levoleucovorin and Toxoplasmosis--Cerebral

Toxoplasmic encephalitis (TE) is the second most common AIDS-related opportunistic infection of the CNS. It occurs in 10%-50% of patients with AIDS who are seropositive for antibodies to Toxoplasma gondii and have CD4+ T lymphocyte counts of < 100/mm3. Primary toxoplasmic infection usually is acquired by ingestion of T. gondii oocysts from soil contaminated by cat feces or by ingestion of tissue cysts present in undercooked red meats. In patients with AIDS, TE probably results from the reactivation of Toxoplasma tissue cysts that remained latent after the primary infection. Detection of IgG antibodies to Toxoplasma indicates prior infection and the possible presence of tissue cysts and, thus, risk for developing TE. A regimen of trimethoprim-sulfamethoxazole or dapsone plus pyrimethamine with leucovorin is recommended for persons infected with the human immunodeficiency virus (HIV) and who are seropositive for IgG to Toxoplasma after their CD4+ T lymphocyte counts fall to < 100/mm3. HIV-infected persons who are seronegative for IgG to Toxoplasma should be counseled to protect themselves from primary toxoplasmic infection by eating only well-cooked meats and washing their hands after outdoor activities involving soil contact; if they have a cat, they should feed it only commercial or well-cooked foods, keep it indoors, and make sure that the litter box is changed daily. HIV-infected persons who are Toxoplasma seropositive may also be advised about these preventive behavioral practices.

Topics: AIDS-Related Opportunistic Infections; Animals; Anti-Infective Agents; Cats; Dapsone; Drug Therapy, Combination; Encephalitis; Humans; Incidence; Leucovorin; Pyrimethamine; Recurrence; Risk Factors; Toxoplasmosis, Animal; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination; United States

The scientific basis for using folinic acid in combination with the antiparasitic drugs prescribed to AIDS patients has been reviewed. In vitro and experimental data are unclear. On the basis of folinic acid metabolism and pharmacology and of clinical experience, we suggest that folinic acid should not be systematically added to the curative treatment of pneumocystosis with cotrimoxazole. Folinic acid may be added to prophylactic regimens using high-dose cotrimoxazole (i.e. 800 mg sulfamethoxazole twice a day) and in malnourished patients. It should be administered as soon as cytopenia occurs in the course of treatment. Concerning toxoplasmosis, the addition of folinic acid is recommended in doses of 10 to 20 mg/day in acute therapy and 5 to 10 mg/day in maintenance therapy. Dosage must be adjusted to the results of blood counts.

Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; Folic Acid; Hematologic Diseases; Humans; Leucovorin; Opportunistic Infections; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadiazine; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination

An increased frequency of toxoplasma encephalitis, caused by Toxoplasma gondii, has been reported in AIDS patients, especially in those with CD4+ T cell counts <100 cells/μL. Several guidelines recommend the combination of pyrimethamine, sulfadiazine, and leucovorin as the preferred regimen for AIDS-associated toxoplasma encephalitis. However, it is not commonly used in China due to limited access to pyrimethamine and sulfadiazine. The synergistic sulfonamides tablet formulation is a combination of trimethoprim (TMP), sulfadiazine and sulfamethoxazole (SMX), and is readily available in China. Considering its constituent components, we hypothesize that this drug may be used as a substitute for sulfadiazine and TMP-SMX. We have therefore designed the present trial, and propose to investigate the efficacy and safety of synergistic sulfonamides combined with clindamycin for the treatment of toxoplasma encephalitis.. This study will be an open-labeled, multi-center, prospective, randomized, and controlled trial. A total of 200 patients will be randomized into TMP-SMX plus azithromycin group, and synergistic sulfonamides plus clindamycin group at a ratio of 1:1. All participants will be invited to participate in a 48-week follow-up schedule once enrolled. The primary outcomes will be clinical response rate and all-cause mortality at 12 weeks. The secondary outcomes will be clinical response rate and all-cause mortality at 48 weeks, and adverse events at each visit during the follow-up period.. We hope that the results of this study will be able to provide reliable evidence for the efficacy and safety of synergistic sulfonamides for its use in AIDS patients with toxoplasma encephalitis.. This study was registered as one of 12 clinical trials under the name of a general project at chictr.gov on February 1, 2019, and the registration number of the general project is ChiCTR1900021195. This study is still recruiting now, and the first patient was screened on March 22, 2019.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antiprotozoal Agents; China; Clindamycin; Drug Therapy, Combination; Female; HIV Infections; Humans; Leucovorin; Male; Prospective Studies; Pyrimethamine; Sulfadiazine; Sulfamethoxazole; Sulfonamides; T-Lymphocytopenia, Idiopathic CD4-Positive; Toxoplasma; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination; Vitamin B Complex

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Animals; Anti-Infective Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; Humans; Leucovorin; Male; Middle Aged; Pneumocystis; Pneumonia, Pneumocystis; Pyrimethamine; Sulfadoxine; Toxoplasma; Toxoplasmosis, Cerebral

Pyrimethamine (50 mg) with folinic acid (15 mg) given three times weekly was assessed as primary prophylaxis for toxoplasmic encephalitis (TE) in 554 human immunodeficiency virus-infected patients seropositive for Toxoplasma gondii and with < 200 CD4 cells/mm3. At 1 year, the incidence of TE was similar in pyrimethamine, 12%, and placebo, 13%, groups (relative risk [RR], 0.9; 95% confidence interval [CI], 0.6-1.4), and the survival rate was also similar, 85% and 80%, respectively (RR, 0.9; 95% CI, 0.7-1.2). Rash was the only adverse event that appeared significantly more frequently in the pyrimethamine arm (7% vs. 1%). In the on-treatment analysis, the incidence of TE was lower in the pyrimethamine arm, 4%, than in the placebo arm, 12% (P < .006). Thus, pyrimethamine cannot be recommended as a first-line regimen for primary prophylaxis of TE if the patient can take cotrimoxazole. However, it should be considered for patients who are intolerant to cotrimoxazole, especially in high-risk patients with < 100 CD4 cells/mm3.

Topics: Adult; AIDS-Related Opportunistic Infections; Animals; Anti-Infective Agents; Antibodies, Protozoan; Double-Blind Method; Drug Therapy, Combination; Encephalitis; Female; Follow-Up Studies; Humans; Leucovorin; Male; Multivariate Analysis; Pyrimethamine; Survival Rate; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Cerebral

Cerebral toxoplasmosis is the most frequent opportunistic infection in patients with acquired immune deficiency syndrome in France. We evaluated the effect of adding folic acid to the standard treatment (including pyrimethamine) on preventing induced cytopenia in order to determine the optimal dose.. From January to September 1990, pyrimethamine (50 mg 3 times per week) was given as primary prophylaxis against toxoplasmosis to 30 patients who were positive for human immunodeficiency virus (CDC classes II or II, CD4 counts < 200/mm3). The patients were randomly divided into three groups given 5, 25 and 0 mg folic acid 3 times per week. Associated treatments were the same in all patients (zidovudine 600 mg/d, pentamidine isethionate aerosol, 300 mg, once a month). Blood cell counts and lymphocyte subset counts were made on days 0, 30, 90 and 180.. Two patients were lost to follow-up and between day 90 and 180, 3 were excluded due to other opportunist infection and 1 due to zidovudine induced anaemia. Between the groups, there was no difference in haemoglobin level or cell counts on day 0. No haematologic toxicity was observed at day 90. Haemoglobin was significantly reduced in the control group (0 mg folic acid) on day 180 (mean haemoglobin on day 180, 13.8, 13.1 and 12.1 g/dl in groups 1, 2 and 3 respectively). No variation in polynuclear neutrophil counts was observed.. These findings suggest that folic acid has a moderate beneficial effect on preventing haematologic disease in patients treated with pyrimethamine. There was no observed dose effect.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Blood Cell Count; Hemoglobin A; Humans; Leucovorin; Prospective Studies; Pyrimethamine; Thrombocytopenia; Toxoplasmosis, Cerebral

Between December 1981 and May 1991, 44 infants and children with congenital toxoplasmosis were referred to our study group. A uniform approach to evaluation and therapy was developed and is described herein along with the clinical characteristics of these infants and children. In addition, case histories that illustrate especially important clinical features or previously undescribed findings are presented. Factors that contributed to the more severe disabilities included delayed diagnosis and initiation of therapy; prolonged, concomitant neonatal hypoxia and hypoglycemia; profound visual impairment; and prolonged, uncorrected increased intracranial pressure with hydrocephalus and compression of the brain. Years after therapy was discontinued, three children developed new retinal lesions (without loss of visual acuity when therapy for Toxoplasma gondii was initiated promptly), and three children experienced a new onset of afebrile seizures. Most remarkable were the normal developmental, neurological, and ophthalmologic findings at the early follow-up evaluations of many--but not all--of the treated children despite severe manifestations, such as substantial systemic disease, hydrocephalus, microcephalus, multiple intracranial calcifications, and extensive macular destruction detected at birth. These favorable outcomes contrast markedly with outcomes reported previously for children with congenital toxoplasmosis who were untreated or treated for only 1 month.

Topics: Animals; Calcinosis; Chemistry, Pharmaceutical; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Feasibility Studies; Humans; Infant; Leucovorin; Magnetic Resonance Imaging; Neutropenia; Physical Examination; Pilot Projects; Prenatal Care; Pyrimethamine; Spiramycin; Sulfadiazine; Tomography, X-Ray Computed; Toxoplasma; Toxoplasmosis, Cerebral; Toxoplasmosis, Congenital; Toxoplasmosis, Ocular; Treatment Outcome

Toxoplasmosis is an important cause of enhancing brain lesions in patients with acquired immunodeficiency syndrome (AIDS), and it is typically associated with low CD4-lymphocyte counts. Extensive toxoplasma encephalitis when the CD4-lymphocyte count is above 100 cells/µl is unusual. Cavitary lung lesions are also not typically associated with toxoplasmosis. Here, we present a case of toxoplasmosis associated with extensive brain masses and cavitary lung lesions, both of which improved with directed toxoplasmosis therapy, in an AIDS patient with a CD4 cell count of 120 cells/µl.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antibodies, Protozoan; Antiprotozoal Agents; Brain; CD4 Lymphocyte Count; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Heterocyclic Compounds, 3-Ring; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Oxazines; Piperazines; Polymerase Chain Reaction; Pyridones; Toxoplasma; Toxoplasmosis, Cerebral; Treatment Outcome

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiprotozoal Agents; Antiretroviral Therapy, Highly Active; Cerebral Hemorrhage; Headache; Hemianopsia; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Paresis; Pyrimethamine; Sulfadiazine; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

The clinical management of perinatal toxoplasmosis involves a gynaecologist during pregnancy and a neonatologist after delivery. Then, in the absence of a uniform approach, early evaluation of infected infants requires a thorough long-term follow-up also in asymptomatic children, who have to be observed for at least one year due to unpredictable sequelae in later life. We retrospectively analyzed pregnancy management of 54 women with certain infection from Toxoplasma gondii (TG) and prospectively enrolled their infants to compare prenatal management with postnatal clinical outcome. All mothers with seroconversion for TG infection were from the Palermo area and were retrospectively analyzed, whereas their newborns referred to G. Di Cristina Children Clinical Hospital between 1999-2004 were prospectively enrolled in a 48-month follow-up. Timing of infection was dated for 24 women (45%) to the first trimester, 18 (33%) to the second and 12 (22%) the third. The maternal-fetal transmission rate was 17.2%. Prenatal diagnosis from amniotic fluid was performed in 25/54 pregnant subjects and showed positive results in 6. Despite diagnosis of TG infection, 9 women were untreated and only 2 with positive amniocentesis received combined therapy. 10/55 enrolled infants were infected and half of them were preterm and/or SGA at birth. None showed peculiar signs of TG at birth but 4 had abnormalities during the follow-up. 9/10 infected children were born to mothers who had undergone neither amniocentesis nor combined therapy.. Our work confirms the difficulty of applying standardized therapeutic protocol for TG infection during pregnancy. The asymptomatic course of TG infection at birth confirms the importance of an instrumental long-term follow-up to identify typical TG lesion to prevent sequelae.

Topics: Adolescent; Adult; Amniocentesis; Animals; Antibodies, Protozoan; Antiprotozoal Agents; Chorioretinitis; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydrocephalus; Immunoglobulin G; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Small for Gestational Age; Infectious Disease Transmission, Vertical; Italy; Leucovorin; Male; Prednisone; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pregnancy Trimesters; Prenatal Care; Prospective Studies; Pyrimethamine; Retrospective Studies; Spiramycin; Sulfadiazine; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Cerebral; Toxoplasmosis, Congenital; Toxoplasmosis, Ocular

The penetration of 3'-amino-3'-deoxythymidine (AMT) into the cerebrospinal fluid (CSF) of HIV-1-infected patients has been investigated. In 23 patients who used zidovudine (ZDV) chronically, CSF and plasma samples were assayed for AMT and ZDV. The influences of time between ZDV oral administration and lumbar puncture, of ZDV dose, and of the medical indication for lumbar puncture based on the concentration of AMT in CSF and on the CSF-plasma concentration ratio were investigated. AMT can be detected in the CSF after oral administration of ZDV; concentrations of AMT in CSF ranged from 0.75 to 4.8 ng/ml (median, 1.7 ng/ml). The median CSF-plasma concentration ratio was 1, and equaled that for ZDV. CSF and plasma concentrations of AMT were approximately threefold higher in patients with cerebral toxoplasmosis; the CSF-plasma concentration ratio remained equal to unity in these cases. This phenomenon might be caused by a pharmacokinetic interaction between AMT and pyrimethamine, sulfadiazine, folinic acid, or a combination of these. The clinical relevance of AMT, especially the possibility of decreased efficacy of ZDV, throughout the body and in the central nervous system, and the involvement of this metabolite in ZDV-induced myelosuppression, remains to be established.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Anti-Infective Agents; Antidotes; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Leucovorin; Male; Middle Aged; Pyrimethamine; Spinal Puncture; Sulfadiazine; Time Factors; Toxoplasmosis, Cerebral; Zidovudine

Topics: Antiprotozoal Agents; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Encephalitis; Humans; Leucovorin; Pyrimethamine; Retrospective Studies; Sulfadiazine; Toxoplasmosis, Cerebral; Treatment Outcome

To determine the natural history of intracranial calcifications in infants with treated congenital toxoplasmosis.. Between January 1982 and March 1994, cranial computed tomography was performed in 56 infants with treated congenital toxoplasmosis when they were newborns and approximately 1 year old. Locations and sizes of intracranial calcifications were noted.. Forty newborns had intracranial calcifications. By 1 year of age, calcifications diminished or resolved in 30 (75%) and remained stable in 10 (25%) of these treated infants. Ten (33%) of the 30 infants whose calcifications diminished versus seven (70%) of the 10 infants with stable calcifications received less intensive antimicrobial treatment than the other treated infants. In contrast, a small number of infants who were untreated or treated 1 month or less had intracranial calcifications that increased or remained stable during their 1st year of life.. Diminution or resolution of intracranial calcifications was an unexpected and remarkable finding in infants with treated, congenital toxoplasmosis, consonant with their improved neurologic functioning.

Topics: Anti-Infective Agents; Brain; Calcinosis; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leucovorin; Pyrimethamine; Sulfadiazine; Time Factors; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral; Toxoplasmosis, Congenital

Life-threatening conditions requiring urgent medical treatment rarely present to the ophthalmologist. This case report describes a patient with precipitious visual loss as the primary complaint and which subsequently led to the diagnosis of Toxoplasmic papillitis and life-threatening cerebral involvement as an initial manifestation of AIDS.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Drug Therapy, Combination; Humans; Leucovorin; Male; Optic Disk; Optic Neuritis; Pyrimethamine; Sulfadiazine; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral; Toxoplasmosis, Ocular; Vision Disorders

Topics: Adult; AIDS-Related Opportunistic Infections; Drug Therapy, Combination; Female; Humans; Kidney Calculi; Leucovorin; Male; Pyrimethamine; Sulfadiazine; Toxoplasmosis, Cerebral

A presumptive diagnosis of toxoplasmic encephalitis was made in 73 of the 428 AIDS patients followed in the Bordeaux Regional Hospital between 1985 and 1990. The sex ratio (M:F) was 2.8:1. The mean age was 36.2 years. Forty-three percent were homosexuals, 30 percent intravenous drug abusers. The encephalitis revealed the HIV infection in 10 percent of the cases; it was the first opportunistic infection in 27 percent. The clinical manifestations were: focal neurologic deficit (62 percent), fever (58 percent), headaches (47 percent), altered consciousness (45 percent), seizures (18 percent). The CT scan findings were focal lesions with (60 percent) or without (40 percent) ring enhancement. Oedema was present in 58 percent of the lesions, and multiple lesions in 59 percent. At the time of diagnosis, the mean CD4 lymphocyte count was 72 per mm3. The initial therapeutic regimens were: pyrimethamine (P) plus sulfadiazine (n = 57), P plus clindamycin (n = 11) and P plus clarithromycin (n = 5). Following acute therapy the patients had a complete (64 percent) or partial (18 percent) response, and 18 percent died. Adverse reactions were noticed in 53 percent. Sixty patients received a maintenance therapy; after a mean follow-up of 8 months, 12 relapsed and died of toxoplasmic encephalitis; 17 died of another cause. The median survival after toxoplasmosis was diagnosed was 7.5 months.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Clarithromycin; Clindamycin; Drug Therapy, Combination; Female; France; Humans; Leucovorin; Male; Middle Aged; Pyrimethamine; Recurrence; Retrospective Studies; Sulfadiazine; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

The clinical efficacy of trimetrexate, a dihydrofolate reductase inhibitor with potent in vitro antitoxoplasma activity, was assessed in 9 sulfonamide-intolerant patients with AIDS and biopsy-proven cerebral toxoplasmosis. The 9 patients were treated for 28-149 days with trimetrexate (30-280 mg/m2/day) plus leucovorin (20-90 mg/m2 every 6 h). Radiographic responses were documented in 8 patients, and clinical responses in 5 patients. Despite continued therapy, all patients deteriorated clinically and radiographically within 13-109 days of their initial improvement. Trimetrexate at very high doses for extended periods was not associated with serious toxicity. Trimetrexate alone had dramatic but transient activity in sulfonamide-intolerant patients and thus is not adequate as single-agent therapy for AIDS-associated toxoplasmosis.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Drug Evaluation; Female; Humans; Leucovorin; Male; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral; Trimetrexate

An HIV-positive patient presented the classical syndrome of pure alexia. Neuroradiologic investigation by computed tomography showed a ring-like lesion in the left posterior white matter. The clinical manifestations as well as the radiologic findings resolved after antiprotozoal treatment.

Topics: Adult; Agraphia; Drug Therapy, Combination; Dyslexia, Acquired; HIV Seropositivity; Humans; Leucovorin; Male; Neuropsychological Tests; Pyrimethamine; Sulfadiazine; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral