Article Text
Abstract
Background and Importance Following the introduction of pharmacokinetic/pharmacodynamic (PK/PD) parameters in preclinical development of antibiotics, the application of PK/PD in guiding doses has been highly encouraged. Previous findings remain controversial and vary greatly, causing difficulties in determining the appropriate PK/PD parameters for individuals in practice.
Aim and Objectives This systematic review aims to identify the PK/PD targets of antibiotics treating gram-negative infections in clinical practice, focusing on multi-drug resistant gram-negative infections.
Material and Methods Database from Cochrane Central, Web of Science, PubMed, Embase and Scopus were searched using defined terms. Studies using PK/PD targets to determine dosing regimens of parenteral antibiotics for patients with gram-negative infections in practice were selected. Studies were excluded if examining the PK/PD targets of antibiotics for healthy participants, virtual patients, and gram-positive infections. Study bias was evaluated using the Cochrane risk of bias tool.
Results A total of 41 studies investigating 21 antibiotics and two combinations involving 799 participants were selected. The majority of eligible studies (21 articles, 51.2%) were case studies, which were evaluated as high risk of bias. Three (5.9%) studies were RCTs and 17 (33.3%) were non-RCTs. Only one RCT was evaluated as at low risk of bias. 58% of the investigated population was treated using predefined PK/PD indices derived from preclinical studies. Yet, among them, more than 60% modified the dosing and the duration of administration to attain a higher target value. Cefiderocol and meropenem were the two antibiotics most prescribed for multi-drug resistant bacteria, usually combined with other antibiotics. Extended infusion of meropenem to at least 30 minutes per administration resulted in the achievement of 100% fT>MIC or 100% fT>4–6 MIC instead of 40% fT>MIC while the prescription of Cefiderocol followed the labelled instruction of use. Still, about 79% of these cases targeted a higher value of predefined 77% fT>MIC derived from preclinical data.
Conclusion and Relevance The PK/PD target values of antibiotics treating resistant gram-negative bacteria are variable and divergent from preclinical data. A range of PK/PD targets may be more realistic in practice to optimise dosing regimens for the facilitation of clinical outcomes, and PK/PD targets should be used to inform dosing regimens. Further research with standardised patient outcomes is required.
Conflict of Interest No conflict of interest.