The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Abstract

The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/ sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/ sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.

Anti-fungal Activity of Sulfamethoxazole toward Aspergillus Species

“…However, some evidence suggests that at least some of the adverse reactions to SMX-TMP might be due to the TMP component 19,28,31) and that sulfonamides such as SMX alone have anti-P. carinii activity. 20,21) In the present study, SMX alone had anti-Aspergillus activity. Thus, sulfonamides may be useful for the prophylaxis of fungal infections by Aspergillus species and P. carinii etc.…”

“…Some research suggests that sulfonamides, such as SMX, alone have anti-P. carinii activity without Trimethoprim. [19][20][21] Figure 3 shows also that the anti-Aspergillus effect depended on SMX, not TMP. Thus, the dihydropteroate synthase (DHPS) that is a target enzyme of sulfonamides may differ between sulfonamide-sensitive fungi, such as P. carinii, Aspergillus and non-sensitive fungi, such as C. albicans.…”

Sulfa Use, Dihydropteroate Synthase Mutations, andPneumocystis jiroveciiPneumonia

“…Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line drug choice for both prophylaxis and therapy. TMP-SMX acts in animals as sulfa monotherapy against the enzyme dihydropteroate synthase (DHPS) ( 11 , 12 ). Dapsone, a sulfone drug also targeting DHPS, is frequently used as a second-line agent for prophylaxis and treatment of PCP.…”

In Vitro Activities of Pentamidine, Pyrimethamine, Trimethoprim, and Sulfonamides against Aspergillus Species

“…The result of decreased folic acid synthesis is a decrease in nucleotides, with subsequent inhibition of growth (21). Sulfonamides exhibit in vitro activity against a broad spectrum of gram-positive and gram-negative bacteria, parasites, and fungi (21), and the combination SXT acts synergistically against Paracoccidioides brasiliensis (3,9,16,17,20). The in vitro antimicrobial activity of sulfonamides is strongly influenced by the composition of the test medium, since the presence of PABA and folic acid in the medium inhibits their activity (21).…”