Optimizing β-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective?

ABSTRACT

Introduction: The pharmacokinetic/pharmacodynamic index determining β-lactam activity is the percentage of the dosing interval (%T) during which their free serum concentration remains above a critical threshold over the minimum inhibitory concentration (MIC). Regrettably, neither the value of %T nor that of the threshold are clearly defined for critically-ill patients.

Areas covered: We review and assess the targets proposed for β-lactams in critical illness by screening the literature since 1997. Depending on the study intention (clinical cure vs. suppression of resistance), targets proposed range from 20%T > 1xMIC to 100%T > 5xMIC. Assessment and comparative analysis of their respective clinical efficacy suggest that a value of 100%T > 4xMIC may be needed. Simulation studies, however, show that this target will not be reached at first dose for the majority of critically-ill patients if using the most commonly recommended doses.

Expert commentary: Considering that critically-ill patients are highly vulnerable and likely to experience antibiotic underexposure, and because effective initial treatment is a key determinant of clinical outcome, we support the use of a target of 100%T > 4xMIC, which could not only maximize efficacy but also minimize emergence of resistance. Clinical and microbiological studies are needed to test for the feasibility and effectiveness of reaching such a demanding target.

KEYWORDS:

• Β-lactams
• critically-ill patients
• PK/PD targets
• first dose
• maximal efficacy

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

1. According to the terminology of the European Committee for Antimicrobial Susceptibility Testing (EUCAST; see http://www.eucast.org) and used for inclusion in the Summary of Product Characteristics in Europe. The US Clinical and Laboratory Standard Institute (CLSI) and the US Food and Drug Administration (FDA) define as resistant an organism with an MIC ≥ to their corresponding ‘R’ breakpoint, which may be different from the ‘R’ EUCAST breakpoint.

2. Web version of the US National Library of Medicine – National Institutes of Health; available at https://www.ncbi.nlm.nih.gov/pubmed.

Additional information

Funding

This paper was funded by the European Union’s (FP7 programme) – Belgian Fonds de la Recherche Scientifique.