Clinical Scorecard: Concurrent Presence of pfkelch13 and pfmdr1 Mutations in Recurring Plasmodium falciparum Infection After Standard Artemether-Lumefantrine Therapy

At a Glance

Key Highlights

• Sequencing identified PfK13 T348I and PfMDR1 T199S variants, along with pfmdr1 N86 and Y184 alleles.

• No evidence of increased pfmdr1 copy number was detected.

• The patient had obesity, type 2 diabetes, hypertension, and ultrasound findings compatible with moderate to severe hepatic steatosis.

• Recurrent parasitemia was 3.5%. The case was managed as ART-LUM treatment failure.

• Following 7 days of intravenous quinine sulfate and oral doxycycline, complete parasitological clearance was confirmed at the 1-week outpatient follow-up.

Guideline-Based Recommendations

The source is a case report that cites malaria guidelines. The following points distinguish the reported care from the authors’ interpretation.

Diagnosis

• Blood smear microscopy confirmed P. falciparum infection.

• PCR and sequencing characterized parasite variants; additional PCR testing ruled out mixed infection with other Plasmodium species.

Management

• The patient received intravenous quinine sulfate and oral doxycycline for 7 days as second-line treatment.

• The authors emphasize optimizing ART-LUM bioavailability and considering weight-based dosing in large or obese adults.

Monitoring & Follow-up

• Follow-up blood testing confirmed complete parasitological clearance.

• The authors emphasize monitoring treatment outcomes whenever feasible.

Risks

• Obesity and metabolic-associated fatty liver disease may affect ART-LUM pharmacokinetics and exposure.

• Plasma drug concentrations were not measured, so a causal relationship between drug exposure and treatment failure could not be established.

Patient & Prescribing Data

The patient weighed 105 kg and had a body mass index of 32.1 kg/m². Recurrent symptoms began approximately 2 weeks after discharge following a standard 3-day ART-LUM course. He reported no travel outside Portugal between discharge and symptom onset.

The report does not establish that the identified variants caused ART-LUM treatment failure.

Clinical Best Practices

• The authors highlight strategies to improve ART-LUM bioavailability, including fat-containing food and an 8-hour interval between the initial doses.

• Metabolic comorbidities warrant further investigation as potential contributors to altered drug exposure and treatment outcomes.

• The effects of PfK13 T348I and PfMDR1 T199S on ART-LUM susceptibility require further in vitro investigation.

Related Resources & Content

• WHO guidelines for malaria — World Health Organization — World Health Organization, August 13, 2025.

• Novel Pfk13 and Pfubp1 genotypes in African Plasmodium falciparum isolates exhibiting reduced susceptibility to the antimalarials artemisinin and lumefantrine — Pratt S, van Schalkwyk DA, Stewart L, et al. — mBio, 2026;17:e0367625.

• Mutation in the Plasmodium falciparum BTB/POZ domain of K13 protein confers artemisinin resistance — Paloque L, Coppée R, Stokes BH, et al. — Antimicrobial Agents and Chemotherapy, 2022;66:e0132021.

• Pharmacokinetic properties of the antimalarial combination therapy artemether–lumefantrine in normal-weight, overweight and obese healthy male adults — Sugiarto SR, Page-Sharp M, Drinkwater JJ, Davis WA, Salman S, Davis TME — International Journal of Antimicrobial Agents, 2022;59:106482.

• The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice — Zhu Y, Chen L, He Y, et al. — Drug Metabolism Reviews, 2023;55:163–180.