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Treatment failure for Plasmodium falciparum malaria is increasing in nonendemic countries. A session organized by the British Infection Association at European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2025, held recently in Vienna, Austria, addressed this issue. Discussions centered on management practices and surveillance strategies in countries with a high number of imported cases and recently published guidelines.

The latest guidelines were discussed, focusing on current management challenges, including the use of second-line drugs, treatment failure, and criteria for outpatient treatment. The discussion also reviewed the role of molecular surveillance in identifying resistance mutations, an essential tool for staying ahead of emerging threats.

Emmanuel Bottieau, PhD, from the Institute of Tropical Medicine in Antwerp, Belgium, led the session. He emphasized the global burden of imported malaria, highlighting the considerable number of cases in the United States and Europe. Last year, 1500 cases were diagnosed in the United States and 7000 in Europe, of which 2000 were in France and 2000 in the United Kingdom. In the United States, 50% of malaria cases were attributed to P falciparum compared with 75% of those in Europe. In Belgium, the annual number of cases has doubled over the past decade, with the exception of a decrease during the COVID-19 pandemic.

Clinical Case

A clinical case was presented to illustrate the type of decisions involved in managing such cases. The case involved a 33-year-old man from Norway who returned 15 days prior from a 7-week trip to Burundi in East Africa, where he had been visiting friends and family. He presented with fever and headache lasting for 3 days and sought consultation at the Institute of Tropical Medicine. Despite normal physical examination findings and unremarkable laboratory parameters, his blood smear was positive for P falciparum with a high trophozoite count (24,731 trophozoites/µL).

One of the most critical decisions to be made was whether the patient required hospitalization or could be managed as an outpatient. At Antwerp University Hospital, Antwerp, Belgium, a clinical algorithm using color-coded “labels” based on severity was adopted. These labels help classify patients according to their risk and determine whether admission is necessary. Stratification is based on severity criteria, a list of risk factors, and parasitemia ranges for each category, as follows:

• Black tag: Parasitemia more than 4%, any organ failure, or meeting three or more of the severity criteria according to the World Health Organization (WHO). Management includes intensive care unit admission and treatment with intravenous artesunate and broad-spectrum antibiotics.
• Red tag: Parasitemia between 2% and 4%, fewer than three WHO severity criteria, or persistent vomiting. The patient was admitted to the intermediate care unit and treated with intravenous artesunate.
• Orange tag: Parasitemia between 1% and 2% or total bilirubin more than 1.3 mg/dL. These patients were admitted to a conventional ward and received oral artemisinin-based combinations.
• Green tag: Parasitemia < 1%. These patients are typically managed on an outpatient basis for 33 days with oral artemether-lumefantrine administration.

Note: The presence of one or more severity risk factors (comorbidities or other patient characteristics) may qualify for a red or orange tag, depending on the clinical discussion in the Infectious Diseases department.

Treatment

The patient was initially treated on an outpatient basis for 33 days with oral artemether-lumefantrine. He did not attend the scheduled follow-up after 33 days but returned a week later with a persistent low-grade fever. Further laboratory tests revealed low parasitemia (25 trophozoites/µL) and elevated C-reactive protein levels of 15 mg/dL (normal value < 10 mg/dL), lactate dehydrogenase levels of 318 U/L (normal value is 246 U/L), and haptoglobin values < 0.01 g/L, indicating treatment failure. This case illustrates the complexity of determining the treatment response, which is a common challenge in clinical practice.

Another complexity in this case is determining the type of treatment response based on WHO classifications: Early treatment failure (within the first 3 days), late clinical or parasitological failure (between days 3 and 28), or an adequate clinical and parasitological response. This is a case of treatment failure, and distinguishing between early or late failure can be difficult in real-world clinical settings. It is also essential to consider whether the recurrence is due to recrudescence, which is more likely to occur in travelers, or reinfection, which is more common in endemic areas.

The causes of treatment failure vary. Artemisinin resistance in Africa and Southeast Asia is a growing concern. However, other factors, such as poor adherence, malabsorption, drug interactions, or underdosing, can also contribute, particularly in patients with high body weight or very high parasitemia levels.

Previously, the Institute of Tropical Medicine reported approximately two cases per year. However, during 2022-2023, they documented eight cases, seven of which were classified as late failures and one as an early failure. Only one case was severe. Resistance mutations to one of the drugs in artemisinin-based combination therapy were found in all cases. This patient had a validated mutation associated with artemisinin resistance and another for decreased susceptibility to lumefantrine.

How to Handle a Case of Treatment Failure

In uncomplicated malaria, the following alternatives are proposed:

• Repeat the same regimen for another cycle.
• Re-administer the same drug at a higher dose or for a longer duration.
• Prolonged treatment (up to 55 days) has been suggested, but this is still under investigation and is not yet a recommended approach. The indication for this treatment is unclear.
• Switch to another drug within the artemisinin-based combination therapies. Artemisinin-based triple combination therapy is currently being researched, but no guidelines are available in Europe.
• Use a different class of drugs, such as atovaquone-proguanil. This option may take 1-2 days, longer for fever or parasitemia to subside but is likely the best alternative.
• New antimalarial drugs, such as cipargamin and ganaplacide, are under development, although they are expected to become available in at least 5-10 years for them to become available.

In cases of severe malaria, adding other drugs, such as quinine, to artesunate is an option and is currently recommended by the WHO.

Key Takeaways

• Outpatient treatment is possible from the outset in up to 50% of patients with uncomplicated malaria, although it remains reasonable to consider an initial 24-hour admission for monitoring.
• There is evidence of an increase in the number of cases of failure of artemisinin-based combination treatment in travelers.
• Evaluating the causes of failure in a clinical setting is complex. It must include the possibility of resistance to treatment.
• Artemisinin-resistant mutations have been documented in travelers with treatment failure.
• The need to establish rigorous monitoring of travelers with malaria is urgent, as well as to implement systematic genomic surveillance of plasmodium.

This story was translated from Univadis Spain using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.