| 1. |
- Bulman, Zackery P., et al.
(author)
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Research priorities towards precision antibiotic therapy to improve patient care
- 2022
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In: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802
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Journal article (peer-reviewed)abstract
- Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.
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| 2. |
- Rayner, Craig R., et al.
(author)
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Model-Informed Drug Development for Anti-Infectives : State of the Art and Future
- 2021
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In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:4, s. 867-891
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Journal article (peer-reviewed)abstract
- Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; "depth" and "breadth" of MIDD methods. "MIDD depth" refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired-resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. "MIDD breadth" refers to greater adoption of model-centered approaches to anti-infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.
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