Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Milo Gatti; Pier Giorgio Cojutti; Renato Pascale; Tommaso Tonetti; Cristiana Laici; Alessio Dell'Olio; Antonio Siniscalchi; Maddalena Giannella; Pierluigi Viale; Federico Pea

doi:10.3390/antibiotics10111311

Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Antibiotics (Basel). 2021 Oct 27;10(11):1311. doi: 10.3390/antibiotics10111311.

Authors

Milo Gatti^{1

2}, Pier Giorgio Cojutti², Renato Pascale³, Tommaso Tonetti^{1

4}, Cristiana Laici⁵, Alessio Dell'Olio^{1

4}, Antonio Siniscalchi⁵, Maddalena Giannella^{1

3}, Pierluigi Viale^{1

3}, Federico Pea^{1

2}

Affiliations

¹ Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy.
² SSD Clinical Pharmacology, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy.
³ Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy.
⁴ Division of Anesthesia and Intensive Care Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy.
⁵ Division of Anesthesiology, Department of Anesthesia and Intensive Care of Abdominal Organ Transplantation and Hepatobiliary Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy.

Abstract

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections.

Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (C_ss/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression.

Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A C_ss/MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6-93.4%) and specificity of 90.5% (CI 74.2-94.4%), and with an AUC of 0.868 (95%CI 0.793-0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were C_ss/MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45-160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11-20.79; p = 0.036).

Conclusions: Early targeting of CI beta-lactams at C_ss/MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

Keywords: Css/MIC; PK/PD target attainment; Pseudomonas aeruginosa; beta-lactams; continuous infusion; critically ill patients; gram-negative infections; microbiological failure; resistance development.