ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1995, p. 1603–1605
0066-4804/95/$04.00ϩ0Copyright ᭧ 1995, American Society for Microbiology
Quinine plus Clindamycin Improves Chemotherapy of
PETER G. KREMSNER,1,2* PAUL RADLOFF,1,3 WOLFRAM METZGER,1,2 ECKART WILDLING,1,3
¨ RG PHILIPPS,1 LARS JENNE,1 MARCEL NKEYI,1
JAVIER PRADA,2 ULRICH BIENZLE,2 AND WOLFGANG GRANINGER3
International Research Laboratory, Albert-Schweitzer-Hospital, Lambare´ne´, Gabon
1; Institut fu
2; and Department of Infectious Diseases, University of Vienna, Vienna, Austria
Received 21 February 1995/Returned for modification 25 April 1995/Accepted 7 May 1995
In a randomized trial, a 4-day quinine-clindamycin regimen was compared with the standard 7-day quinine
regimen for 100 Gabonese children (50 children in each group) with severe Plasmodium falciparum malaria. In
each group, only one patient died. Parasite clearance and fever clearance times were significantly shorter in the
quinine-clindamycin group (P
؍ 0.03 and P
؍ 0.01, respectively) than in the quinine group, and significantly
more recurring fever episodes occurred in the quinine group than in the quinine-clindamycin group shortly
after initial fever clearance and parasite clearance (P < 0.001).
Each year more than 10 million African children suffer from
two treatment groups. One group received the World Health
severe Plasmodium falciparum
malaria, and more than 1 mil-
Organization standard treatment with intravenous quinine, ini-
lion die. The vast majority of these children receive parenteral
tially a 16-mg base per kg of body weight over 4 h, then 8 mg/kg
quinine therapy. However, the usually recommended 7-day
every 8 h administered in continuous 5% glucose infusions for
regimen causes compliance problems if the children leave the
11 doses, and thereafter 12 mg/kg given orally every 12 h to
hospital before treatment is finished (11). Short-term quinine
complete the 7-day regimen. The other group received quinine
regimens were not sufficient to cure Gabonese schoolchildren
as described above for 12 doses plus intravenous clindamycin,
of even uncomplicated P. falciparum
malaria (4). Previous
initially with a 5-mg base per kg given as a short infusion
studies also revealed a considerable rate of concomitant bac-
followed 4 h later by short 5-mg/kg infusions every 8 h for 11
teremia and/or septicemia or localized bacterial infections of
doses. The patients were hospitalized for 7 days. During the
patients with severe malaria (8, 9). In southeast Asia, tetracy-
initial 4 days, vital signs were recorded and clinical examina-
clines are commonly combined with quinine for treating P.
tions were performed every 4 to 8 h. Rectal temperature was
malaria (11). However, because of the side effects
measured every 8 h for 7 days. The parasitemia level was
of these antibiotics, this combination cannot be used for chil-
determined every 8 h until three consecutive blood smears
dren and pregnant women, the two groups most vulnerable to
were negative. Hemocultures of samples from the last 59 pa-
severe malaria. Clindamycin is a lincosamide antibiotic with
tients were performed by using the Oxoid Signal System
antiplasmodial properties which can be given to children (3).
(Unipath, Basingstoke, England), and the isolated bacterial
The use of clindamycin in combination with quinine for treat-
strains were identified and further characterized as previously
ing human volunteers with chloroquine-resistant malaria was
described (8). The hematological and biochemical parameters
first described two decades ago (7). In comparative trials, clin-
of the patients were determined at least every 24 h for 7 days.
damycin combined with quinine improved the cure rate of
Supportive treatment (e.g., blood transfusion or glucose ad-
uncomplicated P. falciparum
malaria for patients in Africa and
ministration) was given as required. Thick blood smears and
South America (4–6). On the basis of this rationale, we have
clinical checks were performed on day 14, 21, and 28 to deter-
compared the 7-day quinine regimen with a 4-day quinine-
mine the parasite recrudescence rate. The two treatment
clindamycin regimen for treating Gabonese children with se-
groups were statistically compared by the Mann-Whitney U
The study took place at the Albert-Schweitzer-Hospital in
One hundred children with severe malaria were enrolled in
´, Gabon. All children with severe P. falciparum
the study. Their prominent clinical feature was severe anemia
malaria treated at the hospital were enrolled. The children had
with hyperparasitemia. The two groups were well comparable
to fulfill at least one of the following criteria: hyperparasitemia
with regard to baseline clinical and laboratory findings (Table
(Ն250,000 parasites per l), severe anemia (hemoglobin score
1). There was no difference between the final cure rates of the
of Ͻ50 g/liter or hematocrit score of Ͻ15%), hypoglycemia
groups. Only four patients in the quinine group and two in the
(glucose, Ͻ2.2 mmol/liter), or cerebral malaria (unrousable
quinine-clindamycin group showed parasite recrudescences by
coma not attributable to another cause) (10). Children with
day 28 of the follow-up. In addition, one patient in the quinine
sickle cell anemia or younger than 6 months were not included.
group died 7 h after admission and one in the quinine-clinda-
Parents or guardians gave informed consent. The study was
mycin group died 20 h after admission. However, parasite
approved by the International Foundation of the Albert-
clearance and fever clearance times were significantly shorter
Schweitzer-Hospital. The children were randomly allocated to
for the quinine-clindamycin group (P
ϭ 0.03 and P
ϭ 0.01,respectively) than for the quinine group. Moreover, signifi-cantly more patients in the quinine group than in the quinine-clindamycin group showed a recurrent fever episode shortly
* Corresponding author. Mailing address: Institut fu
zin, Engeldamm 62, 10179-Berlin, Germany. Phone: 49 30 2746116.
after initial fever clearance and parasite clearance (P
(Table 1). These recurrent fever episodes appeared within 8 h
TABLE 1. Clinical and laboratory findings on admission and efficacy parameters of chemotherapy of patients with severe malariaa
Duration of symptoms before admission (days)
Data indicate means (standard deviations) or numbers of patients, except parasitemia, for which medians (ranges) are given.b P
ϭ 0.03, P
ϭ 0.01, and P
Ͻ 0.001 for differences between groups in parasite clearance, fever clearance, and the number of patients with recurrent fever episodes,
to 3 days after parasite clearance. No parasite recrudescences
came obvious that not only the antiparasitic activity of clinda-
were found during these fever episodes which waned in most
mycin but also other properties, including its possible
cases after 1 or 2 days without treatment. For 59 consecutive
antibacterial effect, may be of value in the treatment of severe
patients from the present study, hemocultures were done on
malaria. As reported earlier (8) and demonstrated again in the
admission and seven of the cultures yielded positive results.
present trial, bacteremia seems to be a common event for
The identified bacterial strains included three Staphylococcus
African children with severe malaria. This infection may
, one Klebsiella pneumoniae
, one Serratia marcescens
worsen the clinical condition either by prolonging fever, by
one Pseudomonas cepacia
, and one Moraxella liquefaciens
causing additional fever episodes, or even by leading to septic
The patient with K. pneumoniae
died 20 h after admission.
shock. We assume that damage of the endothelial lining in
From the other patient who died, no hemoculture was done.
various organs (e.g., intestine and lung) during severe malaria
Hemocultures were done during the same period for a control
(1, 2) allows bacteria to enter the bloodstream. The concom-
group of 45 children with uncomplicated P. falciparum
itant immunodepression may facilitate the development of
(age, 1 to 6 years; parasitemia count, 2,000 to 120,000 parasites
bacteremia. The reduced fever clearance time and the reduced
number of recurring fever episodes in the quinine-clindamycin
Our study indicates that the addition of clindamycin to the
group could partly be a beneficial effect of clindamycin on
standard quinine treatment substantially improves and short-
concurrent bacterial infections. However, this does not imply
ens the chemotherapy of African children with severe malaria.
that clindamycin should be considered a highly efficient anti-
As clindamycin is a slowly acting antimalarial agent, it should
biotic to prevent bacterial infections complicating severe ma-
be used as a single agent only for treating semi-immune ma-
laria. In conclusion, the present study demonstrated that qui-
laria patients (3). However, combined with the fast-acting qui-
nine-clindamycin favorably compared with the standard
nine, it enhanced parasite clearance, as shown in the present
quinine treatment. The slightly increased costs of the quinine-
study and in previous trials involving patients with uncompli-
clindamycin regimen may be equalized by a possibly reduced
cated P. falciparum
malaria (4, 5). From these studies, it be-
ing adult malaria patients in an area in which malaria is hyperendemic.
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