The susceptibility and natural resistance to two nitroheterocyclic derivatives used clinically in Chagas disease (nifurtimox and benznidazole) were investigated in 47 Trypanosoma cruzi strains isolated from human patients, domestic vectors and sylvatic reservoirs or vectors. A large gradient of drug efficacy from 0% to 100% was detected. Drug susceptibility apparently related to geographical distribution of some T. cruzi strains was also observed. Drug resistance was identified among T. cruzi populations isolated from sylvatic vectors from an area where autochthonous human Chagas disease does not exist. Thus, natural drug-resistance of sylvatic strains might be a way of introducing this character into a T. cruzi domestic cycle. Most of the 47 studied strains were either sensitive or resistant to both compounds, an intriguing finding considering that nifurtimox and benznidazole apparently have different mechanisms of action against T. cruzi.

A method is described which permits to determine in vivo and in a short period of time (4-6 hours) the sensitivity of T. cruzi strains to known active chemotherapeutic agents. By using resistant- and sensitive T. cruzi strains a fairly good correlation was observed between the results obtained with this rapid method (which detects activity against the circulating blood forms) and those obtained with long-term schedules which involve drug administration for at least 20 consecutive days and a prolonged period of assessment. This method may be used to characterize susceptibility to active drugs used clinically, provide information on the specific action against circulating trypomastigotes and screen active compounds.

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Single doses of drugs active against Trypanosoma cruzi (megazol, nifurtimox and benznidazole) induce a rapid clearance of the blood parasites in experimentally infected mice. Furthermore, the in vitro phagocytosis and intracellular destruction by mouse peritoneal macrophage of blood forms collected from the treated animals is strongly enhanced as compared with parasites from untreated controls. The uptake of the blood forms by macrophages is significantly higher with megazol than with benznidazole and nifurtimox, a finding that concurs with data showing that megazol is also the most active compound in the living host. The possibility that macrophages participate in a synergic effect between the host immune response and chemotherapeutic effect is discussed.