Background: To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. Methods: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT_>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. Results: A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15–2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01–0.29). Male gender, body mass index > 30 kg/m², augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. Conclusions: Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

The aim of this study was to explore the relationship between cefiderocol pharmacokinetic/pharmacodynamic (PK/PD) target attainment and microbiological outcome in critically ill patients affected by extensively drug-resistant Acinetobacter baumannii (XDR-AB) bloodstream infection (BSI) and/or ventilator-associated pneumonia (VAP). Patients who received compassionate use of cefiderocol to treat documented XDR-AB infections at the intensive care unit of the IRCCS Azienda Ospedaliero-Universitaria of Bologna and who underwent therapeutic drug monitoring (TDM) from 15 March 2021 to 30 April 2021 were retrospectively assessed. Cefiderocol trough concentration (C_min) was determined at steady-state, and the free fraction (fC_min) was calculated according to a plasma protein binding of 58%. The fC_min/MIC ratio was selected as a pharmacodynamic parameter of cefiderocol efficacy and was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The association between fC_min/MIC and microbiological outcome was assessed. A total of 13 patients treated with cefiderocol for the management of XDR-AB infections (6 BSI plus VAP, 5 VAP and 2 BSI) were retrieved. fC_min/MIC ratios were suboptimal in 3 cases (23%) and quasi-optimal or optimal in 5 cases each (38%). Microbiological failure occurred in seven cases (54%; six with VAP and one with VAP plus BSI). Microbiological failure occurred in 80% of patients with suboptimal fC_min/MIC compared with 29% of those achieving optimal or quasi-optimal fC_min/MIC ratio. Suboptimal attainment of PK/PD targets of cefiderocol may lead to microbiological failure of treatment with cefiderocol of critically ill patients affected by XDR-AB VAP.

Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.

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.

Acute kidney injury represents a common complication in critically ill patients affected by septic shock and in many cases continuous renal replacement therapy (CRRT) may be required. In this scenario, antimicrobial dose optimization is highly challenging as the extracorporeal circuit may cause several pharmacokinetic alterations, which add up to volume of distribution and clearance variations resulting from sepsis. Variations in CRRT settings (i.e. modality of solute removal, type of filter material, blood flow rate and effluent flow rate), coupled with the presence of residual and/or recovering renal function, may cause dynamic variations in the clearance of hydrophilic antimicrobials. This means that dose reduction may not always be needed. Nowadays, the lack of pharmacokinetic data for novel antimicrobials during CRRT limits evidence-based dose recommendations for critically ill patients in this setting, thus making available evidence hardly applicable in real-world scenarios. This review aims to summarize the major determinants involved in antimicrobial clearance, and the available pharmacokinetic studies performed during CRRT involving novel antibiotics used for the management of multidrug-resistant Gram-positive and Gram-negative infections (namely ceftolozane–tazobactam, ceftazidime–avibactam, cefiderocol, imipenem–relebactam, meropenem–vaborbactam, ceftaroline, ceftobiprole, dalbavancin, and fosfomycin), providing a practical approach in guiding dose optimization in this special population.

Purpose: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (V_D), and lipophilicity) and PD (values of binding affinity (Ki) and IC₅₀ for serotonin reuptake transporter (SERT) and 5-HT_2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large V_D (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for V_D/Ki SERT ratio (p = 0.05). Discussion: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.