Trimethoprim-Sulfame thoxazole Therapy for Ocular Toxoplasmosis E. Mitchel Opremcak, MD, David K. Scales, MD, Matthew R. Sharpe, MD
Background: Toxoplasmosis is a leading cause of retinochoroiditis. Conventional multidrug therapy using sulfadiazine, pyrimethamine, and folinic acid is increasingly difficult to procure and administer safely. Methods: To evaluate the efficacy of trimethoprim-sulfamethoxazole, a fixed-combination antibiotic, patients with active toxoplasmosis were treated with trimethoprimsulfamethoxazole (Bactrim DS) with or without adjunctive clindamycin and prednisone for 4 to 6 weeks. Results: All pati.ents in this study (n = 16) had resolution of active retinochoroiditis and had improved vision, with an average gain of 5.2 lines of vision. Two patients developed a drug allergy. Conclusion: Trimethoprim-sulfamethoxazole appears to be a safe and effective substitute for sulfadiazine, pyrimethamine, and folinic acid (leucovorin) in treating ocular toxoplasmosis. Ophthalmology 1992;99:920-925
Toxoplasma gondii is the most common cause of posterior uveitis in otherwise healthy individuals. 1 Symptoms include decreased visual acuity, vitreous floaters, pain, and redness of the eye. The combination of pyrimethamine, sulfadiazine, and folinic acid rescue has been the treatment of choice for ocular toxoplasmosis for 40 years. 2•3 Several other drugs have shown in vitro and in vivo efficacy against T. gondii, but the best treatment for patients with ocular toxoplasmosis remains unclear. In a recent survey of members of the American Uveitis Society, physicians were asked questions about their choice of antimicrobial agents for treatment of ocular toxoplasmosis. Eight different antimicrobial drugs were used in various combinations to treat toxoplasmic retinochoroiditis.4 The agents currently used are: pyrimethamine, sulfadiazine, clindamycin, sulfisoxazole, tetracycline, minocycline, and trimethoprim-sulfamethoxazole.
Originally received: September 10, 1991. Revision accepted: December II, 1991. From the Ohio State University, College of Medicine, Department of Ophthalmology, Columbus. Presented as a poster at the American Academy of Ophthalmology Annual Meeting, Anaheim, October 1991. Reprint requests to E. Mitchel Opremcak, MD, The Ohio State University College of Medicine, 456 W Tenth Ave, Columbus, OH 43210.
920
Among the 62 respondents, sulfadiazine is the most widely used drug, administered by 51 (82% ), while pyrimethamine, used by 43 (69%), is the second most commonly used drug. One of the authors (EMO) was the only respondent to use trimethoprim-sulfamethoxazole for this disease. Sulfadiazine and pyrimethamine have become increasingly difficult to procure in some regions of the country. Importantly, systemic side effects and toxicity of pyrimethamine are common. The need for multiple agents on a frequent dosing schedule reduces antibiotic compliance. Our interest in trimethoprim-sulfamethoxazole as treatment for ocular toxoplasmosis was to increase the antibiotic access and compliance, and to reduce the frequency of systemic adverse reactions. Trimethoprim-sulfamethoxazole, as well as pyrimethamine and sulfadiazine, inhibits sequential steps in the synthesis oftetrahydrofolic acid, an essential precursor to purines and DNA. Pyrimethamine and trimethoprim are benzylpyrimidines, and both inhibit bacterial dihydrofolic acid reductase. Sulfadiazine and sulfamethoxazole are sulfonamides, which competitively inhibit para-amino benzoic acid. Trimethoprim-sulfamethoxazole has shown similar efficacy to pyrimethamine and sulfadiazine in its inhibitory effect on T. gondii in infected HeLa cells. 5 Trimethoprim-sulfamethoxazole also has been shown to be effective in mice infected with T. gondii. 6 The half-lives
Opremcak et al · T rimethoprim-Sulfamethoxazole Therapy of trimethoprim and sulfamethoxazole are 9 to 11 hours and 10 to 12 hours, respectively, enabling the dosing to be twice a day. Trimethoprim-sulfamethoxazole is readily available as a fixed combination antibiotic (Bactrim, Septra), and has been shown to be relatively safe, with the advantage of increased patient compliance as a result of easier dosing (one tablet orally twice a day). In this article, we review our experience using trimethoprim-sulfamethoxazole and show it to be a clinically effective substitute for sulfadiazine and pyrimethamine in treating ocular toxoplasmosis.
logically characteristic fundus lesions. In most patients, this consisted of areas of active retinitis adjacent to old chorioretinal scars. A positive toxoplasmosis titer was required for inclusion in this study. Funduscopic photographs were taken before and after treatment to aid in determining the degree of resolution of disease. Fluorescein angiography was performed as indicated to monitor the patient's progress, and to assess for sequelae of inflammation (i.e., cystoid macular edema, retinal detachment, subretinal neovascular membrane). Treatment
Subjects and Methods We reviewed 16 consecutive patients referred to the Uveitis Service at the Ohio State University College of Medicine who were treated for toxoplasmic retinochoroiditis with trimethoprim-sulfamethoxazole combination over an 18-month period between 1989 and 1991. Patients were treated either with trimethoprim-sulfamethoxazole alone or in combination with clindamycin and prednisone. The patient population included 4 males and 12 females ranging in age from 11 to 78 years (Table 1). Diagnosis All patients underwent a complete ocular examination, including medical history, a thorough review of systems, visual acuity testing, biomicroscopic examination, and dilated fundus examination. The diagnosis of active toxoplasmosis was made in all patients by finding morpho-
Patients were categorized according to the location of the lesion as described by Holland et al. 7 Briefly described, zone 1 lesions were considered to be that portion of the retina where infection is immediately sight-threatening and corresponding to an area extending 3000 ~.tm (2 disc diameters) from the fovea (approximately that area enclosed by the major temporal vascular arcades) or 1500 ~.tm from the margins of the optic nerve head; zone 2 were lesions extending anterior from zone 1 to the clinical equator of the eye, identified by the anterior borders of the ampullae of the vortex veins; and zone 3 lesions were extending anterior from zone 2 to the ora serrata. Patients were divided into two groups according to their treatment regimen (Table 1). Patients with lesions in zone 1 or those who had lesions in zone 2 accompanied by severe inflammation or opacified vitreous were typically treated with combination antibiotics (trimethoprim-sulfamethoxazole and clindamycin) and prednisone. Patients
Table 1. Summary of Clinical Data Patient No.
Sex
Zone of Lesion
Drug Regimen
38 12 37 50 37 48 78 69
F F F F M M F M
2 2 2 2 2 2 1 2
T T T T TC TC TC TC
6 6 4 6 6 4 6 6
33 15 21
F F F F F F M F
1 1 1 1 2 2 1 2
TCP TCP TCP TCP TCP TCP TCP TCP
2 6 6 6 6 6 6 6
Age (yrs)
Duration of Treatment
(wks)
Visual Acuity
Complications
Before
After
Of Drugs
20/400
20/30 20/100 20/20 20/30 20/60 20/15 20/40 20/15
Headache
Of Disease
Recurrence
Group 1
1 2 3 4 5 6 7 8
CF
20/20 20/200 20/200 20/25 LP
20/40
ERM Mild rash Diarrhea
0 0 0 0 0 0 0 0
Group 2
9 10 11 12 13
14 15 16
11
33 31 11
41
20/400 CF
20/400 20/200 20/60 20/50 CF
20/200
20/400 20/70 20/20 20/15 20/20 20/30 20/60 20/20
Mild rash Diarrhea Headache
RD SRNVM ERM CME
0 0 0 0 0 0 0 3
T = trimethoprim-sulfamethoxazole; C = clindamycin; P = prednisone; CF = counting fingers; LP = light perception; RD = retinal detachment; ERM = epiretinal membrane; CME = cystoid macular edema; SRNVM = subretinal neovascular membrane.
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with uncomplicated zone 2 lesions were treated with antibiotics alone. Each patient in this study received 160 mg trimethoprim and 800 mg sulfamethoxazole (Bactrim DS), orally twice a day for 4 to 6 weeks. Patients receiving adjunctive therapy were administered clindamycin (Cleomycin) 300 mg 4 times a day for 2 weeks, prednisone 80 mg a day for 2 days tapered 20 mg every other day, down to a dose of 20 mg a day for 4 weeks. Prednisone therapy was begun 2 days after beginning antibiotic therapy.
Evaluation Each patient returned for follow-up at 3 to 4 weeks, then again at 8 weeks. The follow-up periods ranged from 2 months to 18 months. The criterion for resolution of disease was biomicroscopic evidence of complete resolution of active retinitis. Recurrence of disease was defined as evidence of active retinitis after an 8-week period of retinal quiescence. Patients who had recurrences of their disease underwent an additional4 to 6-week course of their initial therapy.
Selected Case Reports Patient 3: Peripheral Toxoplasmosis (Zone 2). A 37-
year-old woman presented with a week long history of floaters, flashes, and decreasing visual acuity in her right eye. She had previous episodes of floaters but had not sought medical attention for them. Her medical history and immunologic survey were remarkable for the presence of shingles. She also had tested positive for toxoplasmosis during a previous pregnancy. Results of ocular examination showed her visual acuity to be 20/20 in both eyes. Examination of her left eye was unremarkable. Examination of her right eye showed fine stellate keratic precipitate with an occasional cell in the anterior chamber. She had mild iris stromal atrophy without transillumination defect. Her vitreous cavity had 1+ active cell and flare. A dilated fundus examination showed multifocal chorioretinal scars with satellite lesions and an active toxoplasmosis lesion within the temporal posterior pole (Fig 1, top left). A positive toxoplasmosis titer supported the diagnosis of zone 2 ocular toxoplasmosis.
The patient began a 4-week course of trimethoprim-sulfamethoxazole (treatment group 1). On follow-up examination 4 weeks later and on subsequent biomicroscopic and fundus examinations, clearing of her vitreous cells and a quiet chorioretinal scar were seen (Fig 1, top right). Visual acuity was 20/20 in both eyes.
Patient 11: Punctate Outer Retinal Toxoplasmosis (Zone 1). A 21-year-old woman presented with a 1-week his-
tory of decreased vision in her left eye without any associated pain or redness. Her immunologic history was remarkable for exposure to a sick cat 3 years before presentation. On ocular examination, visual acuity was 20/20 in the right eye and 20/400 in the left. Examination of her right eye was unremarkable. Examination of the left eye showed 2+ vitreous cell with a quiet anterior chamber. Results of dilated fundus examination showed a large chorioretinal scar in the superior temporal quadrant and several other smaller lesions in the inferior retina. Also present was a pigmented chorioretinallesion adjacent to an area of active retinochoroiditis in the macula (Fig 2, second row left). Vitreous inflammatory cells were found overlying the lesion. A positive toxoplasmosis titer supported the diagnosis of punctate outer retinal toxoplasmosis in zone 1. The patient began a 4-week course oftrimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). On follow-up examination, her visual acuity improved from counting fingers to 20/70 in her affected eye, with biomicroscopic and fundus examination showing complete resolution of active disease (Fig 2, second row right).
Patient 12: Peripapillary Toxoplasmosis in a Child (Zone 1). An 11-year-old girl presented with a 2-month history
of blurring in her left eye. Five years previously, she had toxoplasmosis in the macula of her right eye, which left her with decreased central vision. Her medical history and immunologic survey were unremarkable. On ocular examination, visual acuity was 20/200 in both eyes. Examination of the right eye was remarkable only for the presence of a large inactive chorioretinal scar in her macula. Examination of her left eye showed a 1+ afferent pupillary defect and normal intraocular pressure. Also evident were 3+ mutton fat KP with 2+ cells in the vitreous cavity. A dilated fundus examination showed marked disc edema with an area of active retinitis along the inferior temporal arcades (Fig 3, third row left). A significant amount of vitreous debris also was present. A positive immunofluorescent antibody titer supported the clinical diagnosis of bilateral, congenital toxoplasmosis, and the
Top left, Top right, Figure 1. Patient 3. Peripheral toxoplasmosis (zone 2). Fundus photographs of a 37-year-old woman with floaters and visual acuity of 20/20 in the right eye. Top left shows a mild vitreous haze with multifocal pigmented chorioretinal scars. The inferior lesion had overlying inflammatory cells on biomicroscopy and active retinitis. Top right shows clearing of the vitreous inflammation and a quiet toxoplasmosis lesion after 4 weeks of trimethoprim-sulfamethoxazole therapy. Second row left, Second row right, Figure 2. Patient 11. Punctate outer retinal toxoplasmosis (zone 1). Fundus photographs of a 21-year-old woman with a 1-week history of decreased visual acuity to 20/400. Second row left shows an inactive pigmented chorioretinal scar in the inferior macula and an adjacent active area of punctate outer retinitis. Second row right shows clearing of the retinal edema and focal retinitis following a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Third row left, Third row right, Figure 3. Patient 12. Peripapillary toxoplasmosis in a child (zone 1). Fundus photograph of an 11-year-old girl with an old toxoplasmosis lesion in the macula of her right eye and decreased visual acuity of 20/200 in the left eye. Third row left demonstrates vitreous haze and marked disc and macular edema. A disc diameter area of active retinitis can be observed just below the optic nerve. Third row right shows complete resolution of the vitreitis, retinitis, and optic disc edema after a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Bottom left, Bottom right, Figure 4. Patient 15. Acquired macular toxoplasmosis in a child (zone 1). Fundus photographs of an 11-year-old boy with decreased visual acuity to counting fingers in the right eye. Bottom left shows disc hyperemia and area of active outer retinitis in the macula. Bottom right shows resolution of the retinal lesion after a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone.
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patient began a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). On follow-up examinations, 4 and 8 weeks later, the patient showed continual improvement to a final visual acuity of 20/25. Examination showed that there was marked clearing of vitreous debris, with complete resolution of active retinitis and disc edema (Fig 3, third row right).
Patient 15: Acquired Macular Toxoplasmosis in a Child (Zone 1). An 11-year-old boy presented with a 48-
Toxoplasmosis - TMP-SMZ LP
CF
20/400 !l)
.E
~
·a"'
20/200 20/100
20/80 20/70 20/60
hour history of rapidly decreasing visual acuity in his right eye. His medical history and his immunologic survey were unremarkable. A normal fundus was noted by an ophthalmologist in a prior examination when the patient was 8 years of age. Ocular examination showed visual acuity of counting fingers in the right eye and 20/20 and in the left. Examination of the left eye was unremarkable. Examination of the right eye showed an afferent pupillary defect. Biomicroscopic examination was unremarkable except for a mild amount of posterior vitreous cells. A dilated fundus examination showed mild disc hyperemia and a prominent lesion in the outer retina along the superior arcade (Fig 4, bottom left). A fluorescein ~ngiogram showed early hypofluorescence corresponding to the area of retinitis noted on the fundus examination. The late frames of the angiogram showed marked disc edema, retinal edema, retinal vessel staining, and dye extravasation into the vitreous. Diagnosis of the outer retinitis variant of toxoplasmosis in zone 1 was made, which was supported by a positive toxoplasmosis titer. Because of the sight-threatening nature of his disease, the patient began a regimen of trimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). After a 6-week course of antibiotics and prednisone, the patient showed improvement, with visual acuity increasing from the original level of counting fingers to 20/60. Biomicroscopic and fundus examinations showed complete resolution of his active infection, and development of a discrete, chorioretinal scar in the posterior pole (Fig 4, bottom right). The patient returned for follow-up 5 times in 6 months and had no recurrences.
All the patients in group 2 (n = 8) had resolution of disease, while 7 of the 8 patients had improved visual acuity (Fig 5). One patient retained visual acuity of 20/ 400 after treatment because of a large macular chorioretinal scar. The average initial visual acuity was 20/200. The average visual acuity after treatment was 20/40. The average improvement was 5.8 lines of vision. All patients received trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Five patients had zone 1 lesions, while the other three had sight-threatening complications of disease. Complications of the treatment were: mild rash (n = 2), colitis (n = 2), and headache (n = 2). Sequelae of this infectious disease consisted of the following: epiretinal membrane (n = 2), retinal detachment (n = 1), subretinal neovascularization (n = 1), and cystoid macular edema (n = 1).
Results
Discussion
All patients in this study (n = 16) had resolution of active retinitis and improved or maintained their initial visual acuity at the end of the 4- to 6-week treatment regimen. One patient (patient 16) had 3 recurrences over an 18month period of time and was given an additional 4 to 6 weeks of the same therapy. Patients in group 1 (n = 8) received only antibiotics, either trimethoprim-sulfamethoxazole alone or in conjunction with clindamycin. Four patients received only trimethoprim-sulfamethoxazole, while the other four received trimethoprim-sulfamethoxazole and clindamycin. Patients in this group did not receive prednisone. All patients in group 2 (n = 8) received trimethoprim-sulfamethoxazole, clindamycin, and prednisone. All patients in group 1 (n = 8) had resolution of disease and maintained or improved vision (Table 1). The average initial visual acuity was 20/80. The average visual acuity after treatment was 20/30. The average improvement was 4.6 lines of vision. Seven of eight patients in this group had zone 2 lesions. The one patient with a zone 1 lesion and optic nerve involvement was included in this group because of refusal to take prednisone. Complications of the treatment were headache (n = 1), mild rash (n = 1), and diarrhea (n = 1).
The combination of sulfadiazine and pyrimethamine has been the treatment of choice for ocular toxoplasmosis since its efficacy was first demonstrated by Eyles and Coleman2•3 in the early 1950s. Since then, few prospective randomized clinical studies have evaluated the effectiveness of alternate drugs. Among uveitis specialists in the United States, 82% use sulfadiazine and 69% use pyrimethamine in some combination to treat ocular toxoplasmosis.4 Sulfadiazine and pyrimethamine appear to have regional variability of access to patients in this country, making it necessary to find an effective substitute for these two drugs. Although in vitro and in vivo studies have shown the efficacy of several of the other agents currently used to treat toxoplasmosis, none has demonstrated clinical superiority to the combination of a sulfonamide and a folic acid inhibitor. Recently, a prospective multicenter study of therapies for ocular toxoplasmosis showed a small therapeutic advantage in patients treated with sulfadiazine and pyrimethamine, compared with trimethoprim-sulfamethoxazole or clindamycin. 8 Unfortunately, the number of patients treated with trimethoprim-sulfamethoxazole in that study was small (n = 8), leaving questions regarding its clinical efficacy largely unanswered. In this communication, we report our experience em-
924
20/50 20/40
20/20 20/30 20/40 20/50 20/60 20/70 20180 20/100 20/200 20/400
CF
LP
Visual Acuity AIter
Figure 5. Scattergram of pretreatment and post-treatment vision. Each point represents the visual outcome of one patient. The sloped line represents the axis of no change in vision.
Opremcak et al · Trimethoprim-Sulfamethoxazole Therapy playing trimethoprim-sulfamethoxazole as a substitute for standard sulfadiazine, pyrimethamine, and folinic acid regimens in 16 consecutive patients with ocular toxoplasmosis. Trimethoprim-sulfamethoxazole alone or in combination with clindamycin and prednisone appears to be an effective and safe fixed combination antibiotic for treating active retinal toxoplasmosis. We routinely treat zone 1 lesions with a combination of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Using these medications, we have noted no serious systemic side effects (Table 1). Bactrim has been associated with skin rashes and mild diarrhea. Pseudomembranous colitis is a rare but potentially serious complication of clindamycin. This is a severe form of bloody diarrhea that typically begins 4 to 9 days after the start of oral clindamycin. We have not observed this side effect of clindamycin when used in combination with oral trimethoprim-sulfamethoxazole. Pseudomembranous colitis can be treated by discontinuing the antibiotic and starting oral vancomycin at a dose of 250 mg four times daily. Short courses of oral corticosteroids also may be associated with serious systemic side effects. Patients with diabetes, hypertension, and peptic ulcer disease have a higher risk of adverse reactions when using these agents. Patients should be given adequate informed consent as to the potential side effects of these agents. Uncomplicated zone 2 lesions were successfully treated with trimethoprim-sulfamethoxazole alone or in conjunction with clindamycin. Whether zone 1 lesions can be treated with trimethoprim-sulfamethoxazole alone is unclear. We believe that most of the ocular complications of toxoplasmosis are a result of the necrotizing inflammation that accompanies this protozoal infection. We believe that prednisone plays an important role in abrogating this secondary inflammatory response. The use of periocular corticosteroid injections has been discouraged because of experiences in which it has been associated with uncontrollable spread of infection, presumably due to intense suppression of host protective mechanisms. We used oral prednisone to avoid this complication. Five of 16 patients, nevertheless, developed sequela as a result of infection with toxoplasmosis, requiring further treatment. These included epiretinal membrane, subretinal neovascular membrane, cystoid macular edema, and retinal detachment. One patient with retinal detachment (patient 13) was successfully repaired with scleral buckle surgery, and visual acuity returned to 20/20. Another patient (patient 14) with juxtafoveal subretinal neovascular membrane had focal laser photocoagulation with return of20/ 30 visual acuity. One patient (patient 15) developed vitreous opacification, epiretinal membrane, and a fullthickness macular hole. The patient regained visual acuity of 20/60 and complete closure of the macular hole after vitrectomy and surgical removal of the epiretinal scar. There is no known therapy that can completely eradicate the latent tissue cysts of toxoplasmosis. Therefore, the recurrence rate in patients treated with sulfadiazine and pyrimethamine varies from 13% to 16.9%. 9 •10 In a clinical study of clindamycin (n = 26), 2 patients (7.7%) had recurrences over an 8-year period. 11 As noted in other
drug regimens, trimethoprim-sulfamethoxazole also appears to be inadequate in treating latent toxoplasmosis. In our study, one patient had a recurrence. Pyrimethamine requires weekly blood counts to monitor possible bone marrow suppression. While hematologic evaluation is an important consideration for patients on pyrimethamine, it is not routinely performed during trimethoprim-sulfamethoxazole therapy unless renal failure, advanced age, or extended therapy is involved. Administration of trimethoprim-sulfamethoxazole eliminates the need for weekly follow-up, blood counts, and folinic acid therapy, thereby significantly reducing patient cost. Trimethoprimsulfamethoxazole is generally well tolerated in adults and can be used safely with pediatric suspensions in children. Unlike clindamycin and pyrimethamine, trimethoprimsulfamethoxazole is dosed twice a day, thereby improving patient compliance. A prospective double-masked controlled study is warranted to confirm the value of trimethoprim-sulfamethoxazole as an effective, safe, and cost-efficient substitute for sulfadiazine, pyrimethamine, and folinic acid in the treatment of ocular toxoplasmosis.
References 1. Henderly DE, Genstler AJ, Smith RE, Rao NA. Changing
patterns of uveitis. Am J Ophthalmol 1987;103:131-6. 2. Eyles DE, Coleman N. Synergistic effect of sulfadiazine and daraprim against experimental toxoplasmosis in the mouse. Antibiot Chemother 1953;3:483-90. 3. Eyles DE, Coleman N. The relative activity of the common sulfonamides against experimental toxoplasmosis in the mouse. Am J Trop Med Hyg 1953;2:54-63. 4. Engstrom RE Jr, Holland GN, Nussenblatt RB, Jabs DA. Current practices in the management of ocular toxoplasmosis. Am J Ophthalmol 1991; 111:601-10. 5. Nguyen BT, Stadtsbaeder S, Horvat F. Comparative effect of trimethoprim and pyrimethamine, alone and in combination with a sulfonamide, on Toxoplasma gondii: in vitro and in vivo studies. In: Siegenthaler W, Luthy R, eds. Current Chemotherapy: Proc lOth Int'l Congress of Chemotherapy. Vol. 1. Washington, DC: American Society for Microbiology, 1978;137-40. 6. Grossman PL, Krahenbuhl JL, Remington JS. In vivo and in vitro effects of trimethoprim and sulfamethoxazole on Toxoplasma infection. In: Siegenthaler W, Luthy R, eds. Current Chemotherapy: Proc lOth Int'l Congress of Chemotherapy. Vol. 1. Washington, DC, American Society for Microbiology, 1978;135-7. 7. Holland GN, Buhles WC Jr., Mastre B, eta!. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of standardized system for the assessment of disease outcome. Arch Ophthalmol 1989; 107: 1759-66. 8. Rothova A, Buitenhuis HJ, Meenken C, eta!. Therapy of ocular toxoplasmosis. Int Ophthalmol 1989;13:415-9. 9. Ghosh M, Levy PM, Leopold IH. Therapy of toxoplasmosis uveitis. Am J Ophthalmol 1965;59:55-61. 10. Canamucio CJ, Hallett JW, Leopold IH. Recurrence of treated toxoplasmic uveitis. Am J Ophthalmol 1963;55: 1035-43. 11. Lakhanpal V, Schocket SS, Nirankari VS. Clindamycin in the treatment of toxoplasmic retinochoroiditis. Am J Ophthalmol 1983;95:605-13.
925
Background: Toxoplasmosis is a leading cause of retinochoroiditis. Conventional multidrug therapy using sulfadiazine, pyrimethamine, and folinic acid is increasingly difficult to procure and administer safely. Methods: To evaluate the efficacy of trimethoprim-sulfamethoxazole, a fixed-combination antibiotic, patients with active toxoplasmosis were treated with trimethoprimsulfamethoxazole (Bactrim DS) with or without adjunctive clindamycin and prednisone for 4 to 6 weeks. Results: All pati.ents in this study (n = 16) had resolution of active retinochoroiditis and had improved vision, with an average gain of 5.2 lines of vision. Two patients developed a drug allergy. Conclusion: Trimethoprim-sulfamethoxazole appears to be a safe and effective substitute for sulfadiazine, pyrimethamine, and folinic acid (leucovorin) in treating ocular toxoplasmosis. Ophthalmology 1992;99:920-925
Toxoplasma gondii is the most common cause of posterior uveitis in otherwise healthy individuals. 1 Symptoms include decreased visual acuity, vitreous floaters, pain, and redness of the eye. The combination of pyrimethamine, sulfadiazine, and folinic acid rescue has been the treatment of choice for ocular toxoplasmosis for 40 years. 2•3 Several other drugs have shown in vitro and in vivo efficacy against T. gondii, but the best treatment for patients with ocular toxoplasmosis remains unclear. In a recent survey of members of the American Uveitis Society, physicians were asked questions about their choice of antimicrobial agents for treatment of ocular toxoplasmosis. Eight different antimicrobial drugs were used in various combinations to treat toxoplasmic retinochoroiditis.4 The agents currently used are: pyrimethamine, sulfadiazine, clindamycin, sulfisoxazole, tetracycline, minocycline, and trimethoprim-sulfamethoxazole.
Originally received: September 10, 1991. Revision accepted: December II, 1991. From the Ohio State University, College of Medicine, Department of Ophthalmology, Columbus. Presented as a poster at the American Academy of Ophthalmology Annual Meeting, Anaheim, October 1991. Reprint requests to E. Mitchel Opremcak, MD, The Ohio State University College of Medicine, 456 W Tenth Ave, Columbus, OH 43210.
920
Among the 62 respondents, sulfadiazine is the most widely used drug, administered by 51 (82% ), while pyrimethamine, used by 43 (69%), is the second most commonly used drug. One of the authors (EMO) was the only respondent to use trimethoprim-sulfamethoxazole for this disease. Sulfadiazine and pyrimethamine have become increasingly difficult to procure in some regions of the country. Importantly, systemic side effects and toxicity of pyrimethamine are common. The need for multiple agents on a frequent dosing schedule reduces antibiotic compliance. Our interest in trimethoprim-sulfamethoxazole as treatment for ocular toxoplasmosis was to increase the antibiotic access and compliance, and to reduce the frequency of systemic adverse reactions. Trimethoprim-sulfamethoxazole, as well as pyrimethamine and sulfadiazine, inhibits sequential steps in the synthesis oftetrahydrofolic acid, an essential precursor to purines and DNA. Pyrimethamine and trimethoprim are benzylpyrimidines, and both inhibit bacterial dihydrofolic acid reductase. Sulfadiazine and sulfamethoxazole are sulfonamides, which competitively inhibit para-amino benzoic acid. Trimethoprim-sulfamethoxazole has shown similar efficacy to pyrimethamine and sulfadiazine in its inhibitory effect on T. gondii in infected HeLa cells. 5 Trimethoprim-sulfamethoxazole also has been shown to be effective in mice infected with T. gondii. 6 The half-lives
Opremcak et al · T rimethoprim-Sulfamethoxazole Therapy of trimethoprim and sulfamethoxazole are 9 to 11 hours and 10 to 12 hours, respectively, enabling the dosing to be twice a day. Trimethoprim-sulfamethoxazole is readily available as a fixed combination antibiotic (Bactrim, Septra), and has been shown to be relatively safe, with the advantage of increased patient compliance as a result of easier dosing (one tablet orally twice a day). In this article, we review our experience using trimethoprim-sulfamethoxazole and show it to be a clinically effective substitute for sulfadiazine and pyrimethamine in treating ocular toxoplasmosis.
logically characteristic fundus lesions. In most patients, this consisted of areas of active retinitis adjacent to old chorioretinal scars. A positive toxoplasmosis titer was required for inclusion in this study. Funduscopic photographs were taken before and after treatment to aid in determining the degree of resolution of disease. Fluorescein angiography was performed as indicated to monitor the patient's progress, and to assess for sequelae of inflammation (i.e., cystoid macular edema, retinal detachment, subretinal neovascular membrane). Treatment
Subjects and Methods We reviewed 16 consecutive patients referred to the Uveitis Service at the Ohio State University College of Medicine who were treated for toxoplasmic retinochoroiditis with trimethoprim-sulfamethoxazole combination over an 18-month period between 1989 and 1991. Patients were treated either with trimethoprim-sulfamethoxazole alone or in combination with clindamycin and prednisone. The patient population included 4 males and 12 females ranging in age from 11 to 78 years (Table 1). Diagnosis All patients underwent a complete ocular examination, including medical history, a thorough review of systems, visual acuity testing, biomicroscopic examination, and dilated fundus examination. The diagnosis of active toxoplasmosis was made in all patients by finding morpho-
Patients were categorized according to the location of the lesion as described by Holland et al. 7 Briefly described, zone 1 lesions were considered to be that portion of the retina where infection is immediately sight-threatening and corresponding to an area extending 3000 ~.tm (2 disc diameters) from the fovea (approximately that area enclosed by the major temporal vascular arcades) or 1500 ~.tm from the margins of the optic nerve head; zone 2 were lesions extending anterior from zone 1 to the clinical equator of the eye, identified by the anterior borders of the ampullae of the vortex veins; and zone 3 lesions were extending anterior from zone 2 to the ora serrata. Patients were divided into two groups according to their treatment regimen (Table 1). Patients with lesions in zone 1 or those who had lesions in zone 2 accompanied by severe inflammation or opacified vitreous were typically treated with combination antibiotics (trimethoprim-sulfamethoxazole and clindamycin) and prednisone. Patients
Table 1. Summary of Clinical Data Patient No.
Sex
Zone of Lesion
Drug Regimen
38 12 37 50 37 48 78 69
F F F F M M F M
2 2 2 2 2 2 1 2
T T T T TC TC TC TC
6 6 4 6 6 4 6 6
33 15 21
F F F F F F M F
1 1 1 1 2 2 1 2
TCP TCP TCP TCP TCP TCP TCP TCP
2 6 6 6 6 6 6 6
Age (yrs)
Duration of Treatment
(wks)
Visual Acuity
Complications
Before
After
Of Drugs
20/400
20/30 20/100 20/20 20/30 20/60 20/15 20/40 20/15
Headache
Of Disease
Recurrence
Group 1
1 2 3 4 5 6 7 8
CF
20/20 20/200 20/200 20/25 LP
20/40
ERM Mild rash Diarrhea
0 0 0 0 0 0 0 0
Group 2
9 10 11 12 13
14 15 16
11
33 31 11
41
20/400 CF
20/400 20/200 20/60 20/50 CF
20/200
20/400 20/70 20/20 20/15 20/20 20/30 20/60 20/20
Mild rash Diarrhea Headache
RD SRNVM ERM CME
0 0 0 0 0 0 0 3
T = trimethoprim-sulfamethoxazole; C = clindamycin; P = prednisone; CF = counting fingers; LP = light perception; RD = retinal detachment; ERM = epiretinal membrane; CME = cystoid macular edema; SRNVM = subretinal neovascular membrane.
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with uncomplicated zone 2 lesions were treated with antibiotics alone. Each patient in this study received 160 mg trimethoprim and 800 mg sulfamethoxazole (Bactrim DS), orally twice a day for 4 to 6 weeks. Patients receiving adjunctive therapy were administered clindamycin (Cleomycin) 300 mg 4 times a day for 2 weeks, prednisone 80 mg a day for 2 days tapered 20 mg every other day, down to a dose of 20 mg a day for 4 weeks. Prednisone therapy was begun 2 days after beginning antibiotic therapy.
Evaluation Each patient returned for follow-up at 3 to 4 weeks, then again at 8 weeks. The follow-up periods ranged from 2 months to 18 months. The criterion for resolution of disease was biomicroscopic evidence of complete resolution of active retinitis. Recurrence of disease was defined as evidence of active retinitis after an 8-week period of retinal quiescence. Patients who had recurrences of their disease underwent an additional4 to 6-week course of their initial therapy.
Selected Case Reports Patient 3: Peripheral Toxoplasmosis (Zone 2). A 37-
year-old woman presented with a week long history of floaters, flashes, and decreasing visual acuity in her right eye. She had previous episodes of floaters but had not sought medical attention for them. Her medical history and immunologic survey were remarkable for the presence of shingles. She also had tested positive for toxoplasmosis during a previous pregnancy. Results of ocular examination showed her visual acuity to be 20/20 in both eyes. Examination of her left eye was unremarkable. Examination of her right eye showed fine stellate keratic precipitate with an occasional cell in the anterior chamber. She had mild iris stromal atrophy without transillumination defect. Her vitreous cavity had 1+ active cell and flare. A dilated fundus examination showed multifocal chorioretinal scars with satellite lesions and an active toxoplasmosis lesion within the temporal posterior pole (Fig 1, top left). A positive toxoplasmosis titer supported the diagnosis of zone 2 ocular toxoplasmosis.
The patient began a 4-week course of trimethoprim-sulfamethoxazole (treatment group 1). On follow-up examination 4 weeks later and on subsequent biomicroscopic and fundus examinations, clearing of her vitreous cells and a quiet chorioretinal scar were seen (Fig 1, top right). Visual acuity was 20/20 in both eyes.
Patient 11: Punctate Outer Retinal Toxoplasmosis (Zone 1). A 21-year-old woman presented with a 1-week his-
tory of decreased vision in her left eye without any associated pain or redness. Her immunologic history was remarkable for exposure to a sick cat 3 years before presentation. On ocular examination, visual acuity was 20/20 in the right eye and 20/400 in the left. Examination of her right eye was unremarkable. Examination of the left eye showed 2+ vitreous cell with a quiet anterior chamber. Results of dilated fundus examination showed a large chorioretinal scar in the superior temporal quadrant and several other smaller lesions in the inferior retina. Also present was a pigmented chorioretinallesion adjacent to an area of active retinochoroiditis in the macula (Fig 2, second row left). Vitreous inflammatory cells were found overlying the lesion. A positive toxoplasmosis titer supported the diagnosis of punctate outer retinal toxoplasmosis in zone 1. The patient began a 4-week course oftrimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). On follow-up examination, her visual acuity improved from counting fingers to 20/70 in her affected eye, with biomicroscopic and fundus examination showing complete resolution of active disease (Fig 2, second row right).
Patient 12: Peripapillary Toxoplasmosis in a Child (Zone 1). An 11-year-old girl presented with a 2-month history
of blurring in her left eye. Five years previously, she had toxoplasmosis in the macula of her right eye, which left her with decreased central vision. Her medical history and immunologic survey were unremarkable. On ocular examination, visual acuity was 20/200 in both eyes. Examination of the right eye was remarkable only for the presence of a large inactive chorioretinal scar in her macula. Examination of her left eye showed a 1+ afferent pupillary defect and normal intraocular pressure. Also evident were 3+ mutton fat KP with 2+ cells in the vitreous cavity. A dilated fundus examination showed marked disc edema with an area of active retinitis along the inferior temporal arcades (Fig 3, third row left). A significant amount of vitreous debris also was present. A positive immunofluorescent antibody titer supported the clinical diagnosis of bilateral, congenital toxoplasmosis, and the
Top left, Top right, Figure 1. Patient 3. Peripheral toxoplasmosis (zone 2). Fundus photographs of a 37-year-old woman with floaters and visual acuity of 20/20 in the right eye. Top left shows a mild vitreous haze with multifocal pigmented chorioretinal scars. The inferior lesion had overlying inflammatory cells on biomicroscopy and active retinitis. Top right shows clearing of the vitreous inflammation and a quiet toxoplasmosis lesion after 4 weeks of trimethoprim-sulfamethoxazole therapy. Second row left, Second row right, Figure 2. Patient 11. Punctate outer retinal toxoplasmosis (zone 1). Fundus photographs of a 21-year-old woman with a 1-week history of decreased visual acuity to 20/400. Second row left shows an inactive pigmented chorioretinal scar in the inferior macula and an adjacent active area of punctate outer retinitis. Second row right shows clearing of the retinal edema and focal retinitis following a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Third row left, Third row right, Figure 3. Patient 12. Peripapillary toxoplasmosis in a child (zone 1). Fundus photograph of an 11-year-old girl with an old toxoplasmosis lesion in the macula of her right eye and decreased visual acuity of 20/200 in the left eye. Third row left demonstrates vitreous haze and marked disc and macular edema. A disc diameter area of active retinitis can be observed just below the optic nerve. Third row right shows complete resolution of the vitreitis, retinitis, and optic disc edema after a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Bottom left, Bottom right, Figure 4. Patient 15. Acquired macular toxoplasmosis in a child (zone 1). Fundus photographs of an 11-year-old boy with decreased visual acuity to counting fingers in the right eye. Bottom left shows disc hyperemia and area of active outer retinitis in the macula. Bottom right shows resolution of the retinal lesion after a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone.
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patient began a 6-week course of trimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). On follow-up examinations, 4 and 8 weeks later, the patient showed continual improvement to a final visual acuity of 20/25. Examination showed that there was marked clearing of vitreous debris, with complete resolution of active retinitis and disc edema (Fig 3, third row right).
Patient 15: Acquired Macular Toxoplasmosis in a Child (Zone 1). An 11-year-old boy presented with a 48-
Toxoplasmosis - TMP-SMZ LP
CF
20/400 !l)
.E
~
·a"'
20/200 20/100
20/80 20/70 20/60
hour history of rapidly decreasing visual acuity in his right eye. His medical history and his immunologic survey were unremarkable. A normal fundus was noted by an ophthalmologist in a prior examination when the patient was 8 years of age. Ocular examination showed visual acuity of counting fingers in the right eye and 20/20 and in the left. Examination of the left eye was unremarkable. Examination of the right eye showed an afferent pupillary defect. Biomicroscopic examination was unremarkable except for a mild amount of posterior vitreous cells. A dilated fundus examination showed mild disc hyperemia and a prominent lesion in the outer retina along the superior arcade (Fig 4, bottom left). A fluorescein ~ngiogram showed early hypofluorescence corresponding to the area of retinitis noted on the fundus examination. The late frames of the angiogram showed marked disc edema, retinal edema, retinal vessel staining, and dye extravasation into the vitreous. Diagnosis of the outer retinitis variant of toxoplasmosis in zone 1 was made, which was supported by a positive toxoplasmosis titer. Because of the sight-threatening nature of his disease, the patient began a regimen of trimethoprim-sulfamethoxazole, clindamycin, and prednisone (treatment group 2). After a 6-week course of antibiotics and prednisone, the patient showed improvement, with visual acuity increasing from the original level of counting fingers to 20/60. Biomicroscopic and fundus examinations showed complete resolution of his active infection, and development of a discrete, chorioretinal scar in the posterior pole (Fig 4, bottom right). The patient returned for follow-up 5 times in 6 months and had no recurrences.
All the patients in group 2 (n = 8) had resolution of disease, while 7 of the 8 patients had improved visual acuity (Fig 5). One patient retained visual acuity of 20/ 400 after treatment because of a large macular chorioretinal scar. The average initial visual acuity was 20/200. The average visual acuity after treatment was 20/40. The average improvement was 5.8 lines of vision. All patients received trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Five patients had zone 1 lesions, while the other three had sight-threatening complications of disease. Complications of the treatment were: mild rash (n = 2), colitis (n = 2), and headache (n = 2). Sequelae of this infectious disease consisted of the following: epiretinal membrane (n = 2), retinal detachment (n = 1), subretinal neovascularization (n = 1), and cystoid macular edema (n = 1).
Results
Discussion
All patients in this study (n = 16) had resolution of active retinitis and improved or maintained their initial visual acuity at the end of the 4- to 6-week treatment regimen. One patient (patient 16) had 3 recurrences over an 18month period of time and was given an additional 4 to 6 weeks of the same therapy. Patients in group 1 (n = 8) received only antibiotics, either trimethoprim-sulfamethoxazole alone or in conjunction with clindamycin. Four patients received only trimethoprim-sulfamethoxazole, while the other four received trimethoprim-sulfamethoxazole and clindamycin. Patients in this group did not receive prednisone. All patients in group 2 (n = 8) received trimethoprim-sulfamethoxazole, clindamycin, and prednisone. All patients in group 1 (n = 8) had resolution of disease and maintained or improved vision (Table 1). The average initial visual acuity was 20/80. The average visual acuity after treatment was 20/30. The average improvement was 4.6 lines of vision. Seven of eight patients in this group had zone 2 lesions. The one patient with a zone 1 lesion and optic nerve involvement was included in this group because of refusal to take prednisone. Complications of the treatment were headache (n = 1), mild rash (n = 1), and diarrhea (n = 1).
The combination of sulfadiazine and pyrimethamine has been the treatment of choice for ocular toxoplasmosis since its efficacy was first demonstrated by Eyles and Coleman2•3 in the early 1950s. Since then, few prospective randomized clinical studies have evaluated the effectiveness of alternate drugs. Among uveitis specialists in the United States, 82% use sulfadiazine and 69% use pyrimethamine in some combination to treat ocular toxoplasmosis.4 Sulfadiazine and pyrimethamine appear to have regional variability of access to patients in this country, making it necessary to find an effective substitute for these two drugs. Although in vitro and in vivo studies have shown the efficacy of several of the other agents currently used to treat toxoplasmosis, none has demonstrated clinical superiority to the combination of a sulfonamide and a folic acid inhibitor. Recently, a prospective multicenter study of therapies for ocular toxoplasmosis showed a small therapeutic advantage in patients treated with sulfadiazine and pyrimethamine, compared with trimethoprim-sulfamethoxazole or clindamycin. 8 Unfortunately, the number of patients treated with trimethoprim-sulfamethoxazole in that study was small (n = 8), leaving questions regarding its clinical efficacy largely unanswered. In this communication, we report our experience em-
924
20/50 20/40
20/20 20/30 20/40 20/50 20/60 20/70 20180 20/100 20/200 20/400
CF
LP
Visual Acuity AIter
Figure 5. Scattergram of pretreatment and post-treatment vision. Each point represents the visual outcome of one patient. The sloped line represents the axis of no change in vision.
Opremcak et al · Trimethoprim-Sulfamethoxazole Therapy playing trimethoprim-sulfamethoxazole as a substitute for standard sulfadiazine, pyrimethamine, and folinic acid regimens in 16 consecutive patients with ocular toxoplasmosis. Trimethoprim-sulfamethoxazole alone or in combination with clindamycin and prednisone appears to be an effective and safe fixed combination antibiotic for treating active retinal toxoplasmosis. We routinely treat zone 1 lesions with a combination of trimethoprim-sulfamethoxazole, clindamycin, and prednisone. Using these medications, we have noted no serious systemic side effects (Table 1). Bactrim has been associated with skin rashes and mild diarrhea. Pseudomembranous colitis is a rare but potentially serious complication of clindamycin. This is a severe form of bloody diarrhea that typically begins 4 to 9 days after the start of oral clindamycin. We have not observed this side effect of clindamycin when used in combination with oral trimethoprim-sulfamethoxazole. Pseudomembranous colitis can be treated by discontinuing the antibiotic and starting oral vancomycin at a dose of 250 mg four times daily. Short courses of oral corticosteroids also may be associated with serious systemic side effects. Patients with diabetes, hypertension, and peptic ulcer disease have a higher risk of adverse reactions when using these agents. Patients should be given adequate informed consent as to the potential side effects of these agents. Uncomplicated zone 2 lesions were successfully treated with trimethoprim-sulfamethoxazole alone or in conjunction with clindamycin. Whether zone 1 lesions can be treated with trimethoprim-sulfamethoxazole alone is unclear. We believe that most of the ocular complications of toxoplasmosis are a result of the necrotizing inflammation that accompanies this protozoal infection. We believe that prednisone plays an important role in abrogating this secondary inflammatory response. The use of periocular corticosteroid injections has been discouraged because of experiences in which it has been associated with uncontrollable spread of infection, presumably due to intense suppression of host protective mechanisms. We used oral prednisone to avoid this complication. Five of 16 patients, nevertheless, developed sequela as a result of infection with toxoplasmosis, requiring further treatment. These included epiretinal membrane, subretinal neovascular membrane, cystoid macular edema, and retinal detachment. One patient with retinal detachment (patient 13) was successfully repaired with scleral buckle surgery, and visual acuity returned to 20/20. Another patient (patient 14) with juxtafoveal subretinal neovascular membrane had focal laser photocoagulation with return of20/ 30 visual acuity. One patient (patient 15) developed vitreous opacification, epiretinal membrane, and a fullthickness macular hole. The patient regained visual acuity of 20/60 and complete closure of the macular hole after vitrectomy and surgical removal of the epiretinal scar. There is no known therapy that can completely eradicate the latent tissue cysts of toxoplasmosis. Therefore, the recurrence rate in patients treated with sulfadiazine and pyrimethamine varies from 13% to 16.9%. 9 •10 In a clinical study of clindamycin (n = 26), 2 patients (7.7%) had recurrences over an 8-year period. 11 As noted in other
drug regimens, trimethoprim-sulfamethoxazole also appears to be inadequate in treating latent toxoplasmosis. In our study, one patient had a recurrence. Pyrimethamine requires weekly blood counts to monitor possible bone marrow suppression. While hematologic evaluation is an important consideration for patients on pyrimethamine, it is not routinely performed during trimethoprim-sulfamethoxazole therapy unless renal failure, advanced age, or extended therapy is involved. Administration of trimethoprim-sulfamethoxazole eliminates the need for weekly follow-up, blood counts, and folinic acid therapy, thereby significantly reducing patient cost. Trimethoprimsulfamethoxazole is generally well tolerated in adults and can be used safely with pediatric suspensions in children. Unlike clindamycin and pyrimethamine, trimethoprimsulfamethoxazole is dosed twice a day, thereby improving patient compliance. A prospective double-masked controlled study is warranted to confirm the value of trimethoprim-sulfamethoxazole as an effective, safe, and cost-efficient substitute for sulfadiazine, pyrimethamine, and folinic acid in the treatment of ocular toxoplasmosis.
References 1. Henderly DE, Genstler AJ, Smith RE, Rao NA. Changing
patterns of uveitis. Am J Ophthalmol 1987;103:131-6. 2. Eyles DE, Coleman N. Synergistic effect of sulfadiazine and daraprim against experimental toxoplasmosis in the mouse. Antibiot Chemother 1953;3:483-90. 3. Eyles DE, Coleman N. The relative activity of the common sulfonamides against experimental toxoplasmosis in the mouse. Am J Trop Med Hyg 1953;2:54-63. 4. Engstrom RE Jr, Holland GN, Nussenblatt RB, Jabs DA. Current practices in the management of ocular toxoplasmosis. Am J Ophthalmol 1991; 111:601-10. 5. Nguyen BT, Stadtsbaeder S, Horvat F. Comparative effect of trimethoprim and pyrimethamine, alone and in combination with a sulfonamide, on Toxoplasma gondii: in vitro and in vivo studies. In: Siegenthaler W, Luthy R, eds. Current Chemotherapy: Proc lOth Int'l Congress of Chemotherapy. Vol. 1. Washington, DC: American Society for Microbiology, 1978;137-40. 6. Grossman PL, Krahenbuhl JL, Remington JS. In vivo and in vitro effects of trimethoprim and sulfamethoxazole on Toxoplasma infection. In: Siegenthaler W, Luthy R, eds. Current Chemotherapy: Proc lOth Int'l Congress of Chemotherapy. Vol. 1. Washington, DC, American Society for Microbiology, 1978;135-7. 7. Holland GN, Buhles WC Jr., Mastre B, eta!. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of standardized system for the assessment of disease outcome. Arch Ophthalmol 1989; 107: 1759-66. 8. Rothova A, Buitenhuis HJ, Meenken C, eta!. Therapy of ocular toxoplasmosis. Int Ophthalmol 1989;13:415-9. 9. Ghosh M, Levy PM, Leopold IH. Therapy of toxoplasmosis uveitis. Am J Ophthalmol 1965;59:55-61. 10. Canamucio CJ, Hallett JW, Leopold IH. Recurrence of treated toxoplasmic uveitis. Am J Ophthalmol 1963;55: 1035-43. 11. Lakhanpal V, Schocket SS, Nirankari VS. Clindamycin in the treatment of toxoplasmic retinochoroiditis. Am J Ophthalmol 1983;95:605-13.
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