Artesunate-Clindamycin versus Quinine-Clindamycin in the Treatment of Plasmodium

falciparum Malaria: A Randomized Controlled Trial

Author(s): Michael Ramharter, Sunny Oyakhirome, Peter Klein Klouwenberg, Ayola A.
Adégnika, Sélidji T. Agnandji, Michel A. Missinou, Pierre-Blaise Matsiégui, Benjamin
Mordmüller, Steffen Borrmann, Jürgen F. Kun, Bertrand Lell, Sanjeev Krishna, Wolfgang
Graninger, Saadou Issifou and Peter G. Kremsner
Source: Clinical Infectious Diseases, Vol. 40, No. 12 (Jun. 15, 2005), pp. 1777-1784
Published by: Oxford University Press
Stable URL: http://www.jstor.org/stable/4484296
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 MAJOR ARTICLE

Artesunate-Clindamycan versus Quinine-Clindam

in ie Treatnent of Plasmodium falciparum Malaia:
A Randomized Controlled Tral

Michael Ramharter,1Jn Sunny Oyakhirome,2 Peter Klein Klouwenberg,' Ayola A. Adegnika,'2 Selidii T. Agnandii,
Michel A. Missinou,12 Pierre-Blaise Matsiegui,12 Benjamin Mordmuller,'2 Steffen Borrmann,12 Jurgen F. Kun,2
Bertrand Lell," Sanjeev Krishna,4 Wolfgang Graninger,3 Saadou Issifou,2 and Peter G. Kremsner12
'Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon; 'Institute of Tropical Medicine, Department of Parasitology, University
of TObingen, Tubingen, Germany; 3Department of Internal Medicine 1, Division of Infectious Diseases, Medical University of Vienna, Vienna,
Austria; and 4Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom

Background. Artemisinin-based drug combinations are the mainstay in the fight against drug-resistant malaria
in Africa. Currently available antimalarial drug combinations that include artemisinins are pharmacokinetically
unmatched and are therefore potentially increasing the risk of selection of resistant mutants in areas in which the
rate of transmission of malaria is high. We tested the potential value of artemisinin-based combination therapy
with a short elimination half-life for the treatment of uncomplicated Plasmodium falciparum malaria in sub-
Saharan Africa.
Methods. We conducted an open-label, randomized, controlled clinical trial to evaluate the efficacy and
tolerability of oral artesunate-clindamycin therapy given twice daily for 3 days (artesunate, 2 mg/kg, and clinda-
mycin, 7 mg/kg, per dose), compared with a standard quinine-clindamycin regimen given twice daily for 3 days
(quinine, 15 mg/kg, and clindamycin, 7 mg/kg, per dose), for the treatment of uncomplicated falciparum malaria
in 100 Gabonese children aged 3-12 years. The primary end point of the study was the polymerase chain reaction-
corrected cure rate for the per-protocol population.
Results. The activity of artesunate-clindamycin was comparable to that of quinine-clindamycin in the per-
protocol analysis of cure rates at day 28 of follow-up (87% versus 94%). No serious adverse events were reported,
and tolerability was good and was similar in both groups. Times to clearance of fever and clearance of parasites
were significantly shorter in the artesunate-clindamycin group.
Conclusions. Artesunate-clindamycin and other matching artemisinin-based combinations with a short plasma
half-life merit further attention for use in regions in which the rate of transmission of malaria is high.

During the past decades, the malaria-associated mor- Various drugs have been studied in combination with
bidity and mortality in sub-Saharan Africa have in- artemisinin derivatives [5]. To date, the underlying
creased because of the emergence and spread of resis- principle has been to combine artemisinins with drugs
tance to the most commonly used antimalarials [1, 2]. that have a long plasma elimination half-life. Although
Therefore, artemisinin-based combination therapy has good results have been obtained in regions of low en-
been advocated by the World Health Organization demicity for malaria, combination therapy involving
(WHO) as the mainstay in combating drug-resistant drugs with different pharmacokinetic profiles seems to
malaria in Africa [3]. be inappropriate for patients in areas in which the rate
Combining antimalarial drugs increases their efficacy of transmission of malaria is high, because of the in-
and hinders the development of resistant isolates [4]. creased risk of selection of drug-resistant mutants that

results from prolonged exposure to subtherapeutic drug

levels of the slowly eliminated drug in the combination
Received 20 November 2004; accepted 3 February 2005; electronically published
3 May 2005.
[6, 7]. Combination therapy that involves the use of
Reprints or correspondence: Dr. Peter G. Kremsner, Institute of Tropical Medicine, drugs that have a fast elimination time is thought to
Wilhelmstrasse 27, 72074 Tubingen, Germany (peter.kremsner@uni-tuebingen.de).
lead to reduced selection of and mutual protection
Clinical Infectious Diseases 2005;40:1777-84
? 2005 by the Infectious Diseases Society of America. All rights reserved.
against resistant isolates [4, 7]. However, to date, no
1058-4838/2005/4012-001 1$1 5.00 clinical trial of matching artemisinin-based combina-

Artesunate-Clindamycin for Malaria Treatment * CID 2005:40 (15 June) * 1777

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tion regimens with short half-lives has been reported from sub-
Saharan Africa [5].
Clindamycin was chosen as the most promising drug with
a short half-life that could be used in combination with artem-
isinin derivatives, on the basis of encouraging results from an-
imal models, in vitro studies of Plasmodium falciparum, and
one report of the use of sequential treatment with artesunate
and clindamycin for Brazilian children [8-10]. Characterized
by slow but thorough antimalarial activity, clindamycin exhibits first drug combination, artesunate, 2 mg/kg, was administered
a remarkably short plasma half-life (2-4 h) and a good safety
and tolerability profile in antimalarial therapy [11]. We com-
pared the efficacy and tolerability of artesunate combined with
clindamycin with the efficacy and tolerability of standard qui-
nine-clindamycin therapy for the treatment of uncomplicated
P. falciparum malaria in Gabonese children.
METHODS
Study area. A clinical trial was conducted at the Medical Re-
search Unit of the Albert Schweitzer Hospital in Lambarene,
Gabon, from December 2003 through May 2004. Lambaren6 is
a semiurban city of -30,000 inhabitants that is located amid the
Randomization codes were computer generated in blocks of
10, placed in sealed envelopes, and provided to the Medical
Research Unit at initiation of the study. The study physician
opened each envelope containing the respective treatment al-
location, only after each patient was judged to be eligible for
inclusion in the study.
Study drugs were administered orally with water or other
liquids, under the supervision of a study physician. For the
in combination with clindamycin, 7 mg/kg; for the second drug
combination, quinine sulfate, 15 mg/kg, was administered in
combination with clindamycin, 7 mg/kg. Drugs were admin-
istered every 12 h for a total of 6 doses. If vomiting occurred
within 30 min after drug intake, the same dose was readmin-
istered. If vomiting occurred within 30 min after readminis-
tration of the dose, patients were withdrawn from the clinical
trial and a "rescue treatment" was given. Artesunate (Arsumax;
Sanofi-Synthelabo) was formulated as 50-mg tablets; quinine
sulphate (Pharmamed), as 300-mg tablets; and clindamycin
(Dalacin; Pfizer), as 75-mg and 150-mg capsules.
Patients were followed up twice daily for 3 days or until

tropical rainforest of Gabon. Malaria transmission is perennial, clinical signs resolved and negative results were obtained for 2
and it has a hyperendemic pattern and an entomological inoc- consecutive thick blood smears. Patients were encouraged to

ulation rate of -50 infective bites per person per year [12]. present to the Medical Research Unit if signs or symptoms

Study design and enrollment. The study was designed as reappeared. Follow-up visits were scheduled on days 7, 14, and

an open-label, randomized, controlled clinical trial. One hun- 28 of follow-up. At each follow-up visit, vital signs and tym-

dred children were enrolled in the study. Ethical clearance was panic temperature were assessed, and a thick blood smear was

obtained from the ethics committee of the International Foun- examined. Complete blood counts were determined again on
dation for the Albert Schweitzer Hospital in Lambarene. Pa- days 2 and 28 of follow-up. Dried capillary blood spots were
tients who presented at the outpatient department of the Albert obtained at enrollment and, again, if asexual parasitemia reap-
Schweitzer Hospital were invited to participate in the study if peared, to distinguish reinfections from recrudescent infections
they met the following criteria for inclusion: (1) age of 3-12 by use of PCR-based genotyping.
years, (2) the presence of microscopically confirmed P. falci- Laboratory analysis. DNA extraction and amplification of
parum monoinfection with signs and symptoms of uncompli- merozoite surface antigen 2 were performed as described else-
cated malaria, (3) asexual parasitemia (1000-100,000 parasites/ where [ 15] . Parasite isolates recovered at enrollment and at the
ytL of peripheral blood), (4) body weight of 10-70 kg, (5) ability time of reappearance of asexual parasitemia were compared on
to tolerate oral therapy, and (6) written, informed consent of the basis of their size and the number of fragments, and they
the parents or legal representatives and oral consent of the child. were classified as recrudescing parasite strains or reinfections.
Exclusion criteria consisted of the following: (1) signs and There was no adjustment for a potentially confounding con-
symptoms of severe malaria (as defined by WHO criteria [ 13]),current presence of sexual parasite stages at the time of reap-
(2) current antibiotic treatment or a history of antimalarial pearance of asexual parasites.
drug use in the 7 days preceding presentation, (3) a hematocrit Sample-size calculation and outcome measurements.
of <23%, (4) a WBC count of >15 X 109 cells/L, and (5) the The primary objective of the clinical trial here was to obtain
presence of any other severe underlying disease. an estimate of the cure rate at follow-up day 28 that was as-
Study flow. A study physician examined all patients at en- sociated with the use of a short-course regimen of artesunate-
rollment to assess vital signs, blood pressure, heart rate, and clindamycin, to determine the prospects for the further de-
tympanic temperature. Capillary blood was drawn by finger- velopment of artemisinin combinations that have a short
prick, to perform a complete blood count (QBC; Becton Dick- elimination half-life. For sample-size calculation, the working
inson) and thick blood smear. Thick smears were prepared and hypothesis that was formulated was that artesunate-clinda-
read according to the Lambarene method [14]. mycin therapy would be at least as efficacious as quinine-clin-

1778 * CID 2005:40 (15 June) - Ramharter et al.

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 m~~~etent a llot o

50 Patients allocated to artesunate-clindamycin regimen 50 Patients allocated to quinine-clindamycin regimen

Antimalarial self-treatment (n = 1) Vomiting of readministered study drugs (n = 1)

Treatment visit missed (n = 1) Withdrawal due to tinnitus (n = 1)

| n = 48 | Follow-up n = 48

Antimalarial self-treatment (n = 2) None lost to follow-up

| n = 46 | Analysis n = 48

PCR-corrected cure rate for per-protocol population: PCR-corrected cure rate for per-protocol population:

87% (95% Cl, 74%-94%) 94% (95% Cl, 83%-98%)

Figure 1. Flowchart of the enrollment and follow-up of patients p

damycin therapy. A sample size of 50 were

patients patients
considered per
to have treatment
treatment failure in the ITT
group was computed on the basis population
of the following
(extreme-case scenario).assumptions:
Times to parasite clearance
98% efficacy of the standard medication, a cure
and fever clearance rate efficacy
were secondary associated
end points. Time to
with experimental therapy that was
feverwithin
clearance wasthe 7%
defined of
as the the
first of 2 cure
subsequent mea-
rate associated with standard therapy, and a loss of 10% of surements of a tympanic temperature of <37.5?C.
patients to follow-up (ue = 0.05; power, 80%) [16, 17]. The The end point for the safety and tolerability analysis was the
primary end point of the study was the PCR-corrected cure proportion of subjects who experienced adverse events during
rate for the per-protocol (PP) population. The secondary end the 28-day follow-up after initiation of treatment. Adverse
point was the rate of adverse events in the 2 treatment groups. events were segregated into serious and nonserious adverse
The "cure rate" was defined as the proportion of patients events and were classified according to their severity (mild,
who presented without reappearance of asexual parasitemia moderate, or severe) and the causality of the study drugs (as
during the 28-day follow-up after initial clearance of parasites, judged by the study physician). Evaluation of measurements
as corrected by PCR genotyping. On the basis of current WHO of safety and tolerability was performed for the ITT population.
guidelines, response to treatment was classified as "adequate," Statistical evaluation and data management. Data were
"early treatment failure" (occurring from days 1 to 3 of follow- entered into patient record forms and were subsequently trans-
up), or "late treatment failure" (occurring from days 4 to 28 ferred into an electronic database (Filemaker Pro 5.5; File-
of follow-up) [18]. maker). Data in patient record forms were validated manually
The intention-to-treat (ITT) population included all patientsto produce a final database for further analysis. Statistical analy-
who received at least 1 dose of the study drugs. The PP population sis was performed using a commercial software package (JMP,
excluded patients who were noncompliant with the treatment version 5.0; SAS Institute). Fisher's exact test was used for
regimen, had violated inclusion/exclusion criteria, were lost to comparison of cure rates, and Student's t test was used for
follow-up, or were withdrawn from the study for reasons othercomparison of times to parasite clearance and fever clearance.
than treatment-related adverse events or treatment failure. These Ninety-five percent confidence intervals and P values for testing

Artesunate-Clindamycin for Malaria Treatment * CID 2005:40 (15 June) * 1779

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of noninferiority of efficacy were calculated according to the
method of Blackwelder [16]. For all tests performed, ca =
0.05, and P - .05 was the threshold for statistical significance.
RESULTS
Study flow. Figure 1 shows a flowchart of patient enrollment
and follow-up. The 100 patients who were included in the
clinical trial were randomly assigned to the 2 treatment groups.
Three patients received self-treatment with antimalarials during
the course of the study. One patient missed 1 treatment visit,
and another patient vomited readministered study drugs. One
child was withdrawn from the study because he developed tin-
nitus during the treatment period. All these patients were ex-
cluded from the PP analysis and were classified as having treat-
ment failure in the ITT analysis. One patient erroneously
received a wrong a dose of quinine-clindamycin (quinine, 18.8
group also experienced a faster recovery from fever (21.2 h vs.
30.2 h) (table 2).
Of the patients who were allocated to receive treatment with
artesunate-clindamycin, 7 presented with reappearing parasi-
temia on day 21 of follow-up, and 3 presented with reappearing
parasitemia on day 28 of follow-up. Four of the cases of reap-
pearing parasitemia were found to be reinfections, according
to the results of merozoite surface antigen-2 genotyping. Thus,
the PCR-corrected cure rate associated with artesunate-clin-
damycin therapy was 87% (40 of 46 patients; 95% CI, 74%-
94%) (table 2), and the respective uncorrected cure rate was
78% (36 of 46 patients; 95% CI, 64%-88%).
Two patients who received quinine-clindamycin presented
with asexual parasitemia on day 14 of follow-up. A total of 8
patients who received quinine-clindamycin presented with asex-
ual parasitemia during the 28-day follow-up. Five cases of reap-

mg/kg, and clindamycin, 12.5 mg/kg). This patient developed pearing parasitemia were found to be newly acquired infections,

malaria on day 14 of follow-up and was classified as having according to merozoite surface antigen-2 genotyping. The PCR-

treatment failure in both the PP and the ITT analyses. For all corrected cure rate in the PP population was, therefore, 94% for
other patients, follow-up was successful until day 28 of follow- patients given quinine-clindamycin (45 of 48 patients; 95% CI,

up or until asexual parasitemia reappeared. At enrollment, pa- 83%-98%) (table 2), and the respective uncorrected cure rate

tient characteristics and laboratory values were comparable in was 83% (40 of 48 patients; 95% CI, 70%-91%).

the 2 treatment groups (table 1). No significant difference in the cure rate on day 28 was
Cure rates. Asexual parasitemia was readily cleared in all observed between treatment groups in the respective analyses.
Statistical analysis testing for the noninferiority of efficacy of
patients within the first week of treatment. Parasites were elim-
inated faster in the artesunate-clindamycin group than in the artesunate-clindamycin, compared with the standard quinine-
quinine-clindamycin group (mean time to parasite clearance, clindamycin regimen, showed that P = .34 and P = .49 for the
29.3 h vs. 46.0 h), and patients in the artesunate-clindamycin ITT and PP populations, respectively.

Table 1. Characteristics of patients at enrollment in the study.

Patients Patients
given AC given QC
Characteristic, by class (n = 50) (n = 50)
Demographic

Male sex, no. (%) of patients 23 (46) 30 (60)

Female sex, no. (%) of patients 27 (54) 20 (40)
Age, years 7.1 ? 2.6 7.7 ? 3.3
Weight, kg 22.3 ? 8.0 24.0 ? 10.2
Clinical

Parasitemia, median no. of parasites/4tL (range) 12,000 (1100-96,000) 19,750 (1200-96,000)

Tympanic temperature, ?C 37.6 ? 1.2 37.6 ? 1.2
Blood pressure, mm Hg
Systolic 94 ? 12 99 ? 16
Diastolic 58 ? 11 62 ? 12
Pulse, no. of heartbeats/min 99 ? 20 100 ? 20
Treatment dose received, mean mg/kg

Clindamycin 7.5 ? 1.5 8.0 ? 2.0

Artesunate 2.3 ? 0.5 ...
Quinine ... 15.1 ? 1.7

NOTE. Data are mean values ? SD

clindamycin.

1780 * CID 2005:40 (15 June) - Ramharter et al.

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 Table 2. PCR-corrected cure rates associated with artesunate-clindamycin
(AC) therapy and quinine-clindamycin (QC) therapy on day 28 of follow-up.

Patients Patients
Finding given AC given QC pa

No. of patients included

ITT 50 50 ...
PP 46 48 ...
Cure rate
No. of patientsb
ITT 40 45 .34
PP 40 45 .49
Percentage of patients (95% CI)
ITT 80 (67-89) 90 (79-96)
pp 87 (74-94) 94 (83-98) ...
Time to clearance, mean h (95% CI)
Of parasites 29.3 (26.4-32.1) 46.0 (41.0-51.0) ...
Of feverc 21.2 (16.3-26.1) 30.2 (23.6-36.8)

NOTE. ITT, intent-to-treat population; PP, per-protocol population.

a For the comparison of noninferiority of efficacy of AC with that of QC.
b All unevaluable patients were considered to have treatment failure (i
scenario).
c Clearance of fever was defined by a temperature of <37.5?C.

The evolution of hematological values was comparable in associated with cinchonism (headache, tinnitus, and dizziness)
the 2 treatment groups, although the overall increase in the were uncommon in patients in the artesunate-clindamycin and
hematocrit during the 28-day follow-up was higher for the quinine-clindamycin groups (6 vs. 4 patients). No difference
quinine-clindamycin group (table 3). The gametocyte carrier was found in the overall incidence of adverse events in the 2
rate at follow-up was similarly low in both groups (2 individuals
treatment groups.
in the artesunate-clindamycin group and 5 individuals in the
quinine-clindamycin group) (table 3). DISCUSSION
Adverse events. Both treatment regimens were well toler-
In the present study, a satisfactory efficacy of artesun
ated, and no serious adverse event occurred in the trial. Six
damycin combination therapy was noted. The overall
episodes of moderately severe adverse events were recorded.
in the PP population was within the range of the cure rate
Adverse events judged to be at least probably associated with
the study drugs occurred in 1 patient in the artesunate-clin- associated with the standard quinine-clindamycin regimen. Al-
damycin group (diarrhea) and in 2 children in the quinine- though the P value associated with noninferiority testing was

clindamycin group (diarrhea and tinnitus). The patient who not statistically significant, this finding might be ascribed to

experienced tinnitus on the first day of follow-up had been the lower-than-predicted efficacy of the quinine-clindamycin

assigned to the quinine-clindamycin group. He was withdrawn regimen and the relatively small sample size of the study. Given

from the study and received successful treatment with sulfa- the objective of estimating the overall prospect of further in-

doxine-pyrimethamine. vestigation of artemisinin-based combination regimens with

All remaining episodes of untoward experiences were mild short plasma half-lives, the cure rates that were observed look

in severity (table 4). Gastrointestinal symptoms were the most promising.

common adverse events in the artesunate-clindamycin and qui- Times to fever clearance and parasite clearance, which are

nine-clindamycin groups, and they included abdominal pain considered to be supportive evidence of antimalarial activity,
were shorter in the artesunate-clindamycin group. This finding
( 11 vs. 12 patients), loose stool (9 vs. 12 patients), and increased
stool frequency (defined by not more than 3 episodes of loose is in concordance with those of previous studies that established
stool per day; 20 vs. 18 patients). For patients in the artesunate- sesquiterpene lactones as the fastest-acting antimalarials known
clindamycin and quinine-clindamycin groups, adverse effects to date [4]. However, it is not yet clearly understood whether
other than common cold-like symptoms (13 vs. 8 patients), the faster reduction in the parasite load translates similarly to
vomiting (5 vs. 6 patients), headache (4 vs. 2 patients), and an improved clinical recovery and a lower mortality rate [5].
skin efflorescence (4 vs. 2 patients) were rare. Adverse events The frequency of adverse events was comparable in the 2

Artesunate-Clindamycin for Malaria Treatment * CID 2005:40 (15 June) * 1781

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 Table 3. Laboratory data determined at enrollment in the study and during
follow-up.

Patients Patients
given AC given QC
Variable (n= 50) (n= 50)

Hematocrit, %

On day 0 34.8 ? 5.7 33.7 ? 5.1

On day 2 32.7 ? 4.6 32.3 ? 4.9
On day 28 35.8 ? 4.3 37.1 ? 3.5
Differencea 1.0 ? 5.4 3.5 ? 5.2
Hemoglobin level, g/dL
On day 0 10.6 ? 1.8 10.6 ? 1.9
On day 2 10.0 ? 1.6 9.8 ? 1.7
On day 28 11.2 ? 1.4 11.4 ? 1.4
Differenceb 0.6 ? 2.0 1.0 ? 1.6
Leukocyte count, no. of leukocytes x 1 06/pL
On day 0 7.1 ?2.1 8.3 2.9
On day 2 6.4 ? 1.8 6.2 ? 2.0
On day 28 7.4 ? 3.1 7.9 ? 2.5
Thrombocyte count, no. of thrombocyte
On day 0 196 ? 102 230 ? 107
On day 2 205 ? 77 197 96
On day 28 242 ? 96 259 93
Gametocyte carriage, no. (%) of patients
At admission 1 (2) 1 (2)
At follow-upc 2 (4) 5 (10)

NOTE. Data are mean values ? SD, unless indicated otherwise. AC, artesunate-clinda-
mycin; QC, quinine-clindamycin.
a Difference of values determined on days 0 and 28. The 95% Cis are -0.5% to 2.6%, for
the AC group, and 1.9%-5.1 %, for the QC group.
b Difference of values determined on days 0 and 28. The 95% Cls are 0.0-1.1, for the AC
group, and 0.5-1.14, for the QC group.
c The 95% Cls are 1 %-13%, for the AC group, and 4%-21 %, for the QC group.

groups. Of interest, the number of adverse events similar to is characterized by a relatively short plasma half-life (20 h for
those associated with cinchonism was not increased in the qui- chlorproguanil and 30 h for dapsone) and reasonable efficacy
nine-clindamycin group. Gastrointestinal adverse events were (96%) on day 14 of follow-up; however, cure rates at day 28
the most common side effects and were possibly attributable of follow-up are likely to be considerably lower. In this context,
to the clindamycin component of the regimens. All of the re- the 100% cure rate noted for artesunate-clindamycin on day
ported gastrointestinal disturbances were of mild-to-moderate 14 of follow-up in this trial is promising. Furthermore, the
severity and ceased without medical intervention within a few tolerability of artesunate and clindamycin seems to be favorable,
days. Similarly, in a considerable number of clinical trials, clin- and there seem to be no concerns about safety with regard to
damycin has been shown to be well tolerated when used as an severe hematological side effects associated with chlorpro-
antimalarial [ 1 1 ]. This finding is attributed to the relatively low guanil-dapsone [5, 21].
dosage and short treatment duration used with clindamycin. Fosmidomycin-clindamycin is another antimalarial drug
Most antimalarial combinations tested to date and used in combination that has a short half-life, shows good efficacy, and
sub-Saharan Africa contain a slowly eliminated drug [5]; such results in equally fast parasite clearance and fever clearance
regimens include artesunate-amodiaquine [19], artemether-lu- because of the rapid action of fosmidomycin [22]. One possible
mefantrine [20], and other artemisinin-based combinations. advantage of artesunate-clindamycin, compared with fosmi-
There are reports of only 3 drug combinations that deviate domycin-clindamycin, might, however, be associated with the
from this principle. Chlorproguanil-dapsone is an antimalarial low gametocyte carrier rates noted in the course of convales-
combination treatment that has been registered for the treat- cence after treatment initiation; these low rates may possibly
ment of uncomplicated malaria in sub-Saharan Africa [21]. It lead to diminished recombination and transmission of drug-

1782 * CID 2005:40 (15 June) * Ramharter et al.

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Table 4. Adverse events experienced by patients during the Acknowledgments
28-day follow-up.
We thank the children who participated in this clinical trial and their
parents, and we are thankful for the community of Lambarene's sustained
Patients Patients interest in clinical research.
given AC given QC Potential conflicts of interest. All authors: no conflicts.
Adverse event (n = 50) (n = 50)

Loose stool 9 (18) 12 (24)

Increased stool frequency a 20 (40) 18 (36)
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