title: Determinants of in vitro drug susceptibility testing of Plasmodium vivax.
abstract: In Papua, Indonesia, the antimalarial susceptibility of Plasmodium vivax (n = 216) and P. falciparum (n = 277) was assessed using a modified schizont maturation assay for chloroquine, amodiaquine, artesunate, lumefantrine, mefloquine, and piperaquine. The most effective antimalarial against P. vivax and P. falciparum was artesunate, with geometric mean 50% inhibitory concentrations (IC50s) (95% confidence intervals [CI]) of 1.31 nM (1.07 to 1.59) and 0.64 nM (0.53 to 0.79), respectively. In contrast, the geometric mean chloroquine IC50 for P. vivax was 295 nM (227 to 384) compared to only 47.4 nM (42.2 to 53.3) for P. falciparum. Two factors were found to significantly influence the in vitro drug response of P. vivax: the initial stage of the parasite and the duration of the assay. Isolates of P. vivax initially at the trophozoite stage had significantly higher chloroquine IC50s (478 nM [95% CI, 316 to 722]) than those initially at the ring stage (84.7 nM [95% CI, 45.7 to 157]; P < 0.001). Synchronous isolates of P. vivax and P. falciparum which reached the target of 40% schizonts in the control wells within 30 h had significantly higher geometric mean chloroquine IC50s (435 nM [95% CI, 169 to 1,118] and 55.9 nM [95% CI, 48 to 64.9], respectively) than isolates that took more than 30 h (39.9 nM [14.6 to 110.4] and 36.9 nM [31.2 to 43.7]; P < 0.005). The results demonstrate the marked stage-specific activity of chloroquine with P. vivax and suggest that susceptibility to chloroquine may be associated with variable growth rates. These findings have important implications for the phenotypic and downstream genetic characterization of P. vivax.
authors.affiliation: International Health Program, Infectious Diseases Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Russell
authors.forename: F
authors.initials: F
authors.lastname: Chalfein
authors.forename: B
authors.initials: B
authors.lastname: Prasetyorini
authors.forename: E
authors.initials: E
authors.lastname: Kenangalem
authors.forename: K
authors.initials: K
authors.lastname: Piera
authors.forename: R
authors.initials: R
authors.lastname: Suwanarusk
authors.forename: A
authors.initials: A
authors.lastname: Brockman
authors.forename: P
authors.initials: P
authors.lastname: Prayoga
authors.forename: P
authors.initials: P
authors.lastname: Sugiarto
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.forename: E
authors.initials: E
authors.lastname: Tjitra
authors.forename: N M
authors.initials: NM
authors.lastname: Anstey
authors.forename: R N
authors.initials: RN
authors.lastname: Price
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects* / Q000254:growth & development*; D052939:Schizonts / Q000187:drug effects / Q000254:growth & development; D013997:Time Factors
chemical_list: D000962:Antimalarials; D002738:Chloroquine