Treatment of chloroquine-resistant Plasmodium falciparum infections with clindamycin hydrochloride in Dili, East Timor, Indonesia

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 4, APRIL1994

TREATMENT OF CHLOROQUINE-RESISTANT P L A S M O D I U M FALCIPARUM INFECTIONS WITH CLINDAMYCIN H Y D R O C H L O R I D E I N DILI, E A S T T I M O R , I N D O N E S I A SRI O E M I J A T I , 1 W I T A PRIBADI, 1 K U S U M A WARTATI, 2 PR ARBANI, 3

SRI SUPRIJANTO, 3 AND ROCHIDA RASISI1 1Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, 2General Hospital, Dili, East Timor Province, and 3Subdirectorate of Malaria, Directorate General CDC and EH, Ministry of Health of Indonesia, Jakarta, Indonesia

ABSTRACT The objectives of this study were to determine the efficacy and safety of clindamycin hydrochloride, 300 mg twice daily for 5 days, in the treatment of patients with chloroquine-resistant falciparum malaria in Dili, East Timor, Indonesia. The patients were hospitalized for 28 days and instructed to remain in the screened wards, especially in the late afternoon and night. Thirty-four patients in the clindamycin group and five patients in the sulfadoxine-pyrimethamine group completed the 28-day observation period. Plasmodium vivax was found during the observation period in four patients in the clindamycin group, however. Therefore, 30 patients in the clindamycin group and five patients in the sulfadoxine-pyrimethamine group remained parasite-free until discharge. In the clindamycin group, parasite clearance was obtained between days 3 and 6, with 43.3% cleared by day 4 and a cumulative total of 66.6% by day 5. In the sulfadoxin-pyrimethamine group, parasite clearance was obtained by day 3. After discharge, 4 patients in the clindamycin group returned with malaria: 1 returned on day 37 with P vivax and P falciparum infection; I returned on day 50 with a mixed infection of P vivax and Plasmodium falciparum; 1 returned on day 58 with a P falciparum infection; and 1 returned on day 77 with a P vivax infection. Although reinfections were considered in these patients, late relapses could not be entirely eliminated. In the clindamycin group, a temporary increase of parasite densities from day 0 levels was seen in 11 patients but all decreased to 0 levels between days 3 and 6. The results of this study indicate that clindamycin can be used as an alternative drug in the treatment of chloroquine-resistant P falciparum infections. INTRODUCTION

M a l a r i a r e m a i n s a m a j o r h e a l t h p r o b l e m in I n d o n e s i a . T h e disease is w i d e l y d i s t r i b u t e d t h r o u g h o u t t h e c o u n t r y a n d is found in a l m o s t e v e r y r e g i o n e x c e p t t h e v e r y h i g h m o u n t a i n o u s a r e a s . 1 F o u r species of m a l a r i a Address correspondence to: Dr. David Zambrano, Regional Medical Director, The Upjohn Company, 7000 Portage Road, Kalamazoo, Michigan 49001.

Receivedfor publication on January 14, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 468

0011-393X/94/$3.50

S. OEMIJATIET AL.

parasites have been described in Indonesia: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale. Although the first three species are widely distributed, P malariae is now more difficult to find; P ovale has been reported only in the Irian Jaya, Timor, and Flores islands. Although Jakarta and the other major cities are considered malaria-free, highly endemic areas are still prevalent, especially in rural areas outside the islands of Java and Bali. The grades of malaria endemicity, as determined by splenomegaly and blood smears, differ from one locality to another, ranging from hypoendemic, mesoendemic, to hyperendemic and even holoendemic. Chloroquine-resistant P falciparum was first reported in Indonesia by Verdrager and Arwati, 2 in a patient from East Kalimantan. At present, although resistance has been reported from almost all Indonesian provinces, the proportion of resistant cases is still relatively low except in Irian J a y a and East Timor. 3 It is the policy of the Indonesian government to use chloroquine as a first-line treatment, unless resistance to this drug has been proven. The combination of sulfadoxine-pyrimethamine* is recommended as a second-line treatment; however, resistance to sulfadoxinepyrimethamine has already been reported from Irian Jaya and East Timor. 4-6 Mefloquine, widely used in Thailand and other countries where chloroquine and sulfadoxine-pyrimethamine resistance have been reported, is not yet available in Indonesia. In vitro studies have reported chloroquine, sulfadoxine-pyrimethamine, and quinine resistance, 5 although these parasites are still sensitive in vivo. Because of the increased problems of developing resistance, it is important to evaluate alternative drugs for clinical treatment. One available candidate is clindamycin,t already widely used for the treatment of bacterial infections. Clindamycin is an antibiotic, a 5[s]-chloro-7-deoxy derivative of lincomycin. Advantages of clindamycin include: (1) good absorption from the gastrointestinal tract regardless of the presence of food; (2) good activity against gram-positive cocci and many gram-positive and gram-negative anaerobes as well as against protozoa such as Toxoplasma, Babesia, and P falciparum; and (3) availability in various formulations: oral (clindamycin hydrochloride and clindamycin palmitate hydrochloride) and parenterat (clindamycin phosphate). The General Hospital of Dili, East Timor, was selected as the study site because the hospital's 1987 records showed that a total of 6004 ambulatory malaria patients had been treated during the year with 578 of these admitted to the hospital. Fifty-five percent of the patients had P falciparum infections, 10% had P vivax infections, 10% had mixed P falciparum and P vivax infections, and 25% had falciparum malaria accompanied by * Trademark: Fansidar ® (Roche Laboratories, Nutley, New Jersey). t Trademark: Cleocin HCL ® (The Upjohn Company, Kalamazoo, Michigan). 469

TREATMENT OF PLASMODIUM FALCIPARUM INFECTIONS WITH CLINDAMYCINHYDROCHLORIDE

other diseases. Eighty-five percent of the P falciparum infections showed grade I resistance, 10% grade II, and 5% grade III against chloroquine in vivo (grade I = recrudescence between days 7 to 28; grade II = parasitemia decreased but still present; grade III = parasitemia not decreased and in some cases increased). The objective of this study was to determine the efficacy and safety of clindamycin hydrochloride, 300 mg twice daily for 5 days, in the treatment of Indonesian patients 15 years or older with chloroquine-resistant P falciparum infections. P A T I E N T S AND M E T H O D S

The study was conducted at the General Hospital of Dili, East Timor, between October 1988 and September 1989. Study enrollment was limited to patients 15 years or older, presenting with in vitro chloroquine-resistant P falciparum infections as demonstrated using the World Health Organization (WHO) kit, which provides evidence of chloroquine resistance. All patients with suspected clinical signs and symptoms of malaria were screened for malaria parasites in blood smears. Patients with P falciparum infections had urine samples tested for the presence of chloroquine (Dill Glazko test) and sulfadoxine-pyrimethamine (Lignin test). All parasitologic examinations were done by two of the authors. When chloroquine resistance was proven, those patients who gave their informed consent were enrolled in the study. Severely ill patients, specifically those with complications of the central nervous system; anemia with hemoglobin less than 7 gm/dL; jaundice; hyperpyrexia with rectal temperature >39 °C; hyperparasitemia >5%; hemoglobinuria and black water fever; renal failure; circulatory shock; or secondary infection with pathogens causing brochopneumonia, septicemia, diarrhea, and vomiting were excluded from the study. Also excluded were pregnant or lactating women, malnourished patients, and patients with other diseases requiring concomitant medication that could interfere with the evaluation of response. Patients who had received antimalarial medication in the previous 14 days or who had positive urine tests for chloroquine were also excluded. At enrollment, all patients were admitted to the hospital for observation for a minimum of 28 days. To prevent reinfection, the study ward was screened and sprayed with dichlorodiphenyltrichloroethane; the patients were instructed to remain in the ward as much as possible, particularly in the late afternoon and night. Physical examinations were done daily. Axillary temperature was taken twice daily during hospitalization. Blood examination for malaria and parasite counts concentrating on asexual forms were done twice on days 0 to 7, 14, 21, and 28. Routine blood exam470

S. OEMIJATI ET AL.

inations, including measurement of hemoglobin, leukocyte, erythrocyte and differential counts, hematocrit, platelet count, and blood chemistries (for liver and renal function tests), as well as urine and stool examinations, were done once a week. All patients were observed for signs and symptoms of drug toxicity. After enrollment, patients were treated with clindamycin hydrochloride 300 mg twice daily for 5 days. A control group of patients was treated with sulfadoxine (500 mg)-pyrimethamine (25 mg), 3 tablets in a single dose. RESULTS

A total of 12,278 blood smears from 12,278 patients (Table I) were screened for malaria parasites: 2377 (19.4%) were positive, consisting of 1884 (79.3%) P falciparum, 455 (19.1%) P vivax, and 38 (1.6%) containing mixed infection ofP falciparum and P vivax. No P malariae was found during this period. Among the 1844 patients with P falciparum infection, 1157 were 15 years and older. An in vitro chloroquine-resistant test was performed on only 89 of these 1157 cases. In the remaining 1068 patients, the test could not be performed for various reasons (Table II). Low parasite density (<1000/mm 3 blood) was the most frequent reason for noneligibility (911 patients), followed by a positive test for chloroquine in the urine (127). Twenty patients refused to participate when told that routine blood samples would be taken during the study. Among the 89 patients who were tested, 58 (65.2%) showed resistance to chloroquine (Table III). Among these, 12 patients could not be included in the study for various reasons. The remaining 46, consisting of 37 males aged between 15 and 64 years, and 9 females aged between 15 and 34 years, were enrolled in the study; 39 patients were treated with clindamycin and 7 patients were assigned to the sulfadoxine-pyrimethamine control group (figure). In the clindamycin group, 5 patients did not complete the study: 3 Table I. Results of blood smear examination for malaria parasites in the General Hospital in Diti, East Timor, Indonesia, between October 1988 and September 1989. No. of Species No. of Blood Smears Examined

No. of Smears Positive for Malaria

12,278

2377

Plasmodium falciparum

1884 (79.3%)

471

Plasmodium vivax

Mixed Infection of P falciparum and P vivax

455 (19.1%)

38 (1.6%)

TREATMENT OF PLASMODIUM FALCIPARUM INFECTIONS WITH CLINDAMYCIN HYDROCHLORIDE

Table II. Results ofselection o f p a t i e n t s f o r t h e m i c r o in vitro sensifivitytest of Plasmodium

falciparumtochloroquine. No. of Patients Not Qualified for the Test No. of Patients* with P

Patients with

falciparum Infections

Parasites (
Chloroquine in Urine

Poor Clinical Condition

1157

911

127

8

Pregnancy

Refusal for the Trial

Total

No. of Patients Eligible for the Test

2

20

1068

89

* Patients aged 15 years and older.

were transferred to another hospital and lost to follow-up, 1 patient was determined to be pregnant, and 1 patient showed a mixed infection. Among the 7 patients treated with sulfadoxine-pyrimethamine, 2 discharged themselves from the hospital. Therefore, 34 patients in the clindamycin group and 5 in the sulfadoxine-pyrimethamine group completed the 28-day observation period. The mean parasite count at day 0 was 410/300 white blood cells (WBCs) with a range of 13 to 1519/300 WBCs. Among the 34 patients treated with clindamycin, P vivax was found in four patients during the observation period (one was misdiagnosed and discovered after initiation of treatment), leaving 30 evaluable patients. On discharge from the hospital (day 29), 30 patients treated with clindamycin and the 5 control patients treated with sulfadoxine-pyrimethamine remained free of parasitemia. The occurrences of malaria in these patients after day 28 were considered reinfections, although late relapses could not be entirely eliminated. Four patients returned with malaria: 1 (no. 15) returned on day 37 with a P vivax and P falciparum infection and 1 (no. 25) on day 50 with a mixed infection ofP vivax and P falciparum; 1 patient (no. 13) returned on day 58 with P falciparum malaria and 1 (no. 19) returned on day 77 with a P vivax infection. After treatment with clindamycin, all patients cleared their parasitemia on day 4. In the clindamycin group, parasite clearance occurred between days 3

Table III. Results of the micro in vitro sensitivity test of Plasmodium falciparum to chloroquine.

No. of Positive P

falciparum Infections Total

Children

Adults

No. of Patients Tested

1884

727

1157

89

Failure of Test (Technical)

Total

Sensitive

Resistant

19

70

12

58

472

Success of Test

S. OEMIJATI ET AL.

hz vitro chloroquine resistance:58 patients

A. Not included in trial:12 patients B. Included in trial:46 paticnts

39 patients treated with clindamycin

34 Completed the trial o t h

e

7 patients lreated with sulfadoxine-pyrimc/hamine

5 Discontinued: 3 transferred to r hospilal,

5 Completed the trial

no follow-up. 1 prognai]t 1 showed mixed ction

30

No parasitemia on day 28

2 Discontinued 1 did not come for follow-up: 1 received chloroquine I M + was in poor condition

4

Appearance o f P l a s m o d i , m vivax:2 patients

1 on day 21 2 on day 28 1 misdiagnosed

4

Returned with P. vivax: l on clay 77 Plasmodium falciparum: t on day 58

MixEd refection:2 cases, day 37 and day 50

(patient (patient (patient (patient

no. no. no. no.

19) 13) 15) and 25)

Figure. Selection and follow-up of patients included in the trial of clindamycin group versus the control group (sulfadoxine-pyrimethamine). Patients were selected from 58 in vitro chloroquine-resistant falciparum malaria patients at the General Hospital, Dili, East Timer, Indonesia.

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TREATMENT OF PLASMODIUM FALCIPARUM INFECTIONS WITH CLINDAMYCIN HYDROCHLORIDE

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and 6, with 43.3% cleared by day 4 and a cumulative total of 66.6% cleared by day 5 (Table IV). In the sulfadoxine-pyrimethamine group, parasite clearance was obtained by day 3 (Table V). An increase of parasite densities from day 0 levels was seen in 11 patients (7 on day 1 and 4 on day 2) but all decreased to 0 between days 3 and 6. In 10 of the 30 patients treated with clindamycin, fever was not seen on day 0; 20 of the 30 patients experienced fever for a period of 1 to 4 days with none of the patients experiencing a temperature exceeding 39 °C. Mean hemoglobin at day 0 for the clindamycin treatment group was 11.53% (range, 6.6% to 14.7%). Thirteen of the 32 patients had normal hemoglobin values, 10 had mild anemia, 5 had moderate anemia, and 1 patient enrolled with severe anemia. In 6 patients, no hemoglobin value was determined at the end of treatment. The mean hemoglobin value for the treatment group on day 28 was 12.5% (P > 0.50). In 12 patients, the hemoglobin values increased after clindamycin treatment. Mean hematocrit values were 33.2% on day 0 (range for male patients: 27.0% to 39.0%; range for female patients: 30.8% to 34.4%) and 35.8% on day 28 (P > 0.50). Results of other routine hematologic, biochemical, urine, and stool examinations showed no significant abnormalities. No serious medical events were reported in any patient from either treatment group. D I S C U S S I O N AND C O N C L U S I O N

Although in many countries chloroquine is still the recommended drug for outpatient treatment of P falciparum malaria, in recent years increasing failure rates of chloroquine therapy have been reported. 7's Clindamycin has shown high antimalarial activity in in vitro models as well as in animal and human studies. 9-11 In this study, all 30 evaluable patients with chloroquine-resistant falciparum malaria treated with oral clindamycin 300 mg twice daily for 5 days responded to treatment. Clindamycin has been shown to act against chloroquine-resistant P falciparum in vitro.12 It proved to be highly effective when used for at least 5 days for treating P falciparum malaria in Brazil 13-1s and in the Philippines. 19 Even P falciparum strains highly resistant to other treatments could be eliminated with doses similar to the one used in the present study. 19'2° Kremsner et a121 reported a 97% cure rate in patients with chloroquine-resistant P falciparum using oral clindamycin 5 mg/kg twice daily for 5 days. Our observations on the clearing of parasites from blood also confirm previous studies: Rivera et al ~9 showed that parasite clearing occurs on days 5 to 7 of treatment. Other studies l°'1~ reported similar results. According to in vitro studies, clindamycin needs the time of two asexual parasite life cycles until full antimalarial action is achieved. 12'22-24 As in other field trials with clindamycin for malaria treatment, its 476

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TREATMENTOFPLASMODIUMFALCIPARUMINFECTIONSWITHCLINDAMYCINHYDROCHLORIDE

tolerability in the present study was good. No serious side effects were recorded, including diarrhea. This lack of toxicity has been recorded in most field studies, l°'ll In conclusion, our study confirms that low-dose oral clindamycin may be used as an efficient and safe alternative treatment for falciparum malaria, even in chloroquine-resistant P falciparum malaria.

Acknowledgments We would like to thank The Upjohn Company, Kalamazoo, Michigan, for financial support for this study. We also thank Dr. David Zambrano, Regional Medical Director, The Upjohn Company, for suggestions in the design of the study as well as critical reading of the manuscript; Dr. Djohan T. Saleh, Director of the General Hospital in Dili and his staff; Dr. R. Ungkuswinit, Director of the Provincial Health Laboratory and her staff; and Mr. Tranggono of the Provincial Health Office for its full support and technical assistance in this study. References: 1. Ministry of Health, Republic of Indonesia. Map of Health Problems per Province in Indonesia. Jakarta; Ministry of Health, 1985:1-84. 2. Verdrager J, Arwat P. Resistant Plasmodium falciparum infection from Samarinda, East Kalimantan. Bull Health Studies Indonesia. 1974;2:43-50. 3. Sisirawaty S. Pemeriksaan sensitivitas P falciparum in vitro dan in vivo terhadap klorokuin pada penderita malaria falciparum di Timor Timur (A study on the vivo and in vitro sensitivity ofP falciparum to chloroquine in East Timor). Jakarta, Indonesia: University of Indonesia; 1990:1-120. Thesis. 4. Adjung SA, Dakung LS, Pribadi W, Pramudya J. A case of in vivo resistance to chloroquine and Fansidar from East Timor. Presented at the Technical Meeting, April 1982, Jakarta, Indonesia. 5. Rai NK, Arbani PR, Simanjuntak CH. Review of drug resistant Plasmodium falciparum in Indonesia. Presented at the third Review Meeting of the Regional Collaborative Studies on Drug Resistant Malaria, May 1983, Jakarta, Indonesia. 6. Lestadi Y, Purnomo A, Soemedhi W, et al. Comparative studies of chloroquine and Fansidar to malaria in East Timor. Medika 1983;11:927-932. 7. Oduola AMJ, Mayou-Somo R, Kyle DE, et al. Cloroquine resistant Plasmodium falciparum in indigenous residents of Cameroon. Trans R Soc Trop Med Hyg. 1989;83:308310. 8. Richard-Lenoble D, Kombila M, Martz M, et al. Evolution de la resistence dePlasmodium falciparum a la chloroquine au Gabon entre 1984 et~1987-88. Ann Soc Belg Med Trop. 1989;69:113-119. 9. Zambrano D. Overview of clindamycin in the treatment of malaria. Presented at the clindamycin symposium, Hong Kong, March 30-31, 1989. 478

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10. Kremsner PG. Review. Clindamycin in malaria treatment. J Antimicrob Chemother. 1990;25:9-14. 11. Kremsner PG, Graninger W. Clindamycin in the treatment of experimental and human malaria. Rev Contemp Pharmacother. 1992;3:275-279. 12. Seaberg LS, Parquette AR, Gluzman IY, et al. Clindamycin activity against chloroquineresistant Plasmodium falciparum. J Infect Dis. 1984;150:904-910. 13. Alecrim MGC, Dourado H, Alecrim WD, et al. Treatment of falciparum malaria with clindamycin. Rev Inst Med Trop Sdo Paulo. 1981;23:86-91. 14. Alecrim WD, Albuquerque BC, Alecrim MGC, Dourado H. Treatment of malaria (P. falciparum) with clindamycin II. Dosage scheme in 5 days. Rev Inst Med Trop Sdo Paulo. 1982;24(Suppl 6):40-43. 15. Meira DA, Pereira PCM, Machado JM, et al. Malaria in Humaita county, State of Amazonas, Brazil. XIX--evaluation of clindamycin for the treatment of patients with Plasmodium falciparum infection. Rev Soc Brazil Med Trop. 1988;26:123-129. 16. Kremsner PG, Zotter GM, Feldmeier H, et al. Clindamycin treatment of falciparum malaria. J Antimicrob Chemother. 1989;23:275-281. 17. Pereira PCM, Marcondes J, Barraviera B, et al. Malaria at Humaita county, State of Amazonas, Brazil. XIII--Use of clindamycin in the treatment of patients with infections caused by Plasmodium falciparum. Rev Inst Med Trop Sdo Paulo. 1982;24(Suppl 6):1623. 18. Kremsner PG, Feldmeier H, Rocha RM, Graninger W. Multiresistant malaria cured with low dose clindamycin. Rev Inst Med Trop S~o Paulo. 1988;30:118-119. 19. Rivera DG, Cabrera BD, Lara NT. Treatment of falciparum malaria with clindamycin. Rev Inst Med Trop S(m Paulo. 1982;24(Suppl 6):70-75. 20. Neifer S, Kremsner PG. Drug susceptibility of Plasmodium falciparum in the Western Amazon region, state of Acre, Brazil. Rev Inst Med Trop S~o Paulo. 1991;33:205-211. 21. Kremsner PG, Winkler S, Brandts CL, et al. Curing of chloroquine-resistant malaria with clindamycin. A m J Trop Med Hyg. 1993;49:650-654. 22. Divo AA, Geary TG, Jensen JB. Oxygen-and-time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture. Antimicrob Agents Chemother. 1985;27:21-27. 23. Geary TG, Jensen JB. Effects of antibiotics on Plasmodium falciparum in vitro. A m J Trop Med Hyg. 1983;32:215-221. 24. Geary TG, Divo AA, Jensen JB. Uptake of antibiotics by Plasmodium falciparum in culture. A m J Trop Med Hyg. 1988;38:466-469.

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