Significant reduction of Toxoplasma gondii brain cysts after treatment with spiramycin coadministered with metronidazole in a mouse model

Antimicrob Agents Chemother. 2012 Jan 23. [Epub ahead of print]

Significant reduction of Toxoplasma gondii brain cysts after treatment with spiramycin coadministered with metronidazole in a mouse model of chronic toxoplasmosis.

Chew WK, Segarra I, Ambu S, Mak JW.

Source
Dep. of Human Biology, School of Medicine, International Medical University; No 126 Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur; Malaysia.

Abstract
Toxoplasma gondii is a parasite that generates latent cysts in brain which reactivation may lead to fatal toxoplasmic encephalitis for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and the in vitro reactivation. Male Balb/c mice were fed 1000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later infected mice underwent different treatments: infected untreated group (n=9) which received vehicle, spiramycin only group (n=9), 400 mg/kg daily for 7 days, metronidazole only group (n=9) 500 mg/kg daily for 7 days, and combination group (n=9) which received spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. Uninfected control group (n=10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenate cultured in confluent Vero cells and cysts and tachyzoites counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400 mg/kg) or metronidazole (500 mg/kg) or both. Metronidazole increased 67% brain spiramycin AUC(0-∞) without affecting its plasma disposition. Metronidazole plasma and brain AUC(0-∞) were reduced 9% and 62% respectively after spiramycin coadministration. Enhanced spiramycin brain exposure after coadministration reduced 15-fold brain cysts (79±23 combination treatment versus 1198±153 untreated control group, p<0.05), and 10-fold versus spiramycin only group (768±125). Metronidazole alone showed no effect (1028±149). Tachyzoites were absent in brain. Spiramycin reduced in vitro reactivation. Metronidazole increased spiramycin brain penetration causing a significant reduction of T. gondii brain cysts with potential clinical translatability for chronic toxoplasmosis treatment.


PMID: 22271863 [PubMed - as supplied by publisher]