Moving From Point‐Based Analysis to Systems‐Based Modeling: Integration of Knowledge to Address Antimicrobial Resistance Against MDR Bacteria

Garcia, Estefany; Ly, Neang S.; Diep, John K.; Rao, Gauri G.

doi:10.1002/cpt.2219

Cited by 20 publications

(19 citation statements)

References 83 publications

(166 reference statements)

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“…Garcia et al . highlight the value of a systems modeling approach to optimizing anti‐infective pharmacotherapy 11 . While static point‐based frameworks for design of antibiotic regimens based largely on metrics like the minimum inhibitory concentration and summary pharmacokinetic parameters have been widely used, they fail to consider the time course of the antimicrobial effect, microbiological heterogeneity in sensitivity, host immunodynamics, and associated inter‐relationships.…”

Section: Midd In Anti‐infective Development: a Case For Integrating S...mentioning

confidence: 99%

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

Venkatakrishnan

Graaf

2021

Clin Pharma and Therapeutics

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The Merriam-Webster dictionary offers the essential meaning of a model as "a usually small copy of something," or "a set of ideas and numbers that describe the past, present, or future state of something." Model-informed drug development (MIDD) involves the strategic creation and integration of mathematical models for knowledge management, predictions, and decision making in pharmaceutical research and development. These models can "connect the dots" across various inputs related to drug properties, disease biology, patient characteristics and trial designs, transforming data to knowledge, enhancing efficiency in drug discovery and development, and maximizing therapeutic potential. This issue of Clinical Pharmacology and Therapeutics (CPT) includes Original Research Articles, Reviews, and Perspectives illustrating recent advances in established and emerging areas of MIDD, highlighting opportunities for interdisciplinary and cross-sector collaboration for enhancing impact.

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Section: Midd In Anti‐infective Development: a Case For Integrating S...mentioning

confidence: 99%

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

Venkatakrishnan

Graaf

2021

Clin Pharma and Therapeutics

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“…The rapid development of MDR bacteria due to the improper and overuse of antibiotics, together with their ineffective performance, against the difficult-to-treat biofilm-related infections (BRIs) have urgently called for alternative antimicrobial agents and strategies to combat bacterial infections [ 67 ]. MDR in bacteria may be generated by several mechanisms.…”

Section: Mdr and Antimicrobialsmentioning

confidence: 99%

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

et al. 2022

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Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.

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“…A common advantage of time–kill approaches is that they allow for the evaluation of the complete PK/PD time-course, which overcomes many limitations related to the sequential workflow and dependence on summary endpoints of the PK/PD index approach [ 83 , 84 , 85 , 86 , 87 , 88 ]. Different antibiotics, pathogens, dosing regimens, or shapes of PK profiles can be compared in much more detail, even if these profiles have similar PK/PD index magnitudes and thus would be deemed equally effective in conventional PTA analyses.…”

Section: Time–kill Curve Approachesmentioning

confidence: 99%

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

Zeitlinger

2021

Antibiotics

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Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.

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Moving From Point‐Based Analysis to Systems‐Based Modeling: Integration of Knowledge to Address Antimicrobial Resistance Against MDR Bacteria

Cited by 20 publications

References 83 publications

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

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