Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

Abstract

Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids. This enabled the linking of antibacterial response at a single time point in an animal or in vitro infection model with one of three summary pharmacokinetic (PK) measures of in vivo exposure to the antibiotic. The summary PK exposure measures were normalised to the minimum inhibitory concentration (MIC), an in vitro measure of the pharmacodynamic (PD) potency of the drug. The three PK-PD indices (ratio of maximum concentration to MIC, ratio of area under the concentration-time curve to MIC, time concentration is above MIC) have been used extensively since the 1980s. While these MIC-based summary PK-PD metrics have undoubtedly facilitated the development of new antibiotics and the clinical application of both new and old antibiotics, it is increasingly recognised that they have a number of substantial limitations. In this article we use a historical perspective to review the origins of the three traditional PK-PD indices before exploring in detail their limitations and the implications arising from those limitations. Finally, in the interests of improving antibiotic development and dosing in patients, we consider a model-based approach of linking the full time-course of antibiotic concentrations with that of the antibacterial response. Such an approach enables incorporation of other factors that can influence treatment outcome in patients and has the potential to drive model-informed precision dosing of antibiotics into the future.

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against Pseudomonas aeruginosa for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model

“…The divergent responses achieved in the dynamic in vitro model between the combinations involving the two different modes of administration of piperacillin-tazobactam are consistent with previous studies that have demonstrated the impact of the shape of the exposure profile of an antibiotic on the resultant antibacterial response [ 41 , 42 , 43 , 44 , 45 , 46 ]. The marked reduction in bacterial load, synergy, and suppression of resistance achieved in the dynamic model for the combination of tobramycin administered once daily plus piperacillin-tazobactam via continuous infusion are consistent with required qualities of appropriate initial antibiotic treatment [ 47 ].…”

“…Despite the 2-fold and 8-fold differences in the MICs of tobramycin and piperacillin-tazobactam, respectively, between isolate Pa1281 and CR380, there was little difference in the respective time-courses of the total bacterial population across 120 h with any of the monotherapy regimens. This reinforces the increasing awareness and concern around the limitations of MIC measurements as a guide to antimicrobial chemotherapy and of the applicability of the traditional PK/PD indices ( f T >MIC , f C max /MIC and f AUC/MIC) and the associated exposure targets [ 17 , 45 , 53 , 54 , 55 , 56 , 57 ].…”

Prediction of Pharmacokinetics of IDP-73152 in Humans Using Physiologically-Based Pharmacokinetics

“…PK-PD analysis is likely to be an useful tool to establish the relationship between PK-PD and clinical outcome [59]. In particular, a mechanism-based model, coupled with a pathophysiological PK model, is readily applicable in optimizing the pharmacotherapeutics of antibiotics [60], such as IDP-73152. In this study, the predicted PK profile closely matched that from healthy male volunteers receiving the inhibitor, suggesting that the current PBPK model is adequate in predicting the PK profiles in other population groups (e.g., female volunteers, geriatrics, pediatrics, and patients with infectious disease).…”

Cell wall deficiency – an alternate bacterial lifestyle?

“…The use of an antibiotic MIC alone to determine effectiveness and target dosing concentrations is increasingly coming under scrutiny [140,141]. The observations that tolerance to supra-MIC antibiotic concentrations may occur through conversion to a CWD state provides further argument that the use of the MIC as the sole metric for antibiotic efficacy must be revisited.…”