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 combination with azithromycin, clarithromycin, rifabutin, proguanil, PS-15, trimethoprim, co-trimoxazole, or dapsone were investigated in a SCID mouse model of Pneumocystis carinii pneumonia (PCP). ATQ alone was shown to have a significant dose-related effect, and at 200 mg/kg of body weight 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 extent 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 (25 mg of sulfamethoxazole plus 5 mg of trimethoprim per kg/day) had no significant effect on ATQ, azithromycin (200 mg/kg/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 additive effect with ATQ, and proguanil (25 mg/kg/day) or rifabutin (200 mg/kg/day) had a marked synergistic effect on ATQ. The last result was particularly noteworthy as neither proguanil nor rifabutin was effective against PCP when administered alone. None of the drugs examined antagonized the prophylactic activity of ATQ in experimental PCP in SCID mice. The results suggest that clinical trials of ATQ with synergistic drug combinations may now be justified, particularly if such drug combinations improve ATQ's efficacy and broaden its spectrum of activity.
Comley
J C
JC
Biology Division, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Sterling
A M
AM
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D053626:Atovaquone; D003622:Dapsone / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D051379:Mice; D016513:Mice, SCID; D009285:Naphthoquinones / Q000008:administration & dosage / Q000627:therapeutic use*; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control*; D002727:Proguanil / Q000008:administration & dosage; D017828:Rifabutin / Q000008:administration & dosage; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage
D000935:Antifungal Agents; D009285:Naphthoquinones; D017828:Rifabutin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D003622:Dapsone; D002727:Proguanil; D053626:Atovaquone