In vitro and in vivo activity of iclaprim, a diaminopyrimidine compound and potential therapeutic alternative against Pneumocystis pneumonia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-03

AUTHORS

E. M. Aliouat, E. Dei-Cas, N. Gantois, M. Pottier, C. Pinçon, S. Hawser, A. Lier, D. B. Huang

ABSTRACT

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim-sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose-response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 μg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 μg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia. More... »

PAGES

409-415

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10096-018-3184-z

DOI

http://dx.doi.org/10.1007/s10096-018-3184-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1100348895

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29330709


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