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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´, Gabon1; Institut fu Berlin, Germany2; and Department of Infectious Diseases, University of Vienna, Vienna, Austria3 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 falciparum 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 Ͻ 0.001) (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) a 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 aureus, one Klebsiella pneumoniae, one Serratia marcescens, worsen the clinical condition either by prolonging fever, by one Pseudomonas cepacia, and one Moraxella liquefaciens strain.
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 malaria 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- REFERENCES
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Effects of Metformin on Ovulation and Pregnancy Rate in Women with Clomiphene Resistant Poly Cystic Ovary Syndrome Mahnaz Ashrafi, M.D.1, 2*, Fatemeh Zafarani, B.Sc.2, Ahmad Reza Baghestani, M.Sc.3 1. Endocrinology and Female Infertility Department, Royan Institute 2. Obstetrics and Gynecology Department, Faculty of Medicine, Iran University of Medical Sciences, Akbar Abadi Hospital

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