Treatment of Plasmodium falciparum malaria in the nonendemic setting: a narrative review of toxicity, failure, and emerging resistance

Introduction
For more than 15 years, artemisinin-based combination therapy (ACT) and atovaquone–proguanil have been recommended for treatment of Plasmodium falciparum malaria in most nonendemic countries. However, new challenges have emerged that complicate the management of travelers with malaria, including the occurrence of artemisinin-related hemolysis and the increasing numbers of treatment failures possibly related to drug resistance.

Areas covered
We reviewed the epidemiology, pattern, and risk factors for artemisinin-related hemolysis and for treatment failure with ACT or atovaquone–proguanil among travelers with P. falciparum malaria diagnosed in nonendemic countries. We collected detailed information on clinical features, pharmacokinetic parameters, or mutations conferring resistance observed in failing cases.

Expert opinion
Several factors (e.g. lack of prior immunity, older age, overweight, comorbidities, and comedication) distinguish travelers from people residing in malaria-endemic areas. Yet, current uniform treatment recommendations across settings do not address many considerations that predominantly affect nonimmune travelers with malaria. This population may also be more vulnerable to complications of malaria, as reduced susceptibility to key antimalarial drugs is spreading. We propose specific adaptations to the management of malaria in travelers, with a focus on structured clinical follow-up to detect toxicity and failure, and on systematic genomic surveillance in concert with existing initiatives in endemic countries.