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

• Published in: European Journal of Clinical Microbiology and Infectious Diseases 2018-03, Vol.37 (3), p.409-415
• Main Authors: Aliouat, E. M., Dei-Cas, E., Gantois, N., Pottier, M., Pinçon, C., Hawser, S., Lier, A., Huang, D. B.
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Hormones; Animals; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - pharmacology; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Biocompatibility; Biomedical and Life Sciences; Biomedicine; Chemical compounds; Corticosteroids; Culture techniques; Dihydrofolate reductase; Female; In vivo methods and tests; Internal Medicine; Life Sciences; Medical Microbiology; Microbial Sensitivity Tests; Oral administration; Original Article; Pharmacology; Pneumocystis carinii - drug effects; Pneumonia; Pneumonia, Pneumocystis - microbiology; Pure culture; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats; Rats, Wistar; Sulfamethoxazole; Trimethoprim
• ISSN: 0934-9723; 1435-4373
• DOI: 10.1007/s10096-018-3184-z

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 (E max ) and the drug concentrations needed to reach 50% of E max (EC 50 ) were determined, and the slope of the dose–response curve was estimated by the Hill equation (E max sigmoid model). The iclaprim EC 50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC 50 : 13.2/66 μg/mL) ( p  = 0.002). The TMP/SMX EC 50 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.