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Validated Preclinical Mouse Model for Therapeutic Testing against Multidrug-Resistant Pseudomonas aeruginosa Strains.
Warawa, Jonathan M; Duan, Xiaoxian; Anderson, Charles D; Sotsky, Julie B; Cramer, Daniel E; Pfeffer, Tia L; Guo, Haixun; Adcock, Scott; Lepak, Alexander J; Andes, David R; Slone, Stacey A; Stromberg, Arnold J; Gabbard, Jon D; Severson, William E; Lawrenz, Matthew B.
Afiliação
  • Warawa JM; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Duan X; Department of Microbiology and Immunology, University of Louisvillegrid.266623.5 School of Medicine, Louisville, Kentucky, USA.
  • Anderson CD; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Sotsky JB; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Cramer DE; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Pfeffer TL; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Guo H; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Adcock S; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Lepak AJ; Department of Radiology, University of Louisvillegrid.266623.5 School of Medicine, Louisville, Kentucky, USA.
  • Andes DR; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
  • Slone SA; Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
  • Stromberg AJ; Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
  • Gabbard JD; Dr. Bing Zhang Department of Statistics, University of Kentuckygrid.266539.d, Lexington, Kentucky, USA.
  • Severson WE; Dr. Bing Zhang Department of Statistics, University of Kentuckygrid.266539.d, Lexington, Kentucky, USA.
  • Lawrenz MB; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisvillegrid.266623.5, Louisville, Kentucky, USA.
Microbiol Spectr ; 10(5): e0269322, 2022 10 26.
Article em En | MEDLINE | ID: mdl-36094219
The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD50) analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used as comparators during the future evaluation of novel antimicrobials, and we confirmed that the model can effectively differentiate between successful and unsuccessful treatments, as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa strains, with the ability to provide rapid preclinical evaluation of novel antimicrobials and support data from clinical studies during the investigational drug development process. IMPORTANCE The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials. Successful outcomes in animal models not only justify progression of new drugs into human clinical trials but also can support FDA decisions if clinical trial sizes are small due to a small population of infections with specific drug-resistant strains. However, in both cases the preclinical animal model needs to be well characterized and provide robust and reproducible data. Toward this goal, we have refined an existing mouse model to better predict the efficacy of novel antibiotics. This improved model provides an important tool to better predict the clinical success of new antibiotics.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Amicacina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pseudomonas aeruginosa / Amicacina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article