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

https://cmr.asm.org/content/cmr/31/4/e00057-17.full-text.pdf

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

Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

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Drugs in development for toxoplasmosis: advances, challenges, and current status.

Toxoplasma gondii (T. gondii) is a global protozoan parasite infecting up to one-third of the world population. Pyrimethamine (PYR) and sulfadiazine (SDZ) are the most widely used drugs for treatment of toxoplasmosis; however, several failure cases have been recorded as well; suggesting the existence of drug resistant strains. This review aims to give a systematic and comprehensive understanding of drug resistance in T. gondii including mechanisms of resistance and sites of drug action in parasite. Analogous amino acid substitutions in the Toxoplasma enzyme were identified to confer PYR resistance. Moreover, resistance to clindamycin, spiramycin, and azithromycin is encoded in the rRNA genes of T. gondii. However, T. gondii SDZ resistance mechanism has not been proved yet. Recently there has been a slight increase in SDZ resistance. That is why the majority of studies were carried out using SDZ. Six strains resistant to SDZ were found in clinical cases between 2013 and 2017 which among Brazilian T. gondii isolates, TgCTBr11, Ck3, and Pg1 were identified in human toxoplasmosis, as well as in livestock intended for human consumption. In conclusion, recent experimental studies in clinical cases have clearly shown that drug resistance in Toxoplasma is ongoing. Thus, establishing a more effective therapeutic scheme in the treatment of toxoplasmosis is critically needed. The emergence of T. gondii strains resistant to current drugs, reviewed here, represents a concern not only for treatment failure but also for increased clinical severity in immunocompromised patients. To improve the therapeutic outcome in patients, a greater understanding of the exact mechanisms of drug resistance in T. gondii should be developed. Thus, monitoring the presence of resistant parasites, in food products, would seem a prudent public health program.

/pdf/drug-resistance-in-toxoplasma-gondii-3zldscbdua.pdf

Drug Resistance in Toxoplasma gondii

Human toxoplasmosis-Searching for novel chemotherapeutics.

Artemisinin and its derivatives have now become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although artemisinin was first used for the treatment of malarial ailments, lots of subsequent studies have demonstrated it possesses other multiple pharmacological functions such as antitumor, antiarrhythmic, anti-fibrosis, as well as the activity against schistosomiasis. A wide array of the molecular mechanisms based on above-mentioned functions of artemisinin and its derivatives have also been explored. Experimental evidences suggest that artemisinin compounds may exert its functions via mechanisms like regulating key factors such as apoptosis-related BAX, FASL and caspase-3, multi-drug resistence genes, cytokines such as CD4+ and CD8+, inflammation-related NF-κB and COX2, telomerase, oxidative stress molecules, and so on. In this article, the proposed mechanisms of action of artemisinins are reviewed with the hope of gaining more insight into the multiple actions of these potent drugs and how they work.

The pharmacological activities and mechanisms of artemisinin and its derivatives: a systematic review

Toxoplasmosis continues to be a public health problem, causing significant morbidity worldwide. Currently available medications, effective for acute toxoplasmosis, are nonetheless problematic due to adverse side effects in many patients. In addition, no medication is able to completely eradicate the parasite cysts, rendering infected individuals at risk for reactivation upon becoming immunocompromised. We examined the anti–T. gondii activity of 2 derivatives of artemisinin. In vitro metabolic stability tests revealed that both derivatives are stable in mouse plasma but only the thiazole CPH4-136 is stable in the presence of mouse microsomes. When tested in a mouse model of acute toxoplasmosis, both derivatives showed modest efficacy dependent upon the compound dose and the solvent vehicle. Finally, in a mouse model of chronic T. gondii infection, CPH4-136 at 3 mg/kg once per day for 32 days moderately but significantly decreased mouse brain cyst burden. Collectively, our findings suggest that ar...

https://bioone.org/journals/journal-of-parasitology/volume-100/issue-4/13-451.1/A-Thiazole-Derivative-of-Artemisinin-Moderately-Reduces-Toxoplasma-gondii-Cyst/10.1645/13-451.1.pdf

Robert H. Yolken

Papers

A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii cyst burden in infected mice.