Scientific Papers

Outcomes of trimethoprim/ sulfamethoxazole treatment for ocular toxoplasmosis in Congolese patients | BMC Ophthalmology

In the DRC, OT is the leading cause of infectious uveitis [15]. In addition, it has a significant visual impact because retinochoroidal lesions affect the posterior pole in 74% of patients [16]. Therefore, adequate management of these patients is essential to reduce the risk of visual impairment.

Available treatments for OT include a combination of pyrimethamine and sulfadiazine plus corticosteroids as a classic and standard treatment [2, 7, 8, 17], oral clindamycin (alone or in combination with the classic therapy), TMP/SMX, azithromycin, ubiquinone analogs (atovaquone), and intravitreal injection of clindamycin [2, 18]. However, there is no agreement regarding the best drug combination, and few patient-based studies have compared the efficacy of different drugs [19].

The current therapies for OT have not shown a complete cure since the principal achievement of the treatment is to limit parasite multiplication, which relates to ameliorating retinal and optic nerve tissue damage [20]. Visual impairment due to recurrences, vitritis, macular compromise, or complications such as retinal traction and retinal detachment, among others, could be expected in infection by virulent strains [20, 21]. Furthermore, tachyzoites released from reactivated tissue cysts may spread to other retina sites with a recurrence risk. For these reasons, treating any active lesion should be considered [8, 18, 20, 22].

In the DRC, as in most countries, classic therapy has been the option for treating OT for years. However, several factors, such as the high cost, low availability on the market, the large number of tablets, and the potential risk for serious side effects, may lead to the discontinuation of this treatment. Therefore, TMP/SMX treatment has become an attractive option due to its low cost, wide availability, and tolerability [2, 17, 23]. Even though adverse effects like fever, gastrointestinal upset, weight loss, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, serum sickness, hyperkalemia, and thrombocytopenia have also been reported [2]. Nevertheless, over time, this combination seems to be increasingly used in the treatment of OT. In 1991, only one Uveitis specialist in the USA reported TMP/SMX as his preferred medical treatment for patients with OT; by 2001, this number had risen to 23% [8]. In Brazil, the most commonly prescribed treatment for OT was TMP/SMX, used by 57% of uveitis specialists [19]. Therefore, we conducted this study to assess the evolution under treatment of Congolese patients with OT.

Although the criteria for starting treatment for OT cases vary according to specialists and countries, all our patients received antiparasitic treatment. Several surveys of uveitis specialists indicate that even experts differ in their therapeutic approaches [7]. Whereas some ophthalmologists will only care for sight-threatening lesions, others will treat all lesions independent of their location [7, 17, 22]. Despite limited evidence of treatment effects, uveitis specialists are more likely to treat patients with OT than in the past [7, 8]. In surveys on members of the American Uveitis Society in 1991 and 2001, 6% and 15%, respectively, of the respondents treated all patients with ocular toxoplasmosis, regardless of the ocular findings. In Germany, India, and Brazil, specialists treated all patients with active disease in 45%, 62%, and 68%, respectively [19].

In immunocompetent patients, the host immune response contributes substantially to the intraocular inflammation that follows tachyzoite replication within the retina; this inflammation is also responsible for ocular damage. For this reason, systemic corticosteroids are probably beneficial to patients with OT, and they are frequently added to the anti-microbial cocktail in immunocompetent patients with toxoplasmic retinochoroiditis, although the doses employed, and timing of administration vary widely between uveitis specialists [8, 17]. The authors of a nonrandomized retrospective evaluation on the effectiveness of different treatments for OT found significant improvement in VA when antibiotics were associated with steroids rather than administered alone [17]. In Brazil, systemic steroids were associated with anti-toxoplasmic therapy in most cases by 51% of the specialists [19]. In a documentary study conducted at the University of Sao Paulo, oral corticosteroids were used in conjunction with antitoxoplasmic medication in 76.3% of patients [20]. In our cohort, we added oral corticosteroid therapy to antiparasitic treatment in all patients.

Additionally, to reduce vitreous inflammation, periocular injection of triamcinolone was indicated in 55.6% of our patients. In Brazil, local treatment (periocular or intraocular) with corticosteroids is indicated for selected patients adjunctively to anti-toxoplasmic therapy by 49% of specialists. In contrast, in the United States, periocular corticosteroid injections are an unpopular approach [8, 19]. The administration of local corticosteroids has been associated with disastrous outcomes if administered without concomitant antiparasitic therapy [8], and the administration of steroids alone can result in fulminant toxoplasmosis responsible for legal blindness in most cases [8, 17, 22]. In our series, we used triamcinolone, a long-acting corticosteroid [24]. Some authors have reported cases of fulminant OT with intravitreal triamcinolone if antiparasitic treatment is not associated [25, 26]. In our series, the patients who received triamcinolone were all under antiparasitic treatment, and we had no case of fulminant OT. Two authors have also reported using intravitreal triamcinolone in immunocompetent and immunocompromised patients with OT and under parasitic treatment, with the resolution of inflammation and improvement in visual acuity [27, 28].

Ocular hypertension was noted in 33.3% of our patients; it was present at the initial consultation in 18.5%. Transient hypertension appeared during follow-up in 12.5% of patients, possibly related to corticosteroid therapy. At the end of the follow-up, only two patients (3.7%) had persistent high intraocular pressure (IOP). Likewise, the literature reported an elevated IOP in 30% of patients with OT at initial examination [7]. In their series, Westfall et al. noted an elevation of IOP at the initial consultation in 38% of patients. This hypertension persisted after the resolution of the episode of OT in 3.3% of them [29].

At the end of the follow-up, an improvement in VA was noted in 75.9% of our patients, and the resolution of inflammation in 77.5%. At the initial consultation, 57.4% of our patients had visual impairment. At the end of the follow-up time, this number had decreased to 29.6%, with 11% cases of low vision and 18.5% cases of blindness. Blindness was more frequent among patients with macular lesions (33.3%) than those without macular involvement (12.7%). Although, in our series, improvement in visual acuity was more significant among patients who had not received triamcinolone, the difference was not statistically significant (P = 0.44). The frequency of the occurrence of cataracts was significantly higher (P = 0.02) among patients who received triamcinolone, which could explain the less favorable evolution of visual acuity in this group of patients. Cataract is described as one of the most common side effects of triamcinolone, which may affect 14% of treated eyes [24, 30].

Despite treatment, no improvement in VA was noted in 13 of our patients (24.1%). Cataracts (3.7%), macular scars (3.7%), and vitreous opacities (3.7%) were the most common cause of non-improvement of VA among our patients.

In a retrospective study carried out in Brazil by Casoy et al., irrespective of the treatment regimen prescribed, there was a complete resolution or an improvement in the active ocular lesion in 63.9% of patients, and improvements in vision were observed in 56.3% of the overall patient sample [20]. Moreover, in a prospective randomized, single-blind clinical trial carried out to compare the efficacy of the classic therapy of OT versus a regimen consisting of TMP/SMX plus prednisolone, active toxoplasmosis retinochoroiditis resolved in all patients over six weeks of treatment, with no significant difference in mean reduction of retinochoroidal lesion size between the two treatment groups. Similarly, the two groups found no significant difference in VA after treatment. There was also an insignificant difference in the reduction of vitreous inflammation between groups [31]. Also, in the meta-analysis conducted by Zhang et al., they suggested that when patients are intolerant to pyrimethamine + sulfadiazine, TMP/SMX may be considered as an alternative drug in improving VA, controlling vitreous inflammation, reducing recurrence, and improving drug compliance [9].

In our series, treatment-related adverse events were noted in 18.5% of patients. Gastrointestinal adverse events were the most common (14.8%), while dermatologic adverse events concerned two patients (3.7%). All these adverse events were non-serious and resolved. Using real-world data reported to the FDA adverse event reporting system (FAERS), adverse outcomes associated with the treatment of Toxoplasma gondii infections in patients with various health backgrounds were analyzed, and most of them were caused by pyrimethamine (27% of adverse effects), followed by sulfonamides containing drugs (20% of adverse effects). Additionally, most serious reports were associated with pyrimethamine (26% of serious adverse events). Among the reported cases, those occurring in patients with OT represented only 2% [32].

In a systematic review of 11 studies about the adverse event profile of pyrimethamine-based therapy for OT, treatment-related adverse events (AE) were reported from 2.3 to 100%. Gastrointestinal-related AE were reported in four studies and included diarrhea, gastrointestinal distress, nausea, vomiting, and loss of appetite. Eight studies reported dermatologic AE, including skin rash, pruritus, and Steven–Johnson syndrome. Skin rash was the most common dermatologic AE (2.8–11%) [33]. Soheilian et al. found no difference in AE profile between patients on classic therapy and those on the TMP/SMX regimen. In their series, the only drug reaction in both groups was the development of a skin rash [31]. Zhang et al. found that TMP/SMX was the most effective intervention with less AE than other treatments [9]. Compared to the classic therapy, TMP/SMX seems to be a good alternative treatment of OT in immunocompetent and immunosuppressed patients, particularly since this is associated with an acceptable side-effect profile and prevention of recurrences as prophylactic treatment [1, 34,35,36].

In our series, discontinuation of antiparasitic treatment was indicated in two patients (3.7%) with dermatologic adverse events. In Ben-Harari et al. systematic review of the adverse event profile of pyrimethamine-based therapy, it was noted that discontinuation or change in treatment due to adverse events was reported in a range of 0 to 26% in different studies [33].

The cost for a week of treatment with the TMP/SMX combination was USD 15.3, and the total cost for a 6-week treatment was USD 91.85. On average, one week of treatment with the classic regimen (pyrimethamine, sulfadiazine, and folinic acid) costs USD 89.7. For six weeks, the total cost is USD 358.9, without considering the cost of regular hematological controls to follow pyrimethamine’s possible hematological side effects. In the DRC, patients do not have health insurance and must pay on their own for their health care; hence, the cost of the treatment is an essential element to consider in choosing the therapeutic regimen. The availability of antiparasitic drugs is another factor to consider; in our settings, the molecules of the classic therapy are not readily available. In Colombia, a study investigating the cost-effectiveness of four first-line treatment regimens found that TMP/SMX had the best performance. This antibiotic treatment has been established as an economical alternative, and its effectiveness is similar to the classic therapy for active toxoplasmic retinochoroiditis [23]. Nevertheless, there is no consensus about the best treatment regimens in OT. The selection of therapy regimens must be made individually, considering the safety of each therapeutic regimen, medical history of sulfa allergy, and the availability of medications offered within each nation’s health system [18].

Although our study is the first to describe the treatment of OT in patients from sub-Saharan Africa, we recognize some limitations. For example, the retrospective and descriptive approaches limit the comparison between the treatment regimens; comparative studies could provide more significant insights. In addition, the small sample limits the generalization of our results.

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