| Author (Year) . | Study Arm(s) (Dose) . | N . | Duration of Acute Treatment, Wks . | Male, N (%) . | Mean Age (Standard Deviation), Y . | Corticosteroids, N (%) . | Clinical Response, N (%) . | Radiographic Response, N (%) . | Discontinued Due to Toxicity, N (%) . | All-Cause Mortality, N (%) . | Adverse Events, N (%) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomized controlled trial | |||||||||||
| Chirgwin [36] (2002) | Atovaquone (3 g/d) +Pyrimethamine (200 mg loading dose, followed by 75 mg/d if >60 kg and 50 mg/d if <60 kg) + Folinic Acid (10 mg/d) | 28 | 6 | 22 (78.6) | Median: 35 | NR | 22 (78.6) | 21 (75.0) | NR | NR | NRa |
| Atovaquone (3 g/d) + Sulfadiazine (6 g/d) | 12 | 6 | 10 (83.3) | Median: 37 | NR | 9 (75.0) | 9 (75.0) | NR | NR | NRa | |
| Dannemann [37] (1992) | Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Sulfadiazine (100 mg/kg/d, up to 8 kg/d) + Folinic Acid (10 mg/d) | 33 | 6 | 29 (87.9) | 36 (9) | NR | 23 (69.7) | 20 (60.6) | 11 (30.6) | 2 (6.1) | NRb |
| Clindamycin (4.8 g/d for 3 weeks, 1.2 g/d or 1.35 g/d up to 6 wks) + Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Folinic Acid (10 mg/d) | 26 | 6 | 21 (80.8) | 36 (8) | NR | 17 (65.4) | 19 (73.1) | 6 (23.1) | 5 (19.2) | NRb | |
| Jacobson [44] (2001) | Azithromycin (900 mg/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 9c | 6 | NR | NR | NR | 6 (66.7) | 6 (66.7) | NR | 0 (0.0) | NRa |
| Azithromycin (1.2 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 17c | 6 | NR | NR | NR | 12 (70.6) | 12 (70.6) | NR | 1 (5.9) | NRa | |
| Azithromycin (1.5 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d) + Folinic Acid (5 mg/d) | 4c | 6 | NR | NR | NR | 2 (50.0) | 2 (50.0) | NR | 0 (0.0) | NRa | |
| Katlama [38] (1996) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (at least 50 mg/wk) | 147 | 6 | 129 (87.8) | 33 (8) | NR | 112 (76.2) | 117 (79.6) | 44 (29.9) | 22 (15.0) | Rash or fever: 58 (39.5) Neutropenia: 42 (28.6) Hepatotoxicity: 20 (13.6) Anemia: 18 (12.2) Thrombocytopenia: 11 (7.5) Diarrhea: 8 (5.4) Crystalluria: 5 (3.4) Nephrotoxicity: 2 (1.4) Nausea/Vomiting: 2 (1.4) |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d) + Folinic Acid (at least 50 mg/wk) | 152 | 6 | 133 (87.5) | 34 (9) | NR | 103 (67.8) | 110 (72.4) | 17 (11.2) | 29 (19.1) | Rash or fever: 44 (28.9) Neutropenia: 38 (25.0) Diarrhea: 29 (19.1) Anemia: 11 (7.2) Hepatotoxicity: 9 (5.9) Nausea/Vomiting: 7 (4.6) Thrombocytopenia: 3 (2.0) Nephrotoxicity: 1 (0.7) Crystalluria: 0 (0.0) | |
| Kongsaengdao [39] (2008) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 7 (70.0) | 39.6 (9.4) | 6 (60.0) | NR | NR | 3 (30.0) | 0 (0.0) | Severe rash: 2 (20.0) Steven-Johnson syndrome: 1 (10.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) |
| Pyrimethamine (100 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 8 (80.0) | 38.2 (9.3) | 6 (60.0) | NR | NR | 2 (20.0) | 1 (10.0) | Severe rash: 2 (20.0) Pancytopenia: 1 (10.0) Thrombocytopenia: 1 (10.0) Steven-Johnson syndrome: 0 (0.0) | |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 10 | 6 | 4 (40.0) | 34.2 (10.7) | 6 (60.0) | NR | NR | 0 (0.0) | 3 (30.0) | Severe rash: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) | |
| Torre [40] (1998) | Pyrimethamine (50 mg/d) + Sulfadiazine (60 mg/kg/d) + Folinic Acid (10 mg/d) | 37 | 30 d | 29 (78.4) | 32.4 (4.5) | 33 (89.2) | 30 (81.1) | 23 (62.2) | NR | 0 (0.0) | NRa |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 40 | 30 d | 28 (70.0) | 34.0 (6.4) | 35 (87.5) | 31 (77.5) | 27 (67.5) | NR | 0 (0.0) | NRa | |
| Cohort: trimethoprim-sulfamethoxazole | |||||||||||
| Arens [14] (2007) | Trimethoprim + Sulfamethoxazole (doses not reported) | 25 | NR | 9 (36.0) | Median, 31 (IQR, 27–34) | 18 (72.0) | 11 (44.0) | NR | NR | 4 (16.0) | Nephrotoxicity: 0 (0.0) Hepatotoxicity: 0 (0.0) |
| Beraud [27] (2009) | Trimethoprim (10–15 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 7.5 mg/kg/d) + Sulfamethoxazole (50–75 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 37.5 mg/kg/d) | 83 | 4–6 | 56 (67.5) | 39.8 (11.0) | 14 (16.9) | 77 (92.8) | 71 (85.5) | 6 (7.2) | 2 (2.4) | Rash: 7 (8.4) Neutropenia: 6 (7.2) Pancreatitis: 2 (2.4) Hepatotoxicity: 1 (1.2) Nephrotoxicity: 1 (1.2) Thrombocytopenia: 1 (1.2) |
| Canessa [29] (1992) | Trimethoprim (6.6 mg/kg/d) + Sulfamethoxazole (33.3 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 9 (75.0) | Median, 30 (IQR, 26–37.5) | NR | 9 (75.0) | 9 (75.0) | 1 (8.3) | Unclear | Rash: 2 (16.7) Leukopenia: 2 (16.7) |
| Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 10 (83.3) | Median, 28.5 (IQR, 26.5–37) | NR | 9 (75.0) | 9 (75.0) | 0 (0.0) | 0 (0.0) | Rash: 1 (8.3) Leukopenia: 0 (0.0) | |
| Francis [30] (2004) | Trimethoprim (640 mg/d) + Sulfamethoxazole (3.2 g/d) | 20 | 4 | 10 (50.0) | 32 (NR) | NR | 20 (100.0) | 20 (100.0) | NR | 0 (0.0) | NR |
| Pellegrino [42] (2019) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 46 | 6 | 23 (50.0) | 35 (NR) | 36 (78.3) | 39d (84.8) | 39d (84.8) | 2 (4.3) | 0 (0.0) | Rash: 3 (6.5) Dizziness and tachycardia: 1 (2.2) Electrolyte abnormalities and nephrotoxicity: 1 (2.2) |
| Smadja [34] (1998) | Trimethoprim (640 mg/d for 2 d, then 480 mg/d for 15 d, then in cases of efficacy, 320 mg/d until cure) + Sulfamethoxazole (3.2 g/d for 2 d, then 2.4 g/d for 15 d, then in cases of efficacy, 1.6 g/d until cure) | 21 | 21–67 d | NR | NR | NR | 19d (90.5) | 19d (90.5) | 2 (9.5) | NR | NRd |
| Torre [25] (1998) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) + Folinic Acid (15 mg/d) | 71 | 4 | 58 (81.7) | 30.5 (4.9) | 61 (85.9) | 62 (87.3) | 50 (70.4) | 7 (9.9) | 8 (11.3) | Rash: 22 (31.0) |
| Cohort: pyrimethamine and sulfadiazine | |||||||||||
| Antinori [13] (1992) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4–6 g/d) | 29 | 6–8 | 21 (72.4) | 33.8 (6.1) | NR | 22 (75.9) | 18 (62.1) | 10 (34.5) | NR | Rash: 24 (82.8) Anemia: 12 (41.4) Neutropenia: 10 (34.5) Renal failure: 2 (6.9) |
| Bouree [28] (1997) | Pyrimethamine (100 mg/d) + Sulfadiazine (6 g/d) + Folinic Acid (50 mg/d) | 60 | NR | 46 (76.7) | 40.3 (range, 23–69) | NR | NR | NR | NR | 13 (21.7) | NRa |
| Carrazana [15] (1989) | Pyrimethamine (100 mg loading dose for 2–3 d, followed by 50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (5–15 mg/d) | 24 | NR | NR | NR | 14 (58.3) | 16 (66.7) | 16 (66.7) | 6 (25.0) | 3 (12.5) | NRe |
| Cohn [16] (1989) | Pyrimethamine (25 mg/d) + Sulfadiazine (4–6 g/d) | 36 | NR | NR | NR | NR | 26 (72.2) | 26 (72.2) | NR | NR | NRa |
| Ferrer [17] (1996) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (15 mg/d) | 61 | 4–6 | NR | NR | 55 (90.2) | NR | NR | 14 (23.0) | 5 (8.2) | NR |
| Gervasoni [18] (1995) | Pyrimethamine (100 mg/d loading dose for 3 d, followed by 50–75 mg/d) + Sulfadiazine (4–6 g/d) | 133 | ≥6 | NR | NR | NR | 123 (92.5) | 123 (92.5) | 41 (30.8) | 2 (1.5) | NR |
| Gonzalez-Clemente [31] (1990) | Pyrimethamine (50–100 mg loading dose, followed by 25–50 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 53 | 3–6 | NR | NR | NR | NR | NR | 14 (26.4) | 8 (15.1) | NRc |
| Grunitzky [20] (1995) | Pyrimethamine (75–100 mg/d) + Sulfadiazine (6–8 g/d) | 23 | 6 | 19 (82.6) | 36 (range, 16–52 | NR | 23 (100) | NR | NR | 0 (0.0) | NR |
| Kodym [32] (2015) | Pyrimethamine (200 mg loading dose, followed by 75–100 mg/d) + Sulfadiazine (1.5 g/d) + Folinic Acid (dose not specified) | 21 | >6 | 19 (90.0) | 40.2 (range, 24.7–61.2) | NR | NR | NR | NR | 7 (33.3) | NR |
| Leport [21] (1988) | Pyrimethamine (100–200 mg/d loading dose for 1–2 d, then 50–100 mg/d) + Sulfadiazine (2–6 g/d) + Folinic Acid (5–50 mg/d, adjusted based on complete blood count) | 35 | Mean 8 Range 2–39 | 34 (97.1) | 37.0 (9.9) | NR | 31 (88.6) | 31 (88.6) | NR | 4 (11.4) | NRa |
| Pedrol [33] (1990) | Pyrimethamine (50–75 mg loading dose followed by 25 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 40 | 3 | NR | NR | NR | NR | NR | 12 (30.0) | 6 (15.0) | NR |
| Porter [23] (1992) | Pyrimethamine (25–100 mg/d) + Sulfadiazine (2–6 g/d) | 115f | >6 | 110 (95.7) | 38 (9.8) | NR | 96 (83.5) | 81 (70.4) | 43 (37.4) | 6 (5.2) | Rash: 42 (36.5) Leukopenia: 17 (14.8) Nausea/Vomiting: 14 (12.2) Fever: 5 (4.3) Thrombocytopenia: 4 (3.5) Diarrhea: 2 (1.7) |
| Van Delden [26] (1996) | Pyrimethamine (dose not reported) + Sulfadiazine (dose not reported) + Folinic Acid (in 118/130 patients, dose not reported) | 130 | NR | NR | NR | NR | 83c (63.8) | NR | NR | 6 (4.6) | NR |
| Vidal [35] (2005) | Pyrimethamine + Sulfadiazine (doses not reported) | 55 | NR | 33 (60.0) | 36 (NR) | NR | 48 (87.3) | 51 (92.7) | NR | 7 (12.7) | NR |
| Cohort: pyrimethamine and clindamycin | |||||||||||
| Luft [41] (1993) | Clindamycin (2.4 g/d) + Pyrimethamine (200 mg loading dose, then 75 mg/d) + Folinic acid (10 mg/d) | 49 | 6 | 43 (87.8) | Median, 35 | 14 (28.6) | 35 (71.4) | 37 (75.5) | 8 (16.3) | 1 (2.0) | NRd |
| Ruf [24] (1991) | Clindamycin (2.4 g/d) + Pyrimethamine (1.5 mg/kg/d) + Spiramycin (9 × 106 IU/d) + Folinic Acid (45 mg/d) | 25 | 3 | NR | NR | NR | 23 (92.0) | 23 (92.0) | NR | 2 (8.0) | NRg |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d if patient <65 kg and 75 mg/d if >65 kg) + Folinic Acid (45 mg/d) | 26 | 3 | NR | NR | NR | 24 (92.3) | 24 (92.3) | NR | 2 (7.7) | NRg | |
| Cohort: other regimens | |||||||||||
| Goswami [19] (2014) | Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Clindamycin (1.8 g/d) | 25 | 4–6 | 19 (76.0) | 33.4 (7.4) | NR | 22 (88.0) | 22 (88.0) | 0 (0.0) | 3 (12.0) | Neutropenia: 3 (12.0) Rash: 2 (8.0) Diarrhea: 1 (4.0) Febrile neutropenia: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Severe Thrombocytopenia and bleeding: 0 (0.0) |
| Liu [22] (2018) | Trimethoprim (16.7 mg/kg/d) + Sulfamethoxazole (83.3 mg/kg/d) + Azithromycin (500 mg/d) | 57 | 6 | 47 (82.5) | 41.4 (11.8) | NR | 48 (84.2) | NR | 0 (0.0) | 9 (15.8) | Gastrointestinal reaction: 6 (10.5) |
| Torre [43] (1997) | Atovaquone (3 g/d) | 87 | 6 | NR | NR | 46 (52.9) | 45 (51.7) | 32 (36.8) | NR | 3 (3.5) | NRa |
| Author (Year) . | Study Arm(s) (Dose) . | N . | Duration of Acute Treatment, Wks . | Male, N (%) . | Mean Age (Standard Deviation), Y . | Corticosteroids, N (%) . | Clinical Response, N (%) . | Radiographic Response, N (%) . | Discontinued Due to Toxicity, N (%) . | All-Cause Mortality, N (%) . | Adverse Events, N (%) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomized controlled trial | |||||||||||
| Chirgwin [36] (2002) | Atovaquone (3 g/d) +Pyrimethamine (200 mg loading dose, followed by 75 mg/d if >60 kg and 50 mg/d if <60 kg) + Folinic Acid (10 mg/d) | 28 | 6 | 22 (78.6) | Median: 35 | NR | 22 (78.6) | 21 (75.0) | NR | NR | NRa |
| Atovaquone (3 g/d) + Sulfadiazine (6 g/d) | 12 | 6 | 10 (83.3) | Median: 37 | NR | 9 (75.0) | 9 (75.0) | NR | NR | NRa | |
| Dannemann [37] (1992) | Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Sulfadiazine (100 mg/kg/d, up to 8 kg/d) + Folinic Acid (10 mg/d) | 33 | 6 | 29 (87.9) | 36 (9) | NR | 23 (69.7) | 20 (60.6) | 11 (30.6) | 2 (6.1) | NRb |
| Clindamycin (4.8 g/d for 3 weeks, 1.2 g/d or 1.35 g/d up to 6 wks) + Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Folinic Acid (10 mg/d) | 26 | 6 | 21 (80.8) | 36 (8) | NR | 17 (65.4) | 19 (73.1) | 6 (23.1) | 5 (19.2) | NRb | |
| Jacobson [44] (2001) | Azithromycin (900 mg/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 9c | 6 | NR | NR | NR | 6 (66.7) | 6 (66.7) | NR | 0 (0.0) | NRa |
| Azithromycin (1.2 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 17c | 6 | NR | NR | NR | 12 (70.6) | 12 (70.6) | NR | 1 (5.9) | NRa | |
| Azithromycin (1.5 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d) + Folinic Acid (5 mg/d) | 4c | 6 | NR | NR | NR | 2 (50.0) | 2 (50.0) | NR | 0 (0.0) | NRa | |
| Katlama [38] (1996) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (at least 50 mg/wk) | 147 | 6 | 129 (87.8) | 33 (8) | NR | 112 (76.2) | 117 (79.6) | 44 (29.9) | 22 (15.0) | Rash or fever: 58 (39.5) Neutropenia: 42 (28.6) Hepatotoxicity: 20 (13.6) Anemia: 18 (12.2) Thrombocytopenia: 11 (7.5) Diarrhea: 8 (5.4) Crystalluria: 5 (3.4) Nephrotoxicity: 2 (1.4) Nausea/Vomiting: 2 (1.4) |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d) + Folinic Acid (at least 50 mg/wk) | 152 | 6 | 133 (87.5) | 34 (9) | NR | 103 (67.8) | 110 (72.4) | 17 (11.2) | 29 (19.1) | Rash or fever: 44 (28.9) Neutropenia: 38 (25.0) Diarrhea: 29 (19.1) Anemia: 11 (7.2) Hepatotoxicity: 9 (5.9) Nausea/Vomiting: 7 (4.6) Thrombocytopenia: 3 (2.0) Nephrotoxicity: 1 (0.7) Crystalluria: 0 (0.0) | |
| Kongsaengdao [39] (2008) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 7 (70.0) | 39.6 (9.4) | 6 (60.0) | NR | NR | 3 (30.0) | 0 (0.0) | Severe rash: 2 (20.0) Steven-Johnson syndrome: 1 (10.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) |
| Pyrimethamine (100 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 8 (80.0) | 38.2 (9.3) | 6 (60.0) | NR | NR | 2 (20.0) | 1 (10.0) | Severe rash: 2 (20.0) Pancytopenia: 1 (10.0) Thrombocytopenia: 1 (10.0) Steven-Johnson syndrome: 0 (0.0) | |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 10 | 6 | 4 (40.0) | 34.2 (10.7) | 6 (60.0) | NR | NR | 0 (0.0) | 3 (30.0) | Severe rash: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) | |
| Torre [40] (1998) | Pyrimethamine (50 mg/d) + Sulfadiazine (60 mg/kg/d) + Folinic Acid (10 mg/d) | 37 | 30 d | 29 (78.4) | 32.4 (4.5) | 33 (89.2) | 30 (81.1) | 23 (62.2) | NR | 0 (0.0) | NRa |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 40 | 30 d | 28 (70.0) | 34.0 (6.4) | 35 (87.5) | 31 (77.5) | 27 (67.5) | NR | 0 (0.0) | NRa | |
| Cohort: trimethoprim-sulfamethoxazole | |||||||||||
| Arens [14] (2007) | Trimethoprim + Sulfamethoxazole (doses not reported) | 25 | NR | 9 (36.0) | Median, 31 (IQR, 27–34) | 18 (72.0) | 11 (44.0) | NR | NR | 4 (16.0) | Nephrotoxicity: 0 (0.0) Hepatotoxicity: 0 (0.0) |
| Beraud [27] (2009) | Trimethoprim (10–15 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 7.5 mg/kg/d) + Sulfamethoxazole (50–75 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 37.5 mg/kg/d) | 83 | 4–6 | 56 (67.5) | 39.8 (11.0) | 14 (16.9) | 77 (92.8) | 71 (85.5) | 6 (7.2) | 2 (2.4) | Rash: 7 (8.4) Neutropenia: 6 (7.2) Pancreatitis: 2 (2.4) Hepatotoxicity: 1 (1.2) Nephrotoxicity: 1 (1.2) Thrombocytopenia: 1 (1.2) |
| Canessa [29] (1992) | Trimethoprim (6.6 mg/kg/d) + Sulfamethoxazole (33.3 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 9 (75.0) | Median, 30 (IQR, 26–37.5) | NR | 9 (75.0) | 9 (75.0) | 1 (8.3) | Unclear | Rash: 2 (16.7) Leukopenia: 2 (16.7) |
| Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 10 (83.3) | Median, 28.5 (IQR, 26.5–37) | NR | 9 (75.0) | 9 (75.0) | 0 (0.0) | 0 (0.0) | Rash: 1 (8.3) Leukopenia: 0 (0.0) | |
| Francis [30] (2004) | Trimethoprim (640 mg/d) + Sulfamethoxazole (3.2 g/d) | 20 | 4 | 10 (50.0) | 32 (NR) | NR | 20 (100.0) | 20 (100.0) | NR | 0 (0.0) | NR |
| Pellegrino [42] (2019) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 46 | 6 | 23 (50.0) | 35 (NR) | 36 (78.3) | 39d (84.8) | 39d (84.8) | 2 (4.3) | 0 (0.0) | Rash: 3 (6.5) Dizziness and tachycardia: 1 (2.2) Electrolyte abnormalities and nephrotoxicity: 1 (2.2) |
| Smadja [34] (1998) | Trimethoprim (640 mg/d for 2 d, then 480 mg/d for 15 d, then in cases of efficacy, 320 mg/d until cure) + Sulfamethoxazole (3.2 g/d for 2 d, then 2.4 g/d for 15 d, then in cases of efficacy, 1.6 g/d until cure) | 21 | 21–67 d | NR | NR | NR | 19d (90.5) | 19d (90.5) | 2 (9.5) | NR | NRd |
| Torre [25] (1998) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) + Folinic Acid (15 mg/d) | 71 | 4 | 58 (81.7) | 30.5 (4.9) | 61 (85.9) | 62 (87.3) | 50 (70.4) | 7 (9.9) | 8 (11.3) | Rash: 22 (31.0) |
| Cohort: pyrimethamine and sulfadiazine | |||||||||||
| Antinori [13] (1992) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4–6 g/d) | 29 | 6–8 | 21 (72.4) | 33.8 (6.1) | NR | 22 (75.9) | 18 (62.1) | 10 (34.5) | NR | Rash: 24 (82.8) Anemia: 12 (41.4) Neutropenia: 10 (34.5) Renal failure: 2 (6.9) |
| Bouree [28] (1997) | Pyrimethamine (100 mg/d) + Sulfadiazine (6 g/d) + Folinic Acid (50 mg/d) | 60 | NR | 46 (76.7) | 40.3 (range, 23–69) | NR | NR | NR | NR | 13 (21.7) | NRa |
| Carrazana [15] (1989) | Pyrimethamine (100 mg loading dose for 2–3 d, followed by 50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (5–15 mg/d) | 24 | NR | NR | NR | 14 (58.3) | 16 (66.7) | 16 (66.7) | 6 (25.0) | 3 (12.5) | NRe |
| Cohn [16] (1989) | Pyrimethamine (25 mg/d) + Sulfadiazine (4–6 g/d) | 36 | NR | NR | NR | NR | 26 (72.2) | 26 (72.2) | NR | NR | NRa |
| Ferrer [17] (1996) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (15 mg/d) | 61 | 4–6 | NR | NR | 55 (90.2) | NR | NR | 14 (23.0) | 5 (8.2) | NR |
| Gervasoni [18] (1995) | Pyrimethamine (100 mg/d loading dose for 3 d, followed by 50–75 mg/d) + Sulfadiazine (4–6 g/d) | 133 | ≥6 | NR | NR | NR | 123 (92.5) | 123 (92.5) | 41 (30.8) | 2 (1.5) | NR |
| Gonzalez-Clemente [31] (1990) | Pyrimethamine (50–100 mg loading dose, followed by 25–50 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 53 | 3–6 | NR | NR | NR | NR | NR | 14 (26.4) | 8 (15.1) | NRc |
| Grunitzky [20] (1995) | Pyrimethamine (75–100 mg/d) + Sulfadiazine (6–8 g/d) | 23 | 6 | 19 (82.6) | 36 (range, 16–52 | NR | 23 (100) | NR | NR | 0 (0.0) | NR |
| Kodym [32] (2015) | Pyrimethamine (200 mg loading dose, followed by 75–100 mg/d) + Sulfadiazine (1.5 g/d) + Folinic Acid (dose not specified) | 21 | >6 | 19 (90.0) | 40.2 (range, 24.7–61.2) | NR | NR | NR | NR | 7 (33.3) | NR |
| Leport [21] (1988) | Pyrimethamine (100–200 mg/d loading dose for 1–2 d, then 50–100 mg/d) + Sulfadiazine (2–6 g/d) + Folinic Acid (5–50 mg/d, adjusted based on complete blood count) | 35 | Mean 8 Range 2–39 | 34 (97.1) | 37.0 (9.9) | NR | 31 (88.6) | 31 (88.6) | NR | 4 (11.4) | NRa |
| Pedrol [33] (1990) | Pyrimethamine (50–75 mg loading dose followed by 25 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 40 | 3 | NR | NR | NR | NR | NR | 12 (30.0) | 6 (15.0) | NR |
| Porter [23] (1992) | Pyrimethamine (25–100 mg/d) + Sulfadiazine (2–6 g/d) | 115f | >6 | 110 (95.7) | 38 (9.8) | NR | 96 (83.5) | 81 (70.4) | 43 (37.4) | 6 (5.2) | Rash: 42 (36.5) Leukopenia: 17 (14.8) Nausea/Vomiting: 14 (12.2) Fever: 5 (4.3) Thrombocytopenia: 4 (3.5) Diarrhea: 2 (1.7) |
| Van Delden [26] (1996) | Pyrimethamine (dose not reported) + Sulfadiazine (dose not reported) + Folinic Acid (in 118/130 patients, dose not reported) | 130 | NR | NR | NR | NR | 83c (63.8) | NR | NR | 6 (4.6) | NR |
| Vidal [35] (2005) | Pyrimethamine + Sulfadiazine (doses not reported) | 55 | NR | 33 (60.0) | 36 (NR) | NR | 48 (87.3) | 51 (92.7) | NR | 7 (12.7) | NR |
| Cohort: pyrimethamine and clindamycin | |||||||||||
| Luft [41] (1993) | Clindamycin (2.4 g/d) + Pyrimethamine (200 mg loading dose, then 75 mg/d) + Folinic acid (10 mg/d) | 49 | 6 | 43 (87.8) | Median, 35 | 14 (28.6) | 35 (71.4) | 37 (75.5) | 8 (16.3) | 1 (2.0) | NRd |
| Ruf [24] (1991) | Clindamycin (2.4 g/d) + Pyrimethamine (1.5 mg/kg/d) + Spiramycin (9 × 106 IU/d) + Folinic Acid (45 mg/d) | 25 | 3 | NR | NR | NR | 23 (92.0) | 23 (92.0) | NR | 2 (8.0) | NRg |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d if patient <65 kg and 75 mg/d if >65 kg) + Folinic Acid (45 mg/d) | 26 | 3 | NR | NR | NR | 24 (92.3) | 24 (92.3) | NR | 2 (7.7) | NRg | |
| Cohort: other regimens | |||||||||||
| Goswami [19] (2014) | Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Clindamycin (1.8 g/d) | 25 | 4–6 | 19 (76.0) | 33.4 (7.4) | NR | 22 (88.0) | 22 (88.0) | 0 (0.0) | 3 (12.0) | Neutropenia: 3 (12.0) Rash: 2 (8.0) Diarrhea: 1 (4.0) Febrile neutropenia: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Severe Thrombocytopenia and bleeding: 0 (0.0) |
| Liu [22] (2018) | Trimethoprim (16.7 mg/kg/d) + Sulfamethoxazole (83.3 mg/kg/d) + Azithromycin (500 mg/d) | 57 | 6 | 47 (82.5) | 41.4 (11.8) | NR | 48 (84.2) | NR | 0 (0.0) | 9 (15.8) | Gastrointestinal reaction: 6 (10.5) |
| Torre [43] (1997) | Atovaquone (3 g/d) | 87 | 6 | NR | NR | 46 (52.9) | 45 (51.7) | 32 (36.8) | NR | 3 (3.5) | NRa |
Abbreviations: IQR, interquartile range; NR, not reported or unclear.
Adverse events were only reported for maintenance therapy.
Adverse events were only reported based on the treatment received at the time, not the assigned treatment.
Only adverse events deemed attributable to the treatment were reported.
Only adverse events that led to treatment discontinuation were reported.
Reported adverse events include patients who were toxoplasmic encephalitis–negative by stereotactic biopsy.
One patient was not initially treated with pyrimethamine and sulfadiazine.
Not reported for each arm separately.
| Author (Year) . | Study Arm(s) (Dose) . | N . | Duration of Acute Treatment, Wks . | Male, N (%) . | Mean Age (Standard Deviation), Y . | Corticosteroids, N (%) . | Clinical Response, N (%) . | Radiographic Response, N (%) . | Discontinued Due to Toxicity, N (%) . | All-Cause Mortality, N (%) . | Adverse Events, N (%) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomized controlled trial | |||||||||||
| Chirgwin [36] (2002) | Atovaquone (3 g/d) +Pyrimethamine (200 mg loading dose, followed by 75 mg/d if >60 kg and 50 mg/d if <60 kg) + Folinic Acid (10 mg/d) | 28 | 6 | 22 (78.6) | Median: 35 | NR | 22 (78.6) | 21 (75.0) | NR | NR | NRa |
| Atovaquone (3 g/d) + Sulfadiazine (6 g/d) | 12 | 6 | 10 (83.3) | Median: 37 | NR | 9 (75.0) | 9 (75.0) | NR | NR | NRa | |
| Dannemann [37] (1992) | Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Sulfadiazine (100 mg/kg/d, up to 8 kg/d) + Folinic Acid (10 mg/d) | 33 | 6 | 29 (87.9) | 36 (9) | NR | 23 (69.7) | 20 (60.6) | 11 (30.6) | 2 (6.1) | NRb |
| Clindamycin (4.8 g/d for 3 weeks, 1.2 g/d or 1.35 g/d up to 6 wks) + Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Folinic Acid (10 mg/d) | 26 | 6 | 21 (80.8) | 36 (8) | NR | 17 (65.4) | 19 (73.1) | 6 (23.1) | 5 (19.2) | NRb | |
| Jacobson [44] (2001) | Azithromycin (900 mg/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 9c | 6 | NR | NR | NR | 6 (66.7) | 6 (66.7) | NR | 0 (0.0) | NRa |
| Azithromycin (1.2 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 17c | 6 | NR | NR | NR | 12 (70.6) | 12 (70.6) | NR | 1 (5.9) | NRa | |
| Azithromycin (1.5 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d) + Folinic Acid (5 mg/d) | 4c | 6 | NR | NR | NR | 2 (50.0) | 2 (50.0) | NR | 0 (0.0) | NRa | |
| Katlama [38] (1996) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (at least 50 mg/wk) | 147 | 6 | 129 (87.8) | 33 (8) | NR | 112 (76.2) | 117 (79.6) | 44 (29.9) | 22 (15.0) | Rash or fever: 58 (39.5) Neutropenia: 42 (28.6) Hepatotoxicity: 20 (13.6) Anemia: 18 (12.2) Thrombocytopenia: 11 (7.5) Diarrhea: 8 (5.4) Crystalluria: 5 (3.4) Nephrotoxicity: 2 (1.4) Nausea/Vomiting: 2 (1.4) |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d) + Folinic Acid (at least 50 mg/wk) | 152 | 6 | 133 (87.5) | 34 (9) | NR | 103 (67.8) | 110 (72.4) | 17 (11.2) | 29 (19.1) | Rash or fever: 44 (28.9) Neutropenia: 38 (25.0) Diarrhea: 29 (19.1) Anemia: 11 (7.2) Hepatotoxicity: 9 (5.9) Nausea/Vomiting: 7 (4.6) Thrombocytopenia: 3 (2.0) Nephrotoxicity: 1 (0.7) Crystalluria: 0 (0.0) | |
| Kongsaengdao [39] (2008) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 7 (70.0) | 39.6 (9.4) | 6 (60.0) | NR | NR | 3 (30.0) | 0 (0.0) | Severe rash: 2 (20.0) Steven-Johnson syndrome: 1 (10.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) |
| Pyrimethamine (100 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 8 (80.0) | 38.2 (9.3) | 6 (60.0) | NR | NR | 2 (20.0) | 1 (10.0) | Severe rash: 2 (20.0) Pancytopenia: 1 (10.0) Thrombocytopenia: 1 (10.0) Steven-Johnson syndrome: 0 (0.0) | |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 10 | 6 | 4 (40.0) | 34.2 (10.7) | 6 (60.0) | NR | NR | 0 (0.0) | 3 (30.0) | Severe rash: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) | |
| Torre [40] (1998) | Pyrimethamine (50 mg/d) + Sulfadiazine (60 mg/kg/d) + Folinic Acid (10 mg/d) | 37 | 30 d | 29 (78.4) | 32.4 (4.5) | 33 (89.2) | 30 (81.1) | 23 (62.2) | NR | 0 (0.0) | NRa |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 40 | 30 d | 28 (70.0) | 34.0 (6.4) | 35 (87.5) | 31 (77.5) | 27 (67.5) | NR | 0 (0.0) | NRa | |
| Cohort: trimethoprim-sulfamethoxazole | |||||||||||
| Arens [14] (2007) | Trimethoprim + Sulfamethoxazole (doses not reported) | 25 | NR | 9 (36.0) | Median, 31 (IQR, 27–34) | 18 (72.0) | 11 (44.0) | NR | NR | 4 (16.0) | Nephrotoxicity: 0 (0.0) Hepatotoxicity: 0 (0.0) |
| Beraud [27] (2009) | Trimethoprim (10–15 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 7.5 mg/kg/d) + Sulfamethoxazole (50–75 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 37.5 mg/kg/d) | 83 | 4–6 | 56 (67.5) | 39.8 (11.0) | 14 (16.9) | 77 (92.8) | 71 (85.5) | 6 (7.2) | 2 (2.4) | Rash: 7 (8.4) Neutropenia: 6 (7.2) Pancreatitis: 2 (2.4) Hepatotoxicity: 1 (1.2) Nephrotoxicity: 1 (1.2) Thrombocytopenia: 1 (1.2) |
| Canessa [29] (1992) | Trimethoprim (6.6 mg/kg/d) + Sulfamethoxazole (33.3 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 9 (75.0) | Median, 30 (IQR, 26–37.5) | NR | 9 (75.0) | 9 (75.0) | 1 (8.3) | Unclear | Rash: 2 (16.7) Leukopenia: 2 (16.7) |
| Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 10 (83.3) | Median, 28.5 (IQR, 26.5–37) | NR | 9 (75.0) | 9 (75.0) | 0 (0.0) | 0 (0.0) | Rash: 1 (8.3) Leukopenia: 0 (0.0) | |
| Francis [30] (2004) | Trimethoprim (640 mg/d) + Sulfamethoxazole (3.2 g/d) | 20 | 4 | 10 (50.0) | 32 (NR) | NR | 20 (100.0) | 20 (100.0) | NR | 0 (0.0) | NR |
| Pellegrino [42] (2019) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 46 | 6 | 23 (50.0) | 35 (NR) | 36 (78.3) | 39d (84.8) | 39d (84.8) | 2 (4.3) | 0 (0.0) | Rash: 3 (6.5) Dizziness and tachycardia: 1 (2.2) Electrolyte abnormalities and nephrotoxicity: 1 (2.2) |
| Smadja [34] (1998) | Trimethoprim (640 mg/d for 2 d, then 480 mg/d for 15 d, then in cases of efficacy, 320 mg/d until cure) + Sulfamethoxazole (3.2 g/d for 2 d, then 2.4 g/d for 15 d, then in cases of efficacy, 1.6 g/d until cure) | 21 | 21–67 d | NR | NR | NR | 19d (90.5) | 19d (90.5) | 2 (9.5) | NR | NRd |
| Torre [25] (1998) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) + Folinic Acid (15 mg/d) | 71 | 4 | 58 (81.7) | 30.5 (4.9) | 61 (85.9) | 62 (87.3) | 50 (70.4) | 7 (9.9) | 8 (11.3) | Rash: 22 (31.0) |
| Cohort: pyrimethamine and sulfadiazine | |||||||||||
| Antinori [13] (1992) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4–6 g/d) | 29 | 6–8 | 21 (72.4) | 33.8 (6.1) | NR | 22 (75.9) | 18 (62.1) | 10 (34.5) | NR | Rash: 24 (82.8) Anemia: 12 (41.4) Neutropenia: 10 (34.5) Renal failure: 2 (6.9) |
| Bouree [28] (1997) | Pyrimethamine (100 mg/d) + Sulfadiazine (6 g/d) + Folinic Acid (50 mg/d) | 60 | NR | 46 (76.7) | 40.3 (range, 23–69) | NR | NR | NR | NR | 13 (21.7) | NRa |
| Carrazana [15] (1989) | Pyrimethamine (100 mg loading dose for 2–3 d, followed by 50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (5–15 mg/d) | 24 | NR | NR | NR | 14 (58.3) | 16 (66.7) | 16 (66.7) | 6 (25.0) | 3 (12.5) | NRe |
| Cohn [16] (1989) | Pyrimethamine (25 mg/d) + Sulfadiazine (4–6 g/d) | 36 | NR | NR | NR | NR | 26 (72.2) | 26 (72.2) | NR | NR | NRa |
| Ferrer [17] (1996) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (15 mg/d) | 61 | 4–6 | NR | NR | 55 (90.2) | NR | NR | 14 (23.0) | 5 (8.2) | NR |
| Gervasoni [18] (1995) | Pyrimethamine (100 mg/d loading dose for 3 d, followed by 50–75 mg/d) + Sulfadiazine (4–6 g/d) | 133 | ≥6 | NR | NR | NR | 123 (92.5) | 123 (92.5) | 41 (30.8) | 2 (1.5) | NR |
| Gonzalez-Clemente [31] (1990) | Pyrimethamine (50–100 mg loading dose, followed by 25–50 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 53 | 3–6 | NR | NR | NR | NR | NR | 14 (26.4) | 8 (15.1) | NRc |
| Grunitzky [20] (1995) | Pyrimethamine (75–100 mg/d) + Sulfadiazine (6–8 g/d) | 23 | 6 | 19 (82.6) | 36 (range, 16–52 | NR | 23 (100) | NR | NR | 0 (0.0) | NR |
| Kodym [32] (2015) | Pyrimethamine (200 mg loading dose, followed by 75–100 mg/d) + Sulfadiazine (1.5 g/d) + Folinic Acid (dose not specified) | 21 | >6 | 19 (90.0) | 40.2 (range, 24.7–61.2) | NR | NR | NR | NR | 7 (33.3) | NR |
| Leport [21] (1988) | Pyrimethamine (100–200 mg/d loading dose for 1–2 d, then 50–100 mg/d) + Sulfadiazine (2–6 g/d) + Folinic Acid (5–50 mg/d, adjusted based on complete blood count) | 35 | Mean 8 Range 2–39 | 34 (97.1) | 37.0 (9.9) | NR | 31 (88.6) | 31 (88.6) | NR | 4 (11.4) | NRa |
| Pedrol [33] (1990) | Pyrimethamine (50–75 mg loading dose followed by 25 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 40 | 3 | NR | NR | NR | NR | NR | 12 (30.0) | 6 (15.0) | NR |
| Porter [23] (1992) | Pyrimethamine (25–100 mg/d) + Sulfadiazine (2–6 g/d) | 115f | >6 | 110 (95.7) | 38 (9.8) | NR | 96 (83.5) | 81 (70.4) | 43 (37.4) | 6 (5.2) | Rash: 42 (36.5) Leukopenia: 17 (14.8) Nausea/Vomiting: 14 (12.2) Fever: 5 (4.3) Thrombocytopenia: 4 (3.5) Diarrhea: 2 (1.7) |
| Van Delden [26] (1996) | Pyrimethamine (dose not reported) + Sulfadiazine (dose not reported) + Folinic Acid (in 118/130 patients, dose not reported) | 130 | NR | NR | NR | NR | 83c (63.8) | NR | NR | 6 (4.6) | NR |
| Vidal [35] (2005) | Pyrimethamine + Sulfadiazine (doses not reported) | 55 | NR | 33 (60.0) | 36 (NR) | NR | 48 (87.3) | 51 (92.7) | NR | 7 (12.7) | NR |
| Cohort: pyrimethamine and clindamycin | |||||||||||
| Luft [41] (1993) | Clindamycin (2.4 g/d) + Pyrimethamine (200 mg loading dose, then 75 mg/d) + Folinic acid (10 mg/d) | 49 | 6 | 43 (87.8) | Median, 35 | 14 (28.6) | 35 (71.4) | 37 (75.5) | 8 (16.3) | 1 (2.0) | NRd |
| Ruf [24] (1991) | Clindamycin (2.4 g/d) + Pyrimethamine (1.5 mg/kg/d) + Spiramycin (9 × 106 IU/d) + Folinic Acid (45 mg/d) | 25 | 3 | NR | NR | NR | 23 (92.0) | 23 (92.0) | NR | 2 (8.0) | NRg |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d if patient <65 kg and 75 mg/d if >65 kg) + Folinic Acid (45 mg/d) | 26 | 3 | NR | NR | NR | 24 (92.3) | 24 (92.3) | NR | 2 (7.7) | NRg | |
| Cohort: other regimens | |||||||||||
| Goswami [19] (2014) | Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Clindamycin (1.8 g/d) | 25 | 4–6 | 19 (76.0) | 33.4 (7.4) | NR | 22 (88.0) | 22 (88.0) | 0 (0.0) | 3 (12.0) | Neutropenia: 3 (12.0) Rash: 2 (8.0) Diarrhea: 1 (4.0) Febrile neutropenia: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Severe Thrombocytopenia and bleeding: 0 (0.0) |
| Liu [22] (2018) | Trimethoprim (16.7 mg/kg/d) + Sulfamethoxazole (83.3 mg/kg/d) + Azithromycin (500 mg/d) | 57 | 6 | 47 (82.5) | 41.4 (11.8) | NR | 48 (84.2) | NR | 0 (0.0) | 9 (15.8) | Gastrointestinal reaction: 6 (10.5) |
| Torre [43] (1997) | Atovaquone (3 g/d) | 87 | 6 | NR | NR | 46 (52.9) | 45 (51.7) | 32 (36.8) | NR | 3 (3.5) | NRa |
| Author (Year) . | Study Arm(s) (Dose) . | N . | Duration of Acute Treatment, Wks . | Male, N (%) . | Mean Age (Standard Deviation), Y . | Corticosteroids, N (%) . | Clinical Response, N (%) . | Radiographic Response, N (%) . | Discontinued Due to Toxicity, N (%) . | All-Cause Mortality, N (%) . | Adverse Events, N (%) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomized controlled trial | |||||||||||
| Chirgwin [36] (2002) | Atovaquone (3 g/d) +Pyrimethamine (200 mg loading dose, followed by 75 mg/d if >60 kg and 50 mg/d if <60 kg) + Folinic Acid (10 mg/d) | 28 | 6 | 22 (78.6) | Median: 35 | NR | 22 (78.6) | 21 (75.0) | NR | NR | NRa |
| Atovaquone (3 g/d) + Sulfadiazine (6 g/d) | 12 | 6 | 10 (83.3) | Median: 37 | NR | 9 (75.0) | 9 (75.0) | NR | NR | NRa | |
| Dannemann [37] (1992) | Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Sulfadiazine (100 mg/kg/d, up to 8 kg/d) + Folinic Acid (10 mg/d) | 33 | 6 | 29 (87.9) | 36 (9) | NR | 23 (69.7) | 20 (60.6) | 11 (30.6) | 2 (6.1) | NRb |
| Clindamycin (4.8 g/d for 3 weeks, 1.2 g/d or 1.35 g/d up to 6 wks) + Pyrimethamine (200 mg loading dose, followed by 75 mg/d) + Folinic Acid (10 mg/d) | 26 | 6 | 21 (80.8) | 36 (8) | NR | 17 (65.4) | 19 (73.1) | 6 (23.1) | 5 (19.2) | NRb | |
| Jacobson [44] (2001) | Azithromycin (900 mg/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 9c | 6 | NR | NR | NR | 6 (66.7) | 6 (66.7) | NR | 0 (0.0) | NRa |
| Azithromycin (1.2 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d for 3 wks, followed by 25 mg/d for 3 wks if a partial or complete radiological or clinical response was achieved) + Folinic Acid (5 mg/d) | 17c | 6 | NR | NR | NR | 12 (70.6) | 12 (70.6) | NR | 1 (5.9) | NRa | |
| Azithromycin (1.5 g/d) + Pyrimethamine (200 mg loading dose, then 50 mg/d) + Folinic Acid (5 mg/d) | 4c | 6 | NR | NR | NR | 2 (50.0) | 2 (50.0) | NR | 0 (0.0) | NRa | |
| Katlama [38] (1996) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (at least 50 mg/wk) | 147 | 6 | 129 (87.8) | 33 (8) | NR | 112 (76.2) | 117 (79.6) | 44 (29.9) | 22 (15.0) | Rash or fever: 58 (39.5) Neutropenia: 42 (28.6) Hepatotoxicity: 20 (13.6) Anemia: 18 (12.2) Thrombocytopenia: 11 (7.5) Diarrhea: 8 (5.4) Crystalluria: 5 (3.4) Nephrotoxicity: 2 (1.4) Nausea/Vomiting: 2 (1.4) |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d) + Folinic Acid (at least 50 mg/wk) | 152 | 6 | 133 (87.5) | 34 (9) | NR | 103 (67.8) | 110 (72.4) | 17 (11.2) | 29 (19.1) | Rash or fever: 44 (28.9) Neutropenia: 38 (25.0) Diarrhea: 29 (19.1) Anemia: 11 (7.2) Hepatotoxicity: 9 (5.9) Nausea/Vomiting: 7 (4.6) Thrombocytopenia: 3 (2.0) Nephrotoxicity: 1 (0.7) Crystalluria: 0 (0.0) | |
| Kongsaengdao [39] (2008) | Pyrimethamine (50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 7 (70.0) | 39.6 (9.4) | 6 (60.0) | NR | NR | 3 (30.0) | 0 (0.0) | Severe rash: 2 (20.0) Steven-Johnson syndrome: 1 (10.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) |
| Pyrimethamine (100 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (25 mg/d) | 10 | 6 | 8 (80.0) | 38.2 (9.3) | 6 (60.0) | NR | NR | 2 (20.0) | 1 (10.0) | Severe rash: 2 (20.0) Pancytopenia: 1 (10.0) Thrombocytopenia: 1 (10.0) Steven-Johnson syndrome: 0 (0.0) | |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 10 | 6 | 4 (40.0) | 34.2 (10.7) | 6 (60.0) | NR | NR | 0 (0.0) | 3 (30.0) | Severe rash: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Pancytopenia: 0 (0.0) Thrombocytopenia: 0 (0.0) | |
| Torre [40] (1998) | Pyrimethamine (50 mg/d) + Sulfadiazine (60 mg/kg/d) + Folinic Acid (10 mg/d) | 37 | 30 d | 29 (78.4) | 32.4 (4.5) | 33 (89.2) | 30 (81.1) | 23 (62.2) | NR | 0 (0.0) | NRa |
| Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 40 | 30 d | 28 (70.0) | 34.0 (6.4) | 35 (87.5) | 31 (77.5) | 27 (67.5) | NR | 0 (0.0) | NRa | |
| Cohort: trimethoprim-sulfamethoxazole | |||||||||||
| Arens [14] (2007) | Trimethoprim + Sulfamethoxazole (doses not reported) | 25 | NR | 9 (36.0) | Median, 31 (IQR, 27–34) | 18 (72.0) | 11 (44.0) | NR | NR | 4 (16.0) | Nephrotoxicity: 0 (0.0) Hepatotoxicity: 0 (0.0) |
| Beraud [27] (2009) | Trimethoprim (10–15 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 7.5 mg/kg/d) + Sulfamethoxazole (50–75 mg/kg/d for 3–5 d until clinical improvement, then stepped down to 37.5 mg/kg/d) | 83 | 4–6 | 56 (67.5) | 39.8 (11.0) | 14 (16.9) | 77 (92.8) | 71 (85.5) | 6 (7.2) | 2 (2.4) | Rash: 7 (8.4) Neutropenia: 6 (7.2) Pancreatitis: 2 (2.4) Hepatotoxicity: 1 (1.2) Nephrotoxicity: 1 (1.2) Thrombocytopenia: 1 (1.2) |
| Canessa [29] (1992) | Trimethoprim (6.6 mg/kg/d) + Sulfamethoxazole (33.3 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 9 (75.0) | Median, 30 (IQR, 26–37.5) | NR | 9 (75.0) | 9 (75.0) | 1 (8.3) | Unclear | Rash: 2 (16.7) Leukopenia: 2 (16.7) |
| Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Folinic Acid (15 mg/d) | 12 | 2–4 | 10 (83.3) | Median, 28.5 (IQR, 26.5–37) | NR | 9 (75.0) | 9 (75.0) | 0 (0.0) | 0 (0.0) | Rash: 1 (8.3) Leukopenia: 0 (0.0) | |
| Francis [30] (2004) | Trimethoprim (640 mg/d) + Sulfamethoxazole (3.2 g/d) | 20 | 4 | 10 (50.0) | 32 (NR) | NR | 20 (100.0) | 20 (100.0) | NR | 0 (0.0) | NR |
| Pellegrino [42] (2019) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) | 46 | 6 | 23 (50.0) | 35 (NR) | 36 (78.3) | 39d (84.8) | 39d (84.8) | 2 (4.3) | 0 (0.0) | Rash: 3 (6.5) Dizziness and tachycardia: 1 (2.2) Electrolyte abnormalities and nephrotoxicity: 1 (2.2) |
| Smadja [34] (1998) | Trimethoprim (640 mg/d for 2 d, then 480 mg/d for 15 d, then in cases of efficacy, 320 mg/d until cure) + Sulfamethoxazole (3.2 g/d for 2 d, then 2.4 g/d for 15 d, then in cases of efficacy, 1.6 g/d until cure) | 21 | 21–67 d | NR | NR | NR | 19d (90.5) | 19d (90.5) | 2 (9.5) | NR | NRd |
| Torre [25] (1998) | Trimethoprim (10 mg/kg/d) + Sulfamethoxazole (50 mg/kg/d) + Folinic Acid (15 mg/d) | 71 | 4 | 58 (81.7) | 30.5 (4.9) | 61 (85.9) | 62 (87.3) | 50 (70.4) | 7 (9.9) | 8 (11.3) | Rash: 22 (31.0) |
| Cohort: pyrimethamine and sulfadiazine | |||||||||||
| Antinori [13] (1992) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4–6 g/d) | 29 | 6–8 | 21 (72.4) | 33.8 (6.1) | NR | 22 (75.9) | 18 (62.1) | 10 (34.5) | NR | Rash: 24 (82.8) Anemia: 12 (41.4) Neutropenia: 10 (34.5) Renal failure: 2 (6.9) |
| Bouree [28] (1997) | Pyrimethamine (100 mg/d) + Sulfadiazine (6 g/d) + Folinic Acid (50 mg/d) | 60 | NR | 46 (76.7) | 40.3 (range, 23–69) | NR | NR | NR | NR | 13 (21.7) | NRa |
| Carrazana [15] (1989) | Pyrimethamine (100 mg loading dose for 2–3 d, followed by 50 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (5–15 mg/d) | 24 | NR | NR | NR | 14 (58.3) | 16 (66.7) | 16 (66.7) | 6 (25.0) | 3 (12.5) | NRe |
| Cohn [16] (1989) | Pyrimethamine (25 mg/d) + Sulfadiazine (4–6 g/d) | 36 | NR | NR | NR | NR | 26 (72.2) | 26 (72.2) | NR | NR | NRa |
| Ferrer [17] (1996) | Pyrimethamine (50–75 mg/d) + Sulfadiazine (4 g/d) + Folinic Acid (15 mg/d) | 61 | 4–6 | NR | NR | 55 (90.2) | NR | NR | 14 (23.0) | 5 (8.2) | NR |
| Gervasoni [18] (1995) | Pyrimethamine (100 mg/d loading dose for 3 d, followed by 50–75 mg/d) + Sulfadiazine (4–6 g/d) | 133 | ≥6 | NR | NR | NR | 123 (92.5) | 123 (92.5) | 41 (30.8) | 2 (1.5) | NR |
| Gonzalez-Clemente [31] (1990) | Pyrimethamine (50–100 mg loading dose, followed by 25–50 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 53 | 3–6 | NR | NR | NR | NR | NR | 14 (26.4) | 8 (15.1) | NRc |
| Grunitzky [20] (1995) | Pyrimethamine (75–100 mg/d) + Sulfadiazine (6–8 g/d) | 23 | 6 | 19 (82.6) | 36 (range, 16–52 | NR | 23 (100) | NR | NR | 0 (0.0) | NR |
| Kodym [32] (2015) | Pyrimethamine (200 mg loading dose, followed by 75–100 mg/d) + Sulfadiazine (1.5 g/d) + Folinic Acid (dose not specified) | 21 | >6 | 19 (90.0) | 40.2 (range, 24.7–61.2) | NR | NR | NR | NR | 7 (33.3) | NR |
| Leport [21] (1988) | Pyrimethamine (100–200 mg/d loading dose for 1–2 d, then 50–100 mg/d) + Sulfadiazine (2–6 g/d) + Folinic Acid (5–50 mg/d, adjusted based on complete blood count) | 35 | Mean 8 Range 2–39 | 34 (97.1) | 37.0 (9.9) | NR | 31 (88.6) | 31 (88.6) | NR | 4 (11.4) | NRa |
| Pedrol [33] (1990) | Pyrimethamine (50–75 mg loading dose followed by 25 mg/d) + Sulfadiazine (75 mg/kg/d) + Folinic Acid (10–20 mg/d) | 40 | 3 | NR | NR | NR | NR | NR | 12 (30.0) | 6 (15.0) | NR |
| Porter [23] (1992) | Pyrimethamine (25–100 mg/d) + Sulfadiazine (2–6 g/d) | 115f | >6 | 110 (95.7) | 38 (9.8) | NR | 96 (83.5) | 81 (70.4) | 43 (37.4) | 6 (5.2) | Rash: 42 (36.5) Leukopenia: 17 (14.8) Nausea/Vomiting: 14 (12.2) Fever: 5 (4.3) Thrombocytopenia: 4 (3.5) Diarrhea: 2 (1.7) |
| Van Delden [26] (1996) | Pyrimethamine (dose not reported) + Sulfadiazine (dose not reported) + Folinic Acid (in 118/130 patients, dose not reported) | 130 | NR | NR | NR | NR | 83c (63.8) | NR | NR | 6 (4.6) | NR |
| Vidal [35] (2005) | Pyrimethamine + Sulfadiazine (doses not reported) | 55 | NR | 33 (60.0) | 36 (NR) | NR | 48 (87.3) | 51 (92.7) | NR | 7 (12.7) | NR |
| Cohort: pyrimethamine and clindamycin | |||||||||||
| Luft [41] (1993) | Clindamycin (2.4 g/d) + Pyrimethamine (200 mg loading dose, then 75 mg/d) + Folinic acid (10 mg/d) | 49 | 6 | 43 (87.8) | Median, 35 | 14 (28.6) | 35 (71.4) | 37 (75.5) | 8 (16.3) | 1 (2.0) | NRd |
| Ruf [24] (1991) | Clindamycin (2.4 g/d) + Pyrimethamine (1.5 mg/kg/d) + Spiramycin (9 × 106 IU/d) + Folinic Acid (45 mg/d) | 25 | 3 | NR | NR | NR | 23 (92.0) | 23 (92.0) | NR | 2 (8.0) | NRg |
| Clindamycin (2.4 g/d) + Pyrimethamine (50 mg/d if patient <65 kg and 75 mg/d if >65 kg) + Folinic Acid (45 mg/d) | 26 | 3 | NR | NR | NR | 24 (92.3) | 24 (92.3) | NR | 2 (7.7) | NRg | |
| Cohort: other regimens | |||||||||||
| Goswami [19] (2014) | Trimethoprim (20 mg/kg/d) + Sulfamethoxazole (100 mg/kg/d) + Clindamycin (1.8 g/d) | 25 | 4–6 | 19 (76.0) | 33.4 (7.4) | NR | 22 (88.0) | 22 (88.0) | 0 (0.0) | 3 (12.0) | Neutropenia: 3 (12.0) Rash: 2 (8.0) Diarrhea: 1 (4.0) Febrile neutropenia: 0 (0.0) Steven-Johnson syndrome: 0 (0.0) Severe Thrombocytopenia and bleeding: 0 (0.0) |
| Liu [22] (2018) | Trimethoprim (16.7 mg/kg/d) + Sulfamethoxazole (83.3 mg/kg/d) + Azithromycin (500 mg/d) | 57 | 6 | 47 (82.5) | 41.4 (11.8) | NR | 48 (84.2) | NR | 0 (0.0) | 9 (15.8) | Gastrointestinal reaction: 6 (10.5) |
| Torre [43] (1997) | Atovaquone (3 g/d) | 87 | 6 | NR | NR | 46 (52.9) | 45 (51.7) | 32 (36.8) | NR | 3 (3.5) | NRa |
Abbreviations: IQR, interquartile range; NR, not reported or unclear.
Adverse events were only reported for maintenance therapy.
Adverse events were only reported based on the treatment received at the time, not the assigned treatment.
Only adverse events deemed attributable to the treatment were reported.
Only adverse events that led to treatment discontinuation were reported.
Reported adverse events include patients who were toxoplasmic encephalitis–negative by stereotactic biopsy.
One patient was not initially treated with pyrimethamine and sulfadiazine.
Not reported for each arm separately.
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