Premium
Development of novel in vitro and in vivo models to evaluate antibiotic efficacy against shigellosis
Author(s) -
Arnold Samuel,
McCloskey Molly,
Shaheen Shareef,
Hulverson Matthew,
Choi Ryan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.570.4
Subject(s) - shigellosis , shigella , medicine , azithromycin , dysentery , antibiotics , diarrhea , disease burden , bacillary dysentery , antibiotic resistance , drug resistance , ciprofloxacin , disease , immunology , microbiology and biotechnology , biology , pathology , bacteria , genetics , salmonella
Shigellosis is caused by oral ingestion of the gram‐negative bacteria Shigella . Symptoms of the disease include severe diarrhea and dysentery, and the impact of the disease disproportionately affects children and those in low‐income countries such as sub‐Saharan Africa, Asia, and Latin America. According to a reanalysis of the Global Enteric Multicenter Study (GEMS), Shigella has the highest attributable incidence of pathogen specific moderate to severe diarrhea in children between 12–59 months of age. Recent studies have estimated approximately 90 million shigellosis cases annually, and the Global Burden of Disease 2015 analysis suggests at least 164,000 deaths per year are due to Shigella . Interspecies‐variation with lack of cross‐protection may challenge the development of a broadly‐protective vaccine and no human vaccine candidates are currently approved for treatment. Therapeutic options for shigellosis are limited and globally emerging drug resistance to sulfonamides, tetracyclines, ampicillin, and TMP‐SMX has been reported. With resistance to many “first‐line” antibiotics, ciprofloxacin, azithromycin, and ceftriaxone have been recommended for treatment of shigellosis. However, rapidly evolving resistance has been reported for these antibiotics as well. While there is a clear need for novel therapeutics to treat this disease, current drug development efforts are hindered by a lack of fundamental in vitro and in vivo tools to assess the efficacy of pre‐clinical candidates. We have focused our efforts on establishing in vitro co‐culture systems and in vivo mouse models to evaluate small molecule therapeutics. Our aim is to use these tools to identify PK/PD relationships for established and novel therapeutics to treat Shigella infection. The gastrointestinal localization of the parasite generates a unique challenge for establishing a pharmacokinetic‐pharmacodynamic (PK/PD) relationship for an anti‐ Shigella drug candidate. We have previously reported on our use of physiology based pharmacokinetic (PBPK) modeling to identify an association between gastrointestinal drug concentrations and in vivo efficacy for anti‐ Cryptosporidium drugs and we plan to use a similar technique for the antibiotics used to treat Shigella infection. The presented work will be valuable for the entire research community currently engaged in the development of therapeutics for enteric diseases. Support or Funding Information This work was supported by the Tres Cantos Open Lab Foundation Award: TC246 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .