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4CPS-075 A systematic review of the target pharmacokinetic/pharmacodynamic parameters of antibiotics treating gram-negative infections
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  1. H Tran1,
  2. N Henney2,
  3. J Madden1,
  4. P Penson1,
  5. S Culter1
  1. 1Liverpool John Moores University, School of Pharmacy and Biomolecular Sciences, Liverpool, UK
  2. 2University of Liverpool, School of Medicine, Liverpool, UK

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.

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