • Juan P. Horcajada,
  • Ramón Adalia,
  • Jason Roberts,
  • Luisa Sorlí,
  • Sonia Luque

摘要

Background

Ceftolozane/tazobactam (TOL/TAZ) and ceftazidime-avibactam (CAZ/AVI) are increasingly used to treat pneumonia caused by multidrug-resistant Gram-negative bacilli. However, data on intrapulmonary penetration to confirm dosing adequacy are limited. Therefore, the aim of this study was to compare epithelial lining fluid (ELF) penetration and pharmacokinetic/pharmacodynamic (PK/PD) target attainment of TOL/TAZ versus CAZ/AVI administered by continuous infusion (CI) in critically ill patients with nosocomial pneumonia.

Methods

Single-center, open-label, randomized pharmacokinetic (PK) study. Thirty patients were randomized 1:1 to receive 6 g/3 g of TOL/TAZ or 6 g/1.5 g of CAZ/AVI administered by CI. A population PK model was constructed using plasma and ELF concentrations. Lung penetration was estimated based on the ratio AUC0−8ELF/AUC0−8plasma. Simulations were performed to estimate the probability of attaining predefined joint ELF PK/PD target defined as free concentration 100% fT> minimum inhibitory concentration (MIC) for the β-lactam component and 100% fT> concentration threshold (CT) for the β-lactamase inhibitors, among relevant MIC scenarios. Three different dosing regimens (low, standard and high) were evaluated for each combination.

Results

A total of 298 plasma and 58 ELF samples were analyzed. The median [IQR] age, body mass index, and creatinine clearance were 77 [9.8] years, 26.48 [5.5] kg/m², and 76.0 [96.0] mL/min, respectively. Median intrapulmonary penetration was 0.66 [0.32] for ceftolozane, 0.41 [0.30] for ceftazidime 0.44 [0.05] for tazobactam and 0.44 [0.46] for avibactam. Under the prespecified ELF PK/PD target, standard dosing achieved adequate target attainment for both combinations. Simulations showed that all CAZ/AVI regimens achieved high ELF target attainment under conservative inhibitor threshold assumptions (assuming ceftazidime MIC = 8 mg/L and avibactam CT =1 mg/L), whereas for TOL/TAZ (assuming ceftolozane MIC = 4 mg/L and tazobactam CT 2 mg/L) at least the standard-dose regimen was required. More aggressive target scenarios reduced the probability of target attainment, particularly for inhibitor thresholds of 4 mg/L and for Enterobacterales-oriented joint targets.

Conclusions

In critically ill adults with nosocomial pneumonia receiving TOL/TAZ or CAZ/AVI by CI, standard doses achieved ELF exposures consistent with dual PK/PD target attainment against all susceptible isolates. Interindividual variability and the risk of plasma overexposure support individualized dosing and consideration of therapeutic drug monitoring.

Trial registration

The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT No. 2021-006908-32). Registered 10 February 2022; https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-006908-32/ES.