Pyrimethamine

Pyrimethamine + azithromycin

Azithromycin is efficacious in animal models of toxoplasmic encephalitis. In a Phase I/II dose-escalation study of pyrimethamine (50 mg/day) plus azithromycin (900, 1200, or 1500 mg/day) for induction and maintenance treatment in 30 patients with AIDS and definite or suspected Toxoplasma encephalitis, the overall response rate was 67% after 6 weeks of induction therapy [ ] However, maintenance therapy for 24 weeks with this combination was associated with a high relapse rate (47%); only six patients successfully completed induction and maintenance therapy. Adverse events were common (particularly in those taking azithromycin 1500 mg) and included hepatotoxicity, bone marrow suppression, ototoxicity, and gastrointestinal disturbances, which led 20% of patients to withdraw. All adverse events resolved on withdrawal.

In a prospective, randomized, open, multicenter trial of pyrimethamine + azithromycin versus pyrimethamine + sulfadiazine for the treatment of ocular toxoplasmosis in 46 patients with sight-threatening ocular toxoplasmosis, the two regimens had similar efficacy; however, the adverse effects were significantly less common and severe with pyrimethamine + azithromycin [ ].

Pyrimethamine + clarithromycin

Clarithromycin, a macrolide, and other macrolide and lincosamine antibiotics (azithromycin, clindamycin, spiramycin, and roxithromycin) have been used in combination with pyrimethamine in the treatment of Toxoplasma gondii infections, especially cases of Toxoplasma encephalitis.

Clarithromycin 2 g plus pyrimethamine 75 mg/day has been given for 6 weeks to a few AIDS patients with encephalitis [ ]. The adverse effects were many and severe: severe thrombocytopenia, anemia, neutropenia, liver toxicity of varying degree, nausea, vomiting, rashes, and hearing loss were found in two of three patients tested in a group of 13. The dose of clarithromycin in this study was the maximum dosage used in an earlier investigation of the treatment of mycobacterial infections in HIV-infected patients.

Pyrimethamine + clindamycin

Pyrimethamine 50 mg/day has been used in combination with clindamycin for the treatment of Toxoplasma encephalitis in AIDS. Adverse reactions were common (rash, diarrhea, nausea), but the incidence of hematological reactions was lower than with the combination of sulfadiazine and pyrimethamine [ , ].

Pyrimethamine + dapsone

Pyrimethamine and dapsone are available in fixed combinations:

• 1.

  12.5 mg of pyrimethamine + 100 mg of dapsone = Maloprim.

• 2.

  25 mg of pyrimethamine + 100 mg of dapsone = Deltaprim.

In Britain, the retrospective reported rate for serious reactions with Maloprim was one in 9100, the incidence of blood dyscrasias being one in 20 000. These figures are lower than those reported with Fansidar (pyrimethamine + sulfadoxine) [ ].

• A “dapsone syndrome” was reported in a 30-year-old woman after 4 weeks of treatment with Maloprim and chloroquine base 300 mg/weekly. The symptoms comprised fever, joint and muscle pains, dry cough, and a diffuse red urticarial rash, followed by generalized lymphadenopathy, a painful exudative tonsillitis, and a prominent atypical lymphocytosis.

Pyrimethamine + sulfadoxine

Pyrimethamine 25 mg plus sulfadoxine 500 mg is available in the combination formulation known as Fansidar. This combination, while effective in the prevention and treatment of Plasmodium falciparum malaria, carries a high frequency of adverse effects; hematological and serious skin reactions occur, but there are also reports of polyneuritis, vasculitis, and hepatotoxicity. Most of the severe skin reactions and the cases of vasculitis developed within under a month [ ]. The use of Fansidar for malaria prophylaxis has therefore been virtually abandoned [ ]. However, Fansidar is being increasingly used for the treatment of P. falciparum malaria in Africa. With the higher dosage used for that purpose, an increase in adverse effects, particularly hematological, can be expected. In Britain the retrospective reported rate for all serious reactions to Fansidar was one in 2100 prescriptions and for skin reactions one in 4900 prescriptions, the death rate being one in 11 100 [ ].

In a single-arm, open, prospective study between 1990 and 1995 (before HAART) the prophylactic efficacy of Fansidar was evaluated in 95 HIV-infected patients with successfully treated Pneumocystis jirovecii pneumonia and no history of Toxoplasma encephalitis [ ]. Patients took Fansidar with folinic acid (15 mg) twice weekly and were followed for a median of 19 (range 1–72) months. Five patients had a Pneumocystis relapse, but three had not taken their therapy. Of the 69 patients positive for anti- Toxoplasma IgG antibodies, only one developed toxoplasma encephalitis after 50 months. A rash developed in 16 patients after a median of 3 weeks, and required withdrawal in six. Two developed Stevens–Johnson syndrome after three or four doses. There was no significantly increased risk of adverse reactions to Fansidar in patients with previous hypersensitivity reactions to co-trimoxazole. The results of this study are of particular relevance to areas in which HAART is unavailable and where the antimalarial activity of Fansidar may confer additional benefit.

The efficacy of pyrimethamine + sulfadoxine seems to be unsatisfactory, at least in Laos, where 100 patients with uncomplicated falciparum malaria were randomized to either pyrimethamine + sulfadoxine (a single dose of pyrimethamine 1.25 mg/kg and sulfadoxine 25 mg/kg) or chloroquine (10 mg base/kg immediately, followed by 10 mg/kg 24 hours and 5 mg/kg 48 hours after the start of therapy) [ ]. There were treatment failures in 18% of those treated with pyrimethamine + sulfadoxine and in 36% of those treated with chloroquine. Thus, both regimens were considered inadequate.

In a placebo-controlled study of chemoprophylaxis for malaria, 701 Tanzanian infants were assigned to intermittent pyrimethamine + sulfadoxine (under 5 kg, a quarter of a tablet; 5–10 kg, half a tablet; over 10 kg, one tablet; each tablet contained pyrimethamine 25 mg plus sulfadoxine 500 mg) alongside routine childhood immunizations and iron supplementation at 2, 3, and 9 months of age [ ]. The combination was well tolerated, with no reported adverse events. Episodes of clinical malaria fell by 59% (95% CI = 41, 72) and the incidence of severe anemia by 50% (95% CI = 8, 73%) in the first year of life. Contrary to previous studies involving continuous prophylaxis in infants, there was no increase in the frequency of rebound episodes of malaria up to 18 months of age, suggesting that the development of malaria-specific immunity was unimpaired. Responses to vaccines were unaffected.

Pyrimethamine + sulfadoxine + mefloquine

Pyrimethamine (25 mg), sulfadoxine (500 mg), and mefloquine (250 mg) are available in the combination formulation known as Fansimef. Adverse reactions can be expected to be those that are characteristic of all three components.

Pyrimethamine + trimethoprim

The risk of megaloblastic anemia is higher with the combination of pyrimethamine + trimethoprim than with pyrimethamine alone, which on theoretical grounds might be expected. Concomitant administration of folic acid has been recommended [ ], but the effect of folic acid on efficacy is not known.

Respiratory

Non-cardiogenic pulmonary edema has been reported with pyrimethamine alone [ ].

Dyspnea and pleurisy have been described in patients taking pyrimethamine + sulfadoxine. Of 52 travellers with adverse reactions to Fansidar in Sweden, six had pulmonary infiltrates accompanied by fever [ ]. Such infiltrates have also been described in the past, and in one case a diagnosis of eosinophilic infiltration was made [ ]. A case of non-cardiogenic pulmonary edema was reported in 1989 [ ].

Nervous system

High doses of pyrimethamine can cause rapid development of neurological symptoms such as ataxia, tremor, and convulsions, probably by a direct toxic effect [ ].

An unusual case of extrapyramidal syndrome after sulfadoxine–pyrimethamine has been reported [ ].

• A 39-year-old man with malaria was given three tablets of sulfadoxine–pyrimethamine. After 50 minutes, he developed extrapyramidal signs, with spasmodic torticollis, trismus, and akathisia. He was given intravenous diazepam 10 mg and made a quick recovery with no residual extrapyramidal signs.

As the extrapyramidal signs occurred 50 minutes after a single dose of sulfadoxine–pyrimethamine there is a strong possibility that it was causally related, although sulfadoxine–pyrimethamine has not previously been reported to cause extrapyramidal reactions.

Hematologic