Abstract
The effect of clindamycin (CLI) combined with autovaquone (ATO) was examined in a murine model of acute toxoplasmosis. Swiss Webster mice intraperitoneally infected with 10(2) or 10(4) tachyzoites of the RH strain of Toxoplasma gondii were perorally treated with either drug alone (for ATO, 5, 25, 50, or 100 mg/kg of body weight/day; for CLI, 25, 50, or 400 mg/kg/day) or both combined (for ATO plus CLI, respectively, 5 plus 25, 25 plus 25, 25 plus 50, 50 plus 50, or 100 plus 400 mg/kg/day) starting with day 1 for 14 days. Survival was monitored during 7 weeks. Residual infection was assessed by a bioassay of representative 4-week survivors and by parasite DNA detection by PCR for representative 7-week survivors. An effect of treatment was shown in all treatment groups compared to untreated control mice (P = 0.0000). Among mice infected with 10(2) parasites, ATO and CLI at any dose combination protected significantly more animals than ATO alone (P = 0.0000), but compared to CLI alone, given its good effect, the combined drugs were no more effective (P > 0.05). For mice infected with 10(4) parasites, the drugs combined at the lowest and highest doses (5 plus 25 and 100 plus 400 mg/kg/day) were, similarly, more effective than ATO alone (P = 0.035 and 0.000, respectively) but not than CLI alone (P > 0. 05). However, treatment with ATO plus CLI at 25 plus 25, 25 plus 50, and 50 plus 50 mg/kg/day protected 20, 33, and 78% of mice, respectively, compared to virtually no survivals among those treated with either drug alone (P < 0.0005), thus demonstrating a significant synergistic effect of ATO and CLI against T. gondii. Furthermore, the dose of ATO at a given dose of CLI was shown to be critical to the effect. Moreover, the absence of residual infection in some survivors shows the potential of this drug combination to eliminate the parasite.
Highlights
The inability of any presently available therapeutic regimen to eliminate Toxoplasma gondii from the infected host requires lifelong maintenance therapy for patients with human immunodeficiency virus-induced immunosuppression who develop reactivated toxoplasmosis
We examined in an in vivo experimental model of acute toxoplasmosis whether the addition of ATO to CLI would be beneficial for its anti-T. gondii effect and, if this combination is capable of eliminating the parasite, as suggested
Crease in the dose of ATO significantly enhanced the effect of the combined drugs may offer direction for future clinical trials of the anti-T. gondii potential of this drug combination. This is the first report to date on the anti-T. gondii activity of CLI combined with ATO
Summary
The inability of any presently available therapeutic regimen to eliminate Toxoplasma gondii from the infected host requires lifelong maintenance therapy for patients with human immunodeficiency virus-induced immunosuppression who develop reactivated toxoplasmosis. Clindamycin (CLI) is an alternative drug widely used as a single agent or combined with pyrimethamine [7, 8] It has remarkable but delayed in vitro anti-T. gondii activity, achieved at low drug concentrations [22]. In addition to the well-established anti-T. gondii activity of CLI as a single agent in animal models of infection [1, 10, 19, 29], doses of CLI that were ineffective when used alone were shown to afford protection in acute murine toxoplasmosis if combined with rifabutin [5]. We examined in an in vivo experimental model of acute toxoplasmosis whether the addition of ATO to CLI would be beneficial for its anti-T. gondii effect and, if this combination is capable of eliminating the parasite, as suggested
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