ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1995, p. 245–246
Copyright ? 1995, American Society for Microbiology
Vol. 39, No. 1
High Efficacy of Short-Term Quinine-Antibiotic Combinations
for Treating Adult Malaria Patients in an Area in
Which Malaria is Hyperendemic
WOLFRAM METZGER,1,2BENJAMIN MORDMU ¨LLER,1,3WOLFGANG GRANINGER,3
ULRICH BIENZLE,2AND PETER G. KREMSNER1,2*
International Research Laboratory, Albert-Schweitzer-Hospital, Lambare ´ne ´, Gabon1; Institut fu ¨r Tropenmedizin, 10179
Berlin, Germany2; and Department of Infectious Diseases, University of Vienna, 1090 Vienna, Austria3
Received 15 July 1994/Returned for modification 13 September 1994/Accepted 21 October 1994
In a randomized trial, a three-dose quinine monotherapy was compared with short-term combination
regimens of quinine-clindamycin and quinine-doxycycline for treating adult Gabonese patients with Plasmo-
dium falciparum malaria. In quinine-treated patients, only 38% were ultimately cured. In contrast, more than
90% of patients were cured after treatment with either combination regimen.
The increasing capacity of the malaria parasite Plasmodium
falciparum to resist chemotherapy causes a frightening deteri-
oration of efficacy of the classical antimalarial drugs. Whereas
short courses of quinine monotherapy were still found to be
successful in malaria treatment in Madagascar (4), Zaire (5),
and Liberia (3) in recent years, our group found a high rate of
recrudescence with a short-term quinine regimen in children in
Gabon (9). Clindamycin was found to be highly effective when
used for at least 5 days for the treatment of P. falciparum
malaria in Brazil (1), the Philippines (11), and Gabon (8).
However, clindamycin given alone for 3 days does not cure P.
falciparum malaria (6). Because clindamycin is a slowly acting
drug, clindamycin is a candidate for combination treatment
with fast-acting drugs, such as quinine (10) and chloroquine
(9). The antimalarial effect of tetracyclines is well recognized.
In areas where there is multidrug resistance of P. falciparum, a
tetracycline is administered in addition to other antimalarial
drugs such as quinine (12). In African countries, tetracyclines
are broadly used for the treatment of bacterial infections. On
the basis of this rationale, we investigated the efficacy of a
three-dose quinine regimen because it is widely used in Africa
and combined it with antibiotics to see whether they can im-
prove quinine chemotherapy in adult malaria patients in an
area in which malaria is hyperendemic.
The study took place at the Albert-Schweitzer-Hospital in
Lambare ´ne ´, Gabon. From July 1993 to February 1994, all
malaria patients attending the outpatient clinic of the hospital
who fulfilled the following criteria were included in the study:
(i) proven monoinfection with P. falciparum; (ii) asexual par-
asitemia of more than 200/?l of blood; (iii) the possibility of
complete observation for 24 h after parasite clearance; (iv) no
antimalarial therapy within the preceding 7 days, confirmed by
tests for chloroquine and sulfonamides in urine; (v) age ex-
ceeding 15 years; (vi) not being pregnant; and (vii) having
provided informed consent for inclusion in the study. The
study was approved by the International Foundation of the
Albert-Schweitzer-Hospital. One hundred twenty patients
were admitted into the study. They were randomly allocated to
receive one of the three oral, open-labeled treatment regi-
mens. One group (40 patients) received quinine (12 mg/kg of
body weight per dose; three doses; a dose every 12 h) (group
Q). One group (40 patients) received quinine (12 mg/kg per
dose; three doses) plus clindamycin (5 mg/kg per dose; six
doses; a dose every 12 h) (group QCl), and one group received
quinine (12 mg/kg per dose; three doses) plus doxycycline (2
mg/kg per dose; six doses; a dose every 12 h) (group QD).
Clinical signs and symptoms were recorded every 12 h until the
patients were free of symptoms for 24 h. For 1 h after admin-
istration of the drugs, patients were observed for the occur-
rence of vomiting. Thick blood smears were prepared every 12
h until the smears were free of asexual parasites for 24 h.
Thereafter, smears were prepared on days 14, 21, and 28 after
admission. Parasite counts were made with Giemsa-stained
thick blood smears as described previously (10). The grading of
the treatment response was performed according to World
Health Organization criteria (13). A patient was considered to
be cured if the thick blood smear became negative after treat-
ment and remained parasite free until day 28 of follow-up.
Low-grade resistance was defined as the disappearance of par-
asites from peripheral blood within the first 7 days, followed by
recrudescence on day 14, 21, or 28. Statistical analysis was
performed by the Mann-Whitney and Kruskal-Wallis tests.
Proportional data were tested by the chi-square test.
Of the 120 patients admitted to the study, 108 could be
monitored for 28 days, and 12 (10%) (3 from group Q, 4 from
group QCl, and 5 from group QD) were lost to follow-up. All
patients presented with an uncomplicated, mild form of ma-
laria. The three treatment groups were comparable with re-
spect to clinical signs, symptoms, and parasitemia on admission
(Table 1). The patients complained of having fever, headache,
chills, dizziness, nausea, and abdominal pain (symptoms listed
in decreasing frequency). All patients were considered semi-
immune, because they had had malaria during their childhood
many times. The efficacies of the three treatment regimens are
as follows. Fourteen (38%) of the 37 patients in group Q were
ultimately cured, but 23 (62%) had malaria resistant to the
three-dose quinine regimen. All of these 23 patients had low-
grade-resistant P. falciparum malaria, as indicated by recrudes-
cences on days 14 (6 patients), 21 (9 patients), and 28 (8
patients). None of the patients showed high-grade-resistant
malaria. In contrast, 33 (92%) of the 36 patients in group QCl
were ultimately cured, and only 3 patients (8%) showed recru-
descent malaria on day 21 (2 patients) or 28 (1 patient) of
* Corresponding author. Mailing address: Institut fu ¨r Tropenmedi-
zin, Engeldamm 62, 10179 Berlin, Germany. Phone: 49 30 2746116.
Fax: 49 30 2746736.
(P ? 0.001). In group QD, 32 (91%) of the 35 patients were Download full-text
ultimately cured and 3 patients (9%) had recrudescent malaria
on day 21 (2 patients) or 28 (1 patient) of follow-up (P ? 0.001
compared with group Q). The median duration of symptoms
after the start of chemotherapy was 2 days in all three groups.
Table 1 shows the course of parasitemia in the three groups.
The mean durations of parasitemia were 2.2 days in group Q,
2.4 days in group QCl, and 2.2 days in group QD and were not
significantly different. All three groups already showed a sig-
nificant decrease of parasitemia by 24 h after the start of
chemotherapy (P ? 0.001). All three treatment regimens were
well tolerated; there were no severe side effects. Overall, 25%
of all the patients complained of dizziness and 42% of all the
patients reported mild gastrointestinal symptoms with abdom-
inal pain (20%), nausea (18%), diarrhea (12%), and vomiting
(11%). There were no significant differences between the three
treatment groups, and all side effects were mild and self-lim-
iting (disappeared after 1 to 2 days).
For a long time, quinine has been the mainstay of the treat-
ment of severe malaria in children; nowadays it is also used for
treating uncomplicated P. falciparum malaria in children as
well as in adults. The preferential means of administrating
quinine is as a short-term regimen. In Central Africa, quinine
is commonly given as oral medication or in intramuscular in-
jections in three to six doses (4). A six-dose quinine regimen
was found inefficient to cure uncomplicated P. falciparum ma-
laria in children in Gabon (9). In this study, we showed that the
same is true for the three-dose quinine regimen in Gabonese
adults. The idea to combine a tetracycline or clindamycin with
quinine has been investigated in South-East Asia (12) and
Brazil (2) for tetracyclines and in Brazil (10) and Gabon (9) for
clindamycin. Although neither doxycycline nor clindamycin is
sufficient to cure P. falciparum malaria when given alone for 3
days, we obtained excellent cure rates when we combined them
with a three-dose quinine regimen. In contrast to a previous
trial (7) in which chloroquine-clindamycin was superior to
chloroquine-doxycycline, no significant differences between
groups QD and QCl were detected with respect to parasite
clearance and final cure rate in this study. Thus, these two
short-term combination regimens can be recommended for
treating semiimmune malaria patients but not for treating non-
Wolfram Metzger was supported by the Deutscher Akademischer
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TABLE 1. Characteristics of malaria patients on admission and
course of parasitemia after treatment
Value for treatment group
Axillary temp (?C)
Parasitema (per ?l of
100 100 100
aPWUP, patients with undetectable parasitemia.
246NOTESANTIMICROB. AGENTS CHEMOTHER.