Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

Abstract

Primary Toxoplasma gondii infection is usually subclinical, but cervical lymphadenopathy or ocular disease can be present in some patients. Active infection is characterized by tachyzoites, while tissue cysts characterize latent disease. Infection in the fetus and in immunocompromised patients can cause devastating disease. The combination of pyrimethamine and sulfadiazine (pyr-sulf), targeting the active stage of the infection, is the current gold standard for treating toxoplasmosis, but failure rates remain significant. Although other regimens are available, including pyrimethamine in combination with clindamycin, atovaquone, clarithromycin, or azithromycin or monotherapy with trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone, none have been found to be superior to pyr-sulf, and no regimen is active against the latent stage of the infection. Furthermore, the efficacy of these regimens against ocular disease remains uncertain. In multiple studies, systematic screening for Toxoplasma infection during gestation, followed by treatment with spiramycin for acute maternal infections and with pyr-sulf for those with established fetal infection, has been shown to be effective at preventing vertical transmission and minimizing the severity of congenital toxoplasmosis (CT). Despite significant progress in treating human disease, there is a strong impetus to develop novel therapeutics for both the acute and latent forms of the infection. Here we present an overview of toxoplasmosis treatment in humans and in animal models. Additional research is needed to identify novel drugs by use of innovative high-throughput screening technologies and to improve experimental models to reflect human disease. Such advances will pave the way for lead candidates to be tested in thoroughly designed clinical trials in defined patient populations.

Keywords: T. gondii; Toxoplasma gondii; animal models; clindamycin; in vitro; in vivo; pyrimethamine; sulfadiazine; therapy; treatment.

FIG 1

Developmental timeline of anti-T. gondii drugs in clinical use.

FIG 2

Parasite pathways targeted by anti-T. gondii drugs in clinical use.

FIG 3

Survival of T. gondii-infected mice treated with drug combinations. The graph shows the survival of infected mice treated with the combination of pyrimethamine plus sulfadiazine compared to that of mice treated with monotherapy with either drug alone or with other treatment regimens (4). CLINDA, clindamycin; PYR, pyrimethamine; RIF, rifampin; SULFA, sulfadiazine.

FIG 4

(A) Murine model of reactivated toxoplasmosis to investigate the efficacy of drugs for acute therapy. Following induction of latent infection in immunodeficient (IRF-8^−/−) mice by use of sulfadiazine, treatment is withdrawn to allow reactivation. The specific treatment of interest, e.g., atovaquone nanosuspensions, is then administered. Histological changes in brain tissue, including parasite counts, and survival of mice can be determined to evaluate the efficacy of treatment for reactivated infection. (Modified from reference with permission.) (B) Murine model of reactivated infection to investigate the efficacy of drugs for maintenance therapy. Following induction of latent infection in immunodeficient (IRF-8^−/−) mice by use of sulfadiazine, treatment is withdrawn to allow reactivation. Acute therapy against reactivation is then administered, and maintenance treatment (secondary prophylaxis) with the drug of interest is initiated. Histological changes in brain tissue, including parasite counts, and survival of mice can be evaluated to determine the potency of maintenance treatment. (Modified from reference with permission.) ANS, atovaquone nanosuspensions; i.v., intravenous.

FIG 5

Survival of mice following treatment of reactivated toxoplasmosis with artemisinin derivatives. (Republished from reference with permission.)