Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure

• Published in: Journal of antimicrobial chemotherapy 2022-03, Vol.77 (4), p.1005-1011
• Main Authors: Ursing, Johan, Johns, Rasmus, Aydin-Schmidt, Berit, Calçada, Carla, Kofoed, Poul-Erik, Ghanchi, Najia Karim, Veiga, Maria Isabel, Rombo, Lars
• Format: Article
• Language: English
• Subjects: Antimalarials - pharmacology; Antimalarials - therapeutic use; Chloroquine - pharmacology; Chloroquine - therapeutic use; Drug Resistance; Humans; Malaria, Falciparum - drug therapy; Medicin och hälsovetenskap; Original Research; Plasmodium falciparum
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkac008

Abstract Background Plasmodium falciparum strains that are resistant to standard-dose chloroquine can be treated by higher chloroquine concentrations maintained for a longer time in vivo. Objectives To determine the relative importance of chloroquine concentrations versus exposure time for elimination of chloroquine-susceptible and -resistant P. falciparum in vitro. Methods Chloroquine-susceptible (3D7) and -resistant (FCR3) strains were exposed in vitro to 1, 2, 4, 8, 16 or 32 times their respective 90% inhibitory chloroquine concentrations for 3, 5, 7 or 14 days and then followed until recrudescence, or not, by 42 days after the end of exposure. Results Exposure to chloroquine appeared to eliminate susceptible and resistant parasites, leaving small pyknotic apparently dead parasites. Chloroquine-susceptible and -resistant parasites recrudesced after 3 and 5 days of chloroquine exposure. Recrudescence occurred in one out of four 7 day exposure series but not after 14 days exposure. The median time to recrudescence was 13 to 28 days with a range of 8 to 41 days after the end of exposure. Time to recrudescence after the end of exposure increased with duration of exposure for susceptible and resistant strains (P < 0.001). Time to recrudescence did not correlate with concentrations greater than 1× IC90. Conclusions Chloroquine-susceptible and -resistant P. falciparum probably become dormant. Elimination of dormant parasites is primarily dependent upon the duration of chloroquine exposure. Exposure to effective drug concentrations for 7 days eliminates most parasites in vitro. The results support in vivo data indicating that elimination of chloroquine-resistant P. falciparum correlates with Day 7 chloroquine concentrations.