Treatment of imported severe malaria with artesunate instead of quinine--more evidence needed? Cramer, J.P.; López-Vélez, R.; Burchard, G.D.; Grobusch, M.P.; de Vries, P.J

Jakob P Cramer

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Treatment of imported severe malaria with artesunate instead of quinine--more evidence
needed?
Cramer, J.P.; López-Vélez, R.; Burchard, G.D.; Grobusch, M.P.; de Vries, P.J.
Published in:
Malaria Journal
DOI:
10.1186/1475-2875-10-256
Link to publication
Citation for published version (APA):
Cramer, J. P., López-Vélez, R., Burchard, G. D., Grobusch, M. P., & de Vries, P. J. (2011). Treatment of
imported severe malaria with artesunate instead of quinine--more evidence needed? Malaria Journal, 10(1), 256.
https://doi.org/10.1186/1475-2875-10-256
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COMMENTARY Open Access
Treatment of imported severe malaria with
artesunate instead of quinine - more evidence
needed?
Jakob P Cramer1*, Rogelio López-Vélez2, Gerd D Burchard1, Martin P Grobusch3 and Peter J de Vries3
Abstract
Rapid and fast acting anti-malarials are essential to treat severe malaria. Quinine has been the only option for
parenteral therapy until recently. While current evidence shows that intravenous artesunate is more effective than
quinine in treating severe malaria in endemic countries, some questions remain regarding safety profiles and drug
resistance. For imported severe malaria, additional unanswered questions are related to generalizability of the
findings from endemic countries and to legal aspects, as there is no Good Manufacturing Practice-conform drug
available yet. Here, the implications of existing evidence for the treatment of imported severe malaria are
discussed.
Background
Treatment of severe malaria requires prompt administra-
tion of safe and fast acting anti-malarials. While approxi-
mately 4% of all imported malaria cases progress to severe
malaria, the overall mortality rate of imported Plasmo-
dium falciparum malaria in Europe is 0,4% [1]. Until
recently, quinine was the only option for parenteral ther-
apy. Two large multinational randomized controlled
unblinded trials (RCTs) have been conducted to compare
intravenous quinine versus artesunate in malaria-endemic
countries in Southeast Asia (SEAQUAMAT) and in sub-
Saharan Africa (AQUAMAT) [2,3]. The evidence from
these and some smaller trials supports the choice of arte-
sunate over quinine in the treatment of severe malaria in
endemic regions. But is this evidence sufficient to finally
implement this anti-malarial in the treatment of imported
severe malaria in non-endemic countries?
Discussion
First, is it of concern that none of the existing trials has
been performed as a double blind comparative study?
This appears to be less important with respect to effec-
tiveness as the end-point of the two large studies was
mortality. However, some limitations regarding outcomes
such as adverse events or (neurologic) sequelae remain
and from a regulatory perspective this may well be of
concern.
Second, can the existing evidence from endemic coun-
tries be generalized to imported severe malaria in indus-
trialized, non-endemic, countries? Clinical manifestations,
supportive intensive medical care and patient characteris-
tics differ in endemic versus non-endemic countries. In
particular, the following limitations have to be addressed: i)
most evidence has been obtained from children while the
great majority of patients with imported severe malaria are
adults, ii) quinine monotherapy was used which does not
completely reflect the often used combination of quinine
with doxycycline or clindamycin in imported severe
malaria, iii) the study population included a large variety of
individuals from Southeast Asia, India and Africa. The
characteristics of the study population with regard to eth-
nic, nutritional and general health aspects as well as to
immunologic aspects (semi-immunity) may be different for
patients with imported malaria (mostly caucasians,
migrants). And lastly but possibly most importantly, iv),
supportive care other than anti-malarial treatment may dif-
fer significantly in endemic settings versus hospitals in
industrialized countries. Patients with imported malaria are
monitored on intensive care units (ICU) and organ replace-
ment therapy can be initiated promptly in case of renal or
pulmonary insufficiency. Albeit speculative due to lacking
* Correspondence: cramer@bni-hamburg.de
1Bernhard Nocht Clinic for Tropical Medicine, I. Department of Tropical
Medicine, University Medical Center Hamburg-Eppendorf, Bernhard-Nocht-
Strasse 74, 20359 Hamburg, Germany
Full list of author information is available at the end of the article
Cramer et al. Malaria Journal 2011, 10:256
http://www.malariajournal.com/content/10/1/256
© 2011 Cramer 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.
evidence, these aspects appear to be major reasons why
mortality is lower in imported versus endemic severe
malaria.
The beneficial characteristics of artesunate are well
known: it is a fast acting drug against several parasite
stages including gametocytes [4,5], it has an apparently
beneficial safety profile, and it reduces cytoadherence
[6,7]. Better survival rates are observed among patients
with severe malaria, particularly in those with high parasi-
taemia. This in turn may shorten the stay in the intensive
care unit, which is beneficial for both the patient and the
hospital. Shorter hospitalization also subsequently
decreases the risk of nosocomial infections, which are
quite frequently observed also in imported severe malaria
[8]. Clinical benefits have been summarized recently in a
meta-analysis [9].
Quinine, on the other hand, is rightfully claimed to be a
drug with a narrow therapeutic window bearing the risk of
a range of potential side effects like hypoglycaemia, agra-
nulocytosis, bleeding disorders, cardiovascular effects and
others which are particularly relevant for elderly patients
[10]. While the administration of a bolus injection of arte-
sunate is simple, the administration of quinine by continu-
ous infusion is more complex. Furthermore, artesunate
does not require dose reduction in renal insufficiency and
there are no known drug-interactions while previous
intake of mefloquine necessitates dose modifications
of quinine. However, the adverse effects of quinine are
well known and can be closely monitored under ICU-
conditions.
Although artesunate has been used for the treatment of
large numbers of patients, both in trials and under rou-
tine conditions, data on tolerability and safety on artesu-
nate treatment are still limited for various reasons such
as short hospitalization and follow-up time or incomplete
laboratory measurements of adverse events in endemic
countries. For example, cases of late-onset haemolysis
have been reported recently occurring after artesunate
treatment and this effect had not been documented in
the published trials [11]. Furthermore, the relevance of
additional safety aspects, including neurotoxicity, haema-
totoxicity/neutropaenia, embryotoxicity as well as allergic
reactions, has not finally been clarified: toxic effects have
been described in animals, but not in humans and they
appear to be - in part - dose-dependent or may be related
to delayed drug release after intramuscular application of
arthemether/arteether but not to intravenous artesunate
[12,13]. Not to forget that unanswered questions remain
with respect to early evidence of drug resistance arising
from Southeast Asia [14,15].
Finally, the currently available artesunate, produced by
Guilin Pharmaceutical Company - the same product that
was used in the -QUAMAT trials - is not being produced
under conditions of full Good Manufacturing Practice
(GMP). Guilin Pharmaceutical Company received pre-
qualification by the World Health Organization in
November 2010 but this is not the same as GMP certifi-
cation by the European Medicines Agency (EMA) or US
Food and Drug Agency. While there is no GMP-artesu-
nate available in most countries and no licensed artesu-
nate in any developed country, the availability of quinine
is quite heterogeneous as well. In most industrialized
countries, quinine is available through extemporaneous
preparation. However, quinine is difficult to obtain or
not available for intravenous administration in some
European countries and the USA. Instead, a mixture of
the four cinchona alkaloids (Quinimax®) rather than
pure quinine salt is used in some European countries,
which renders the therapy more heterogeneous with
respect to pharmacokinetics and pharmacodynamics.
While in the USA, a GMP-conform iv-artesunate has
been made available but is not FDA-registered quinidine,
which is more toxic than quinine still remains the first-
line drug [16,17]. This background contributes to the fact
that with the exception of the Netherlands and Australia,
artesunate has not (yet) been incorporated as clear first-
line drug in developed countries despite existing clear
evidence on anti-malarial superiority of artesunate over
quinine. In this context, it appears adequate to note that
the manufacturing process and the quality of the quinine
used in the -QUAMAT trials made by Indus Pharma,
Karachi/Pakistan, may not be comparable with those of
the artesunate from Guilin, which has been inspected to
its compliance with WHO requirements for essential
drugs.
Conclusion
So, is additional evidence needed for replacing quinine as
the drug of first choice in Europe and the USA? First, the
anti-malarial superiority of artesunate over quinine has
been established in endemic countries, but the effect could
be smaller in developed countries. Second, additional data
on drug safety are necessary, but can most likely only be
obtained from surveys in developed countries. One may
argue that none of the drugs currently used to treat
imported severe malaria was ever studied by appropriate
clinical trials and that evidence has always been extrapo-
lated from paediatric treatment data in endemic areas. But
this appears to be a flimsy argument in times of evidence-
based treatment guidelines. However, a comparative study
on imported severe malaria appears not to be feasible for
several reasons: i) an unrealistically high number of sub-
jects was needed if the outcome was mortality while other
(combined) outcomes may not unequivocally answer rele-
vant questions, ii) returning travellers are a very heteroge-
neous patient group requiring stratification (e.g. migrants
visiting family and friends versus tourist travellers), and,
probably most important, iii) many travel medicine experts
Cramer et al. Malaria Journal 2011, 10:256
http://www.malariajournal.com/content/10/1/256
Page 2 of 3
would not be willing to randomize patients into artesunate
versus quinine arms anymore given existing evidence and
respective recommendations.
Despite the fact that artesunate is not a licensed drug in
Europe it has been made available within compassionate
use programmes via a few import companies (e.g. ACE
Pharmaceuticals BV, the Netherlands, or Idis Pharma, UK)
or it can be ordered directly from the manufacturer, Guilin
Pharmaceutical Corporation in China. In the USA, the
FDA has approved an investigational new drug protocol
and GMP-conform intravenous artesunate has been made
available via CDC/Walter Reed Army Institute of Research
[6]. There are several pharmaceutical initiatives that aim
for production under full GMP conditions (e.g. Sigma
Tau, Italy) but it is still unclear when GMP-conform intra-
venous artesunate will become available in Europe. Several
centers specialized in tropical/travel medicine have started
to use intravenous artesunate and anecdotally confirm the
clear shortening of the critical illness phase using artesu-
nate in imported severe malaria supporting first data from
the USA [18].
The most realistic approach is allowing the product to
be used in a controlled fashion and to proactively docu-
ment efficacy and toxicity. Since there are no established
legal procedures for such a careful introduction of a still
unregistered drug, clinicians and researchers have to take
the lead. We have to organize ourselves and start collect-
ing data on the use of artesunate for severe malaria in a
concerted action. Properly collected post-introduction
data are the most realistic alternative to the impossible
option of prospectively collecting data in a comparative
clinical trial. Such initiatives have already been put in
place in Europe.
Author details
1Bernhard Nocht Clinic for Tropical Medicine, I. Department of Tropical
Medicine, University Medical Center Hamburg-Eppendorf, Bernhard-Nocht-
Strasse 74, 20359 Hamburg, Germany. 2Department of Infectious Diseases,
Tropical Medicine and Clinical Parasitology, Ramón y Cajal Hospital,
University of Alcalá, Carretera de Colmenar Km 9,1, 28034 Madrid, Spain.
3Division of Infectious Diseases, Tropical Medicine and AIDS, Department of
Medicine, Amsterdam Medical Center, University of Amsterdam, PO Box
22600, 1100 DE Amsterdam, The Netherlands.
Conflicts of interests
The authors declare that they have no competing interests.
Received: 1 July 2011 Accepted: 7 September 2011
Published: 7 September 2011
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doi:10.1186/1475-2875-10-256
Cite this article as: Cramer et al.: Treatment of imported severe malaria
with artesunate instead of quinine - more evidence needed? Malaria
Journal 2011 10:256.
Cramer et al. Malaria Journal 2011, 10:256
http://www.malariajournal.com/content/10/1/256
Page 3 of 3


Treatment of imported severe malaria with artesunate instead of quinine - more evidence needed?

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Treatment of imported severe malaria with artesunate instead of quinine - more evidence needed?

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