Artemether-lumefantrine is currently first-line therapy of Plasmodium falciparum malaria in many countries. This report describes a treatment failure despite adequate drug concentrations in a traveller returning from sub-Saharan Africa. Genotyping confirmed recrudescence and suggested reduced sensitivity. Potential sub-optimal effect of artemether-lumefantrine highlights the need to follow non-immune individuals the weeks after treatment

Färnert, Anna

Karlsson, Lillemor

Lindegårdh, Niklas

Rono, Josea

Sparrelid, Elda

Tolfvenstam, Thomas

Ursing, Johan

English

Digital Library of the Tanzania Health Community

CASE REPORT Open Access
Artemether–lumefantrine treatment failure
despite adequate lumefantrine day 7
concentration in a traveller with Plasmodium
falciparum malaria after returning from Tanzania
Anna Färnert
1,2*, Johan Ursing
1,2, Thomas Tolfvenstam
1,2, Josea Rono
1, Lillemor Karlsson
3, Elda Sparrelid
2 and
Niklas Lindegårdh
4,5ˆ
Abstract
Artemether-lumefantrine is currently first-line therapy of Plasmodium falciparum malaria in many countries. This
report describes a treatment failure despite adequate drug concentrations in a traveller returning from sub-Saharan
Africa. Genotyping confirmed recrudescence and suggested reduced sensitivity. Potential sub-optimal effect of
artemether-lumefantrine highlights the need to follow non-immune individuals the weeks after treatment.
Keywords: Malaria, P. falciparum, Artemisinin, Lumefantrine, Sensitivity, non-immune
Background
Artemisinin-based combination therapy (ACT) is recom-
mended by the World Health Organization as first-line
treatment of uncomplicated Plasmodium falciparum
malaria in sub-Saharan Africa [1]. The combination
comprises a fast-acting artemisinin derivative with rapid
effect on parasite clearance, and a long-acting drug to
prevent recrudescence and development of resistance.
The fixed-dose oral combination artemether-lumefantrine
(CoArtem
W/Riamet
W, Novartis, Switzerland) is increasing-
ly used for treatment of P. falciparum malaria in travellers
returning to non-endemic areas, and is the first-line drug
for uncomplicated malaria at Karolinska University Hospi-
tal in Stockholm since 2010. The drug combination is also
recommended as follow-up treatment to artesunate in
patients recovering from severe P. falciparum malaria. The
present report describes artemether-lumefantrine treatment
failure in a traveller with P. falciparum malaria after
returning from Tanzania.
Case Report
A 57-year old man of Swedish descent presented at
Karo-linska University Hospital, on June 29, 2011, with a
one-day history of fever, chills, headache and loose stool,
two weeks after returning from Tanzania where he had
been working intermittently for a few years. He had dis-
continued atovaquone-proguanil chemoprophylaxis one
month before leaving endemic area. He reported being
previously healthy except an episode of necrotizing fasci-
itis in the left thigh six months earlier.
On examination, the patient had prominent chills
without any other clinical findings and C-reactive pro-
tein (CRP) was 166 mg/l, haemoglobin 171 g/l, platelet
72x10
9/l, bilirubin 33 μmol/l. He was started on intra-
venous cefotaxime and fluids for a suspected bacteremia,
and artemether-lumefantrine (20 mg/120 mg Riamet
W;4
tablets per dose at 0, 8, 24, 36, 48 and 60 hours) was
prescribed after microscopy had shown 0.1% P.
falciparum infected erythrocytes. The first dose was
however delayed and parasitaemia peaked at 1.3% before
decreasing promptly during treatment (Figure 1). Due to
persistent fever and high CRP (369 mg/l) on the second
day, cefotaxime was changed to ceftazidime and a single
dose gentamicin for treatment of a potential concurrent
bacteraemia. The patient was discharged free of symp-
tom after five days and prescribed one week oral
* Correspondence: anna.farnert@ki.se
ˆDeceased
1Infectious Diseases Unit, Department of Medicine Solna, Karolinska Institutet,
Stockholm, Sweden
2Department of Infectious Diseases, Karolinska University Hospital, SE-171 76
Stockholm, Stockholm, Sweden
Full list of author information is available at the end of the article
© 2012 Färnert et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Färnert et al. Malaria Journal 2012, 11:176
http://www.malariajournal.com/content/11/1/176ciprofloxacin. Cultures from blood, urine and stool taken
at and during admission were all negative. Malaria micros-
copy was negative at discharge as well as two days later.
On July 23 (24 days after treatment start), the patient
presented at the emergency room with high fever since
two-three days, jaundice, hypotension (systolic blood
pressure 80) and slightly impaired consciousness. He
responded promptly to intravenous fluids. CRP was
64 mg/l, hemoglobin 115 g/l, platelet count 116x10
9/l,
bilirubin 49 μmol/l, arterial blood gas and other tests
were normal. Blood films were again positive for P.
falciparum and oral mefloquine was started based on
0.4% parasitaemia estimated by the physician on call.
The initial parasitaemia was reevaluated to 2.6% by the
microbiology department the following day. The patient
recovered promptly and the mefloquine course was
completed. He was discharged three days after admis-
sion. On follow up one month later, the patient reported
no symptoms since discharge and microscopy of blood
films was negative for malaria parasites.
In order to elucidate the cause of treatment failure, fro-
zen EDTA plasma and blood, sampled as part of a mal-
aria immunology study, were assessed with the patient’s
consent. Species-specific PCR of the ssRNA gene con-
firmed the presence of only P. falciparum. Genotyping of
the polymorphic merozoite surface protein 2 gene (msp2)
[2] detected the same two alleles (336 bp FC27 and
487 bp IC-1 fragments) at both episodes.
Drug concentrations were measured by liquid chromatog-
raphy coupled to tandem mass-spectrometry (LC-MS/MS)
in plasma collected on day 6 and 25 after initiating
artemether-lumefantrine (Figure 1). Both artemether and
dihydroartemisinin concentrations were below the limit of
d e t e c t i o n( 0 . 5n g / m l )i na l ls a m p l e sa se x p e c t e db e c a u s eo f
their very short half-lives (2–3 hrs) [3]. The lumefantrine
concentrations were 498 ng/ml on day 6 and 39.5 ng/ml
on day 25, while the metabolite desbutyl lumefantrine was
2.94 ng/ml and below detection (0.25 ng/ml), respectively.
Genotyping of drug resistance markers [4] revealed
the same profiles at both episodes; the P. falciparum
chloroquine resistance (pfcrt) 76 K allele, the multidrug
resistance 1 (pfmdr1) 86 N allele, and single copies of
the pfmdr1 gene.
Discussion
Artemether-lumefantrine is one of the most widely used
ACT for treatment of uncomplicated P. falciparum mal-
aria in sub-Saharan Africa. Previous four-dose regime
was associated with 15% treatment failure, whereas, the
now recommended six-dose regime showed, in a recent
pooled analysis, a 28-day PCR-corrected parasitological
cure rate of 97% in malaria endemic areas [5].
The effect of anti-malarial drugs in patients treated in
non-endemic areas is less studied, but can be highly
informative since patients are non-immune and not sub-
ject to re-exposure. Treatment failures with artemether-
lumefantrine have been reported in two travellers after
visiting Sierra Leone [6]and Congo [7]. Since lumefan-
trine is highly lipophilic and bioavailability depends on
concurrent food intake [8], these failures have, in the
Figure 1 Recrudescence of P. falciparum in a traveller treated with artemether-lumefantrine (Riamet
W, Novartis). The P. falciparum
parasitaemia (% infected erythrocytes as filled circles) decreased promptly after artemether-lumefantrine treatment was initiated (day 0) and
symptoms reappeared on day 21. The second episode was treated successfully with mefloquine. Plasma concentrations of artemether,
dihydroartemisinin, lumefantrine and desbutyl lumefantrine were assessed on day 6 and day 25. Lumefantrine concentrations (open triangles)
are shown in the graph whereas the other results are stated in the text.
Färnert et al. Malaria Journal 2012, 11:176 Page 2 of 4
http://www.malariajournal.com/content/11/1/176absence of pharmacological assessments, been specu-
lated to be due to sub-optimal lumefantrine concentra-
tions. Also different sets of parasite populations have
been suggested to have caused the recurrent episodes.
Here, a late treatment failure of artemether-lumefantrine
is described in a traveller despite adequate plasma
concentrations of lumefantrine. Genotyping showed the
same msp2, pfcrt and mdr1 patterns, confirming parasite
recrudescence. Despite that the patient reported nausea
(without vomiting) and not eating the first day, the lume-
fantrine concentration (498 ng/ml) on day 6 corresponded
to what has been estimated to be sufficient to prevent re-
crudescence, i.e. day 7 concentration >280 ng/mL [8,9].
Artemether and dihydroartemisinin were, as expected due
to their short half-lives, below the level of detection on day
6. A recent publication points to desbutyl lumefantrine
possibly being a better predictor for treatment outcome
than lumefantrine [10], and the desbutyl lumefantrine con-
centration in the traveller (2.96 ng/ml) was in the same but
lower range of that in children with successful outcome
(mean 15.5 range 0.6-58.2 ng/ml). Little is known about
the pharmacokinetics of desbutyl lumefantrine and the
exact relevance of a therapeutic threshold for the metabol-
ite needs further studies.
Reduced in vivo sensitivity to artemisinin has so far
only been reported from Cambodia as reduced parasite
clearance time [11]. Reduced in vitro susceptibility to ar-
temisinin has also been described in a traveller returning
from South East Asia [12]. Here, the prompt reduction
of parasitaemia suggests good effect of artemether/
dihydroartemisinin. The late treatment failure might,
however, suggest reduced sensitivity to lumefantrine
since the concentrations were well above therapeutic
cut-off. This is further supported by the finding of pfcrt
76 K and pfmdr1 86 N alleles that have been associated
with a five-fold increase of lumefantrine inhibitory con-
centration in vitro (IC50) and also found to be selected
for after treatment with artemether-lumefantrine
in vivo in Kenya [13] and Tanzania [14]. Not finding
multiple copies of pfmdr1, also associated with reduced
sensitivity to lumefantrine, might argue against this.
However, multiple copies of pfmdr1 have only rarely
been described in Africa. In vitro susceptibility testing
could have confirmed resistance however parasites
were not available for culture.
The patient was administered several antibiotics and
paracetamol at the time of artemether-lumefantrine
treatment. Some reduced effect (higher recrudescence
rates) have been seen when co-medicated with quinine,
a drug with the same biotransformation pathway as
lumefantrine (CYP 3A4) [15]. Moreover, ciprofloxacin
which has been shown to have anti-malarial effect [16]
was administered for one week. Although the present co-
medication is not expected to have affected concentrations,
interactions with other drugs might need further
investigations.
In the current, as well as previous treatment failures in
travellers, symptoms reappeared on day 14–24 after start-
ing artemether-lumefantrine, reflecting late clinical failure
[6,7]. Interestingly, the symptoms were more pronounced
and the parasite densities higher at recrudescence [7].
Although this is probably due to patients waiting longer
before seeking care (not believing it to be malaria again),
milder symptoms might have been expected considering
potential “strain-specific” immunity.
Rapid reduction of parasite biomass and symptoms to-
gether with few side effects has forwarded artemether-
lumefantrine as an attractive alternative to mefloquine
and atovaquone-proguanil for treatment of uncompli-
cated P. falciparum malaria in travellers. Although
several studies show that artemether-lumefantrine does
not have full efficacy, the drug combination has meet
WHO>95% cure rates [1], and is recommended as six-
dose regimen in all areas irrespective of levels of drug
resistance or host immunity.
The treatment failure described here might have been
due to reduced sensitivity to lumefantrine but subopti-
mal concentrations of desbutyl lumefantrine and a
missed dose cannot be fully ruled out even if the lume-
fantrine concentrations were adequate. Drugs chosen
for treatment of P. falciparum malaria, especially in
non-immune highly vulnerable individuals such as chil-
dren and travellers, should preferably be efficacious
enough to allow for single missed doses or uneven drug
absorption. In endemic areas, partial immunity is likely
to contribute to the effect of antimalarial drugs and thus
overestimate cure rates. In line with this, decreasing ef-
fect of artemether-lumefantrine was indeed seen in an
area of decreasing malaria transmission and immunity
[17].
The present case forwards the need to further monitor
the effect of artemether-lumefantrine treatment of P.
falciparum malaria. Patients should be well informed to
seek prompt care in the event of fever the weeks after
completing artemether-lumefantrine treatment.
Conflicts of interest
All authors declare no conflicts.
Acknowledgements
We wish to thank Professor Nicholas White for kind support.
Author details
1Infectious Diseases Unit, Department of Medicine Solna, Karolinska Institutet,
Stockholm, Sweden.
2Department of Infectious Diseases, Karolinska University
Hospital, SE-171 76 Stockholm, Stockholm, Sweden.
3Department of Clinical
Microbiology, Karolinska University Hospital, Stockholm, Sweden.
4Mahidol-
Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine,
Mahidol University, Bangkok, Thailand.
5Centre for Tropical Medicine, Nuffield
Department of Clinical Medicine, University of Oxford, Oxford, UK.
Färnert et al. Malaria Journal 2012, 11:176 Page 3 of 4
http://www.malariajournal.com/content/11/1/176Authors’ contributions
AF, JU and NL conceived the case report. TT, LK and ES were involved in the
management of the patient. JU and JR performed molecular typing. NL was
responsible for analysis of drug concentrations. AF, TT, JU and NL wrote the
paper. The authors read and approved the final manuscript.
Received: 22 March 2012 Accepted: 25 May 2012
Published: 25 May 2012
References
1. World Health Organization: Guidelines for the treatment of malaria.
http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf.
2. Liljander A, Wiklund L, Falk N, Kweku M, Martensson A, Felger I, Färnert A:
Optimization and validation of multi-coloured capillary electrophoresis
for genotyping of Plasmodium falciparum merozoite surface proteins
(msp1 and 2). Malar J 2009, 8:78.
3. Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U,
Gathmann I, Mull R, Bakshi R: A clinical and pharmacokinetic trial of six
doses of artemether-lumefantrine for multidrug-resistant Plasmodium
falciparum malaria in Thailand. AmJTrop Med Hyg 2001, 64:247–256.
4. Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S,
Nash D, Singhasivanon P, Anderson TJ, Krishna S, White NJ, Nosten F:
Molecular and pharmacological determinants of the therapeutic
response to artemether-lumefantrine in multidrug-resistant Plasmodium
falciparum malaria. Clin Infect Dis 2006, 42:1570–1577.
5. Makanga M, Bassat Q, Falade CO, Premji ZG, Krudsood S, Hunt P, Walter V,
Beck HP, Marrast AC, Cousin M, Rosenthal PJ: Efficacy and safety of
artemether-lumefantrine in the treatment of acute, uncomplicated
Plasmodium falciparum malaria: a pooled analysis. AmJTrop Med Hyg
2011, 85:793–804.
6. Mizuno Y, Kato Y, Kudo K, Kano S: First case of treatment failure of
artemether-lumefantrine in a Japanese traveler with imported
falciparum malaria. Jpn J Infect Dis 2009, 62:139–141.
7. Repetto EC, Traverso A, Giacomazzi CG: Possible clinical failure of
artemether-lumefantrine in an italian traveler with uncomplicated
falciparum malaria. Mediterr J Hematol Infect Dis 2011, 3:e2011041.
8. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ:
Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol)
in acute falciparum malaria. Antimicrob Agents Chemother 2000,
44:697–704.
9. Methods and techniques for assessing exposure to antimalarial drugs in clinical
field studies. http://www.wwarn.org/sites/default/files/
AssessingExposureToAntimalarials.pdf.
10. Wong RP, Salman S, Ilett KF, Siba PM, Mueller I, Davis TM: Desbutyl-
lumefantrine is a metabolite of lumefantrine with potent in vitro
antimalarial activity that may influence artemether-lumefantrine
treatment outcome. Antimicrob Agents Chemother 2011, 55:1194–1198.
11. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F,
Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K,
Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegårdh N,
Socheat D, White NJ: Artemisinin resistance in Plasmodium falciparum
malaria. N Engl J Med 2009, 361:455–467.
12. Pradines B, Bertaux L, Pomares C, Delaunay P, Marty P: Reduced in vitro
susceptibility to artemisinin derivatives associated with multi-resistance
in a traveller returning from South-East Asia. Malar J 2011, 10:268.
13. Mwai L, Kiara SM, Abdirahman A, Pole L, Rippert A, Diriye A, Bull P, Marsh K,
Borrmann S, Nzila A: In vitro activities of piperaquine, lumefantrine, and
dihydroartemisinin in Kenyan Plasmodium falciparum isolates and
polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother 2009,
53:5069–5073.
14. Sisowath C, Strömberg J, Mårtensson A, Msellem M, Obondo C, Björkman A,
Gil JP: In vivo selection of Plasmodium falciparum pfmdr1 86 N coding
alleles by artemether-lumefantrine (Coartem). J Infect Dis 2005, 191:1014–
1017.
15. Lefevre G, Carpenter P, Souppart C, Schmidli H, Martin JM, Lane A, Ward C,
Amakye D: Interaction trial between artemether-lumefantrine (Riamet)
and quinine in healthy subjects. J Clin Pharmacol 2002, 42:1147–1158.
16. Goodman CD, Su V, McFadden GI: The effects of anti-bacterials on the
malaria parasite Plasmodium falciparum. Mol Biochem Parasitol 2007,
152:181–191.
17. Borrmann S, Sasi P, Mwai L, Bashraheil M, Abdallah A, Muriithi S, Fruhauf H,
Schaub B, Pfeil J, Peshu J, Hanpithakpong W, Rippert A, Juma E, Tsofa M,
Mosobo M, Lowe B, Osier F, Fegan G, Lindegardh N, Nzila A, Peshu N,
Mackinnon M, Marsh K: Declining responsiveness of Plasmodium
falciparum infections to artemisinin-based combination treatments on
the Kenyan coast. PLoS One 2011, 6:e26005.
doi:10.1186/1475-2875-11-176
Cite this article as: Färnert et al.: Artemether–lumefantrine treatment
failure despite adequate lumefantrine day 7 concentration in a traveller
with Plasmodium falciparum malaria after returning from Tanzania.
Malaria Journal 2012 11:176.
Submit your next manuscript to BioMed Central
and take full advantage of: 
• Convenient online submission
• Thorough peer review
• No space constraints or color ﬁgure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at 
www.biomedcentral.com/submit
Färnert et al. Malaria Journal 2012, 11:176 Page 4 of 4
http://www.malariajournal.com/content/11/1/176

A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. AmJTrop Med Hyg

Amakye D: Interaction trial between artemether-lumefantrine (Riamet) and quinine in healthy subjects.

CG: Possible clinical failure of artemether-lumefantrine in an italian traveler with uncomplicated falciparum malaria. Mediterr J Hematol Infect Dis

Färnert A: Optimization and validation of multi-coloured capillary electrophoresis for genotyping of Plasmodium falciparum merozoite surface proteins (msp1 and 2). Malar J

First case of treatment failure of artemether-lumefantrine in a Japanese traveler with imported falciparum malaria.

GI: The effects of anti-bacterials on the malaria parasite Plasmodium falciparum. Mol Biochem Parasitol

JP: In vivo selection of Plasmodium falciparum pfmdr1 86 N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis

Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis

Nzila A: In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother

Organization: Guidelines for the treatment of malaria.

PJ: Efficacy and safety of artemether-lumefantrine in the treatment of acute, uncomplicated Plasmodium falciparum malaria: a pooled analysis. AmJTrop Med Hyg

Reduced in vitro susceptibility to artemisinin derivatives associated with multi-resistance in a traveller returning from South-East Asia. Malar J

techniques for assessing exposure to antimalarial drugs in clinical field studies. http://www.wwarn.org/sites/default/files/ AssessingExposureToAntimalarials.pdf.

TM: Desbutyllumefantrine is a metabolite of lumefantrine with potent in vitro antimalarial activity that may influence artemether-lumefantrine treatment outcome. Antimicrob Agents Chemother

White NJ: Artemisinin resistance in Plasmodium falciparum malaria.

White NJ: Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother

Artemether-Lumefantrine Treatment Failure despite adequate lumefantrine day 7 Concentration in a Traveller with Plasmodium Falciparum Malaria after Returning from Tanzania.

http://ihi.eprints.org/2218/1/Anna_F%C3%A4rnert.pdf

Artemether-Lumefantrine Treatment Failure despite adequate lumefantrine day 7 Concentration in a Traveller with Plasmodium Falciparum Malaria after Returning from Tanzania.

Abstract

Similar works

Full text

Available Versions

Digital Library of the Tanzania Health Community