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A retrospective study of treatment of cerebral toxoplasmosis in AIDS patients with trimethoprin-sulphamethoxazole
Journal of Infection (1998) 37. 15-18
A Retrospective Study of Treatment of Cerebral Toxoplasmosis in AIDS Patients with Trimethoprim-sulphamethoxazole D. Torre .1, F. Speranza, R. Martegani, C. Zeroli, M. Banfi and M. Airoldi Division of Infectious Diseases, Regional Hospital, Viale Borri 57, 2 1 1 0 0 Varese, Italy Aims of the study: a retrospective study was designed to evaluate efficacy and tolerance of trimethoprim-sulphamethoxazole (TMP-SMZ) in AIDS patients with cerebral toxoplasmosis (TE). Patients and methods: we reviewed 471 patients with AIDS, and we analysed 71 AIDS patients with TE, who received intravenous therapy with TMP-SMZ (TMP: 10 mg/kg/day, SMZ: 50 mg/kg/day) for 4 weeks. Results: 35 patients (49.2%) had a complete regression of clinical signs, and a complete resolution of radiological lesions was noted in 41 patients (57.7%). Improvement of clinical signs and radiological lesions were observed in 27 patients (38%), and in nine patients (12.6%), respectively. In contrast, nine patients (12.6%) did not show any clinical change, or worsened. Twenty-two patients (30.9%) suffered from adverse cutaneous reactions, whereas many patients had haematological toxicity. Conclusions: TMP-SMZ seems to be an efficient therapy for TE in AIDS patients, although further prospective, randomized therapeutic trials are required to confirm these results.
Introduction Cerebral toxoplasmosis (TE) is the most frequent cause of focal brain lesions in patients with AIDS; the incidence of TE was estimated to range between 3% and 40%. 1-3 The standard therapy for acute TE still remains the combination of pyrimethamine-sulfadiazine. 45 Several chemotherapeutic agents, including clindamycin, spiramycin, toxithromycin and azythromycin have shown to possess antitoxoplasma activity in vitro, in experimental animal models, and in vivo. ~ Among these agents, combination of trimethoprimsulphamethoxazole (TMP-SMZ) was studied in vitro and in vivo. 6 Trimethoprim possesses a mechanism of action similar to that of pyrimethamine, and it is less toxic to the bone marrow. 6 However, pyrimethamine and sulfadiazine are plagued with toxicity rates (cutaneous reactions and haematological toxic effects) that may preclude its use in up to 40%-50% of patients with AIDS, 7'8 whereas TMP-SMZ cause toxic effects in 21% of patients with TE. 9 Treatment with pyrimethamine is further complicated by the erratic levels of this agent found in serum of AIDS patients with TE. 1° Furthermore, AIDS patients with TE treated with pyrimethamine and sulfadiazine showed a clinical and radiological improvement which ranged from 58% to 85%. 6 However, the efficacy of TMP-SMX has not been established in therapy of AIDS patients with TE, either in randomized, prospective studies or in large
* Please address correspondence to: D. Torre. 0163M:453/98/040015 +04 $12.00/0
retrospective studies. In fact, two studies of a small number of AIDS patients have shown a resolution or improvement of clinical and radiological signs in 42% and 75%, respectively. 9'11 The aim of this study is to evaluate the efficacy and tolerance of TMP-SMZ in AIDS patients with TE in a large retrospective study.
Patients and Methods From January 1986 to December 1994 all AIDS patients with CT, who were treated with TMP-SMZ at our Division, were retrospectively studied. Seventy-one out of 471 AIDS patients suffered from CT. Diagnosis of acute CT was based on clinical signs including fever, headache, disorientation or lethargy and meningismus, and neurological manifestations such as hemiparesis, cranial nerve palsy, extrapyramidal and cerebellar signs and seizures. Radiological diagnosis, performed by brain computed tomography scan, was based on multiple bilateral lesions, and/or on lesions which exhibit contrast ring enhancement involving the basal glanglia. In addition, a further diagnostic criteria was resolution or improvement of radiological lesions after 2-3 weeks of treatment with TMP-SMZ. roxoplasrna gondii IgG serological assay was determined in HIV-l-positive patients by indirect immunofluorescence technique until 1991, and from 1992 by an immunoenzymatic assay. Patients were treated with TMP (lOmg/kg/day) and SMZ (50mg/kg/day), given © 1998 The British Infection Society
16
D. Torre et al,
intravenously for 4 weeks, i n a s m u c h as most of the patients were critically ill or comatose. It should be noted that p y r i m e t h a m i n e and sulfadiazine are not commercially available in Italy. Steroid treatment was started in those patients (61 out of 71 patients) w h o presented cerebral oedema a n d / o r lesions with a mass effect, and consisted on dexam e t h a s o n e at the dosage of 8 m g twice daily for 7 - 1 0 days. All patients received folinic acid given at the dosage of 15 m g once a day. Secondary prophylaxis consisted of administration of TMP-SMZ, given orally, once a day at reduced dosage (50%). The definitions used for the clinical evaluations of efficacy were: complete response, resolution of all neurological signs and symptoms related to TE; partial response, more t h a n 50% improvement in neurological examination; no c h a n g e or progression, lack of a n y improvement, or increasing severity of neurological signs. The patients were seen and reviewed by a neurologist. The clinical response to therapy was assessed 4 weeks after starting therapy. The definitions used for the radiological evaluations of efficacy were: complete response, a n o r m a l study or complete resolution of oedema and contrast e n h a n c e m e n t with or w i t h o u t minimal residual small areas of encephalomalacia; partial response, more t h a n 50% decrease in size or n u m b e r of lesions; no c h a n g e or progression, increased size or n u m b e r of lesions. Reported or observed adverse reactions were m a n a g e d as follows: severe toxicity (diffuse and severe skin reactions with haematological toxicity) required withdrawal of the drug, whereas lesser toxicity (moderate skin reactions w i t h o u t haematological toxicity) was m a n a g e d initially with reduction in the dose of the drug, but persistent toxicity unresponsive to dosage modification required the use of an alternative drug. Data are reported as m e a n and standard deviation (SD).
Results Seventy-one patients with TE were reviewed in this study. Baseline characteristics, including demographic data, patient histories, physical findings, laboratory values and brain imaging results before starting therapy with TMPSMZ are summarized in Table I. Fifty-two patients (73.2%) h a d IgG antibody to T. gondii, whereas only two patients were found positive to IgM antibody. However, levels of IgG antibody to T. gondii were negative in six patients, and were not determined in 13 patients. Table II shows clinical and radiological responses of 71 patients treated with TMP-SMZ. As can be seen, 35 (49.2%) patients had a complete response to the therapy,
Table I. Demographic and clinical characteristics of 71 AIDS patients with cerebral toxoplasmosis. Characteristics Age (year) Male n (%) Female n (%)
30.5 __4.9 58 (81.7%) 13 (18.3%)
Risk factor for AIDS, n (%) Intravenous drug abuse Homosexual Heterosexual contact
60 (84.5%) 3 (4.2%) 8 (11.2%)
Presenting symptoms, n (%) Fever Headache Vomiting Seizures
35 (49.2%) 44 (61.9%) 11 (15.4%) 9 (12.6%)
Mental status changes, n (%) Alert Comatose
64 (90.1%) 7 (9.9%)
Paresis, n (%) Upper/lower extremities Cranial nerves Cerebeltar findings
42 (59.1%) 23 (32.3 %) 19 (26.7%)
Brain imaging findings, n (%) Single lesion Multiple lesions
21 (29.5%) 50 (70.4%)
Laboratory values Leucocyte count ( x 109/1) Haemoglobin (g/dl) Platelets ( x 109/1) CD4 lymphocytes count ( x 106/1) CD4 lymphocytes, n (%) >50 pl <50 p.1
4.2 + 1.9 12.1 _+2.0 179.5 _+70.0 46.7 + 54.5 12 (16.9%) 31 (43.6%)
and 27 (38%) showed a partial response. In contrast, nine (12.6%) patients did not show any change, or worsened. Radiological response in our patients was also evaluated. A complete resolution of lesions was noted in 41 (5 7.7%) patients, and a partial resolution in nine (12.6%) patients. In contrast, nine (12.6%) patients did not show a n y c h a n g e or worsened (Table II). Furthermore, we analysed clinical and radiological response in eight patients w h o were not treated with steroids. A complete
Table II. Clinical and radiological evaluation for efficacy of therapy with TMP-SMZin 71 AIDSpatients with cerebral toxoplasmosis. Treatment response
Number of patients responding to the therapy (%) Clinical Radiological response response
Complete Partial No change or progression Not done
35 (49.2%) 27 (38.0%) 9 (12.6%) --
41 9 9 12
(57.7%) (1Z6%) (i2.6%) (16.9%)
Trimethoprim-sulphamethoxazole in Cerebral Toxoplasmosis clinical and radiological response was noted in four (50%) patients, whereas two (25 %) patients had a partial clinical response, and one (12.5%) patient had a partial radiological response. No change or progression of clinical signs was noted in two (25%) patients, whereas no patient showed no change or progression of radiological lesions. Mortality related to TE was noted in 14 (19.7%) patients: eight patients died during the course of therapy, and six patients died during a 9-month period of followup. As autoptic examination was not done in these patients, lymphoma of central nervous system or infection caused by Nocardia sp., which mimic lesions due to T. gondii, cannot be ruled out. On the other hand, relapses after primary course of the therapy were observed in five (7%) patients, after a mean period of 4.2 + 2.2 months. Adverse cutaneous reactions were noted in 22 (30.9%) patients treated with TMP-SMZ. Patients with prior cutaneous reactions to TMP-SMZ did not show a significant increase in skin reactions after re-exposure to TMP-SMZ: three of 22 (13.6%) patients with skin reactions, and three of 49 (6.4%) patients without skin reactions. Seven patients with adverse reactions to TMP-SMZ were subsequently treated with pyrimethamine and clindamycin, whereas in seven patients treatment with TMP-SMZ was started again after a treatment period with antihistamine drugs. However, a good outcome was noted in patients with adverse reactions to TMP-SMZ. In addition, we found no significant differences between the 22 reactive patients and the 49 non-reactive patients in regard to the following parameters: sex, mean age, mean CD4 cell count, the presence of serum p-24 antigen, and in particular adjuvant steroid therapy. Such treatment was not able to prevent or significantly diminisl~ skin reactions; in fact, these were noted in 18 of 22 (81.8%) patients treated with steroids, whereas no skin reactions were observed in 43 of 49 (87.7%) treated patients~
Discussion This large and retrospective study attempted to evaluate the efficacy and tolerance of therapy with TMP-SMZ in AIDS patients with TE. In this study, clinical response (resolution and improvement) was noted in 62 (87.3%) patients, whereas complete and partial resolution of radiological signs were noted in 50 (70.4%) patients. Solbreux et al. 11 have retrospectively evaluated the efficacy of TMP-SMZ in 12 AIDS patients with TE, and showed a clinical and radiotogical response in five (41.6%) patients. In contrast, Canessa et al. 9 treated 24 AIDS patients with TE with two different dosage regimens of TMP-SMZ: a group
17
treated with TMP at the dosage of 6.6 mg/kg/day and SMZ at the dosage of 33 mg/kg/day, with the other group receiving TMP at the dosage of 20 mg/kg/day and SMZ at the dosage of 100mg/kg/day. These investigators showed clinical and radiological responses in 18 of 24 (75%) patients, and there was no difference in response rates between patients treated with the two dosage regimens of TMP-SMZ. These two small studies show similar data with respect to our retrospective study about rates of clinical and radiological response in AIDS patients treated with TMP~SMZ. It should be noted that there are several advantages in adopting TMP-SMZ as a therapy of TE in AIDS patients. TMP-SMZ can be given intravenously, especially in comatose patients, and in those with gastric intolerance (vomitus, nausea). In fact, in our study many patients admitted to our Division with a presumptive diagnosis of TE were confused, lethargic or comatose, and thus intravenous administration of TMP-SMZ was useful to achieve adequate concentrations in serum, and in particular in the damaged brain areas. However, intravenous administration of TMP-SMZ is also advisable in conscious patients who suffer from gastro-intestinal disturbances, in order to ameliorate their compliance to these drugs. Therapy and secondary prophylaxis with TMP-SMZ in AIDS patients with TE may also prevent opportunistic infections susceptible to this drug, including pneumonia due to Pneumocystis carinii, bacterial infections caused by Salmondla sp., Shigella sp., Listeria monocytogenes, Legionella sp., and some unusual infections caused by Isospora belli, Nocardia sp., Psuedomonas cepacia and Pseudomonas maltophiIia.I2 Moreover, good penetration of TMP-SMZ has been found in cerebrospinal fluid either of infected patients or in patients with normal meninges. ~3'14 Adverse cutaneous reactions to TMP-SMZ occurred in our study in 22 (30.9%) patients, but none of our patients had severe skin reactions such as Steven-Johnson syndrome of Lyell's syndrome. Adverse reactions have also been reported occurring with high incidence in AIDS patients with P. carinii pneumonia treated with TMPg N U . 15
In this study AIDS patients were treated with the standard dosage of TMP (20mg/kg/day), and SMZ (100 mg/kg/day) for treatment of P. carinii. It should be noted that suspension of the therapy leads to resolution of skin reactions in AIDS patients. It has been found that corticosteroid therapy decreases the frequency of hypersensitivity and cutaneous reactions in AIDS patients with P. carinii pneumonia treated with TMP (20mg/kg/day) and SMZ (100mg/kg/day). 16 In our study, adjuvant steroid therapy did not significantly decrease skin reactions in treated patients.
18
D. Torre et al.
In conclusion, TMP-SMZ may be effective in therapy of TE in AIDS patients, it is useful in comatose patients, in whom intravenous injection is needed, and finally TMP-SMZ is also an effective drug for the therapy of opportunistic infections and in primary and secondary prophylaxis for TE. However, further prospective, randomized trials are required to confirm the efficacy and tolerance of TMP-SMZ versus pyrimethaminesulfadiazine.
References 1 Luft BI, Hafner R, Korzun AH et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. N Engl I Med 1993; 329: 996-1000. 2 Luft BI, Conley FK, Remington JS. Outbreak of central nervous system toxoplasmosis in Western Europe and North America. Lancet 1983; 1: 781-784. 3 Luft BJ, Brooks RG, Conley FK et aI. Toxoplasmic encephalitis in patients with AIDS. lAMA 1984; 252: 913-917. 4 Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992; 15: 211-222. 5 Leport C, Raffi F, Matheron Set aI. Treatment of central nervous system toxoplasmosis with pyrimethamine-sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous treatment. Am ] Med 1988; 84: 94-100. 6 Georgiev VT, Opportunistic nosocomial infections. Treatment and developmental therapeutics. Toxoplasmosis. Med Res Rev 1993; 13: 529-568.
7 ttaverkos ttW. Assessment of therapy of toxoplasma encephalitis. The TE study group. Am J Med 1987; 82: 907-914. 8 Dannemann B, McCutchan JA, Israelski D et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992; 116: 33-43. 9 Canessa A, Del Bono V, De Leo P, PiersanteIli N, Terragna A. Cotrimoxazole therapy of Toxoplasma gondii encephalitis in AIDS patients. Eur J Clin Microbiol Infect Dis 1992; 11: 125-130. 10 Weiss LM, Harris C, Berger M, Tanowitz HB, Wittner M. Pyrimethamine concentrations in serum and cerebrospinal fluid during treatment of acute toxoplasma encephalitis in patients with AIDS. J Infect Dis 1988; 157: 580-583. 11 Solbreux P, Sonnet I, Zech F. A retrospective study about the use of cotrimoxazole as diagnostic support and treatment of suspected cerebral toxoplasmosis in AIDS. Acta Clin Belg 1990; 45: 85-96. 12 Young LS, Hindler J. Use of trimethoprim-sulphamethoxazolesingly and in combination with other antibiotics in immunocompromised patients. Rev Infect Dis 1987; 9 (Suppl. 2): S177-$183. 13 Svedhem A, Iwarson S. Cerebrospinal fluid concentrations of trimethoprim during oral and parenteral treatment. J Antimicrob Chemother 1979; 5: 717-720. 14 Dudley MN, Levitz RE, Quintiliani R, Hickingbotham JM, Nightgale LH. Pharmacokinetics of trimethoprim and sulphamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges. Antimicrob A~lents Chemother 1984; 26: 811-814. 15 Gordin FM, Simon GL, Wosfy CB. Adverse reactions to trimethoprim sulphamethoxazole in acquired immunodeficiency syndrome. Ann Intern Med 1984; 100: 495-499. 16 Caumes E, Roudier C, Rogeaux O, Bricaire F, Gentilini M. Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulphamethoxazole during treatment of AIDS-associated Pneumocystis earinii pneumonia, Clin Infect Dis 1994; 18: 319-323.
A Retrospective Study of Treatment of Cerebral Toxoplasmosis in AIDS Patients with Trimethoprim-sulphamethoxazole D. Torre .1, F. Speranza, R. Martegani, C. Zeroli, M. Banfi and M. Airoldi Division of Infectious Diseases, Regional Hospital, Viale Borri 57, 2 1 1 0 0 Varese, Italy Aims of the study: a retrospective study was designed to evaluate efficacy and tolerance of trimethoprim-sulphamethoxazole (TMP-SMZ) in AIDS patients with cerebral toxoplasmosis (TE). Patients and methods: we reviewed 471 patients with AIDS, and we analysed 71 AIDS patients with TE, who received intravenous therapy with TMP-SMZ (TMP: 10 mg/kg/day, SMZ: 50 mg/kg/day) for 4 weeks. Results: 35 patients (49.2%) had a complete regression of clinical signs, and a complete resolution of radiological lesions was noted in 41 patients (57.7%). Improvement of clinical signs and radiological lesions were observed in 27 patients (38%), and in nine patients (12.6%), respectively. In contrast, nine patients (12.6%) did not show any clinical change, or worsened. Twenty-two patients (30.9%) suffered from adverse cutaneous reactions, whereas many patients had haematological toxicity. Conclusions: TMP-SMZ seems to be an efficient therapy for TE in AIDS patients, although further prospective, randomized therapeutic trials are required to confirm these results.
Introduction Cerebral toxoplasmosis (TE) is the most frequent cause of focal brain lesions in patients with AIDS; the incidence of TE was estimated to range between 3% and 40%. 1-3 The standard therapy for acute TE still remains the combination of pyrimethamine-sulfadiazine. 45 Several chemotherapeutic agents, including clindamycin, spiramycin, toxithromycin and azythromycin have shown to possess antitoxoplasma activity in vitro, in experimental animal models, and in vivo. ~ Among these agents, combination of trimethoprimsulphamethoxazole (TMP-SMZ) was studied in vitro and in vivo. 6 Trimethoprim possesses a mechanism of action similar to that of pyrimethamine, and it is less toxic to the bone marrow. 6 However, pyrimethamine and sulfadiazine are plagued with toxicity rates (cutaneous reactions and haematological toxic effects) that may preclude its use in up to 40%-50% of patients with AIDS, 7'8 whereas TMP-SMZ cause toxic effects in 21% of patients with TE. 9 Treatment with pyrimethamine is further complicated by the erratic levels of this agent found in serum of AIDS patients with TE. 1° Furthermore, AIDS patients with TE treated with pyrimethamine and sulfadiazine showed a clinical and radiological improvement which ranged from 58% to 85%. 6 However, the efficacy of TMP-SMX has not been established in therapy of AIDS patients with TE, either in randomized, prospective studies or in large
* Please address correspondence to: D. Torre. 0163M:453/98/040015 +04 $12.00/0
retrospective studies. In fact, two studies of a small number of AIDS patients have shown a resolution or improvement of clinical and radiological signs in 42% and 75%, respectively. 9'11 The aim of this study is to evaluate the efficacy and tolerance of TMP-SMZ in AIDS patients with TE in a large retrospective study.
Patients and Methods From January 1986 to December 1994 all AIDS patients with CT, who were treated with TMP-SMZ at our Division, were retrospectively studied. Seventy-one out of 471 AIDS patients suffered from CT. Diagnosis of acute CT was based on clinical signs including fever, headache, disorientation or lethargy and meningismus, and neurological manifestations such as hemiparesis, cranial nerve palsy, extrapyramidal and cerebellar signs and seizures. Radiological diagnosis, performed by brain computed tomography scan, was based on multiple bilateral lesions, and/or on lesions which exhibit contrast ring enhancement involving the basal glanglia. In addition, a further diagnostic criteria was resolution or improvement of radiological lesions after 2-3 weeks of treatment with TMP-SMZ. roxoplasrna gondii IgG serological assay was determined in HIV-l-positive patients by indirect immunofluorescence technique until 1991, and from 1992 by an immunoenzymatic assay. Patients were treated with TMP (lOmg/kg/day) and SMZ (50mg/kg/day), given © 1998 The British Infection Society
16
D. Torre et al,
intravenously for 4 weeks, i n a s m u c h as most of the patients were critically ill or comatose. It should be noted that p y r i m e t h a m i n e and sulfadiazine are not commercially available in Italy. Steroid treatment was started in those patients (61 out of 71 patients) w h o presented cerebral oedema a n d / o r lesions with a mass effect, and consisted on dexam e t h a s o n e at the dosage of 8 m g twice daily for 7 - 1 0 days. All patients received folinic acid given at the dosage of 15 m g once a day. Secondary prophylaxis consisted of administration of TMP-SMZ, given orally, once a day at reduced dosage (50%). The definitions used for the clinical evaluations of efficacy were: complete response, resolution of all neurological signs and symptoms related to TE; partial response, more t h a n 50% improvement in neurological examination; no c h a n g e or progression, lack of a n y improvement, or increasing severity of neurological signs. The patients were seen and reviewed by a neurologist. The clinical response to therapy was assessed 4 weeks after starting therapy. The definitions used for the radiological evaluations of efficacy were: complete response, a n o r m a l study or complete resolution of oedema and contrast e n h a n c e m e n t with or w i t h o u t minimal residual small areas of encephalomalacia; partial response, more t h a n 50% decrease in size or n u m b e r of lesions; no c h a n g e or progression, increased size or n u m b e r of lesions. Reported or observed adverse reactions were m a n a g e d as follows: severe toxicity (diffuse and severe skin reactions with haematological toxicity) required withdrawal of the drug, whereas lesser toxicity (moderate skin reactions w i t h o u t haematological toxicity) was m a n a g e d initially with reduction in the dose of the drug, but persistent toxicity unresponsive to dosage modification required the use of an alternative drug. Data are reported as m e a n and standard deviation (SD).
Results Seventy-one patients with TE were reviewed in this study. Baseline characteristics, including demographic data, patient histories, physical findings, laboratory values and brain imaging results before starting therapy with TMPSMZ are summarized in Table I. Fifty-two patients (73.2%) h a d IgG antibody to T. gondii, whereas only two patients were found positive to IgM antibody. However, levels of IgG antibody to T. gondii were negative in six patients, and were not determined in 13 patients. Table II shows clinical and radiological responses of 71 patients treated with TMP-SMZ. As can be seen, 35 (49.2%) patients had a complete response to the therapy,
Table I. Demographic and clinical characteristics of 71 AIDS patients with cerebral toxoplasmosis. Characteristics Age (year) Male n (%) Female n (%)
30.5 __4.9 58 (81.7%) 13 (18.3%)
Risk factor for AIDS, n (%) Intravenous drug abuse Homosexual Heterosexual contact
60 (84.5%) 3 (4.2%) 8 (11.2%)
Presenting symptoms, n (%) Fever Headache Vomiting Seizures
35 (49.2%) 44 (61.9%) 11 (15.4%) 9 (12.6%)
Mental status changes, n (%) Alert Comatose
64 (90.1%) 7 (9.9%)
Paresis, n (%) Upper/lower extremities Cranial nerves Cerebeltar findings
42 (59.1%) 23 (32.3 %) 19 (26.7%)
Brain imaging findings, n (%) Single lesion Multiple lesions
21 (29.5%) 50 (70.4%)
Laboratory values Leucocyte count ( x 109/1) Haemoglobin (g/dl) Platelets ( x 109/1) CD4 lymphocytes count ( x 106/1) CD4 lymphocytes, n (%) >50 pl <50 p.1
4.2 + 1.9 12.1 _+2.0 179.5 _+70.0 46.7 + 54.5 12 (16.9%) 31 (43.6%)
and 27 (38%) showed a partial response. In contrast, nine (12.6%) patients did not show any change, or worsened. Radiological response in our patients was also evaluated. A complete resolution of lesions was noted in 41 (5 7.7%) patients, and a partial resolution in nine (12.6%) patients. In contrast, nine (12.6%) patients did not show a n y c h a n g e or worsened (Table II). Furthermore, we analysed clinical and radiological response in eight patients w h o were not treated with steroids. A complete
Table II. Clinical and radiological evaluation for efficacy of therapy with TMP-SMZin 71 AIDSpatients with cerebral toxoplasmosis. Treatment response
Number of patients responding to the therapy (%) Clinical Radiological response response
Complete Partial No change or progression Not done
35 (49.2%) 27 (38.0%) 9 (12.6%) --
41 9 9 12
(57.7%) (1Z6%) (i2.6%) (16.9%)
Trimethoprim-sulphamethoxazole in Cerebral Toxoplasmosis clinical and radiological response was noted in four (50%) patients, whereas two (25 %) patients had a partial clinical response, and one (12.5%) patient had a partial radiological response. No change or progression of clinical signs was noted in two (25%) patients, whereas no patient showed no change or progression of radiological lesions. Mortality related to TE was noted in 14 (19.7%) patients: eight patients died during the course of therapy, and six patients died during a 9-month period of followup. As autoptic examination was not done in these patients, lymphoma of central nervous system or infection caused by Nocardia sp., which mimic lesions due to T. gondii, cannot be ruled out. On the other hand, relapses after primary course of the therapy were observed in five (7%) patients, after a mean period of 4.2 + 2.2 months. Adverse cutaneous reactions were noted in 22 (30.9%) patients treated with TMP-SMZ. Patients with prior cutaneous reactions to TMP-SMZ did not show a significant increase in skin reactions after re-exposure to TMP-SMZ: three of 22 (13.6%) patients with skin reactions, and three of 49 (6.4%) patients without skin reactions. Seven patients with adverse reactions to TMP-SMZ were subsequently treated with pyrimethamine and clindamycin, whereas in seven patients treatment with TMP-SMZ was started again after a treatment period with antihistamine drugs. However, a good outcome was noted in patients with adverse reactions to TMP-SMZ. In addition, we found no significant differences between the 22 reactive patients and the 49 non-reactive patients in regard to the following parameters: sex, mean age, mean CD4 cell count, the presence of serum p-24 antigen, and in particular adjuvant steroid therapy. Such treatment was not able to prevent or significantly diminisl~ skin reactions; in fact, these were noted in 18 of 22 (81.8%) patients treated with steroids, whereas no skin reactions were observed in 43 of 49 (87.7%) treated patients~
Discussion This large and retrospective study attempted to evaluate the efficacy and tolerance of therapy with TMP-SMZ in AIDS patients with TE. In this study, clinical response (resolution and improvement) was noted in 62 (87.3%) patients, whereas complete and partial resolution of radiological signs were noted in 50 (70.4%) patients. Solbreux et al. 11 have retrospectively evaluated the efficacy of TMP-SMZ in 12 AIDS patients with TE, and showed a clinical and radiotogical response in five (41.6%) patients. In contrast, Canessa et al. 9 treated 24 AIDS patients with TE with two different dosage regimens of TMP-SMZ: a group
17
treated with TMP at the dosage of 6.6 mg/kg/day and SMZ at the dosage of 33 mg/kg/day, with the other group receiving TMP at the dosage of 20 mg/kg/day and SMZ at the dosage of 100mg/kg/day. These investigators showed clinical and radiological responses in 18 of 24 (75%) patients, and there was no difference in response rates between patients treated with the two dosage regimens of TMP-SMZ. These two small studies show similar data with respect to our retrospective study about rates of clinical and radiological response in AIDS patients treated with TMP~SMZ. It should be noted that there are several advantages in adopting TMP-SMZ as a therapy of TE in AIDS patients. TMP-SMZ can be given intravenously, especially in comatose patients, and in those with gastric intolerance (vomitus, nausea). In fact, in our study many patients admitted to our Division with a presumptive diagnosis of TE were confused, lethargic or comatose, and thus intravenous administration of TMP-SMZ was useful to achieve adequate concentrations in serum, and in particular in the damaged brain areas. However, intravenous administration of TMP-SMZ is also advisable in conscious patients who suffer from gastro-intestinal disturbances, in order to ameliorate their compliance to these drugs. Therapy and secondary prophylaxis with TMP-SMZ in AIDS patients with TE may also prevent opportunistic infections susceptible to this drug, including pneumonia due to Pneumocystis carinii, bacterial infections caused by Salmondla sp., Shigella sp., Listeria monocytogenes, Legionella sp., and some unusual infections caused by Isospora belli, Nocardia sp., Psuedomonas cepacia and Pseudomonas maltophiIia.I2 Moreover, good penetration of TMP-SMZ has been found in cerebrospinal fluid either of infected patients or in patients with normal meninges. ~3'14 Adverse cutaneous reactions to TMP-SMZ occurred in our study in 22 (30.9%) patients, but none of our patients had severe skin reactions such as Steven-Johnson syndrome of Lyell's syndrome. Adverse reactions have also been reported occurring with high incidence in AIDS patients with P. carinii pneumonia treated with TMPg N U . 15
In this study AIDS patients were treated with the standard dosage of TMP (20mg/kg/day), and SMZ (100 mg/kg/day) for treatment of P. carinii. It should be noted that suspension of the therapy leads to resolution of skin reactions in AIDS patients. It has been found that corticosteroid therapy decreases the frequency of hypersensitivity and cutaneous reactions in AIDS patients with P. carinii pneumonia treated with TMP (20mg/kg/day) and SMZ (100mg/kg/day). 16 In our study, adjuvant steroid therapy did not significantly decrease skin reactions in treated patients.
18
D. Torre et al.
In conclusion, TMP-SMZ may be effective in therapy of TE in AIDS patients, it is useful in comatose patients, in whom intravenous injection is needed, and finally TMP-SMZ is also an effective drug for the therapy of opportunistic infections and in primary and secondary prophylaxis for TE. However, further prospective, randomized trials are required to confirm the efficacy and tolerance of TMP-SMZ versus pyrimethaminesulfadiazine.
References 1 Luft BI, Hafner R, Korzun AH et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. N Engl I Med 1993; 329: 996-1000. 2 Luft BI, Conley FK, Remington JS. Outbreak of central nervous system toxoplasmosis in Western Europe and North America. Lancet 1983; 1: 781-784. 3 Luft BJ, Brooks RG, Conley FK et aI. Toxoplasmic encephalitis in patients with AIDS. lAMA 1984; 252: 913-917. 4 Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992; 15: 211-222. 5 Leport C, Raffi F, Matheron Set aI. Treatment of central nervous system toxoplasmosis with pyrimethamine-sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous treatment. Am ] Med 1988; 84: 94-100. 6 Georgiev VT, Opportunistic nosocomial infections. Treatment and developmental therapeutics. Toxoplasmosis. Med Res Rev 1993; 13: 529-568.
7 ttaverkos ttW. Assessment of therapy of toxoplasma encephalitis. The TE study group. Am J Med 1987; 82: 907-914. 8 Dannemann B, McCutchan JA, Israelski D et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992; 116: 33-43. 9 Canessa A, Del Bono V, De Leo P, PiersanteIli N, Terragna A. Cotrimoxazole therapy of Toxoplasma gondii encephalitis in AIDS patients. Eur J Clin Microbiol Infect Dis 1992; 11: 125-130. 10 Weiss LM, Harris C, Berger M, Tanowitz HB, Wittner M. Pyrimethamine concentrations in serum and cerebrospinal fluid during treatment of acute toxoplasma encephalitis in patients with AIDS. J Infect Dis 1988; 157: 580-583. 11 Solbreux P, Sonnet I, Zech F. A retrospective study about the use of cotrimoxazole as diagnostic support and treatment of suspected cerebral toxoplasmosis in AIDS. Acta Clin Belg 1990; 45: 85-96. 12 Young LS, Hindler J. Use of trimethoprim-sulphamethoxazolesingly and in combination with other antibiotics in immunocompromised patients. Rev Infect Dis 1987; 9 (Suppl. 2): S177-$183. 13 Svedhem A, Iwarson S. Cerebrospinal fluid concentrations of trimethoprim during oral and parenteral treatment. J Antimicrob Chemother 1979; 5: 717-720. 14 Dudley MN, Levitz RE, Quintiliani R, Hickingbotham JM, Nightgale LH. Pharmacokinetics of trimethoprim and sulphamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges. Antimicrob A~lents Chemother 1984; 26: 811-814. 15 Gordin FM, Simon GL, Wosfy CB. Adverse reactions to trimethoprim sulphamethoxazole in acquired immunodeficiency syndrome. Ann Intern Med 1984; 100: 495-499. 16 Caumes E, Roudier C, Rogeaux O, Bricaire F, Gentilini M. Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulphamethoxazole during treatment of AIDS-associated Pneumocystis earinii pneumonia, Clin Infect Dis 1994; 18: 319-323.