FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development

Byrne, James M; Waack, Ursula; Weinstein, Edwin A.; Joshi, Abhay; Shurland, Simone M.; Iarikov, Dmitri; Bulitta, Jürgen B.; Diep, Binh An; Guina, Tína; Hope, William; Lawrenz, Matthew B.; Lepak, Alexander J.; Luna, Brian; Miesel, Lynn; Phipps, Andrew J.; Walsh, Thomas J.; Weiss, Jason; Amini, Thushi; Farley, John

doi:10.1128/aac.01983-20

Cited by 13 publications

(18 citation statements)

References 6 publications

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“…The standard animal infection model is the mouse thigh infection model, which is relatively easy to handle. Given the move toward less clinical data and larger reliance on preclinical data, larger and more sophisticated animal models that better mimic the clinical picture in patients are being developed in rats, rabbits, and pigs 12 …”

Section: Preclinical Studies Of Antibioticsmentioning

confidence: 99%

Pivotal Role of Translation in Anti‐Infective Development

Friberg

2021

Clin Pharma and Therapeutics

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The value of model‐based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de‐risk later development stages. The importance of time‐dependencies, which are typically species‐dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low‐information end points used. It is time to recognize the limitations of using time‐collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time‐course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species‐differences in the PK profiles driving the killing. Furthermore, with a model‐based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.

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Section: Preclinical Studies Of Antibioticsmentioning

confidence: 99%

Pivotal Role of Translation in Anti‐Infective Development

Friberg

2021

Clin Pharma and Therapeutics

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“…However, organizations such as the Food and Drug Administration (FDA) have recently pushed for the continued advancement of in vitro and in vivo animal models for clinical studies that would not be plausible using in vivo animal models. These studies could gain information on the effects of drugs or processes that would be unethical to perform on humans and with the use of additional models provide greater confidence in results (Byrne et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of soap and water‐based skin decontamination using in vitro animal models: A systematic review

Green

Kashetsky

Feschuk

et al. 2021

J of Applied Toxicology

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Water and/or soap and water solutions have historically been used as first-line decontamination strategies for a wide variety of dermal contaminants from workplace exposure, environmental pesticides, and civilian chemical warfare. Although water and/or soap and water solutions are often considered a gold standard of decontamination, many studies have found other decontamination methods to be superior. This systematic review summarizes the available data on in vitro animal models contaminated with a various chemicals and their decontamination with water and/or soap and water solutions using in vitro animal models. A comprehensive literature search was performed using Concordance, Embase, PubMed, Medline, Web of Science, and Google Scholar to find in vitro animal studies that provided data on dermal decontamination using water and/or soap and water solutions. Five studies were included that analyzed 11 contaminants across two in vitro animal models (rats and pigs). Water alone was used as a decontamination method for 63.6% of the contaminants (n = 7/11) and water and soap solutions for decontamination in 54.6% of contaminants (n = 6/11). Water alone provided incomplete contaminant removal of five of seven contaminants studied; soap and water did not show significant difference in decontamination when compared with other solutions for all four contaminants and was superior to water for both contaminants studied. Water and/or soap and water are used as decontamination strategies for a variety of dermal contamination events, but for many contaminants, they do not provide complete contamination when compared with newer decontamination solutions studied with in vitro animal models.

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“…Animal models for bacterial infection are often considered valuable tools for developing new drugs and vaccines ( Byrne et al 2020 ). Some mouse models of A. baumannii infection have been established, and immune responses and treatments against the pathogen have been analyzed ( Crandon et al 2009 ; Qiu et al 2009a ; 2009b ; Jacobs et al 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Histopathological Analysis of Acinetobacter baumannii Lung Infection in a Mouse Model

Tansho-Nagakawa

Sato

Ubagai

et al. 2021

Polish Journal of Microbiology

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Acinetobacter baumannii is the main causative pathogen of noso¬comial infections that causes severe infections in the lungs. In this study, we analyzed the histopathological characteristics of lung infection with two strains of A. baumannii (ATCC 19606 and the clinical isolate TK1090) and Pseudomonas aeruginosa PAO-1 in C3H/HeN mice to evaluate the virulence of A. baumannii. Survival was evaluated over 14 days. At 1, 2, 5, or 14 days postinfection, mice of C3H/HeN were sacrificed, and histopathological analysis of lung specimens was also performed. Histopathological changes and accumulation of neutrophils and macrophages in the lungs after infection with A. baumannii and P. aeruginosa were analyzed. Following intratracheal inoculation, the lethality of ATCC 19606- and TK1090-infected mice was lower than that of PAO-1-infected mice. However, when mice were inoculated with a sub-lethal dose of A. baumannii, the lung bacterial burden remained in the mice until 14 days post-infection. Additionally, histopathological analy¬sis revealed that macrophages infiltrated the lung foci of ATCC 19606-, TK1090-, and PAO-1-infected mice. Although neutrophils infiltrated the lung foci of ATCC 19606- and TK1090-infected mice, they poorly infiltrated the lung foci of PAO-1-infected mice. Accumulation of these cells in the lung foci of ATCC 19606- and TK1090-infected mice, but not PAO-1-infected mice, was observed for 14 days post-infection. These results suggest that A. baumannii isnot completely eliminated despite the infiltration of immune cellsin the lungs and that inflammation lasts for prolonged periods in the lungs. Further studies are required to understand the mecha¬nism of A. baumannii infection, and novel drugs and vaccines should be developed to prevent A. baumannii infection.

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FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development

Cited by 13 publications

References 6 publications

Pivotal Role of Translation in Anti‐Infective Development

Pivotal Role of Translation in Anti‐Infective Development

Efficacy of soap and water‐based skin decontamination using in vitro animal models: A systematic review

Histopathological Analysis of Acinetobacter baumannii Lung Infection in a Mouse Model

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