@article{PAR00012011,
  title = {{E}mergence of resistance to {A}tovaquone-{P}roguanil in malaria parasites : insights from computational modeling and clinical case reports},
  author = {{C}ottrell, {G}illes and {M}usset, {L}. and {H}ubert, {V}. and {L}e {B}ras, {J}. and {C}lain, {J}.},
  editor = {},
  language = {{ENG}},
  abstract = {{T}he usefulness of atovaquone-proguanil ({AP}) as an antimalarial treatment is compromised by the emergence of atovaquone resistance during therapy. {H}owever, the origin of the parasite mitochondrial {DNA} (mt{DNA}) mutation conferring atovaquone resistance remains elusive. {H}ere, we report a patient-based stochastic model that tracks the intrahost emergence of mutations in the multicopy mt{DNA} during the first erythrocytic parasite cycles leading to the malaria febrile episode. {T}he effect of mt{DNA} copy number, mutation rate, mutation cost, and total parasite load on the mutant parasite load per patient was evaluated. {C}omputer simulations showed that almost any infected patient carried, after four to seven erythrocytic cycles, de novo mutant parasites at low frequency, with varied frequencies of parasites carrying varied numbers of mutant mt{DNA} copies. {A} large interpatient variability in the size of this mutant reservoir was found; this variability was due to the different parameters tested but also to the relaxed replication and partitioning of mt{DNA} copies during mitosis. {W}e also report seven clinical cases in which {AP}-resistant infections were treated by {AP}. {T}hese provided evidence that parasiticidal drug concentrations against {AP}-resistant parasites were transiently obtained within days after treatment initiation. {A}ltogether, these results suggest that each patient carries new mt{DNA} mutant parasites that emerge before treatment but are killed by high starting drug concentrations. {H}owever, because the size of this mutant reservoir is highly variable from patient to patient, we propose that some patients fail to eliminate all of the mutant parasites, repeatedly producing de novo {AP} treatment failures.},
  keywords = {{ASIE} {DU} {SUD} {EST}},
  booktitle = {},
  journal = {{A}ntimicrobial {A}gents and {C}hemotherapy},
  volume = {58},
  numero = {8},
  pages = {4504--4514},
  ISSN = {0066-4804},
  year = {2014},
  DOI = {10.1128/aac.02550-13},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00012011},
}