Susceptibility of Various Genotypic Strains to Pyrimethamine, Sulfadiazine and Atovaquone

Antimicrob Agents Chemother. 2008 Jan 22 [Epub ahead of print]

Toxoplasma gondii: In Vitro Susceptibility of Various Genotypic Strains to Pyrimethamine, Sulfadiazine and Atovaquone

Meneceur P, Bouldouyre MA, Aubert D, Villena I, Menotti J, Sauvage V, Garin JF, Derouin F.

Laboratory of Parasitology (EA 3520), University Denis Diderot, 15 rue de l'école de médecine, 75250 Paris cédex 06, France; Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, 1, avenue Claude Vellefaux, 75010, Paris, France; Laboratory of Parasitology (EA 3800), and Biological Resource Centre Toxoplasma; University of Reims Champagne-Ardennes and Hôpital Maison-Blanche, 45 rue Cognacq-Jay, 51092 Reims cédex, France.

Sulfadiazine, pyrimethamine and atovaquone are widely used for treatment of severe toxoplasmosis. Their in vitro activities have been almost exclusively demonstrated on laboratory strains belonging to genotype I. We determined the in vitro activities of these drugs against 17 strains of T. gondii belonging to various genotypes and examined the correlations between IC50's, growth kinetics, strain genotype and mutations on drug target genes. Growth kinetics was determined in THP-1 cell cultures using real-time PCR. IC50's were determined in MRC-5 cell cultures using a T. gondii specific ELISA performed on cultures. Mutations in DHFR, DHPS and Cytochrome b genes were looked for by sequencing. Pyrimethamine IC50's ranged between 0.07 and 0.39 mg/L with no correlation with the strain genotype but a significant correlation with growth kinetics. Several mutations found on DHFR gene were not linked to a lower susceptibility. Atovaquone IC50's were in a narrow range of concentrations (mean 0.06+/-0.02 mg/L); no mutation was found on the Cytochrome b gene. IC50's for sulfadiazine ranged between 3 and 18.9 mg/L for 13 strains and were >50 mg/L for 3 strains. High IC50's were not correlated to strain genotypes or growth kinetics. A new mutation of the DHPS gene was demonstrated in one of these strains. In conclusion, we found variability in the susceptibility of T. gondii strains to pyrimethamine and atovaquone with no evidence of drug resistance. A higher variability was found for sulfadiazine with a possible resistance for 3 strains. No relationship was found between drug susceptibility and strain genotype.

PMID: 18212105 [PubMed - as supplied by publisher]