The present data demonstrate that conventional doses of chloroquine are associated with initial parasite clearance that is both faster in knowlesi malaria than vivax malaria and amongst the most rapid reported for any human malaria [13–17]. No recurrences of knowlesi parasitaemia were detected during the 28-day follow-up period, including by PCR, suggesting either a low intensity of local transmission of P. knowlesi or prophylactic efficacy of relatively low plasma chloroquine concentrations in the tail of the terminal elimination phase. One early treatment failure occurred in the vivax group which was likely due to the increased incidence of chloroquine-resistant P. vivax in Java, Indonesia, where the patient had resided until three months prior to hospital admission . The exclusion of R1 resistance in the vivax group was not possible since too few patients completed follow up.
Although approximately one-third of the knowlesi patients experienced a transient rise in parasitaemia during the first 6 hours compared with only 13% of patients from the vivax group, this is likely to reflect several factors. First, the divided dose chloroquine regimen produces peak plasma concentrations that occur well after the first dose. Secondly, even if adequate plasma concentrations were reached quickly, the stage specificity of chloroquine  would allow late stage parasites to mature to schizogony during at least the first few hours of treatment with production of early ring forms that, as evidenced by previous own stage specific clearance times, are also relatively resistant. Thirdly, the 24 hour lifecycle of P. knowlesi is half that of P. vivax which means that, consistent with the relatively high parasite densities that are regularly observed in P. knowlesi infections , the more rapid maturation of late stage parasites would increase the likelihood of an initial rise in parasitaemia amongst the knowlesi patients. Indeed, early studies with chloroquine indicated that P. malariae, with an erythrocytic replication cycle of 72 hours, cleared more slowly than P. vivax . Lastly, since most of the knowlesi patients denied a previous history of malaria, a lack of immunity might also have attenuated the effect of chloroquine on initial parasite clearance.
The study participants were aged > 15 years and lived and/or worked on tributaries of the Rejang river in close proximity to the jungle where long-tailed and pig-tailed macaques have been sighted. Despite this, previous malaria infections, and in particular recent infections, were unusual (reported by only 16 of 73 or 22% of the knowlesi malaria patients). This suggests a low level of knowlesi malaria transmission and, therefore, low background levels of immunity in the population. The successful response to treatment with chloroquine and primaquine also implies that these infections are chloroquine and primaquine naïve, supporting a zoonotic mode of transmission.
FCTs and PCTs were similar in the knowlesi group, while fever cleared before parasitaemia in the vivax group. This suggests that knowlesi malaria has a higher pyrogenic density than vivax malaria but it may also reflect differences in immune status between the two groups. Under Malaysian Ministry of Health treatment guidelines, oral primaquine was administered to knowlesi malaria patients for two days in this study as a gametocidal drug. The effect of this on both asexual and sexual forms of P. knowlesi is difficult to quantify. Using primaquine would seem unnecessary since gametocytes appeared sensitive to chloroquine in the first 24 hours. P. knowlesi is not known to have a hypnozoite stage . If persistent liver stages did occur, and consistent with use of primaquine to prevent relapses of vivax and ovale malaria, longer duration treatment would be probably be necessary. Furthermore, there have been three case reports of chloroquine alone being successful in the treatment of knowlesi malaria [6, 22, 23].
Besides chloroquine, other anti-malarial agents have been used with apparent success for knowlesi malaria. These include mefloquine , quinine [10, 25], atovaquone/proguanil  and sulphadoxine-pyrimethamine . In animal models and in vitro drug studies, P. knowlesi is sensitive to most antimalarial drugs including clindamycin , naphthoquine , sulphonamides , tetracyclines , trimethoprim  and erythromycin . In Rhesus macaques, a high level of innate resistance to mefloquine has been seen with the P. knowlesi W1 strain, while proguanil and pyrimethamine resistance were inducible in experiments with the P. knowlesi Nuri strain [33–35]. Although knowlesi sensitivity to artemisinin derivatives has not been reported in man, it seems very likely that it would be successful as seen in experiments in Rhesus macaques [28, 36, 37].
In the 1980's, oral chloroquine was thought to be more effective than oral quinine as treatment for chloroquine sensitive falciparum malaria . Chloroquine was also effective and well tolerated when administered parentally or via nasogastric tube in severe falciparum malaria . It may be that the use of chloroquine for severe knowlesi malaria is effective, provided that the possibility of chloroquine-resistant P. falciparum or P. vivax co-infection had been excluded. Further studies using alternative anti-malarial drugs, including artemisinin derivatives, would be desirable to define optimal management strategies for P. knowlesi.