TABLE 2.
A comprehensive list of clinically available human or veterinary drugs evaluated against the parasite Toxoplasma gondii, ordered by common clinical usesa
| Drug or drug class | Common clinical use | Reference(s) | In vitro IC50 | In vivo lethal challenge(s) | In vivo parasite burden for indicated tissue or animal and treatment (reference[s]) |
|---|---|---|---|---|---|
| Miltefosine | Antimicrobial | 42 | ND | 20 mg/kg/day, 5% increased survival* | 78% significant reduction of brain cyst count; treatment lasted 15 days, starting 60 days postinfection |
| Niclosamide | Antimicrobial | 43 | ∼0.25 μM | ND | ND |
| Triclosan | Antimicrobial | 44–48 | 0.02 μM | 200–300 mg/day, no difference in survival compared to control (45, 46) | Significant reduction in parasite burden (45, 47, 48); treatment lasted 4 days (45) |
| Artemisinins | Antiprotozoal | 49–52 | Artemisinin, 0.64 μM; artesunate, 0.213 μM; artemether, 0.31 μM; dihydroartemisinin, 0.35 μM | Artemisinin, 10 mg/kg/day, 20% survival (49) | ND |
| Veterinary anticoccidials | Antiprotozoal | 53–60 | Halofuginone, 0.00094 μM; monensin, 0.0015 μM; diclazuril, 0.006 μM; decoquinate, 0.011 μM; arprinocid N-oxide, 0.05 μM; salinomycin, 0.053 μM; robenidine, 0.09 μM; toltrazuril, 0.94 μM; clopidol, 5.21 μM; arprinocid, 7.2 μM | Arprinocid, 100 μg/day, 100% survival (53); ponazuril, 10 mg/kg/day, 100% survival (58); diclazuril, 1 mg/kg/day, 100% survival (56, 57) | Toltrazuril (sheep), significant reduction in muscle and heart cyst burden (59); treatment lasted 14 days |
| Fusidic acid | Antibacterial | 61 | 7.74 μM | 60 mg/kg/day, no difference in survival | No reduction in parasite burden; treatment lasted 5 days |
| Pristinamycins | Antibacterial | 62 | Synercid, 1.57 μM | Synercid, 200 mg/kg/day, 100% survival | ND |
| Rifamycins | Antibacterial | 32, 40, 63, 64 | ND | Rifabutin, 300 mg/kg/day, 100% survival (63); rifapentine, 50–200 mg/kg/day, 100% survival (32) | ND |
| Quinolones | Antibacterial | 65–67 | Gatifloxacin, 0.56 μM; trovafloxacin, 1.85–2.35 μM; enrofloxacin, <69.5 μM | Gatifloxacin, 400 mg/kg/day, 20% survival (66); enrofloxacin, 3 mg/kg/day, 17% survival (67); trovafloxacin, 100 or 200 mg/kg/day, 100% survival (65) | Enrofloxacin, 68% parasite cyst reduction (67); treatment lasted 25 days |
| Azoles | Antifungal | 68–70 | Itraconazole, 0.05 μM; fluconazole, 3.1 μM | Itraconazole, 10 mg/kg/day, 12% increased survival* (69); fluconazole, 20 mg/kg/day, 37% increased survival (69) | Itraconazole, significant reduction of brain cysts (69), treatment lasted 10 days; fluconazole, no significant reduction of brain cysts (69), treatment was carried out for 10 consecutive days, starting 4 days postinfection |
| Antiretrovirals | Antiretroviral | 71–74 | Didanosine, 0.21 μM; atazanavir, 1.97 μM; saquinavir, 3.88 μM; fosamprenavir, 5.29 μM | Didanosine, ∼1 mg/day, 100% survival (71) | Didanosine, <70% reduction in cerebral cysts (71); treatment lasted 30 days |
| 5-Fluorouracil | Anticancer | 75 | 0.08–0.77 μM | ND | ND |
| Crizotinib | Anticancer | 76 | 0.4–4 μM | ND | ND |
| Gefitinib | Anticancer | 76 | 5–10 μM | ND | ND |
| Methotrexate | Anticancer | 15 | Piritrexim, 0.02 μM; trimetrexate, 0.02 μM | ND | ND |
| Cyclosporine | Immunosuppression | 16, 77, 78 | 0.83 μM | 150 mg/kg/day, treatment led to earlier time of death (78) | Variable effects (77) |
| Purine nucleoside analogues | Immunosuppression | 77, 79 | Adenine arabinoside, 1.5 μM | Azathioprine, 10 mg/kg/day, 100% survival (77) | Azathioprine, no significant reduction in parasite burden (77) after treatment for 7–100 days |
| Auranofin | Immunosuppression | 80 | 0.28 μM | ND | Significantly reduced parasite burden in chicken embryo; one dose was administered |
| Antischizophrenic, antipsychotic, or mood-stabilizing agents | Psychiatric disorder treatment | 81–83 | Thioridazine, 1.2 μM; fluphenazine, 1.7 μM, trifluoperazine, 3.8 μM, chlorpromazine, 7.3 μM; zuclopenthixol, 8 μM | ND | ND |
The lowest observed IC50 values are reported when multiple values were found in the literature. With one exception (didanosine), none of these drugs have been described in published toxoplasmosis clinical case reports. *, not statistically significant; ND, not determined. The term “in vivo lethal challenge” used here refers to an experiment where model organisms are exposed to a 100% lethal infectious dose of parasite, often via intraperitoneal injection. The strain of the parasite and the recipient host affect the absolute number of parasites required to produce a lethal infection, which often manifests 7 to 15 days after infection. “In vivo parasite burden” refers to the tissue or fluid count of parasites isolated from a host following a nonlethal infection (typically accomplished by administration of a low dose of parasites and/or delivery of parasites via the oral route and/or the use of a low-virulence strain). Notably, parasite burden measurements are performed in a manner which typically quantifies both tachyzoite and bradyzoite parasite stages (most often by PCR). However, studies which aim to evaluate bradyzoite “cyst” counts (usually determined >30 day postinfection, since by this time the tachyzoites have been cleared by the immune system) are noted in the parasite burden column as such.