Delayed parasite elimination in human infections treated with clindamycin parallels ‘delayed death’ of Plasmodium falciparum in vitro

Abstract

Clindamycin is safe and effective for the treatment of Plasmodium falciparum malaria, but its use as monotherapy is limited by unacceptably slow initial clinical response rates. To investigate whether the protracted action is due to an accumulative, time of exposure-dependent or a delayed effect on parasite growth, we studied the in vivo and in vitro pharmacodynamic profiles of clindamycin against P. falciparum. In vivo, elimination of young, circulating asexual parasite stages during treatment with clindamycin displayed an unusual biphasic kinetic: a plateau phase was followed by a precipitated decline of asexual parasite densities to nearly undetectable levels after 72 and 60 h in adult patients and asymptomatic children, respectively, suggesting an uninhibited capacity to establish a second, but not third, infectious cycle. In vitro, continuous exposure of a laboratory-adapted P. falciparum strain to clindamycin with concentrations of up to 100 μM for two replication cycles (96 h) did not produce inhibitory effects of >50% compared with drug-free controls as measured by the production of P. falciparum histidine-rich protein II ( PfHRP2). PfHRP2 production was completely arrested after the second cycle (96–144 h) (>10,000-fold decrease of mean half-inhibitory concentrations measured at 96–144 h compared to 48–96 h). Furthermore, incubation with clindamycin during only the first (0–48 h) versus three (0–144 h) parasite replication cycles led to comparable inhibition of P fHRP2 production in the third infectious cycle (96–144 h) (mean IC 99 of 27 and 22 nM, respectively; P = 0.2). When parasite cultures were exposed to different concentrations of clindamycin ranging from 50 to 1,000 nM for 72 h and followed up in an experiment designed to simulate a typical 3-day treatment regimen, parasitaemia was initially suppressed below the microscopic detection threshold. Nonetheless, parasites reappeared in a dose-dependent manner after removal of drug at 72 h but not in continuously drug-exposed controls. The delayed, but potent, antimalarial effect of clindamycin appears to be of greatest potential benefit in new combinations of clindamycin with rapidly acting antimalarial combination partners.