Dataset Information

Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model.

ABSTRACT: Cryptosporidiosis causes life-threatening diarrhea in infants, but the best available treatment is only modestly efficacious. Rodents infected with relevant Cryptosporidium species do not develop diarrhea, which complicates drug development. Cryptosporidium parvum infection of dairy calves, however, causes an illness like that seen in infants. Here, the clinical and microbiologic anti-Cryptosporidium efficacy of the piperazine-based compound MMV665917 was demonstrated in neonatal calves. Oral administration of MMV665917 (22 mg/kg once daily) was begun two days after the onset of severe diarrhea and continued for seven days. Treatment resulted in prompt resolution of diarrhea, and reduced total fecal oocyst shedding by ~94%. MMV665917 was useful for treatment, rather than just prophylaxis, since it was safe and effective when administered well after the onset of diarrhea. Furthermore, even though all animals received intensive supportive care, there was a strong trend towards improved secondary health outcomes, including general health, appetite, and dehydration measures amongst treated animals. These data establish MMV665917 as an outstanding lead compound for Cryptosporidium drug development.

SUBMITTER: Stebbins E

PROVIDER: S-EPMC5774826 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model.

Stebbins Erin E Jumani Rajiv S RS Klopfer Connor C Barlow John J Miller Peter P Campbell Mary A MA Meyers Marvin J MJ Griggs David W DW Huston Christopher D CD

PLoS neglected tropical diseases 20180108 1

Cryptosporidiosis causes life-threatening diarrhea in infants, but the best available treatment is only modestly efficacious. Rodents infected with relevant Cryptosporidium species do not develop diarrhea, which complicates drug development. Cryptosporidium parvum infection of dairy calves, however, causes an illness like that seen in infants. Here, the clinical and microbiologic anti-Cryptosporidium efficacy of the piperazine-based compound MMV665917 was demonstrated in neonatal calves. Oral ad ...[more]

PMID: 29309415

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Project description:Health problems can be thought of as phenotypic expressions of the complex relationships between genes, environments, and phenomes as a whole. Detailed evaluations of phenotypic expressions of illness are required to characterize important biological outcomes. We hypothesized that classifying dairy calf mortality phenotypes via a systematic postmortem analysis would identify different cause-of-death diagnoses than those derived from treatments alone. This cross-sectional study was carried out on a dairy calf ranch in the northwestern United States from June to September 2017 and focused on calves ≤90 d of age. Comparisons were made between causes of death based on 3 levels of information: on-farm treatment records alone, necropsy-based postmortem analyses in addition to treatment records, and Washington Animal Disease Diagnostic Laboratory (WADDL) results in addition to all other information. A total of 210 dairy calves were necropsied during this study, of which 122 cases were submitted to WADDL. Necropsy- and WADDL-derived mortality phenotypes were in almost perfect agreement (Cohen's κ = 0.86) when broadly categorized as diarrhea, respiratory, diarrhea and respiratory combined, or other causes. The level of agreement between on-farm treatment records and postmortem-derived results was low and varied by the level of diagnostic detail provided. There was just fair agreement (κ = 0.22) between treatment-based and necropsy-based phenotypes without WADDL input and only slight agreement (κ = 0.13) between treatment-based and corresponding necropsy-based phenotypes with WADDL input. Even for those cases in which causes of death aligned along a comparable pathologic spectrum, the lack of detail inherent to standard treatment-based causes of death failed to identify meaningful target areas for intervention. This was especially apparent for numerous cases of necrotizing enteritis and typhlitis (cecal inflammation) that were variously categorized as diarrhea and pneumonia by treatment-based diagnoses. The specificity of these lesions stood in stark contrast to the otherwise generic cause of death diagnoses derived from treatments. The findings from this study supported the hypothesis and highlighted the value of on-farm necropsies and laboratory-based diagnostics to (1) detect antemortem disease misclassifications, (2) provide detail regarding disease processes and mortality phenotypes, and (3) direct disease mitigation strategies.

Project description:BackgroundAnimal studies are pivotal in allowing experimentation to identify efficacious treatment protocols for resolution of peri-implantitis. The purpose of this investigation was to characterize an expedited dog peri-implantitis model clinically, radiographically, and microbiologically.MethodsEight hound dogs underwent extractions (week 0) and implant (3.3?×?8.5?mm) placement with simultaneous surgical defect creation and ligature placement for induction of peri-implantitis (week 10). Ligatures were replaced at 6?weeks (week 16) and removed after 9?weeks (week 19) when supporting bone loss involved approximately 50% of the peri-implant bone. Microbial samples from the defects and healthy control implant sites collected at week 19 were analyzed utilizing a microarray. Clinical measures of inflammation were obtained and radiographic bone loss was measured from periapical radiographs. Radiographic depth and width measurements of bony defect were repeated at weeks 10 (baseline), 16, and 19. Canonical analysis of principal coordinates was used to visualize overall differences in microbial abundance between peri-implantitis and healthy implants.ResultsThis accelerated disease protocol led to intrabony defect creation with a mean depth and width of 4.3?mm and 3.5?mm, respectively after 9?weeks of ligature placement. Microbial identification revealed 59 total bacteria in peri-implant sites, 21 of which were only present in peri-implant sites as compared to healthy controls. Overall microbial beta diversity (microbial between-sample compositional diversity) differed between peri-implantitis and healthy implants (p?=?0.009).ConclusionsWithin the limitations of this study, this protocol led to expedited generation of peri-implant defects with a microbial profile indicative of a shift to disease and defect patterns conducive to regenerative treatment. However, the possibility of potential spontaneous resolution of lesions due to the lack of a chronicity interval as compared to chronic disease models need to be further clarified and considered during preclinical peri-implantitis model selection.

Dataset Information

Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model.

Publications

Clinical and microbiologic efficacy of the piperazine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model.

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