View source for WBR0434

 {{WBRQuestion
|QuestionAuthor= {{YD}} (Reviewed by  {{YD}} and  {{AJL}})
|ExamType=USMLE Step 1
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|MainCategory=Microbiology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|SubCategory=Neurology
|MainCategory=Microbiology
|MainCategory=Microbiology
|SubCategory=Neurology
|Prompt=A 28-year-old HIV-positive woman is brought to the emergency department (ED) with an episode of tonic-clonic seizure. The patient's family reports that the patient has recently lost weight and has been having complaints of high-grade fever and headaches for the past few days. The patient has been non-compliant with her anti-retroviral therapy for the past few weeks. Laboratory work-up in the ED is remarkable for CD4 count=80 cells/µL. Head computed tomography (CT) scan demonstrates multiple ring-enhancing lesions in the frontal lobes. The patient is administered empiric pharmacotherapy and is admitted to the hospital. What is the mechanism of action of the drug administered to this patient to treat her condition?
|Explanation=''Toxoplasma gondii'' is an obligatory intracellular opportunistic parasite that commonly infected patients with advanced HIV disease. It is transmitted as cysts in meat or in cat feces. ''Toxoplasma gondii'' infection is typically latent, whereby patients remain asymptomatic until the parasite reactivates at low CD4 levels < 100 cells/µL. Infection with ''Toxoplasma gondii'' typically manifests with [[cerebral toxoplasmosis]], which is characterized by a subacute-onset of high-grade fever and headache that eventually progress to involve focal neurological deficits, seizures, confusion, and death.  Multiple [[ring-enhancing lesions]] on head CT scan or brain MRI are characteristic and are an indication for initiation of empiric therapy for coverage of cerebral toxoplasmosis among HIV-positive patients. The diagnosis of cerebral toxoplasmosis is usually confirmed with elevated anti-toxoplasma IgG concentrations. First-line therapy for cerebral toxoplasmosis includes combination of pyrimethamine (dihydrofolate reductase inhibitor) and sulfadiazine (dihydropteroate synthetase inhibitor). Leucovorin is also added to the combination to reduce the risk of hematologic adverse events associated with pyrimethamine-induced inhibition of folic acid synthesis. Patients usually report improvement in symptoms within 2 days of administration of pharmacotherapy, and complete resolution follows within 2 weeks of pharmacotherapy. Less commonly, patients present with extracerebral toxoplasmosis, such as chorioretinitis or pneumonitis.
|AnswerA=Inhibition of heme polymerase activity
|AnswerAExp=[[Chloroquine]] is an antimalarial drug that acts by inhibition of plasmodium heme polymerase.
|AnswerB=Inhibition of dihydrofolate reductase activity
|AnswerBExp=[[Pyrimethamine]] is a dihydrofolate reductase inhibitor indicated for the treatment of [[cerebral toxoplasmosis]] when combined with sulfadiazine. Leucovorin is often added to the combination to reduce the risk of hematologic adverse events associated with pyrimethamine-induced inhibition of folic acid synthesis.
|AnswerC=Free radical toxicity of organism’s DNA
|AnswerCExp=[[Metronidazole]] is an antimicrobial agent that forms free radical metabolites, which are toxic to bacterial DNA.
|AnswerD=Blockade of peptide bond formation at the 50S ribosomal subunit
|AnswerDExp=Several [[antibiotics]], including [[chloramphenicol]], [[macrolides]], [[clindamycin]], [[streptogramins]], and [[linezolid]], block peptide bond formation at the 50S ribosomal subunit.
|AnswerE=Inhibition of DNA polymerase activity
|AnswerEExp=Antiviral medications, such as [[acyclovir]], [[ganciclovir]], [[foscarnet]], and [[cidofovir]], are DNA polymerase inhibitors.
|EducationalObjectives=Infection with ''Toxoplasma gondii'' typically manifests with [[cerebral toxoplasmosis]], which is characterized by a subacute-onset of high-grade fever, headache that eventually progress to involve focal neurological deficits, seizures, confusion, and death. It is commong among HIV-positive patients with low CD4 levels < 100 cells/µL. Leucovorin is also added to the combination to reduce the risk of hematologic adverse events associated with pyrimethamine-induced inhibition of folic acid synthesis.
|References=Jayawardena S, Singh S, Burzyantseva O, et al. Cerebral toxoplasmosis in adult patients with HIV infection. Clin Med J Resid Hosp Physician. 2008;44(7):17-24.<br>
First Aid 2014 page 151
|RightAnswer=B
|WBRKeyword=Toxoplasma gondii, Fever, Cerebral toxoplasmosis, Leucovorin, Sulfadiazine, Mechanism of action, Toxomplasmosis, HIV, Seizure, Ring enhancing lesion, Pyrimethamine, Dihydrofolate reductase inhibitor
|Approved=Yes
}}