Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

PICO 1: SYSTEMIC TREATMENTS

Comparison 1a: thrimethoprim/sulfamethoxazole (TMP/SMX) vs. pyrimethamine/sulfadiazine (PYR/SDZ)

Soheilian, 2005

Type of study: RCT

Setting and country: Labbafinejad Medical Center Uveitis Clinic in Tehran, Iran, from January 2000-February 2004

Funding and conflicts of interest: Supported in part by the Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Inclusion criteria:

Patients with ocular toxoplasmosis and:

· Location of lesion within zone 1 of the retina (region extending 3000 mm from the foveal center) or a lesion >2 disc diameters in size with 3 to 4+ vitreous inflammation within zones 2 or 3.

Zone 2 is defined as the region extending anteriorly from the border of zone 1 to te equator, and zone 3 is defined as the region from the border of zone 2 to the ora serrata)

· Presence of retinal lesion at least 500 µm outside the center of the macula.

· Lack of history of allergic reaction to the drugs used in this study.

· Lack of any other ocular disease.

Exclusion criteria:

· visual acuity of <20/200 in the fellow eye

· location of the lesion within the center (500 mm) of the macula.

· development of allergic reaction to the medication.

· leukopenia (white blood cell count <5000 or platelet count <120,000/ml.

· lesions <2 disc diameters in zones 2 and 3.

N total at baseline:

TMP/SMX: n=36

PYR/SDZ: n=35

Important prognostic factors²:

Age ± SD:

TMP/SMX: 26.6 +/- 11.7 y

PYR/SDZ: 23.5 +/- 7.4 y

Sex:

TMP/SMX: 60% M

PYR/SDZ: 62.1% M

Groups comparable at baseline? Yes

TMP/SMX

Treatment regimen:

2 tablets of TMP (80 mg)/SMX (400 mg) every 12h for 6 weeks. Oral prednisolone was administered at 1 mg/kg daily starting from the third day of therapy, and the dose was tapered over 2 weeks.

PYR/SDZ

Treatment regimen:

Initial dose of 100 mg of PYR daily for 2 days, followed by a 25-mg dose daily, 2g of SDZ daily for 2 days followed by 500-mg dosing every 6h, and 5 mg of folinic acid daily for 6 weeks. Oral prednisolone was administered at 1 mg/kg daily starting from the third day of therapy, and the dose was tapered over 2 weeks.

Length of follow-up: at least 24 months after completion of treatment

Loss-to-follow-up:

TMP/SMX: 6/36 (17%)

N (%)

Reasons (describe): 1 due to development of drug allergy and 5 due to incomplete follow-up

PYR/SDZ: 5/35 (14%)

N (%)

Reasons (describe): 1 due to development of allergic reaction to SDZ and 4 due to incomplete follow-up

Incomplete outcome data:

TMP/SMX: 5/36 (16%)

N (%)

Reasons (describe): incomplete follow-up

PYR/SDZ: 4/35 (13%)

N (%)

Reasons (describe): incomplete follow-up

Lesion size reduction, % (range %)

TMP/SMX: 59% (10%-100%)

PYR/SDZ: 61% (10%-100%)

Vitreous inflammation, events/total (%)

Reduction of vitreous inflammatory cells (0 trace cells) 6 wks after treatment

TMP/SMX: 17/30 (56.7)

PYR/SDZ: 20/29 (69)

RR = 0.82 (95% CI: 0.55, 1.22)

Author’s conclusion: “Our study revealed no significant difference between classic treatment with PYR/SDZ and TMP/ SMX for ocular toxoplasmosis retinochoroiditis in terms of reduction in lesion size. […] The results of this study suggest TMP/SMX

as an alternative to classic treatment, with

greater availability, less cost, and a safer drug profile in

immunocompetent patients with two functional eyes and

with lesions outside of immediate (>500 mm) proximity to the macula. As such, we would not currently recommend using TMP/SMX for active central foveal lesions.”

Limitations of the study:

• Inability to mask evaluating physicians completely to the patients’ assigned treatment regimen and the inability to obtain fundus photographs in some patients

Comparison 1b: TMP/SMX vs. azithromycin

Lashay, 2017

Type of study: RCT

Setting and country: Retinal Department of Farabi Eye Hospital, Tehran, Iran, from March 2010-October 2013

Funding and conflicts of interest: none reported

Inclusion criteria:

Patients with ocular toxoplasmosis and:

· age between 16 and 75 years

· A lesion within 3000 µm from the foveal center (zone 1) or a lesion >2 disc diameters in size with 3-4 (+) vitreous inflammation within the region beyond the borders of zone 1 (zones 2 and 3)

Exclusion criteria:

· Presence of other ocular diseases including other causes of uveitis, glaucoma, any retinal lesion, and systemic conditions such as uncontrolled diabetes, pregnancy,

· Any history of hypersensitivity to azithromycin and sulfonamides, immunosuppression especially HIV or consumption of immunosuppressive drugs

· history of any previous adverse drug reaction

· corticosteroid treatment within 1 month prior to visit

· BCVA <20/400 (1.3 logMAR) on the Snellen chart in either eye

N total at baseline:

TMP/SMX: n=13

Azithromycin: n=14

Important prognostic factors²:

Age ± SD:

TMP/SMX: 28 ± 1.5 y

Azithromycin: 24.9 ± 1.6 y

Sex:

TMP/SMX: 61.6% M

Azithromycin: 42.8% M

Groups comparable at baseline? Yes

TMP/SMX

Treatment regimen

Patients received TMP 160 mg/SMX (800 mg) twice daily. The group also received prednisolone 1 mg/kg daily from the third day, and the dose was tapered over 2 weeks based on vitritits control. Treatment continued for 6-12 weeks.

Azithromycin

Treatment regimen

500 mg as a loading dose for one day followed by azithromycin 250 mg daily. The group also received prednisolone 1 mg/kg daily from the third day, and the dose was tapered over 2 weeks based on vitritits control. Treatment continued for 6-12 weeks.

Length of follow-up: at least 9 months after completion of treatment

Loss-to-follow-up:

TMP/SMX: not reported

N (%)

Reasons (describe): NA

Azithromycin: not reported

N (%)

Reasons (describe): NA

Incomplete outcome data:

TMP/ SMX: not reported

N (%)

Reasons (describe): NA

Azithromycin: not reported

N (%)

Reasons (describe): NA

Lesion size reduction

Lesion size before treatment, mean ± SD

TMP/SMX: 7.18 +/- 1.3 mm²

Azithromycin: 6.4 +/- 1.4 mm²

Lesion size after treatment, mean ± SD

TMP/SMX: 4.9 +/-1.2 mm²

Azithromycin: 5.1 +/- 1.3 mm²

Lesion size reduction, mean ± SD percentage

TMP/SMX: 36.6 ± 4.6

Azithromycin: 24.2 ± 6.5

MD = 12.4 (95% CI: 8.18, 16.62) in favour of TMP + SMX

Vitreous inflammation

Resolved signs 12 weeks after treatment, events/total (%)

TMP/SMX: 10/13 (76.9)

Azithromycin: 7/14 (50)

RR = 1.54 (95% CI: 0.84, 2.81)

Author’s conclusion: “In summary, the positive response of toxoplasmic retinochoroiditis to azithromycin was shown by visual improvement, lesion size, sharpening of margins of the lesions, and reduction of satellite lesions. Although there was no significant

difference in time to respond to treatment between the 2

treatment groups, the difference may be clinically important. On the basis of our findings, treatment with azithromycin could be an appropriate alternative to treatment with trimethoprim/

sulfamethoxazole, and therefore, it might be an acceptable choice instead of standard treatment with pyrimethamine and

sulfadiazine for ocular toxoplasmosis if confirmed with further large scale studies. Treatment with azithromycin is, however,

better tolerated and has fewer side effects.”

Limitations of the study:

• small sample size and this study was rather a pilot study

• Single-blind study

• No control group of patients treated with standard regimen of PYR + SDZ

Comparison 1c: PYR/SDZ vs. azithromycin

Ghavidel 2017

Type of study: RCT

Setting and country: Department of Ophthalmology, Nikookari Eye Center, Tabriz, Iran, from January 2014-October 2016

Funding and conflicts of interest: none reported

Inclusion criteria:

· Location of the lesion within region extending 3000 µm from the foveal center and at least 500 µm outside the center of the macula

· or a lesion with 2 disc diameters or larger in size with 3-4 plus vitritits within the region extending anteriorly from 3000 µm from the fovea to the equator

· Positive serological evaluation for IgG and negative for IgM anti-toxoplasmosis antibody

Exclusion criteria:

· Low vision in the fellow eye (VA of <20/200)

· Central lesions (within the 500 mm of the fovea)

· Active intra-ocular inflammation

· Patients younger than 18 y

· Pregnancy

· Immunodeficiency

· Leukopenia (white blood cell count less than 5000 or platelet count <120,000/mL)

· Peripheral lesion <2 disc diameters or causing £2 vitreous inflammation

· Severe media opacity precluding clear photography

· History of intolerance or hypersensitivity to macrolides or PYR/SDZ

· Febrile illness or other infectious diseases

· History of any antibiotic therapy at last 30 days

· Any immunodeficiency condition

N total at baseline:

PYR/SDZ: n=36

Azithromycin: n=36

Important prognostic factors²:

Age (range):

PYR/SDZ: 37.56 (20-60) y

Azithromycin: 41.94 (27-56) y

Sex:

PYR/SDZ: 55.4% M

Azithromycin: 50% M

Groups comparable at baseline? Yes

PYR/SDZ

Treatment regimen

Initial loading dose of 100 mg, followed by a dose of 50-mg daily for PYR, and a loading dose of 2 g followed by 500-mg every 6h daily for SDZ, and 5 mg folinic acid once daily. Patients also received prednisolone 1 mg/kg daily starting from the third day after initial therapy. This was tapered over 14 days. Treatment duration continued for 6 weeks.

Azithromycin

Treatment regimen

1 tablet of azithromycin 250 mg daily was used. Patients also received prednisolone 1 mg/kg daily starting from the third day after initial therapy. This was tapered over 14 days. Treatment duration continued for 6 weeks.

Length of follow-up: 24 months

Loss-to-follow-up:

PYR + SDZ: not reported

N (%)

Reasons (describe): NA

Azithromycin: not reported

N (%)

Reasons (describe): NA

Incomplete outcome data:

PYR + SDZ: not reported

N (%)

Reasons (describe): NA

Azithromycin: not reported

N (%)

Reasons (describe): NA

Changes in lesion size

Before treatment, µm (SD not reported)

PYR/SDZ: 972.22

Azithromycin: 862.50

6 weeks after treatment, µm (SD not reported)

PYR/SDZ: 311.11

Azithromycin: 507.64

Reduction during treatment, µm (SD not reported)

PYR/SDZ: 638.89

Azithromycin: 354.86

P value: 0.098

Vitreous inflammation

Not reported

Author’s conclusion: “In conclusion considering an increased interest for alternative choices for toxoplasmic chorioretinitis, this study introduced azithromycin monotherapy (as an inexpensive and available regimen) as an alternate treatment with equal efficacy, higher compliance and lower side effects than standard treatment.”

Limitations of the study:

• short time of follow-up

• no placebo group

• limited number of patients

Comparison 1d: Quadruple-drug therapy vs. triple therapy

Kartasasmita 2017

Type of study: RCT

Setting and country: Cicendo Eye Hospital, Bandung, Indonesia

Funding and conflicts of interest: none reported

Inclusion criteria:

Patients with a new case of chorioretinitis or those with recurrent disease with new lesions in a new location.

Exclusion criteria:

· Presence of vitreous opacities that interfere with the examination of retinal lesions

· Undergoing treatment or receiving antitoxoplasma therapy

· A history of allergy to the antibiotics used

N total at baseline:

Quadruple therapy: n=14

Triple therapy: n=14

Important prognostic factors²:

Age ± SD:

Quadruple therapy: 32.1 ± 14.1 y

Triple therapy: 27.7 ± 12.5 y

Sex:

Quadruple therapy: 85.7% M

Triple therapy: 50% M

Groups comparable at baseline? Yes, at an alpha of 0.1

Quadruple therapy

Treatment regimen

Cotrimoxazole (TMP/SMX), two tables, 480 mg twice daily

Oral clindamycin, 300 mg, 4 times daily

Oral methylprednisolone 1 mg/kg daily, tapered off each week.

Treatment duration is 3 weeks.

Triple therapy

Treatment regimen

PYR tablet 25 mg, three times daily at the start of therapy, and then tapered to once daily.

SDZ tablet 1000 mg, twice daily at the start of therapy, and then once daily.

Oral methylprednisolone 1 mg/kg daily, and tapered off each week.

Treatment duration is 3 weeks, with an addition of oral folic acid 5 mg that is given three times per week interval alternate days.

Length of follow-up: 3 weeks

Loss-to-follow-up:

Quadruple therapy: not reported

N (%)

Reasons (describe): NA

Triple therapy: not reported

N (%)

Reasons (describe): NA

Incomplete outcome data:

Quadruple therapy: not reported

N (%)

Reasons (describe): NA

Triple therapy: not reported

N (%)

Reasons (describe): NA

Lesion size reduction, mean % (SD not reported)

From baseline to first week

Quadruple therapy: 71.7

Triple therapy 19.8

P value 0.001*, in favour of quadruple therapy

From baseline to 3^rd week

Quadruple therapy: 57.5

Triple therapy: 52.5

P value 0.720*

*P value based on 90% confidence degree

Vitreous inflammation

Not reported

Author’s conclusion: “we found that the quadruple-drug therapy has a faster therapeutic effect, thereby providing a reduction in treatment duration where long-term treatment may potentially cause treatment side effects. This rapid reduction of lesions also has the advantage of rapid recovery on visual acuity, resulting in an overall faster recovery process.”

Limitations of the study:

· No complete data about systemic diseases that might accompany the disease under study

· No complete serial data on patient’s IgG and IgM to correlate the clinical changes with the titer of IgG and IgM. The patient’s immunology status is also considered as a confounding factor.

Comparison 1e: PYR/azithromycin vs. PYR/SDZ

Bosch-Driessen, 2002

Type of study: RCT

Setting and country: five ophthalmologic departments of the University Hospitals in Netherlands recruited between July 1997 and June 2000

Funding and conflicts of interest: supported in part by the Dr. F.P. Fisher Foundation, The Netherlands

Inclusion criteria:

· Active toxoplasmic retinochoroidal lesion located centrally within the major temporal vascular arcades or a juxtapapillary lesion (within a distance of 1 disk diameter) in either eye

· Ages between 16 and 80 years

Exclusion criteria:

· patients on immunosuppressive medication

· patients with AIDS

· patients with other ocular diseases

· used antiparasitic drugs in a period 3 months prior to the study

N total at baseline:

PYR + Azithromycin: n=24

PYR + SDZ: n=22

Important prognostic factors²:

Age ± SD: not reported

Sex:

Not reported

Groups comparable at baseline? Yes, but visual acuity £0.1 almost statistically significantly different between both groups

PYR/azithromycin

Treatment regimen:

PYR: 100 mg on day 1, followed by 50 mg daily

Azithromycin: 250 mg daily, n=7, 500 mg every other day, n=17

Additional treatment:

Folinic acid: 15 mg daily

Prednisone: 40 mg from day 3 to day 10, followed by a gradual tapering off

Treatment duration at least 4 weeks

PYR/SDZ

Treatment regimen:

PYR: 100 mg on day 1, followed by 50 mg daily

SDZ: 4000 mg daily

Additional treatment:

Folinic acid: 15 mg daily

Prednisone: 40 mg from day 3 to day 10, followed by a gradual tapering off

Treatment duration at least 4 weeks

Length of follow-up: 15 months

Loss-to-follow-up:

PYR/azithromycin: 0/24 (0%)

N (%)

Reasons (describe): NA

PYR/SDZ: 3/22 (14%)

N (%)

Reasons (describe): side effects

Incomplete outcome data:

Outcome = lesion size

PYR/azithromycin: 9/24 (37.5%)

N (%)

Reasons (describe): presence of vitreous opacities

PYR/SDZ: 11/22 (50%)

N (%)

Reasons (describe): presence of vitreous opacities

Outcome = vitreous inflammation

PYR + azithromycin: 4/24 (16.7%)

N (%)

Reasons (describe): presence of vitreous opacities

PYR + SDZ: 5/22 (22.7%)

N (%)

Reasons (describe): presence of vitreous opacities

Lesion size, events/total (%) 

Decrease in size >0.5 optic disk diameters at 3 months

PYR/azithromycin: 9/22 (41%)*

PYR/SDZ: 9/20 (45%)*

*data could not be determined

for all patients in the group

RR = 0.91 (95% CI: 0.45, 1.83)

Decrease in size of retinal lesion

PYR/azithromycin: 7/15 (47%)*

PYR/SDZ: 7/11 (63%)*

*data could not be determined

for all patients in the group

RR = 0.73 (95% CI: 0.36, 1.48)

Decrease in size of retinal lesion = difference between the size of the area of active inflammation and the size of the final retinal scar.

Vitreous inflammation, events/total (%)

Disappearance of inflammatory cells from vitreous within 4 weeks

PYR/azithromycin: 14/20 (70%)*

PYR/SDZ: 12/17 (71%)*

*data could not be determined

for all patients in the group

RR = 0.99 (95% CI: 0.65, 1.51)

Author’s conclusion: “the efficacy of short-term multidrug treatment containing PYR and azithromycin was similar to the standard treatment for ocular toxoplasmosis consisting of PYR and SDZ. The treatment containing azithromycin was however better tolerated and had fewer side effects. For these reasons, multidrug therapy with the combination of PYR and azithromycin is at present our current treatment of choice for sight-threatening ocular toxoplasmosis.”

Limitations of the study:

• the trial was unmasked with regard to medication. This might have biased the interpretation of the results of the therapies by the ophthalmologist

• small sample size

PICO 2: INTRAVITREAL VS. SYSTEMIC TREATMENT

Comparison 2a: Intravitreal clindamycin + dexamethasone (IVCD) vs. oral PYR/SDZ

Soheilian, 2011

Type of study: RCT

Setting and country: uveitis clinic of Labbafinejad Medical Center, Tehran, Iran, from January 2004 to September 2006

Funding and conflicts of interest: none reported

Inclusion criteria:

Diagnosis of ocular toxoplasmosis and at least 1 of following criteria:

· Optic nerve or macular involvement or threat thereof by

an adjacent lesion

· A lesion adjacent to large retinal vessels

· Severe vitreous inflammation (> 2+)

Exclusion criteria:

· Visual acuity (VA) of worse than 20/200 in the fellow eye

· Location of the lesion within the center (500 µm) of the macula

· VA better than 20/30 in the involved eye

· Peripheral lesions causing ≤ 2+ vitreous inflammation

· Severe media opacity precluding clear photography

N total at baseline:

IVCD: n=34

PYR/SDZ: n=34

Important prognostic factors:

Age ± SD:

IVCD: 24.5 ± 6 y

PYR/SDZ: 23.3 ± 6.1 y

Sex:

IVCD: 47.1% M

PYR/SDZ: 52.9% M

Groups comparable at baseline? Yes

IVCD

Treatment regimen

1-3 intravitreal injections of 1 mg clindamycin + 400 µg dexamethasone

PYR/SDZ

Treatment regimen

PYR 25 mg daily (initial dose of 75 mg daily for 2 days)

SDZ 500 mg every 6 hours (initial dose of 4 g daily for 2 days)

5 mg folinic acid daily for 6 weeks

Oral prednisolone 1 mg/kg daily for 3 weeks starting from the third day of therapy

Length of follow-up: 2 years

Loss-to-follow-up:

IVCD:6/40 (15%)

N (%)

Reasons (describe): not reported

PYR/SDZ: 7/41 (17%)

N (%)

Reasons (describe): 5 patients not reported, 1 patient had a severe skin rash and patient had thrombocytopenia

Incomplete outcome data:

IVCD: 9/34 (26.5)

N (%)

Reasons (describe): retinal lesion size was not measurable because of unaccepted quality of fundus photography

PYR/SDZ: 8/34 (23.5)

N (%)

Reasons (describe): retinal lesion size was not measurable because of unaccepted quality of fundus photography

Lesion size, pixels ± SD

At baseline

IVCD: 206,769 ± 207,123

PYR/SDZ: 155,968 ± 224,466

6 weeks after treatment

ICVD: 58,259 ± 73,643

PYR/SDZ: 66,362 ± 96,906

Reduction during treatment, pixels ± SD

IVCD: 116,994 ± 143,997

PYR/SDZ: 89,606 ± 651,573

MD = 27,388 (95% CI: -240,662 to 295,438) pixels

Reduction during treatment, mean ± SD percentage

IVCD: 58.4 ± 29.3

PYR/SDZ: 57 ± 27.6

MD = 1.4 (95% CI: -14.6 to 17.4) %

Note: results are based on n=25 cases (IVCD) and n=26 cases (PYR/SDZ)

Vitreous inflammation, events/total (%)

Resolution after 6 weeks of treatment

IVCD: 5/34 (17.2)

PYR/SDZ: 10/34 (37.0)

RR = 0.50 (95% CI: 0.19, 1.31)

Author’s conclusion: “This clinical trial demonstrated that IVCD overall was almost equally as effective as PYR/SDZ in toxoplasmosis retinochoroiditis in terms of lesion size reduction.”

Limitations of the study:

· Patients were not masked

· Lack of fundus photographs in some patients

Baharivand, 2013

Type of study: RCT

Setting and country: 2 referral teaching eye centers (Nikookari and Alavi), Tabriz, Iran, from January 2009 to July 2011

Funding and conflicts of interest: none reported

Inclusion criteria:

· Patients with active Toxoplasmic retinochoroiditis (TRC)

Exclusion criteria:

· Patients with previous therapies for TRC

· History of allergic reaction to the drugs used in this study

· Presence of other ocular diseases

N total at baseline:

IVCD: n=32

PYR/SDZ: n=34

Important prognostic factors²:

Age ± SD:

IVCD: 25.69 ± 4.4 y

PYR/SDZ: 27.21 ± 5.06 y

Sex:

IVCD: 46.9% M

PYR/SDZ: 41.2% M

Groups comparable at baseline? Yes

IVCD

Treatment regimen

1-2 intravitreal injections of 1 mg clindamycin + 400 µg dexamethasone

PYR/SDZ

Treatment regimen

PYR 25 mg daily (initial dose of 75 mg daily for 2 days)

SDZ 1 g every 6 hours (initial dose of 2 g daily for 2 days)

5 mg folinic acid daily for 6 weeks

Oral prednisolone 50 mg/kg daily for 3 weeks starting from the third day of therapy

Length of follow-up: 6 months after treatment

Loss-to-follow-up:

4 patients were lost-to-follow-up (but not reported to which group they were allocated). Reasons also not reported.

Incomplete outcome data:

IVCD: 9/34 (26.5)

N (%)

Reasons (describe): retinal lesion size was not measurable because of unaccepted quality of fundus photography

PYR/SDZ: 8/34 (23.5)

N (%)

Reasons (describe): retinal lesion size was not measurable because of unaccepted quality of fundus photography

Lesion size, events/total (%)

Change (improved) after 6 months of treatment  

IVCD: 21/32 (65.6)

PYR/SDZ: 23/34 (67.6)

RR = 0.97 (95% CI: 0.69, 1.37)

Vitreous inflammation

Number (%) with 0/Trace at 6 months

IVCD: 28/32 (87.5)

PYR/SDZ: 28/34 (82.4)

RR = 1.06 (95% CI: 0.87, 1.30)

Author’s conclusion: “In conclusion, the present study suggests that an

intravitreal injection of clindamycin and dexamethasone

is as effective as conventional oral therapy in the treatment of TRC with fewer systemic side-effects.”

Limitations of the study:

· Patients were not blinded

· Small sample size

· Study not powered for secondary outcomes (only for reduction in lesion size)

· No intention-to-treat analysis and reasons for loss to follow-up not reported

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

PICO1: SYSTEMIC TREATMENTS

Comparison 1a: TMP/SMX vs. PYR/SDZ

Soheilian, 2005

Definitely yes;

Reason: Block randomization using randomization tablets.

No information

Probably yes;

Reason: Patients blinded, only fundus photographs and amount of vitreous inflammation evaluated by 2 independent masked observers, other assessments unmasked.

Definitely yes;

Reason: Loss to follow-up 17% and 14% and was infrequent in intervention and control group.

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW (lesion size reduction and vitreous inflammation)

Reason: Lesion size reduction and amount of vitreous inflammation is measured by masked observers. This does not affect the risk of bias.

Comparison 1b: TMP/SMX vs. azithromycin

Lashay, 2017

No information

No information

Definitely no

Reason: Patients were not blinded. Ophthalmologists were blinded.

No information

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW (lesion size reduction)

Reason: Lesion size reduction is measured by masked observers. This does not affect the risk of bias.

Comparison 1c: azithromycin vs. PYR/SDZ

Ghavidel, 2017

Definitely yes

Reason: Randomization done by using computer-generated randomization list

No information

Definitely no

Reason: Assumption that only patients were not blinded, since the word ‘single-blind study’ was used

No information

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW (lesion size reduction)

Reason: Assumption that outcome assessors were blinded, which does not affect the risk of bias.

Comparison 1d: Quadruple-drug therapy vs. triple therapy

Kartasasmita, 2017

Definitely yes

Reason: Random block permutation methods were used

No information

Definitely no

Reason: a blinded trained technician made the calculation of the retinal lesion using computer software. Patients were not blinded.

No information

Definitely yes;

Reason: All relevant outcomes were reported

Definitely no

Reason: There is no complete data on systemic diseases that might accompany the disease under study. No data about immunology status (IgM and IgG).

Some concerns (lesion size reduction)

Reason: missing data about immunology status and systemic diseases that might accompany the disease under study, this could affect the risk of bias.

Comparison 1e: PYR/azithromycin vs. PYR/SDZ

Bosch-Driessen, 2002

No information

No information

Probably no

Reason: no blinding of patients. Only fundus photographs of the retinochoroidal lesions and the optic disk were evaluated by two independent ophthalmologists in a masked way.

Definitely no

Reason: there is more loss-to-follow-up in the PYR+SDZ group (14%) vs. PYR+azithromycin group (0%). Incomplete outcome data is higher in the PYR+SDZ group than PYR+azithromycin group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

Some concerns (lesion size)

Reason: There is considerably more loss to FU in one group compared to the other. This could have affected the risk of bias. Lesion size is measured by masked observers. This does not affect the risk of bias.

PICO2: INTRAVITREAL VS. SYSTEMIC TREATMENT

Comparison 2a: Intravitreal clindamycin + DEX vs. oral PYR/SDZ

Soheilian, 2011

Definitely yes

Reason: Block randomization using computer-generated randomized list

Definitely yes

Reason: A group sequence (written on the card) in appropriate envelopes labelled by ordered number.

Definitely no

Reason: Retina specialists (outcome assessors) were blinded. Fundus photographs were evaluated by 2 masked retina specialists. Patients were not blinded.

Definitely yes

Reason: loss to FU 15% and 17% in groups (= roughly equal). Incomplete outcome data roughly equal.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW (lesion size reduction)

Reason: Lesion size reduction is measured by masked observers. This does not affect the risk of bias.

Baharivand, 2013

Definitely yes

Reason: randomization by computer random number generation

No information

Definitely no

Reason: patients were not blinded, but outcomes under study were evaluated by masked retina specialists.

No information

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW (lesion size reduction)

Reason: Lesion size reduction is measured by masked observers. This does not affect the risk of bias.

Reference

Reason for exclusion

PICO 1 + 2

Feliciano-Alfonso JE, Muñoz-Ortiz J, Marín-Noriega MA, Vargas-Villanueva A, Triviño-Blanco L, Carvajal-Saiz N, de-la-Torre A. Safety and efficacy of different antibiotic regimens in patients with ocular toxoplasmosis: systematic review and meta-analysis. Syst Rev. 2021 Jul 19;10(1):206. doi: 10.1186/s13643-021-01758-7. PMID: 34275483; PMCID: PMC8287816.

Lack of crucial tabular data needed for this guideline

Garweg JG, Pleyer U. Treatment Strategy in Human Ocular Toxoplasmosis: Why Antibiotics Have Failed. J Clin Med. 2021 Mar 5;10(5):1090. doi: 10.3390/jcm10051090. PMID: 33807871; PMCID: PMC7961948.

Narrative review (lack of crucial tabular data needed for this guideline)

Kalogeropoulos D, Sakkas H, Mohammed B, Vartholomatos G, Malamos K, Sreekantam S, Kanavaros P, Kalogeropoulos C. Ocular toxoplasmosis: a review of the current diagnostic and therapeutic approaches. Int Ophthalmol. 2022 Jan;42(1):295-321. doi: 10.1007/s10792-021-01994-9. Epub 2021 Aug 9. PMID: 34370174; PMCID: PMC8351587.

Narrative review and review includes overlapping studies

Melo LA, Paiva MRB, Fernandes-Cunha GM, Silva-Cunha A, Mol MPG, Fialho SL. Clinical outcomes of intravitreal treatment for ocular toxoplasmosis: systematic review and meta-analysis. Rev Soc Bras Med Trop. 2023 May 22;56:e05522022. doi: 10.1590/0037-8682-0552-2022. PMID: 37222350; PMCID: PMC10204153.

Comparison is not clear and studies from table 1 are case series (low quality of evidence)