LAUSR

Pharmacokinetic/Pharmacodynamic (PK/PD) principles have become a backbone of antibiotic drug development and dose selection for novel as well established antimicrobials (Palmer et al.). The ultimate aim obviously is to optimize treatment of patients suffering from an infection, but other goals like accelerating access to novel antibiotics and reduction of development costs as well as prevention of development of bacterial resistance and setting of appropriate breakpoints are of high relevance, too. As seen for every novel approach it took some time to establish applicable PK/PD paradigms, but in parallel the complexity of the models (both in vitro and in vivo) and the understanding of the processes has increased dramatically. In the present Research Topic prominent experts in the field of PK/PD set out to challenge some of these paradigms, either by a reality check or by improvements of the currently used models. Since preclinical PK/PD thresholds are a cornerstone of PK/PD studies that are used to determine the best dosing regimen in patients, two manuscripts dealt with PK/PD targets of βLactam antibiotics. While for meropenem 40% T > MIC is associated with optimal killing of pathogens, Nussbaumer et al. for the first time could demonstrate that the distribution of the % T >MIC periods throughout the day did impact the bacterial eradication. In line with this Berry and Kuti identified the need for targets that are specific to each antibiotic and pathogen, in particular during dosage regimen development and susceptibility breakpoint assessment. Thereby both studies demonstrated that some common paradigms of PD thresholds might be over-simplified. Although the importance of the bacterial inoculum is well known in vitro, in another oversimplification most animal PDmodels use a standardized inoculum, and few in vivo studies have investigated the impact of inoculum size on survival or antibiotic efficacy. The study by Chauzy et al., therefore, set out to investigate the influence of inoculum size on polymyxin B against A. baumannii confirming an inoculum effect. Even if appropriate PK/PD parameters are identified given all the methodological challenges mentioned above, achieving the desired exposure in individual patients remains challenging. Thus, another study on Polymyxin B addressed the problem of correctly dosing this potentially nephrotoxic drug in obese patients, Wang et al. identified an adjusted body weight (ABW)-based regimen that has a high likelihood of achieving the targeted exposure. Alternative to using body weight adapted dosing regimens, TDM (therapeutic drug monitoring) approaches can be used to individualize dosing of antibiotics. Yet, in clinical practice often only sparse PK is available and results may not be timely to impact patient care. Thus, a clinical OPEN ACCESS