Mefloquine
Mefloquine, a quinolinemethanol derivative, is often used as artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria. Several studies indicated that copy number polymorphisms of pfmdr1 gene were associated with altered mefloquine susceptibility in Plasmodium falciparum.
- Single nucleotide polymorphisms in pfmdr1 are associated with increased mefloquine susceptibility in vitro, but not in vivo (Price RN,et al, 2004).
- Parasites with multiple pfmdr1 copies have higher mefloquine IC50 values than those of the parasites with single pfmdr1 copy (Price RN,et al, 2004, Lancet; Lim P, et al, 2013, Antimicrobial agents and chemotherapy).
- Knocking down 1 out of 2 pfmdr1 copies increases the mefloquine susceptibility (Sidhu AB, et al, 2006, The Journal of infectious diseases).
Although amplification of pfmdr1 has been associated with reduced mefloquine susceptibility, the evidence supporting that considering pfmdr1 copy number as a marker for mefloquine treatment failure is not consistently strong. Therefore we recommend to interpret the phenotype of mefloquine resistance with cautions. The markers of artemisinin resistance should also be considered to predict the efficacy of artesunate-mefloquine combination therapy.
- Locus utilized : amplification of PF3D7_0523000 (pfmdr1)
- Field utilized : geno_mdr1_amp
| Change | Coding | Interpretation | Phenotype |
|---|---|---|---|
| Missing | geno_mdr1_amp == "Missing" | Missing | Undetermined/missing |
| Single copy | geno_mdr1_amp == "WT" | Single copy | Sensitive |
| Multiple copies | geno_mdr1_amp == "Amplified" | Multiple copies | Resistant |
| Reference | Method | Location/Sample size/Genetic background | Finding summary |
|---|---|---|---|
| Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet (London, England). 2004;364(9432):438-47. | - Amplification of pfmdr1 gene was determined by real-time PCR assay. - Drug susceptibility determined by using hypoxanthine incorporation assay. - SNPs of pfmdr1 was assessed by PCR-RFLP. |
- Northwestern border of Thailand. - 4,624 parasite isolates from patients during 1990-2002 |
- Multiple copies pfmdr1 were associated with reduced mefloquine sensitivity. - Mefloquine IC50 of the parasites with multiple pfmdr1 copies (64.3 ng/ml) was 3.5-time higher than that of the parasites with single pfmdr1 copy (18.7 ng/ml). - Median mefloquine IC50 of parasites with single pfmdr1 copy and N86Y mutation (8.0 ng/ml) was 2.6-time lower than that of the parasties with wild-type pfmdr1 gene (20.8 ng/ml). - There was no significant relationship between any mutation in pfmdr1 and mefloquine treatment failure. |
| Lim P, Dek D, Try V, Eastman RT, Chy S, Sreng S, et al. Ex vivo susceptibility of Plasmodium falciparum to antimalarial drugs in western, northern, and eastern Cambodia, 2011-2012: association with molecular markers. Antimicrobial agents and chemotherapy. 2013;57(11):5277-83. | - Amplification of pfmdr1 gene was determined by real-time PCR assay. - Ex vivo drug susceptibility assay with SYBR green I was used to determine mefloquine sensitivity. |
- 3 provinces in Cambodia; Pursat (western), Preah vihear (northern) and Rattanakiri (eastern). - 360 parasite isolates from patients during 2011-2012. |
- Geometric mean MQ IC50 of the parasites with multiple pfmdr1 copies (22.9 nM) was 1.4-fold higher than that of the parasites with single mdr1 copy (15.7 nM). |
| Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI, Sriprawat K, et al. Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai–Myanmar Border (2003–2013): The Role of Parasite Genetic Factors. Clinical Infectious Diseases. 2016;63(6):784-91. | - Amplification of pfmdr1 gene was determined by real-time PCR assay. - 3 polymorphic loci (MSP1, MSP2 and GLURF) were used to distinguish recrudescence from reinfection. |
- Northwestern border of Thailand. - 1,005 patients during 2003-2013 |
- 81.5% of recurrent isolates had multiple pfmdr1 copies, while only 51.9% of admission isolates had multiple copies. - Mutations in kelch13 gene were associated with pfmdr1 amplification. |
| Reference | Method | Location/sample size/genetic background | Finding summary |
|---|---|---|---|
| Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. The Journal of infectious diseases. 2006;194(4):528-35. | - 1 out of 2 pfmdr1 copies in mefloquine-resistant FCB line was disrupted by using single-site cross over with a plasmid containing pfmdr1 fragment and BSD marker. The endogenous pfmdr1-5'UTR and pfmdr1-3'UTR were separated by the BSD selectable marker. | - FCB line (Colombian strain) | - Mefloquine IC50 of the transgenic parasites (6 nmol/L), with 1 remaining functional copy of pfmdr1, was 3-time lower than the MQ IC50 value of the parent FCB line (22.1 nmol/L). - The pfmdr1 knockdown parasites also showed increased sensitivity of lumefantrine, halofantrine, artemisinin and quinine, while the IC50 of chloroquine was not affected. |