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Ciprofloxacin Treatment of Drug-Resistant Falciparum Malaria George Watt, G. Dennis Shanks, Michael D. Edstein, Katchrinnee Pavanand, H. Kyle Webster, and Suwit Wechgritaya

Departments of Medicine and Immunology, Armed Forces Research Institute ofMedical Sciences, Bangkok; Surasinghanart Army Hospital, Aranyaprathet, Thailand

There is an urgent need for new drugs active against falciparum malaria. In Thailand, high-level resistance precludes the use of both chloroquine and sulfadoxine and pyrimethamine (Fansidar; Roche, Nutley, NJ) [1] and the effectiveness of mefloquine is declining [2]. Similarities in chemical structure between chloroquine and fluoroquinolone antibiotics suggested that this family of antimicrobials might possess antimalarial activity [3]. Several quinolones were effective against malaria in vitro at therapeutic concentrations [3, 4], and a 3-day course of norfloxacin cured all nine falciparum infections in adult patients from India [5]. Because Indian strains of Plasmodium falciparum remain susceptible to most antimalarials, it remained to be determined whether fluoroquinolones would be effective in treatment of chloroquine-resistant malaria [5, 6]. Thus we evaluated the effectiveness ofciprofloxacin in the treatment of uncomplicated malaria in Thailand, where rnultidrug-resistant strains of P. falciparum are prevalent. Ciprofloxacin was selected because it has rapid and reliable oral absorption [7], few side effects [8], and better antimalarial activity in vitro than other quinolones [4, 9]. It also has the most potent DNA gyrase activity, thought to be the mechanism of action of this family of antimicrobials [10]. Unlike

Received 14 February 1991; revised 13 May 1991. Written informed consent was obtained from study subjects. The study protocol was approved by and the research was conducted according to guidelines of the US Surgeon General's Human Subjects Research Review Board and by the Human Use Committee of the Royal Thai Army. The opinions or assertions herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US or Royal Thai armies. Financial support: US Army Research and Development Command. Reprints or correspondence: Dr. George Watt. Department of Medicine, AFRIMS. APO San Francisco. CA 96346-5100. The Journal of Infectious Diseases 1991;164:602-4 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6403-0027$01.00

norfloxacin, ciprofloxacin is recommended for severe infections [II].

Patients and Methods Royal Thai Army militiamen admitted to Surasinghanart Army Hospital in Aranyaprathet, southeastern Thailand, with 103-105 P. jalciparum-infected erythrocytes in I mrrr' of blood were eligible for the study. Volunteers were included if they had not vomited and had no signs or symptoms of severe malaria. Study subjects were randomized to receive oral treatment with ciprofloxacin for 7 days (Miles Pharmaceuticals, West Haven, CT) at its maximum recommended dose of 750 mg every 12 h or the control regimen, quinine sulfate (650 mg by mouth three times a day) with tetracycline (250 mg orally four times a day). A study nurse measured vital signs every 4 h and closely monitored patients for vomiting after the antimalarial medication was given. The study was designed for 50 patients with predetermined criteria for stopping early should an unacceptable number of ciprofloxacin treatment failures occur (more than three failures among the first 10 patients). Plasma and erythrocyte ciprofloxacin concentrations were measured at 90 min after dosing, the expected time to reach peak concentration [7]. Trough levels were measured immediately before the next dose. Ciprofloxacin was assayed by reversed-phase high-performance liquid chromatography using difloxacin as the internal standard [12]. Fluorescence detection was used and the compounds were extracted from the three biologic fluids using protein precipitation followed by a single-step liquid-liquid extraction. The interassay coefficient of variation and accuracy of the method was ~9.1 %at 0.5 and 5.0 ~g/ml and the limit ofdetection was 25 ng/ml. In vitro drug sensitivities to ciprofloxacin, norfloxacin, chloroquine, and quinine were measured by parasite incorporation of radiolabeled hypoxanthine, and results expressed as the

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A randomized, open study of high-dose ciproftoxacin (750 mg every 12 h) in uncomplicated falciparum malaria was conducted in Thailand. No patient completed the planned l-week treatment course. Because of rising parasitemia (threefold higher at 36 h than on admission) and deterioration of clinical status, three individuals required quinine treatment 36 h after commencing ciproftoxacin; a fourth was given quinine at 54 h. The study was terminated early for safety reasons after only four ciproftoxacin and four control patients had been enrolled. Ciproftoxacin was well absorbed and efficiently entered erythrocytes; median plasma and red cell concentrations 90 min after the first dose were 4.0 (range, 3.7-6.8) and 5.1 (3.8-6.0) #g/ml, respectively. However, 50% inhibition of parasite growth in vitro required 6.6 #g/ml (5.6-9.6). Ciproftoxacin should not be used alone to treat chloroquine-resistant falciparum malaria.

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Concise Communications

ID so, the amount of drug required to inhibit hypoxanthine uptake by 50% [13]. Patients were examined every 8 h, and quinine was given immediately if there was a fall in blood pressure, change in level of consciousness, evidence of renal dysfunction (raised serum creatinine or oliguria), > lOs P. jalciparum-infected erythrocytes in 1 mm ' of blood or any other sign of clinical deterioration or severe malaria. Clinical status, side effects, and routine hematologic and biochemical determinations were recorded on standardized code sheets.

Eight male soldiers were enrolled in the study, but none of the four randomized to receive ciprofloxacin could complete the scheduled l-week regimen. Deteriorating clinical status and increasing parasitemia mandated a change to quinine after 36 h in three patients and after 54 h in the fourth; intravenous quinine was required for one. Parasitemia had increased by a median of 292% per patient (figure I) 36 h after ciprofloxacin was started. Quinine and tetracycline promptly cured the four patients who did not respond to ciprofloxacin and another four who received this drug combination from the outset (figure I). Among the four failures was an individual who was inadvertently given triple the first dose of ciprofloxacin (2250 mg instead of 750 mg). The median initial parasitemia in the ciprofloxacin group was 29,949/mm 3 (range, 2600-84,372) compared with 5130 (1300-9200) in the quinine group (P = .19). The median parasitemia of the four ciprofloxacin failures was 142,668 (61,140-259,880) at the time quinine was begun; 36 h later, this had fallen to 6720 (1460-28,480). There were no significant differences between the quinine and ciprofloxacin groups in median weight (62 and 58 kg, respec-

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It-._ 0.01 ~g/ml). The median ID so values for ciprofloxacin, norfloxacin, and quinine were 6.6 ~g/ml (5.6-9.6), 11.6 ~g/ml (10.8-18.7), and 0.15 ~g/ml (0.06-0.22), respectively. No differences between the pre- and posttreatment ciprofloxacin ID so levels were seen in the one patient from whom paired isolates were available (5.6 ~g/ml for both).

Discussion High-dose ciprofloxacin was of no discernible benefit when administered to patients with falciparum malaria acquired in Thailand (figure 1). Parasitemia in the ciprofloxacin group was three times higher 36 h after beginning treatment than it was at admission, although it was markedly reduced by 36 h in patients who received quinine as primary treatment and in those who were given quinine because they had failed ciprofloxacin. The shape of the parasite clearance curves varied (figure I), presumably reflecting differences in synchronicity of infection and in parasite sequestration, and emphasizes that increases in peripheral parasitemia during the first 24 h do not imply eventual treatment failure nor do decreases during this time guarantee treatment success. It is unlikely that better results would have been obtained with norfloxacin, the quinolone antibiotic used successfully in India [5]. The median ID so ofnorfloxacin against parasites from our patients was twice that of ciprofloxacin (11.6 vs. 6.6 ~g/ml), and almost 10 times that of the reported peak serum concentration (1.5 ~g/ml) expected from the dose used in India [7]. Midgely et al. [9] also found a higher ID so

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Results

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soon as the evidence for ciprofloxacin's lack of efficacy became conclusive so that other patients were not needlessly exposed to the risks ofinadequate therapy. The four patients treated with ciprofloxacin were monitored closely, suffered no serious complications, and were promptly cured by quinine. Our data do not support the use of quinolone antibiotics as sole treatment for drug-resistant strains of P. falciparum. Acknowledgments

We thank Roger Echols, Miles Pharmaceuticals, for the ciprofloxacin, and M. G. Phung Phintuyothin, John W. Boslego, and Kittithep Krinchai for invaluable help in executing the study. References I. Lobel HO. Campbell Cc. Malaria prophylaxis and distribution of drug . resistance. Clin Trop Med Communicable Dis 1986; I:225-42. 2. Nosten F, Ter Kuile F. Chongsuphajaisiddhi T. et al. Mefoquine-resistant falciparum malaria on the Thai-Burmese border. Lancet 1991; 337: 1140-3. 3. Krishna S, Davis TME, Chan PCY. Wells RA, Robson KJH. Ciprofloxacin and malaria. Lancet 1988; I: 1231-2. 4. Divo AA, Sartorelli AC, Patton CL. Bia FJ. Activity offluoroquinolone antibiotics against Plasmodium falciparum in vitro. Antimicrob Agents Chemother 1988;32: 1182-6. 5. Sarma PS. Norfloxacin: a new drug in the treatment offalciparum malaria. Ann Intern Med 1989;111:336-7. 6. Wyler DJ. Fluoroquinolones for malaria: the newest kid on the block? Ann Intern Med 1989; III :269-71. 7. Wise R. Lister D. McNulty CAM, Griggs D. Andrews JM. The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 1986;18:71-81. 8. Halkin H. Adverse effects of the f1uoroquinolones. Rev Infect Dis 1988; 10:S258-61. 9. Midgley JM. Keter DW. Phillipson JD. Grant S. Warhurst DC. Quinolones and multiresistant Plasmodium falciparum. Lancet 1988; I:281. 10. Hooper DC, Wolfson JS. Mode of action of the quinolone antimicrobial agents. Rev Infect Dis 1988; IO:S14-21. II. Ciprofloxacin. Med Lett Drugs Ther 1988;30:11-3. 12. Teja-lsavadharm P. Keeratithakul D. Watt G. Webster HK, Edstein MD. Measurement of ciprofloxacin in human plasma. whole blood and erythrocytes by high-performance liquid chromatography. Ther Drug Monit (in press). 13. Webster HK. Boudreau EF. Pavanand K. Yongvanitchit K, Pang LW. Antimalarial drug susceptibility testing of Plasmodium falciparum in Thailand using a microdilution radioisotope method. Am J Trop Med Hyg 1985;34:228-35. 14. Ciprofloxacin product information. Compendium of preclinical and clinical data. New York: Marcel Dekker. 1988:26. 15. Desjardins RE. Doberstyn EO. Wernsdorfer WHo The treatment and prophylaxis of malaria. In: Wernsdorfer WH, McGregor I, eds. Malaria: principles and practice of malariology. Edinburgh: Churchill Livingstone, 1988;827-64. 16. Bergan T. Thorsteinsson SB. Kolstad 1M. Johnsen S. Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. Eur J Clin Microbiol 1986;5: 187-92.

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for norfloxacin than ciprofloxacin against a multidrug-resistant falciparum isolate from Thailand (13.3 vs. 5.2 J.Lg/ml). The poor therapeutic response was not due either to erratic drug absorption or to failure of ciprofloxacin to reach intraerythrocytic parasites. Peak ciprofloxacin concentrations after a 750-mg dose in healthy subjects ranged from 2.0 to 3.4 J.Lg/ml [14], lower than any of our patients' peak levels (range, 3.7-6.8 J.Lg/ml), whereas erythrocyte concentrations tended to be greater (median, 5.1; range, 3.8-6.0). Lack of immunity also is not a likely explanation for the disparity between our findings and those from the Indian study, as one of our ciprofloxacin treatment failures reported had three recent episodes of malaria. The data suggest that ciprofloxacin treatment failed because Thai strains of P. falciparum are insensitive to fluoroquinolones. In vitro drug sensitivity testing does not correlate precisely with therapeutic response in malaria but provides an approximate guide to efficacy. There is clearly cause for concern when the drug level required to inhibit parasite growth in vitro (10 50 ) exceeds the peak plasma concentration. This was the case with ciprofloxacin; median peak plasma levels reached 4.0 J.Lg/ml, but the 1050 was 6.6 J.Lg/ml. Quinine, in contrast, was clinically effective. The 1050 (0.2 J.Lg/ml) was considerably less than therapeutic quinine plasma levels (5-10 J.Lg/ml) [15]. We gave the maximum recommended dosage ofciprofloxacin, 750 mg every 12 h [11]. Peak plasma concentrations after one oral dose of 1000 mg only reach 5.6 J.Lg/ml [16], which is still less than the in vitro inhibitory level we measured. One patient was inadvertently given an initial dose of 2250 mg yet still required a change to quinine at 36 h. It is therefore unlikely that patients infected with chloroquine-resistant malaria can be cured with the doses of ciprofloxacin currently used in clinical practice. In vitro drug sensitivity data was not reported in Sarma's norfloxacin study [5], but Indian strains of falciparum remain generally sensitive to chloroquine. The median ciprofloxacin 1050 for three chloroquine-sensitive strains (two from Malaysia, one from the Philippines) measured in our laboratory was 3.2 J.Lg/ml, about half that of chloroquine-resistant isolates (unpublished data). Divo et al. [4] also found that twice as much ciprofloxacin was required to inhibit the growth of chloroquine-resistant parasites. This is the most likely explanation for the success of quinolones in India and their failure in Thailand. Slowly acting drugs such as tetracycline are useful antimalarials when combined with more rapidly acting compounds. The possibility that ciprofloxacin has a delayed effect cannot be excluded by results of this study because it was necessary to discontinue ciprofloxacin after only 36 h in three patients and after 54 h in the fourth. The study was terminated as

lID 1991; 164 (September)

Ciprofloxacin treatment of drug-resistant falciparum malaria.

A randomized, open study of high-dose ciprofloxacin (750 mg every 12 h) in uncomplicated falciparum malaria was conducted in Thailand. No patient comp...
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