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

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 (Css/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 Css/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 Css/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 Css/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.

An Evidence-Based Multidisciplinary Approach Focused on Creating Algorithms for Targeted Therapy of Infection-Related Ventilator-Associated Complications (IVACs) Caused by Pseudomonas aeruginosa and Acinetobacter baumannii in Critically Ill Adult Patients

“…In regard to recommended dosages, some well-established evidence may support the use of CI over intermittent infusion in administering traditional antipseudomonal beta-lactams in critically ill patients [ 21 ]. Additionally, we recently showed in a large cohort of critically ill patients having documented Gram-negative infections treated with CI traditional beta-lactams that early achievement of an aggressive PK/PD target of Css/MIC > 5 within the first 72 h was significantly associated with both microbiological eradication and prevention of resistance development [ 22 ]. In the same study, Pseudomonas aeruginosa -related infections were independently associated with higher risk of microbiological failure [ 22 ].…”

“…Additionally, we recently showed in a large cohort of critically ill patients having documented Gram-negative infections treated with CI traditional beta-lactams that early achievement of an aggressive PK/PD target of Css/MIC > 5 within the first 72 h was significantly associated with both microbiological eradication and prevention of resistance development [ 22 ]. In the same study, Pseudomonas aeruginosa -related infections were independently associated with higher risk of microbiological failure [ 22 ]. Accordingly, we consider that when treating IVACs caused by multi-susceptible Pseudomonas aeruginosa isolates, the use of CI piperacillin–tazobactam and/or ceftazidime, and/or cefepime after loading may represent a valuable approach for rapidly achieving and maintaining an aggressive PK/PD target helpful at achieving microbiological eradication.…”

“…Monte Carlo simulation showed that higher meropenem dosages by CI should be recommended for dealing tackling appropriately Pseudomonas aeruginosa and Acinetobacter baumannii infections in critically ill patients with preserved renal function [ 68 ]. Likewise, a similar aggressive PK/PD target of Css/MIC > 5 within the first 72 h was significantly associated with both microbiological eradication and prevention of resistance development in a large cohort of critically ill patients having documented Gram-negative infections treated with CI traditional beta-lactams [ 22 ]. In regard to cefiderocol, we recently showed in a descriptive case series of PK/PD target attainment and microbiological outcome in critically ill patients with documented severe XDR Acinetobacter baumannii BSI and/or VAP that treatment with cefiderocol at the standard 3 #h infusion was ineffective in achieving the aggressive PK/PD of 100%fT > 4 × MIC in more than 50% of included patients.…”

“…Monte Carlo simulation showed that, according to cumulative fraction of response, higher meropenem dosages by CI should be recommended for the management of Acinetobacter baumannii related infections among patients with preserved renal function [ 68 ]. Likewise, a similar aggressive PK/PD target of Css/MIC > 5 within the first 72 h was significantly associated with both microbiological eradication and prevention of resistance development in a large cohort of critically ill patients having documented Gram-negative infections treated with CI traditional beta-lactams [ 22 ].…”

“…This aggressive strategy should be pursued also in the treatment of infections caused by wild-type strains. Optimal exposure into the ELF is difficult to be achieved and maintained with intermittent infusion of piperacillin–tazobactam, ceftazidime, and/or cefepime due to the limited penetration rates of these hydrophilic agents, and conversely, Pseudomonas aeruginosa was found to be an independent predictor of microbiological failure in critically ill patients affected by documented Gram-negative infections [ 22 ]. Clinicians must be aware that the antibiotic dosing regimens that we recommended throughout the manuscript are focused only on treatment of patients with normal renal function.…”