Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii

Abstract

The efficacy of atovaquone (ATO) combined with clindamycin (CLI) against Toxoplasma gondii was examined in murine models of infection with a mouse-non-virulent (Me49) strain. Swiss-Webster mice inoculated by mouth with 10 or 20 cysts were treated with ATO and CLI alone or combined at dosages of ATO 5-100 and CLI 25-400 mg/kg/day for 2-4 weeks. Drug treatment was initiated (i) day 4 post-infection (acute infection), (ii) 3 months post-infection (chronic infection) and (iii) following a 2-3 week course of treatment with dexamethasone (DXM) alone or combined with cortisone-acetate (CA) introduced 3 months post-infection (reactivated toxoplasmosis). In acute infection, whereas treatment with any drug or drug combination significantly enhanced survival and reduced the brain cyst burden, in mice treated with ATO alone or combined with CLI, the cyst counts were significantly lower than in mice treated with CLI alone. In chronic infection, the decrease in the cyst burden observed 2 weeks after treatment with either drug alone was significant only in mice treated with the combined drugs. Most importantly, in reactivated toxoplasmosis, whereas an effect for the combined drugs was shown in mice suppressed with both DXM alone and combined with CA, in mice pre-treated with DXM a 3 week course of ATO > or = 25 and CLI 50 mg/kg/day significantly increased survival and markedly decreased the cyst burden. The latter effect was long-term, since the cyst burdens in treated mice continued to decrease up to 3 months later, whereas they increased in the untreated mice. The results warrant clinical evaluation of the combination of ATO and CLI in the treatment of toxoplasmosis in both immunocompetent and, more importantly, immunosuppressed patients.

Donor CD8+T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8+T Cell Population

“…Nevertheless, moribund mice in all cases exhibited low cyst numbers and a high degree of leukocyte parasitization (4). Similar results in terms of reduced cyst burden were noted in another study involving a dexamethasone-induced model of reactivated toxoplasmosis (42). It is possible that in moribund mice, due to severely attenuated CD8 response as well other potential immune deficits (16), nonencysted parasite are not forced to re-encyst like mice infected at week 10.…”

Repurposing the Open Access Malaria Box To Discover Potent Inhibitors of Toxoplasma gondii and Entamoeba histolytica

“…Overall, the quinolone scaffold represents a target group for detailed medicinal chemistry for anti-Toxoplasma drug discovery. MMV085203 is a 2,3-diaminonaphthoquinone with an IC 50 of 4.54 M and can be compared to the P. falciparum mitochondrial cytochrome bc 1 complex (1) inhibitor atovaquone, which has known anti-Toxoplasma activity (36).…”

Atovaquone Maintenance Therapy Prevents Reactivation of Toxoplasmic Encephalitis in a Murine Model of Reactivated Toxoplasmosis

“…Con- centrations achieved in the brains of infected mice (0.22 to 0.34 g/mg) also fell above the MIC of 0.01 g/ml for T. gondii. In the past, acute therapy for TE has been investigated in murine models by using drug-induced immunosuppression (10). In mice latently infected with the cystogenic ME49 strain, reactivation of TE was induced by a 2-week course of dexamethasone.…”