Vol. 11, No. 2
Article
125
Eur. j. Clin. Microbiol. Infect. Dis., February 1992, p. 125-130 0934-9723/92/02 0125-06 $3.00/0
Cotrimoxazole Therapy of Toxoplasma gondii Encephalitis in AIDS Patients A. C a n e s s a l , , V. D e l B o n o 1, R D e L e o 1, N. Piersantelli 2, A. T e r r a g n a I t
Twenty.four consecutive HIV-positive patients affected by Toxoplasma gondii encephalitis received trimethoprim-sulfamethoxazole (cotrimoxazole) as acute-phase treatment. Two dosage regimens of cotrimoxazole were used: 40 mg/kg/day (12 patients) or 120 mg/kg/day (12 patients) of total compound (trimethoprim plus suifamethoxazole). Clinical and radiologicai responses to treatment were evaluated, and the product-limit method for survival data analysis was used. Eighteen of 24 patients showed both a clinical and radiological response (75 % response rate). There were no differences in response rates between patients receiving the two dosage regimens of cotrimoxazole. Adverse reaction consisted of leukopenia (two cases) and skin rash (three cases) which led to the discontinuation of the drug in one case. These results suggest that a randomized, controlled clinical trial should be carried out comparing cotrimoxazole versus sulfadiazine-pyrimethamine in AIDS patients with Toxoplasma gondii encephalitis.
The drug combination of sulfadiazine plus pyrimethamine is considered the therapy of choice in central nervous system (CNS) toxoplasmosis in AIDS patients since the first reports of it in the literature (1). However, as neither sulfadiazine nor pyrimethamine are marketed in Italy, therapeutic alternatives are urgently needed in this COUntry for the treatment of this potentially lethal OpPortunistic infection. A number of reports have shown the activity of trimethoprim plus sulfamethoxazole against Toxoplasma gondii both in vitro, at concentrations easily attainable in man after administration of conventional doses (2, 3), and in vivo, in exPerimental infection of mice (2, 4, 5) and nonhuman primates (6). Howe,~er, the animal studies are difficult to interpret because the pharmacokinetics of trimethoprim vary considerably across species (2); therefore, the issue of the ac!ivity of cotrimoxazole against Toxoplasraa gondii ~s still unsettled. Nonetheless, on the basis of experimental evidence as well as of clinical studies (7, 8), some authors in Europe have suggested the Use of cotrimoxazole in human toxoplasmosis,
Department of Infectious Diseases, University of Genoa, Viale 2D . Benedetto . . . XV 10 16132 Genoa, Ital y. wmslonof Infectious Diseases, Galliera Hospital, Genoa, Italy. tDeceased.
particularly in the treatment of CNS infection (9, 10). These facts and the promising results obtained with cotrimoxazole in individual cases of CNS toxoplasmosis (11) prompted us to use this drug in the acute-phase treatment of Toxoplasma gondii encephalitis in A I D S patients. In this paper, we report the results of cotrimoxazole treatment of CNS toxoplasmosis in 24 consecutive cases.
Patients and Methods
Study Patients and Admission Criteria. HIV-infected patients with clinical, neuro|ogicat and computed tomographie (CT) scan manifestations consistent with a first episode of CNS toxoplasmosis (1, 12) were consecutively treated from September 1985 to September 1989. Patients who had had a brain biopsy or autopsy performed within 30 days after the onset of therapy with no histologic evidence of Toxoplasma gondii encephalitis were not evaluated. Twenty-four patients were thus evaluable.
Definitive Diagnosis. Toxoplasma gondii antibodies in serum and cerebrospinal fluid (CSF) were measured by dye test and immunofluorescence IgG and IgM antibody assay, with determination of intrathecal antibody synthesis in comparison with total immunoglobulin concentration (13), Multiple sections from brain autopsy specimens were stained by Giemsa method, hematoxytineosin and periodic acid Sehiff stains. Proven diagnosis
126
Eur. J. Clin. Microbiol. Infect. Dis.
of Toxoplasma gondii encephalitis was available in 14 patients through demonstration of intrathecal antibody synthesis, the isolation of Toxoplasma gondii in mice inoculated with C S E or through histologie examination of brain autopsy specimens.
Weekly monitoring of toxic effects included complete blood counts, serum electrolytes, glucose, creatinine, blood urea nitrogen, bilirubin and liver enzymes. Leukopenia was defined by a W B C count of less than 2,O00/cu mm, neutropenia by a PMN leukocyte count of less than 1,000/cu mm.
Drug Dosages and Admin&tration. Informed consent from patients or their nearest relatives was obtained. Two dosage regimens of cotrimoxazole were used. Patients recruited at the University Department of Infectious Diseases were given cotrimoxazole at the total daily dose of 40 mg/kg (6.6 mg/kg trimethoprim plus 33.3 mg/kg sulfamethoxazole); patients recruited at the Division of Infectious Diseases, Galliera Hospital, were given cotrimoxazole 120 mg/kg daily (20 mg/kg trimethoprim). Cotrimoxazole was administered orally, unless a comatose or lethargic status was present, in which case it was given intravenously. Therapy had a mean duration of 25 days (range 14-28 days). Folinie acid was also administered, 15 mg once a day. After a full-course therapy, 500 mg sulphamethopyrazine plus 25 mg pyrimethamine (the only pyrimethamine-containing drug formulation available in Italy) twice weekly were prescribed as maintenance treatment. Four patients received zidovudine concomitantly with cotrimoxazole (one in the 40 mg/kg group and three in the 120 mg/kg group); five additional patients were given zidovudine after completion of the full-course treatment until death. Table 1:
Case no.
Efficacy Criteria. Efficacy of therapy was evaluated according to clinical and radiological criteria. Clinical response was defined as the complete disappearance of clinical and neurological signs: fever, altered mental status and focal neurologic signs. Radiologieal response was defined as the disappearance or significant reduction (more than 50 % decrease in number and/or size) of focal lesions on subsequent CT scans compared with the initial ones. Comparative CT scan evaluations were performed by independent radiologists who were unaware of the suspected diagnosis and therapy. Responding patients were thus defined as those who showed both a clinical and a radiological response. Non-responders were patients with either unchanged or worsened clinical or radiological manifestations. Relapse of Toxoplasma gondii encephalitis was defined as the reappearance of neurological signs along with C T scan evidence of new lesions. Statistical Methods. Survival of patients since the onset of therapy was computed by the Kaplan-Meier survival
C~inical~urseandsurviva~fpatientswithT~x~p~asmag~ndiien~epha~itis(TE)treat~dwithc~trim~xaz~e. Age, sex
Clinicalpresentation
T E diagnosis
Dosage a (mg/kg qd)
Response b
Survivalc (days)
Relapse
40 40 40 40 40 40 40 40 40 40 40 40 120 120 120 120 120 120 120 120 120 120 120 120
yes yes yes yes yes yes yes yes yes no no no yes yes yes yes yes yes yes yes yes no no no
270 f 133 f 354 909 175 169 120 399 135 34 121 22 247 155 510 f 180 121 177 ~ 205 526 f 180 84 47 127
no no yes no no yes no no no no no no yes no no no no yes -
Proven d Probable e 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 t8 19 20 21 22 23 24
48, M 29, F 53, M 31, M 21, M 34, F 29, M 26, M 32, F 26, M 36, M 51, M 24, F 29, M 24,M 40, M 27, M 36, M 48, M 31, F 28, M 27, M 42, M 23, M
hemiparesis, lethargy hemiparesis, seizures hemiparesis hemiparesis hemiparesis, ataxia headache lethargy lethargy, hemiparesis hemiparesis coma hemiparesis, seizures coma lethargy hemiparesis seizures hemiparesis hemiparesis hemiparesis lethargy hemiparesis, seizures hemiparesis seizures hemiparesis coma
* * * * * * * * * * * * * * * * * * * * * * * *
a Daily dosage of trimethoprim plus sulfamethoxazole. bClinica[ and radiological response as defined in Materials and Methods. c From the onset of therapy. dBy detection of intrathecal antibody synthesis (cases no. 1, 2, 5, 7, 9), by isolation of Toxoplasma gondii from CSF (cases no. 4, 8, 9, 10, 24) or by histological examination of brain autopsy specimens (cases no. 5, 11, 13, 14, 22, 23). e According to clinical and CT scan manifestations. f Still alive.
Vo1.11,1992
127
curve (14). The median survival time after initiation of therapy was also calculated, and was defined as the time at which the cumulative probability of survival by product limit analysis was 50 %. Differences were compared by the chi-square test or by Fisher's exact test.
(range 47-526) in the 40 mg/kg group and 120 mg! kg group, respectively (Figure 1) (p > 0.10). T h e cumulative median survival time o f patients from both groups was 172 days. Nine out of 12 patients (75 % ) receiving 40 mg/kg cotrimoxazole and ten out of 12 (77 % ) of those taking 120 mg/kg cotrimoxazole survived for more than 120 days. Responding patients survived significantly longer than non-responders (p < 0.01) (Figure 2).
Results The relevant data of the patients included in the study is summarized in Table 1.
Toxoplasma gondii encephalitis relapsed in four patients (17 %), all of whom reportedly took maintenance treatment with sulphamethopyrazine-pyrimethamine; however, their actual compliance with the prophylactic regimen could not be assessed.
Clinical and radiological responses occurred in nine out of 12 patients treated with 40 mg/kg Cotrimoxazole, as well as in nine out of 12 patients receiving 120 mg/kg. Responding patients were compared with nonresponders for any differences in clinical features (Table 2). The presence of coma on clinical presentation was strongly correlated with a p o o r prognosis (p = 0.0098, Fisher's exact test). Other differences were not statistically significant. However, the poor statistical power of comparisons with such small numbers of patients strongly hampers significant conclusions.
Both dose regimens of cotrimoxazole were generally well tolerated. Skin rashes occurred in three cases, two in the 40 mg/kg group and one in the 120 mg/kg group. In two cases, skin reactions subsided following administration of antihistamines for a few days, whereas in one case cotrimoxazole had to be discontinued after 14 days and was replaced with clindamycin plus pyrimethamine (case no. 2).
The median survival time from the onset of therapy was 169 days (range 22-909) and 177 days
Marrow toxicity occurred in two cases, with
Table 2: Clinical features of responders and non-respondcrs to treatment with cotrimoxazole for Toxoplasmagondiiencephalitis. Responders (n = 18)
Non-responders (n = 6)
P value (two sided)
33 (21-53)
31 (23--42)
ns
13
6
ns
5
0
ns
14 2
5 1
ns ns
2
0
ns
2
0
ns
13
2
ns
Seizures
3
3
ns
Lethargy
5
0
ns
Coma
0
3
0.0098
Zidovudine treatment
4
0
ns
Median age (range) Male Female Risk factor for HIV infection: Intravenous drug abuse Homosexuality Heterosexual intercourse with HIV-infected individuals Prior diagnosis of AIDS Focal deficits
ns = not significant
128
Eur. J. Clin. Microbiol. Infect. Dis.
PERCENT lO0~~~l
~
100
80
80
601
60 40
ii 0 --
~ERCENT
L_
,
I 100
1 i
200
I
I
I
,,,
300 DAYS
~
400
20 i 500
6O0
0 0
i
100
200
300
,
i
400
,,I
500
600
DAYS
Figure 1: Survival of patients treated with cotrimoxazole for Toxoplasma gondii encephalitis in AIDS. Survival was calculated by product limit analysis. Heavy line: patients (n = 12) receiving cotrimoxazole 120 mg/kg qd (20 mg/kg trimethoprim). Thin line: patients (n = I2) receiving cotrimoxazole 40 mg/kg qd (6.6 mg/kg trimethoprim). P value not significant (chi-square test).
Figure 2: Survival of patients treated with cotrimoxazole for ToJcoplasmagondii encephalitis in AIDS. Survival was calculated by product limit analysis. Heavy line: patients (n = 6) not responding to therapy. Thin line: patients (n = 18) responding to therapy. P value < 0.01 (chi-square test).
Table 3: Autopsy findings in 11 patients treated with cotrimoxazole for Toxoplasmagondii encephalitis. Case no. a 5 7 11 9 8 24 13 22 16 14 23
Response
Survival (days)
yes yes no yes yes no yes no yes yes no
175 120 121 135 399 127 247 84 180 155 47
Major autopsy findingsb CNS toxoplasmosis, CMV pneumonia CMV encephalitis CNS toxoplasmosis, visceral leishmaniasis Primary CNS lymphoma CMV pneumonia Primary CNS lymphoma CNS toxoplasmosis CNS toxoplasmosis, Pneumocystiscarinii pneumonia Disseminated tuberculosis CNS toxoplasmosis CNS toxoplasmosis
a Case number as in Table 1. bCMV = Cytomegalovirus.
leukopenia developing after 28 and 21 days of treatment (cases no. I and 11, respectively).
Discussion
The four patients receiving zidovudine concomitantly with cotrimoxazole did not show marrow toxicity during or shortly after the combined treatment,
Experimental data in vitro and in vivo strongly suggest that Toxoplasma gondii encephalitis in AIDS patients results from reactivation of a latent infection, following the severe depletion of CD4+ cells which play a major role in defense against this parasite (15, 16). As a consequence, whereas serology is of great value in diagnosing acute infection (17), it has proven of little help in these patients who frequently have low-titer serum IgG in the absence of IgM antibodies (18). On the contrary, Toxoplasmagondii serology in this setting may have a very high negative predictive value. Thus, diagnosing Toxoplasma gondii encephalitis in patients with AIDS must often rely
Brain autopsy results were available from 11 patients in both treatment groups (Table 3). Histologic features of CNS toxoplasmosis were found in three patients who had responded to therapy and in three patients who had not. Brain autopsies from the remaining five patients (four responders and one non-responder) did not show histologic findings of active or quiescent CNS toxoplasmosis.
Vol. 11, 1992
on brain biopsy or evidence of intrathecal antibody synthesis or, retrospectively, on isolation of the parasite from CSF or upon autopsy results (18). However, as empirically treated AIDS patients with intracraniaI mass lesions have been Shown to have response rates similar to those of patients with biopsy-proven Toxoplasma gondii encephalitis (19), the response to empiric therapy ~s CUrrently being considered a diagnostic criterion by many authors (20). In this paper, it is shown that 18 of 24 (75 %) AIDS patients with proven or probable CNS toxoplasmosis responded both clinically and radiologically (on CT scan examination) to treatment with cotrimoxazole. In this study, response to antitoxoplasmic therapy was not considered a diagnostic criterion; thus, the results were not biased by selection criteria according to the diagnosis. Instead, more than half of the patients had diagnosis of Toxoplasma gondii encephalitis confirmed by isolation of the parasite from the CSE or by evidence of antibody synthesis in the CSF, or at autopsy. The finding that some of the responding patients Showed features of CNS toxoplasmosis at autopsy further supports the notion that Toxoplasma gondii parasites can persist in brain tissue despite adequate therapy (20). More interestingly, two of the four non-responders on whom an autopsy was performed had an associated disease which could have considerably contributed to death, whereas another non-responder who had had Toxoplasma gondii isolated from the CSF was apparently CUred but was found to have a CNS lymphoma (Table 3). After responding to cotrimoxazole treatment, Patients received long-term suppressive treatment with sulfamethopyrazine-pyrimethamine. Moreover, nine responding patients were also given zidovudine after the acute ToxopIasmagondii episode until death. Thus, survival of patients Was determined not only by effective acute-phase treatment of the opportunistic infection, but also by the above-mentioned therapies, whereas the efficacy of cotrimoxazole in long-term maintenance therapy of CNS toxoplasmosis still has to be evaluated. The response rate and survival of patients treated With cotrimoxazole for CNS toxoplasmosis compare well with those published in previous reports showing response rates of 44-89 % and median SUrvival times of 90-294 days following standard SUlfadiazine-pyrimethamine treatment (11, 12, 19, 20). However, a comparison of our data with
129
figures from other reports is very difficult to carry out, due to possible differences in diagnostic criteria as well as stratification of patients according to factors affecting the outcome of Toxoplasma gondii encephalitis, such as prior diagnosis of AIDS, presence of coma or seizures at clinical onset, delay in starting therapy, duration of treatment, etc. Adverse reactions to cotrimoxazole occurred in a small proportion of the study patients (5/24) and required the discontinuation of the drug in one case only, in marked contrast with the high incidence of toxicity with sulfadiazine-pyrimethamine previously reported (11, 19, 20). However, toxicity from cotrimoxazole has also been reported as occurring with high incidence in many series of AIDS patients treated for Pneumocystis carinii pneumonia (21). Whether the discrepancy of our toxicity data is due to population differences, as suggested by previous reports (22, 23), or to other factors, remains to be elucidated. Likewise, toxicity of cotrimoxazote in the long-term maintenance treatment must be investigated. Although a comparative, randomized study involving a large number of patients is necessary to ascertain whether trimethoprim-sulfamethoxazole is as effective as sulfadiazine-pyrimethamine in treating CNS toxoplasmosis of patients with AIDS, we conclude that cotrimoxazole may prove useful in the acute management of this condition in at least some circumstances, i.e. when the intravenous route is preferable to oral administration, or in countries where sulfadiazine and pyrimethamine are not marketed.
Acknowledgement
We would like to thank Dr. P. Bruzzi for advice on statistical methods, and Dr. E. Bicoechi for help in the copy editing. This work was supported by a grant from the Ministero della SanitY, lstituto Superiore di Sanit'~, 111 Research Project on AIDS 1990, Rome, Italy.
References 1. Luft BJ, Conley F~Remington JS, Laverdiere M, Wagner KF, Levine JF, Craven PC, Slamberg DA, File TM, Rice N, Meunier-Carpentier F: Outbreak of central nervous system toxoplasmosis in Western
Europe and North America. Lancet 1983, i: 781-783.
130
2. Grossmao PL, Remington JS: The effect of trimethoprim and sulfamethoxazole on Toxoplasmagondii in vitro and in vivo. American Journal of Tropical Medicine and Hygiene 1979, 28: 445--455. 3. Derouin F, Chaslang C: In vitro effects of folate inhibitors on Toxoplasmagondii. Antimicrobial Agents and Chemotherapy 1989, 33: 1753-1759. 4. Terragna A, Rossolini A, Cellesi C, Figura N, Barbieri A: Activity of the combination trimethoprim-sulfamethoxazole on experimental toxoplasmosis. Arzneimittel-Forsehung (Drug Research) 1973, 23: 1328-1331. 5. Nguyen BT, Sladlsbaeder S: Comparative effects of cotrimoxazole and spiramycin in pregnant mice infected with Toxoplasma gondii (Beverley strain). British Journal of Pharmacology 1985, 85: 713-716. 6. Harper JS, London WT, Sever JL: Five drug regimens for treatment of acute toxoplasmosis in squirrel monkeys. American Journal of Tropical Medicine and Hygiene 1985, 34: 50-57. 7. Domart A, Robineau N, Carbon C: La toxoplasmose acquis6: une nouvelle chimioth6rapie: l'association sulfam6thoxazole-trim6thoprime. Nouvelle Presse M6dieale 1973, 2: 321-322. 8. Norrby R, Eilard T, Svedheim AS, Lycke E: Treatment of toxoplasmosis with trimethoprim-sulfamethoxazole. Scandinavian Journal of Infectious Diseases 1975, 7: 72-75. 9. Nye FJ: Treating toxoplasmosis. Journal of Antimicrobial Chemotherapy 1979, 5: 244-246. 10. Nguyen BT, Stadlsbaeder S: Avenir th6rapeutique du trim6thoprime-sulfam6thoxazole dans [a toxoplasmose. Presse M6dicale 1983, 12: 331-333. 11. Haverkos HW and the Toxoplasma Encephalilis Slndy Group: Assessment of therapy for Toxoplasma encephalitis. American Journal of Medicine 1987, 82: 907-914. 12. Navia BA, Petilo CK, Gold JWM, Cho E-S, Jordan BD, Price RW: Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome. Clinical and neuropathological findings in 27 patients, Annals of Neurology 1986, 19: 224-238. 13. Potasman I, Resnick L, Lull BJ, Remington JS: Intrathecal production of antibodies against Toxoptasma gondii in patients with toxoplasmic encephalitis and the acquired immunodeficiency syndrome. Annals of Internal Medicine 1988, 108: 49-51.
Eur. J. Clin. Microbiol. Infect. Dis.
14. Lee ET: Statistical methods for survival data analysis. Lifetime Learning Publication, Belmont, California 1980. 15. Vollmer TL, Waldor MK, Steinman L, Conley FK: Depletion of T4+ lymphoeytes with monoelonal antibody reactivates toxoplasmosis in the central nervous system: a model of superinfeetion in AIDS. Journal of Immunology 1987, 138: 3737-3741. 16. Canessa A, Pisloia V, Roncella S, Merli A, Melioli G, Terragna A, Ferrarini M: An in vitro model for Toxoplasma infection in man. Interaction between CD4+ monoclonat T cells and macrophages results in killing of trophozoitcs. Journal of Immunology 1988, 140: 3580-3588. 17. Del Bono V, Canessa A, Bruzzi P, Fiorelli MA, Terragna A: Significance of specific immunoglobulin M in the chronological diagnosis of 38 cases of toxoplasmic lymphadenopathy. Journal of Clinical Microbiology 1989, 27: 2133-2135. 18. Luft BJ, Reminglon JS: Toxoplasmic encephalitis. Journal of Infectious Diseases 1988, 157: 1-6. 19. Cohn JA, MeMeeking A, Cohen W, Jacobs J, Holzman RS: Evaluation of the policy of empiric treatment of suspected Toxoplasmaencephalitis in patients with the Acquired lmmunodeficiency Syndrome. American Journal of Medicine 1989, 86: 521-527. 20. Lepnrt C, Raffi F, Matheron S, Katlama C, Regnier B, Saimot GA, Marehe C, Vedrenne C, Vilde JL: Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodefieiency syndrome. Efficacy of long-term continuous therapy. American Journal of Medicine 1988, 84: 94-100. 21. Gordin FM, Simon GL, Wosfy CB: Adverse reactions to trimethoprim sulfamethoxazole in acquired immunodeficiency syndrome. Annals of Internal Medicine 1984, 100: 495-499. 22. De Hovitz JA, Johnson WD, Pape W J: Cutaneous reactions to trimethoprim-sul lamer hoxazole in Haitians. Annals of Internal Medicine 1985, 103: 479480. 23. Pape W J, Vardier RI, Johnson WD: Treatment and prophylaxis of tsospora belli infection in patients with the acquired immunodeficieney syndrome. New England Journal of Medicine 1989, 320: 1044-1047.
Article
125
Eur. j. Clin. Microbiol. Infect. Dis., February 1992, p. 125-130 0934-9723/92/02 0125-06 $3.00/0
Cotrimoxazole Therapy of Toxoplasma gondii Encephalitis in AIDS Patients A. C a n e s s a l , , V. D e l B o n o 1, R D e L e o 1, N. Piersantelli 2, A. T e r r a g n a I t
Twenty.four consecutive HIV-positive patients affected by Toxoplasma gondii encephalitis received trimethoprim-sulfamethoxazole (cotrimoxazole) as acute-phase treatment. Two dosage regimens of cotrimoxazole were used: 40 mg/kg/day (12 patients) or 120 mg/kg/day (12 patients) of total compound (trimethoprim plus suifamethoxazole). Clinical and radiologicai responses to treatment were evaluated, and the product-limit method for survival data analysis was used. Eighteen of 24 patients showed both a clinical and radiological response (75 % response rate). There were no differences in response rates between patients receiving the two dosage regimens of cotrimoxazole. Adverse reaction consisted of leukopenia (two cases) and skin rash (three cases) which led to the discontinuation of the drug in one case. These results suggest that a randomized, controlled clinical trial should be carried out comparing cotrimoxazole versus sulfadiazine-pyrimethamine in AIDS patients with Toxoplasma gondii encephalitis.
The drug combination of sulfadiazine plus pyrimethamine is considered the therapy of choice in central nervous system (CNS) toxoplasmosis in AIDS patients since the first reports of it in the literature (1). However, as neither sulfadiazine nor pyrimethamine are marketed in Italy, therapeutic alternatives are urgently needed in this COUntry for the treatment of this potentially lethal OpPortunistic infection. A number of reports have shown the activity of trimethoprim plus sulfamethoxazole against Toxoplasma gondii both in vitro, at concentrations easily attainable in man after administration of conventional doses (2, 3), and in vivo, in exPerimental infection of mice (2, 4, 5) and nonhuman primates (6). Howe,~er, the animal studies are difficult to interpret because the pharmacokinetics of trimethoprim vary considerably across species (2); therefore, the issue of the ac!ivity of cotrimoxazole against Toxoplasraa gondii ~s still unsettled. Nonetheless, on the basis of experimental evidence as well as of clinical studies (7, 8), some authors in Europe have suggested the Use of cotrimoxazole in human toxoplasmosis,
Department of Infectious Diseases, University of Genoa, Viale 2D . Benedetto . . . XV 10 16132 Genoa, Ital y. wmslonof Infectious Diseases, Galliera Hospital, Genoa, Italy. tDeceased.
particularly in the treatment of CNS infection (9, 10). These facts and the promising results obtained with cotrimoxazole in individual cases of CNS toxoplasmosis (11) prompted us to use this drug in the acute-phase treatment of Toxoplasma gondii encephalitis in A I D S patients. In this paper, we report the results of cotrimoxazole treatment of CNS toxoplasmosis in 24 consecutive cases.
Patients and Methods
Study Patients and Admission Criteria. HIV-infected patients with clinical, neuro|ogicat and computed tomographie (CT) scan manifestations consistent with a first episode of CNS toxoplasmosis (1, 12) were consecutively treated from September 1985 to September 1989. Patients who had had a brain biopsy or autopsy performed within 30 days after the onset of therapy with no histologic evidence of Toxoplasma gondii encephalitis were not evaluated. Twenty-four patients were thus evaluable.
Definitive Diagnosis. Toxoplasma gondii antibodies in serum and cerebrospinal fluid (CSF) were measured by dye test and immunofluorescence IgG and IgM antibody assay, with determination of intrathecal antibody synthesis in comparison with total immunoglobulin concentration (13), Multiple sections from brain autopsy specimens were stained by Giemsa method, hematoxytineosin and periodic acid Sehiff stains. Proven diagnosis
126
Eur. J. Clin. Microbiol. Infect. Dis.
of Toxoplasma gondii encephalitis was available in 14 patients through demonstration of intrathecal antibody synthesis, the isolation of Toxoplasma gondii in mice inoculated with C S E or through histologie examination of brain autopsy specimens.
Weekly monitoring of toxic effects included complete blood counts, serum electrolytes, glucose, creatinine, blood urea nitrogen, bilirubin and liver enzymes. Leukopenia was defined by a W B C count of less than 2,O00/cu mm, neutropenia by a PMN leukocyte count of less than 1,000/cu mm.
Drug Dosages and Admin&tration. Informed consent from patients or their nearest relatives was obtained. Two dosage regimens of cotrimoxazole were used. Patients recruited at the University Department of Infectious Diseases were given cotrimoxazole at the total daily dose of 40 mg/kg (6.6 mg/kg trimethoprim plus 33.3 mg/kg sulfamethoxazole); patients recruited at the Division of Infectious Diseases, Galliera Hospital, were given cotrimoxazole 120 mg/kg daily (20 mg/kg trimethoprim). Cotrimoxazole was administered orally, unless a comatose or lethargic status was present, in which case it was given intravenously. Therapy had a mean duration of 25 days (range 14-28 days). Folinie acid was also administered, 15 mg once a day. After a full-course therapy, 500 mg sulphamethopyrazine plus 25 mg pyrimethamine (the only pyrimethamine-containing drug formulation available in Italy) twice weekly were prescribed as maintenance treatment. Four patients received zidovudine concomitantly with cotrimoxazole (one in the 40 mg/kg group and three in the 120 mg/kg group); five additional patients were given zidovudine after completion of the full-course treatment until death. Table 1:
Case no.
Efficacy Criteria. Efficacy of therapy was evaluated according to clinical and radiological criteria. Clinical response was defined as the complete disappearance of clinical and neurological signs: fever, altered mental status and focal neurologic signs. Radiologieal response was defined as the disappearance or significant reduction (more than 50 % decrease in number and/or size) of focal lesions on subsequent CT scans compared with the initial ones. Comparative CT scan evaluations were performed by independent radiologists who were unaware of the suspected diagnosis and therapy. Responding patients were thus defined as those who showed both a clinical and a radiological response. Non-responders were patients with either unchanged or worsened clinical or radiological manifestations. Relapse of Toxoplasma gondii encephalitis was defined as the reappearance of neurological signs along with C T scan evidence of new lesions. Statistical Methods. Survival of patients since the onset of therapy was computed by the Kaplan-Meier survival
C~inical~urseandsurviva~fpatientswithT~x~p~asmag~ndiien~epha~itis(TE)treat~dwithc~trim~xaz~e. Age, sex
Clinicalpresentation
T E diagnosis
Dosage a (mg/kg qd)
Response b
Survivalc (days)
Relapse
40 40 40 40 40 40 40 40 40 40 40 40 120 120 120 120 120 120 120 120 120 120 120 120
yes yes yes yes yes yes yes yes yes no no no yes yes yes yes yes yes yes yes yes no no no
270 f 133 f 354 909 175 169 120 399 135 34 121 22 247 155 510 f 180 121 177 ~ 205 526 f 180 84 47 127
no no yes no no yes no no no no no no yes no no no no yes -
Proven d Probable e 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 t8 19 20 21 22 23 24
48, M 29, F 53, M 31, M 21, M 34, F 29, M 26, M 32, F 26, M 36, M 51, M 24, F 29, M 24,M 40, M 27, M 36, M 48, M 31, F 28, M 27, M 42, M 23, M
hemiparesis, lethargy hemiparesis, seizures hemiparesis hemiparesis hemiparesis, ataxia headache lethargy lethargy, hemiparesis hemiparesis coma hemiparesis, seizures coma lethargy hemiparesis seizures hemiparesis hemiparesis hemiparesis lethargy hemiparesis, seizures hemiparesis seizures hemiparesis coma
* * * * * * * * * * * * * * * * * * * * * * * *
a Daily dosage of trimethoprim plus sulfamethoxazole. bClinica[ and radiological response as defined in Materials and Methods. c From the onset of therapy. dBy detection of intrathecal antibody synthesis (cases no. 1, 2, 5, 7, 9), by isolation of Toxoplasma gondii from CSF (cases no. 4, 8, 9, 10, 24) or by histological examination of brain autopsy specimens (cases no. 5, 11, 13, 14, 22, 23). e According to clinical and CT scan manifestations. f Still alive.
Vo1.11,1992
127
curve (14). The median survival time after initiation of therapy was also calculated, and was defined as the time at which the cumulative probability of survival by product limit analysis was 50 %. Differences were compared by the chi-square test or by Fisher's exact test.
(range 47-526) in the 40 mg/kg group and 120 mg! kg group, respectively (Figure 1) (p > 0.10). T h e cumulative median survival time o f patients from both groups was 172 days. Nine out of 12 patients (75 % ) receiving 40 mg/kg cotrimoxazole and ten out of 12 (77 % ) of those taking 120 mg/kg cotrimoxazole survived for more than 120 days. Responding patients survived significantly longer than non-responders (p < 0.01) (Figure 2).
Results The relevant data of the patients included in the study is summarized in Table 1.
Toxoplasma gondii encephalitis relapsed in four patients (17 %), all of whom reportedly took maintenance treatment with sulphamethopyrazine-pyrimethamine; however, their actual compliance with the prophylactic regimen could not be assessed.
Clinical and radiological responses occurred in nine out of 12 patients treated with 40 mg/kg Cotrimoxazole, as well as in nine out of 12 patients receiving 120 mg/kg. Responding patients were compared with nonresponders for any differences in clinical features (Table 2). The presence of coma on clinical presentation was strongly correlated with a p o o r prognosis (p = 0.0098, Fisher's exact test). Other differences were not statistically significant. However, the poor statistical power of comparisons with such small numbers of patients strongly hampers significant conclusions.
Both dose regimens of cotrimoxazole were generally well tolerated. Skin rashes occurred in three cases, two in the 40 mg/kg group and one in the 120 mg/kg group. In two cases, skin reactions subsided following administration of antihistamines for a few days, whereas in one case cotrimoxazole had to be discontinued after 14 days and was replaced with clindamycin plus pyrimethamine (case no. 2).
The median survival time from the onset of therapy was 169 days (range 22-909) and 177 days
Marrow toxicity occurred in two cases, with
Table 2: Clinical features of responders and non-respondcrs to treatment with cotrimoxazole for Toxoplasmagondiiencephalitis. Responders (n = 18)
Non-responders (n = 6)
P value (two sided)
33 (21-53)
31 (23--42)
ns
13
6
ns
5
0
ns
14 2
5 1
ns ns
2
0
ns
2
0
ns
13
2
ns
Seizures
3
3
ns
Lethargy
5
0
ns
Coma
0
3
0.0098
Zidovudine treatment
4
0
ns
Median age (range) Male Female Risk factor for HIV infection: Intravenous drug abuse Homosexuality Heterosexual intercourse with HIV-infected individuals Prior diagnosis of AIDS Focal deficits
ns = not significant
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Eur. J. Clin. Microbiol. Infect. Dis.
PERCENT lO0~~~l
~
100
80
80
601
60 40
ii 0 --
~ERCENT
L_
,
I 100
1 i
200
I
I
I
,,,
300 DAYS
~
400
20 i 500
6O0
0 0
i
100
200
300
,
i
400
,,I
500
600
DAYS
Figure 1: Survival of patients treated with cotrimoxazole for Toxoplasma gondii encephalitis in AIDS. Survival was calculated by product limit analysis. Heavy line: patients (n = 12) receiving cotrimoxazole 120 mg/kg qd (20 mg/kg trimethoprim). Thin line: patients (n = I2) receiving cotrimoxazole 40 mg/kg qd (6.6 mg/kg trimethoprim). P value not significant (chi-square test).
Figure 2: Survival of patients treated with cotrimoxazole for ToJcoplasmagondii encephalitis in AIDS. Survival was calculated by product limit analysis. Heavy line: patients (n = 6) not responding to therapy. Thin line: patients (n = 18) responding to therapy. P value < 0.01 (chi-square test).
Table 3: Autopsy findings in 11 patients treated with cotrimoxazole for Toxoplasmagondii encephalitis. Case no. a 5 7 11 9 8 24 13 22 16 14 23
Response
Survival (days)
yes yes no yes yes no yes no yes yes no
175 120 121 135 399 127 247 84 180 155 47
Major autopsy findingsb CNS toxoplasmosis, CMV pneumonia CMV encephalitis CNS toxoplasmosis, visceral leishmaniasis Primary CNS lymphoma CMV pneumonia Primary CNS lymphoma CNS toxoplasmosis CNS toxoplasmosis, Pneumocystiscarinii pneumonia Disseminated tuberculosis CNS toxoplasmosis CNS toxoplasmosis
a Case number as in Table 1. bCMV = Cytomegalovirus.
leukopenia developing after 28 and 21 days of treatment (cases no. I and 11, respectively).
Discussion
The four patients receiving zidovudine concomitantly with cotrimoxazole did not show marrow toxicity during or shortly after the combined treatment,
Experimental data in vitro and in vivo strongly suggest that Toxoplasma gondii encephalitis in AIDS patients results from reactivation of a latent infection, following the severe depletion of CD4+ cells which play a major role in defense against this parasite (15, 16). As a consequence, whereas serology is of great value in diagnosing acute infection (17), it has proven of little help in these patients who frequently have low-titer serum IgG in the absence of IgM antibodies (18). On the contrary, Toxoplasmagondii serology in this setting may have a very high negative predictive value. Thus, diagnosing Toxoplasma gondii encephalitis in patients with AIDS must often rely
Brain autopsy results were available from 11 patients in both treatment groups (Table 3). Histologic features of CNS toxoplasmosis were found in three patients who had responded to therapy and in three patients who had not. Brain autopsies from the remaining five patients (four responders and one non-responder) did not show histologic findings of active or quiescent CNS toxoplasmosis.
Vol. 11, 1992
on brain biopsy or evidence of intrathecal antibody synthesis or, retrospectively, on isolation of the parasite from CSF or upon autopsy results (18). However, as empirically treated AIDS patients with intracraniaI mass lesions have been Shown to have response rates similar to those of patients with biopsy-proven Toxoplasma gondii encephalitis (19), the response to empiric therapy ~s CUrrently being considered a diagnostic criterion by many authors (20). In this paper, it is shown that 18 of 24 (75 %) AIDS patients with proven or probable CNS toxoplasmosis responded both clinically and radiologically (on CT scan examination) to treatment with cotrimoxazole. In this study, response to antitoxoplasmic therapy was not considered a diagnostic criterion; thus, the results were not biased by selection criteria according to the diagnosis. Instead, more than half of the patients had diagnosis of Toxoplasma gondii encephalitis confirmed by isolation of the parasite from the CSE or by evidence of antibody synthesis in the CSF, or at autopsy. The finding that some of the responding patients Showed features of CNS toxoplasmosis at autopsy further supports the notion that Toxoplasma gondii parasites can persist in brain tissue despite adequate therapy (20). More interestingly, two of the four non-responders on whom an autopsy was performed had an associated disease which could have considerably contributed to death, whereas another non-responder who had had Toxoplasma gondii isolated from the CSF was apparently CUred but was found to have a CNS lymphoma (Table 3). After responding to cotrimoxazole treatment, Patients received long-term suppressive treatment with sulfamethopyrazine-pyrimethamine. Moreover, nine responding patients were also given zidovudine after the acute ToxopIasmagondii episode until death. Thus, survival of patients Was determined not only by effective acute-phase treatment of the opportunistic infection, but also by the above-mentioned therapies, whereas the efficacy of cotrimoxazole in long-term maintenance therapy of CNS toxoplasmosis still has to be evaluated. The response rate and survival of patients treated With cotrimoxazole for CNS toxoplasmosis compare well with those published in previous reports showing response rates of 44-89 % and median SUrvival times of 90-294 days following standard SUlfadiazine-pyrimethamine treatment (11, 12, 19, 20). However, a comparison of our data with
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figures from other reports is very difficult to carry out, due to possible differences in diagnostic criteria as well as stratification of patients according to factors affecting the outcome of Toxoplasma gondii encephalitis, such as prior diagnosis of AIDS, presence of coma or seizures at clinical onset, delay in starting therapy, duration of treatment, etc. Adverse reactions to cotrimoxazole occurred in a small proportion of the study patients (5/24) and required the discontinuation of the drug in one case only, in marked contrast with the high incidence of toxicity with sulfadiazine-pyrimethamine previously reported (11, 19, 20). However, toxicity from cotrimoxazole has also been reported as occurring with high incidence in many series of AIDS patients treated for Pneumocystis carinii pneumonia (21). Whether the discrepancy of our toxicity data is due to population differences, as suggested by previous reports (22, 23), or to other factors, remains to be elucidated. Likewise, toxicity of cotrimoxazote in the long-term maintenance treatment must be investigated. Although a comparative, randomized study involving a large number of patients is necessary to ascertain whether trimethoprim-sulfamethoxazole is as effective as sulfadiazine-pyrimethamine in treating CNS toxoplasmosis of patients with AIDS, we conclude that cotrimoxazole may prove useful in the acute management of this condition in at least some circumstances, i.e. when the intravenous route is preferable to oral administration, or in countries where sulfadiazine and pyrimethamine are not marketed.
Acknowledgement
We would like to thank Dr. P. Bruzzi for advice on statistical methods, and Dr. E. Bicoechi for help in the copy editing. This work was supported by a grant from the Ministero della SanitY, lstituto Superiore di Sanit'~, 111 Research Project on AIDS 1990, Rome, Italy.
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Europe and North America. Lancet 1983, i: 781-783.
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