Introduction Toxoplasmosis caused by the zoonotic protozoan Toxoplasma gondii is one of the most prevalent parasites globally infecting virtually all animals, including humans (9). Cats and other Felidae are the only final host of T. gondii and they host all three infectious stages: Tachyzoites, bradyzoites and sporozoites in oocysts (5). In natural infections, the parasite spread throughout the host with latent infections as bradyzoites that can replicate and disseminate to tachyzoites causing systemic infections upon immunosuppression. Infected cats shed oocysts via feces thus represent a significant risk of transmission of toxoplasmosis (9).
Clinical manifestations of toxoplasmosis in cats include anorexia, dyspnea, fever, lethargy, vomiting, diarrhea, icterus, neurologic disorder, sudden death and ophthalmic manifestations consisting of retinochoroiditis and uveitis (15). The clinical signs are not pathognomic and therefore the reported cases are relatively few in comparison with the serologic prevalence (15). In Finland 6 out of 193 (3.1%) cats were diagnosed with toxoplasmosis post mortem (12). In Denmark fatal toxoplasmosis has been diagnosed post mortem in 5 out of 155 cats (3.2%) (10). Severe, generalized toxoplasmosis can be fatal in the early stages of the disease (20), which also indicates that the diagnosis in cats too often is reached post-mortem. The most consistent pathologic lesion is interstitial pneumonia, with focal necrosis. The liver and central nervous system are also commonly affected organs (11).
Evidence of effective therapy for clinical toxoplasmosis in cats is limited. The drug of choice for treating clinical toxoplasmosis in cats is clindamycin (19). However, clindamycin has been shown to cause a detrimental effect on cats suffering acute, experimental toxoplasmosis (4). In Denmark there are currently no drugs registered for treating toxoplasmosis in cats (18).
Recent case reports have shown that veterinarians experience difficulties in diagnosis and treatment of clinical toxoplasmosis (10; 1; 3; 21). When diagnosed in clinics toxoplasmosis was often treated with multiple drugs combined with drugs only tested on other species than cats. Furthermore, when treatment was reported successful, it was not possible to conclude, if a drug was being efficacious or if the disease was simply self-limiting (1; 3).
The aim of this systematic review was, to investigate if there is any evidence for efficacy and safety of drugs, used in the treatment of experimental toxoplasmosis in cats.
Materials and methods
A systematic literature search was carried out using the following databases: Ovid, Web of Science, PubMed and Google Scholar. The following combinations of key words were deployed: [cat*] OR [feline*] OR [fel*] AND [toxopla*] AND [treat*] OR [antibiotic*] OR [drug*] OR [clindamycin*] OR [anticoccidal*] AND [efficac*] OR [effect*] NOT [rodents] NOT [vaccine]. Articles in other languages than English and Danish were excluded. Studies on treatment of toxoplasmosis in rodents or trials with vaccines were excluded. Only experiments, which evaluated the efficacy or safety of drugs in cats experimentally infected with T. gondii were included. An active search through reference lists of obtained articles was also conducted. This search led to a total of seven primary sources.
Analysis
Results concerning the safety and efficacy of treatment of toxoplasmosis in cats are summarized in Table 1. Treatments included antibiotics or antiparasitic agents. Efficacy and safety of the drugs were measured by the suppression of oocysts shedding, elimination of bradyzoites and tachyzoites, resolution of clinical manifestations of toxoplasmosis and adverse effects. Articles included covers experimental trials completed from 1976 to March 2019. Common for most of the studies were the very low number of cats in the treatment groups.
Efficacy of drugs on oocyst shedding
Clindamycin has been tested at various doses, time intervals and routes of administration (Table 1). Providing clindamycin, either once daily in a dose of 11mg/kg per oral (PO) or twice daily in a dose of 12.5mg/kg (PO), day seven to 28 after inoculated of tachyzoites in Arteria carotis resulted in no oocyst shedding even though cats were clinically ill (4). Clindamycin was also proven to be effective against oocyst shedding when administered PO once daily at a dosage of 20mg/kg from three days before experimental infection to 24 days after infection (17; 19). Two controlled trials were performed to investigate the efficacy of pyrimethamine, sulfadiazine and 2-sulfamoyl-4,4-diamniophenylsulfone (SDDS) on oocyst shedding (6; 23). Different drug combinations, doses and time intervals were tested, but none were able to eliminate the shedding of oocysts completely.
Antiparasitic agents with potential efficacy on oocyst shedding have also been evaluated (7; 22; 19). Monensin at 3-16mg/kg provided in cat food from 3/2 days before and continued for six to 21 days post infection resulted in complete arrest of oocyst shedding (7; 19). However, the treatment was not efficient when administered later than three days post infection. Frenkel and Smith (1982) reported that monensin could be effective when used up to two days post infection in a dosage of 6-8mg/kg. However, this was only based on results of very few cats. In an experimental study with 87 cats toltrazuril was administered at different times before and after infection at different dosages. Results showed that the drug prevented oocyst shedding in some cases when administered prior to infection, but the results were not reproducible in all cases (22).
Efficacy of drugs tested on ocular toxoplasmosis
Only clindamycin has been tested in a controlled trial on cats with ocular toxoplasmosis, and here it was shown to have poor efficacy and many side effects (6). The efficacy and safety of glucocorticoids have been discussed but need documentation for their efficacy. Thus, at presence there is no evidence for efficacious treatment of ocular toxoplasmosis in cats.
Efficacy of drugs tested on generalized toxoplasmosis
The effect of clindamycin on extra intestinal stages of T. gondii infection in cats has been reported from two studies (4; 6). In one study the result of giving clindamycin to cats with toxoplasmosis at a dosage of 11 or 25mg/kg daily from day seven to 28 post infection showed multiple tachyzoites in necropsied cat (4). In the other study where clindamycin was provided at a dose of 100-250mg/ kg from day three to nine post infection no tachyzoites were found in the tissue of the treated cats (6). Some efficacy of SDDS, pyrimethamine and sulfadiazine on extra intestinal stages T. gondii has also been reported in a few studies (6; 23). However, the sample sizes in each test group were very small, and the authors failed to provide clear information regarding which dose, route of administration and time interval proved most efficacious.
Toltrazuril was shown not to effectively eliminate T. gondii from tissues of cats. Even when administering the drug preventively five days before infection and continuing for 83 days organs were still positive of T. gondii (22).
Side effects of drugs
It was reported that clindamycin did not cause any side effects, in a dose of 100250 mg/kg (6). Paradoxically, a study showed that healthy cats treated only with clindamycin, in a dose of 25-50mg/ kg, developed gastrointestinal side effects such as vomiting and diarrhea (8). When administering clindamycin preventively to treat toxoplasmosis it did not show any side effects at a dosage of 10-20mg/kg (17; 19). However, these studies did not mention any details on how side effects were monitored and evaluated. When treating toxoplasmosis upon clinical signs clindamycin was used in a dosage of 11-25 mg/kg daily (4). This was reported by Davidson (1996) to be the highest tolerable dosage for cats without the occurrence of gastrointestinal side effects or changes in hematological parameters. Clindamycin at this dosage was associated with higher incidence of morbidity, mortality and clinical signs in cats with systemic toxoplasmosis and overall showed an unfavorable effect (4). The mechanisms behind these side effects were unknown, although it was suspected that clindamycin might influence phagocytic function and delay antitoxoplasmic effect. This could allow the parasite to undergo uncontrolled replication causing clinical disease in the cats (4). Side effects in this study could have been amplified by the inoculation of 10.000 tachyzoites through A. carotis.
It has been addressed that pyrimethamine combined with sulfonamide drugs were an effective treatment for human toxoplasmosis, but commonly resulted in toxicity in cats (13). In one study reviewed one cat died when treated with 2 mg pyrimethamine per kg combined with 100 mg sulfadiazine per kg (23). Sulfadiazine alone was shown to be fatal to one cat treated with 240mg/kg. When combining pyrimethamine with sulfadiazine or SDDS, the treatment resulted in leukopenia (6). A more insignificant side effect was that pyrimethamine given intramuscularly, induced transient irritation (23). The cognisance of toxicity of pyrimethamine, discouraged using higher dosages (23).
No side effects were observed when treating with anticoccidial drugs (7;22; 19). However, these studies did not comment on how side effects were monitored.
Whether to use corticosteroids for the treatment of ocular toxoplasmosis has been controversial (15). The effect of glucocorticoid administration on oocysts shedding, serology and cell-mediated immune response of eight cats with recent or chronic toxoplasmosis, was evaluated by Lappin et al. (1991). The conclusion was that a clinical dosage of prednisolone would not induce repeated oocysts shedding in cats recently or chronically infected with T. gondii. Another study by Malmasi et al. (2009) concluded that treatment with dexamethasone 45 days after the primary infection with T. gondii made cats shed oocysts once more. A case report stated that topical administration of glucocorticoids alone was contraindicated because it would lead to a more intense intraocular infection and thereby greater inflammation in seropositive cats (2). However, the authors also found that if glucocorticoid was combined with clindamycin a positive effect of the treatment of ocular toxoplasmosis was observed. Additional case reports suggested that immunosuppression, by diseases or drugs, could be fatal in cats with latent toxoplasmosis and that immunosuppressive drugs, especially cyclosporine, should be administered with great care (1; 3; 15; 16; 21). Cyclosporine should not be administered to cats, when the cat’s present status of T. gondii infection is not known, since reactivation of the parasite is likely (1).
Discussion
None of the studies included in this review mention a specific study design. Common for all experiments was that cats free of T. gondii, were infected with the parasite prior to or after initiation of treatment. All experiments had controls, although some of them had very few. No studies mention if cats were allocated randomly to the study groups. One study mentions the use of placebo and stated that clinical monitoring was done in an examiner-blinded fashion but without further description (4). Sample size were generally too low to apply statistical analyses. In Dubey and Yeary (1977) only two cats were used to evaluate the efficacy and safety of clindamycin with only one control cat. Clearly, such study does not qualify as proper clinical trial due to the inadequate sample size, but still this study has been used by many authors to conclude that clindamycin is an efficient treatment for toxoplasmosis (4; 17; 19).
As Table 1 illustrates, most of the studies did not contribute knowledge regarding clinical toxoplasmosis, because drugs were provided prior to infection, thus not allowing the parasite to manifest in the host, before it was eliminated, why the efficacy of drugs on extra intestinal stages could not be evaluated. The very few studies conducted to assess the efficacy of treatment of cats with experimental clinical toxoplasmosis show contradicting results.
Conclusion and perspectives
Clindamycin was efficient on oocysts shedding even when administered upon clinical signs in a dosage of either 11mg/kg once daily PO or 12.5mg/kg twice daily PO. Monensin was efficient on oocyst shedding when used preventively in a dosage of 6-16mg/kg. No drugs were found effective to treat ocular toxoplasmosis or to eliminate T. gondii in cats. Pyrimethamine, sulfadiazine and clindamycin showed some degree of toxicity in cats, while clindamycin also was suspected to have immunosuppressing activity.
Case reports have indicated the absence of knowledge in clinical practices which often used multiple drugs regarding the treatment of clinical toxoplasmosis in cats with varying outcomes.
Public awareness towards the parasite is a key factor to prevent transmission of toxoplasmosis and to reduce the prevalence in cats, other animals and humans (3). This could be achieved by not feeding cats raw meat, by preventing cats from eating intermediate host or mechanical vectors and by denying cats access to buildings where food producing animals are housed or food is stored (9). Although these steps might be effective, it seems unlikely that this approach is possible.
The number of drugs tested until now has been inadequate, leaving practitioners with limited choices. There have not been enough controlled studies on cats to evaluate the efficacy and safety of potential drugs against T. gondii. Further studies should investigate if there are other drugs, with better safety and efficacy, which could potentially eliminate the parasite. These studies should include a greater number of treated and control cats and consider all variables affecting the efficacy and safety of drugs.
