Cerebral toxoplasmosis

AIDS (acquired immunodeficiency syndrome) is the final stage of disease caused by infection with HIV. In this stage, the vims infection has severely affected the immune system, causing a depletion of CD4+ T-helper cells. AIDS is characterized by the manifestation of typical diseases caused by opportunistic infections (Pneumocystis carinii pneumonia, CMV retinitis, candidiasis of the esophagus, cerebral toxoplasmosis), neurological manifestations, cachexia, or certain tumors (Kaposi sarcoma of the skin, B-cell lymphoma). 

Intermediate-acting sulfonamides include sulfadiazine and sulfamethoxazole. Sulfamethoxazole is combined with trimethoprim in co-trimoxazole. Sulfadiazine shows good penetration into the cerebrospinal fluid and is effective for cerebral Toxoplasmosis. It has an elimination half-life 10-17 hours which prolonged in renal impairment. 

A 24-year-old AIDS patient is interested in starting chemoprophylaxis for Pneumocystis pneumonia (PCP) and cerebral toxoplasmosis. He has no drug allergies. Which of the following prophylactic agents is appropriate for the prevention of both PCP and cerebral toxoplasmosis ... 

Progressive loss of strength and difficulty in swallowing and eye opening after the first dose of clarithromycin (2 g/day) occurred in a patient with cerebral toxoplasmosis and AIDS (15). This myasthenic syndrome resolved within 6 hours of withdrawal of clarithromycin and administration of pyridostigmine. 

Successful desensitization has been described in a 35-year-old woman who developed a generalized rash after taking clindamycin (600 mg 6-hourly) and pyrimethamine for 12 days for AIDS-associated cerebral toxoplasmosis the rash resolved after withdrawal of clindamycin (44). Subsequent oral rechallenge was performed (without pretreatment with glucocorticoids or antihistamines), starting with three doses of 20 mg on day 1, 40 mg on day 2, 80 mg on day 3, and so on, until a dose of 600 mg qds was reached on day 7. A transient rash lasting 5 hours developed after the second dose of... 

A large bibliography exists from the 1940 s related to crystalluria and acute kidney injury associated with the use of sulfadiazine [1, 10, 11]. Sulfadiazine disappeared from clinical use for a long time until it re-emerged again in the AIDS era. More recently, the number of reports in adults and children has increased substantially because of the use of sulfadiazine and pyrimethamine, as the treatment of choice for cerebral toxoplasmosis associated with AIDS, other immunosuppressive states or specific infections [7, 12-35]. Acute kidney injury secondary to sulfadiazine crystalluria has been also reported in renal transplant patients [36, 37]. 

Figure 1. Sulfadiazine nephrotoxicity (crystalluria and acute renal failure). 35 year old man with AIDS and cerebral toxoplasmosis treated for 33 days with 4-6 g/dayofsulfadiazine.The patient received oral hydration and possibly had an episode of transient renal impairment during days 8-13. By day 29 of treatment, crystalluria, hematuria, flank pain, renal calculi, and acute renal failure developed. Urine was alkalinized late in the course.

With increasing frequency, clindamycin in combination with pyrimethamine is been used as the replacement drug for sulfadiazine in the treatment of cerebral toxoplasmosis. Perhaps this new combination again may send sulfadiazine nephrotoxicity into "oblivion". Nevertheless, until this possibility occurs, primary care physicians should be aware that sulfadiazine can cause renal toxicity and that effective preventive measures are available. 

Pyrimethamine is a folic acid antagonist that for many years has been used as an antimalarial drug [193-195], specially for chloroquine-resistant P. falciparum. Due to its synergistic activity, pyrimethamine also has been used, in combination with sulfadiazine or dapsone for the treatment or prophylaxis of cerebral toxoplasmosis or PCP in patients with AIDS [196]. 

Farinas MC, Echevarria S, Sampedro I, Gonzalez A, Perez del Molino A, Gonzalez-Macias J. Renal failure due to sulphadiazine in AIDS patients with cerebral toxoplasmosis. Journal of internal medicine. 1993 Apr 233(4) 365-7. 

AIDS." A primary infection that is treated with the combination is PCP. The sulfonamide-trimethoprim combination can be used fur treatment and prophylaxis. Additionally, cerebral toxoplasmosis con be treated in active infection or prophyluctically. Urinary tract infections and bum therapy" " " round out the list of therapeutic applications. The sulfonamides arc drugs of choice for a few other types of infections, but their u.sc is quite limited in modem antimicrobial chemotherapy." " "... 

Herald A, Hepp M, Chave J-P, et al. Treatment for cerebral toxoplasmosis protects against Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1991 115 760-763. 

Nath A, Sinai AP. Cerebral toxoplasmosis. Curr Treat Options Neurol. 2003 5 3-12. 

In some cases, as in cerebral toxoplasmosis, which is frequently seen in HIV patients but may occur with at)q)ical manifestations, it is extremely important to do the differential diagnosis from several other neurological infections like lymphoma and other cancers (Montoya, 2002). 

The diagnosis of cerebral toxoplasmosis might be done in association with complementary methods such as imaging and immunological... 

When studied as a 4-week therapy at 300 mg b.i.d. for cryptosporidial diarrhea, roxithromycin produced symptomatic improvement and clinical cure rates of 25% and 50%, respectively, in patients with AIDS [181, 182]. The drug also showed efficacy in HIV-infected patients for the prevention of Pneumocystis car-inii pneumonia and cerebral toxoplasmosis [183]. Given once weekly, 900 mg of roxithromycin was more effective than once monthly aerosolized pentamidine 300 mg therapy in preventing these HIV-related opportunistic infections. 

In vitro studies have shown that azithromycin is active against Toxoplasma gondii, and that this activity is additive with pyrimethamine [291]. In vivo studies have shown that azithromycin has some prophylactic and therapeutic activity [292-294]. Only a handful of human cases of cerebral toxoplasmosis treated with azithromycin have been described in the hterature [295-297]. Early results with escalating doses of oral azithromyein of 900, 1200, or 1500 mg daily plus pyrimethamine in 32 evaluable patients with known or suspected toxoplasma encephalitis have been reported [298]. It was concluded that azithromycin plus pyrimethamine is not as effective as the standard therapy for cerebral toxoplasmosis and should be regarded as second-line or salvage therapy. 

Raffi, F, Stmillou, L., Ninin, E., Reliquet, V., Billaud, E., and Milpied, B. (1995). Breakthrough cerebral toxoplasmosis in patients with AIDS who are being treated with clarithromycin [letter]. Clin. Infect. Dis. 20, 1076-1077. 

Durant, J., Hazime, F., Carles, M., Pechere, J. C., and Dellamonica, P. (1995). Prevention of Pneumocystis carinii pneumonia and of cerebral toxoplasmosis by roxithromycin in HIV-infected patients. Infection 23, S33-S38. 

Distribution Clindamycin is widely distributed in many fluids and tissues, including bone. Significant concentrations are not attained in CSF, but concentrations sufficient to treat cerebral toxoplasmosis are achieved. The drug readily crosses the placenta. Ninety percent or more of clindamycin is bound to plasma proteins. Clindamycin accumulates in polymorphonuclear leukocytes and alveolar macrophages and in abscesses. 

However, NO may also have a role in inhibiting infectious processes. Neutralization of TNF and down-regulation of iNOS promote induction of acute cerebral toxoplasmosis and enhanced pathology in mice chronically infected with Toxoplasma gondii (Gazzinelli et al., 1993). However, N-monomethyl-L-arginine (NMMA) does not affect the antitoxoplasma activity of TNF and IL-6 produced by human microglia in vitro (Chao et al.,... 

Gazzinelli, R. T., Eltoum, I., Wynn, T. A., and Sher, A. (1993). Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNFa and correlates with the down regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. /. Immunol. 151, 3672-3681. 

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