EFFECT OF ATOVAQUONE AND ATOVAQUONE DRUG-COMBINATIONS ON PROPHYLAXIS OF PNEUMOCYSTIS-CARINII PNEUMONIA IN SCID MICE

The prophylactic efficacies of atovaquone (ATQ) alone and in combinati on with azithromycin, clarithromycin, rifabutin, proguanil, PS-15, tri methoprim, co-trimoxazole, or dapsone were investigated in a SCID mous e model of Pneumocystis carinii pneumonia (PCP), ATQ alone was shown t o have a significant dose-related effect, and at 200 mg/kg of body wei ght per day administered orally, the efficacy of ATQ was comparable to that of Septrin (co-trimoxazole). Of the drugs investigated orally in combination with ATQ, only dapsone (25 mg/kg/ day) and to a lesser ex tent PS-15 (5 mg/kg/day) had any noteworthy antipneumocystis activity (at the doses examined) when administered alone, ATQ drug combinations affected the prophylactic efficacy of a subcurative dosage of ATQ (50 mg/kg/day given orally) in the following ways: dapsone (25 mg/kg/day) or co-trimoxazole (35 mg of sulfamethoxazole plus 5 mg of trimethopri m per kg/day) had no significant effect on ATQ, azithromycin (200 mg/k g/day) or clarithromycin (200 mg/kg/day) had a slight additive effect with ATQ, trimethoprim (100 mg/kg/day) or PS-15 (5 mg/kg/day) had an a dditive effect with ATQ, and proguanil (25 mg/kg/day) or rifabutin (20 0 mg/kg/day.) had a marked synergistic effect on ATQ. The last result was particularly noteworthy as neither proguanil nor rifabutin was eff ective against PCP when administered alone. None of the drugs examined antagonized the prophylactic activity of ATQ in experimental PCP in S CID mice. The results suggest that clinical trials of ATQ with synergi stic drug combinations may nor be justified, particularly if such drug combinations improve ATQ's efficacy and broaden its spectrum of activ ity.