TRANSACTIONS OFTHE Short courses ROYAL SOCIETY of ofloxacin OFTROPICAL MEDICINE for the treatment AND HYGIENE (1997) 91,347-349 347 of enteric fever Nguyen Tran Chinhl, Tom Solomon 2p3, Mai Xuan Thong’, Nguyen Thi Lyl, N yen Thi Tuyet Hoa ,jlohn Par&v and Wain2y3, To Song Diepl, Michael D Smith 2p3, Nicholas I? J Da333, Le Thi Phi K”, Christopher ICentre for Tropical Diseases, Cho Quart Hospital, Ho Chi Mirth City, Viet Nam;2NufFeld DepartNicholas J Whit&y3 Oxford, OX3 9DU, UK;3 Wellcome Trust Clinical Research ment of Clinical Medicine, John RadcliSfe Hospital, Headington, Unit, Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Viet Nam Keywords: enteric fever, typhoid, Salmonella typhi, Salmonella paratyphi, chemotherapy, ofloxacin Introduction With more than 12.5 million cases occurring each year throughout the world, typhoid fever continues to present a considerable health problem, particularly in developing countries (EDEL,MAN & LEVINE, 1986) Chloramphenicol has been the traditional treatment of choice, although the emergence of plasmid-mediated chloramphenicol resistance (PANICKER & VIMALA, 1972; BUTLER et al., 1973), has led to increasing use of the alternatives ampicillin and trimethoprim-sulphamethoxazole (BUTLER et al., 1982) In recent years, outbreaks of Salmonella typhi resistant to all the first-line drugs, i.e., chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole, have been reported from the Indian sub-continent, south-east Asia, and Africa (JESUDASON & JOHN, 1990; WALLACE & YOUSIF, 1990) In southern Viet Nam, where typhoid is endemic, these multi-drug resistant strains of S typhi have emerged rapidly since 1992, and currently they account for 80% of isolates (HOA et al., 1992) The third generation cephalosporins and fluoroquinolone antibiotics are both effective in vitro against multi-drug resistant strains of S typhi Several clinical trials have confirmed the efficacy of parenteral third generation cephalosporins in treating enteric fever @SLAM et al., 1988) However, recent trials in Viet Nam have shown that oral fluoroquinolones are more effective (SMITH et al., 1994; ACHAYARA et al., 1995) These drugs have therefore become first-line treatment for patients with enteric fever in Viet Nam Although Salmonella species resistant to ciprofloxacin have been reported from the Indian subcontinent (LEWIN et al., 1991; ROWE et al., 1995), until now no quinolone resistance has been reported from south-east Asia The optimal length of treatment with fluoroquinolones for multi-drug resistant typhoid remains unknown Short course treatment has the advantage of reduced cost and increased compliance During a recent epidemic in southern Viet Nam a d course of oral ofloxacin was found to be as effective as treatment for d (HIEN et al., 1995) In the present open, randomized study, we have compared d versus d oral ofloxacin in adults with uncomplicated enteric fever, most of which was caused by multi-drug resistant strains of S typhi, and in some cases these isolates were found to be quinolone resistant also Materials and Methods The study was conducted in the adult typhoid ward of the Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Viet Nam-the main referral centre for patients with infectious diseases in southern Viet Nam The study was approved by the scientific and ethics committee of the Centre for Tropical Diseases, and informed consent was obtained from patients before enrolment Patients Between November 1993 and December 1995, adults (> 15 years old) with clinically suspected uncomplicated enteric fever were included in the study In mild cases such as these, antibiotic treatment was started only when culture results became available Patients were excluded if they were pregnant, had severe disease requiring intensive care, had known hypersensitivity to quinolones, or had received treatment with quinolones in the week before admission Patients who had received previous treatment with chloramphenicol, ampicillin, cephalosporins or trimethoprim-sulphamethoxazole were also excluded if they had shown a clinical response to these drugs Sample size On the basis of our previous study (HIEN et al., 1995), the failure rate with d ofloxacin was expected to be low The study was therefore designed to detect a difference in failure rates of 25% or greater, with 95% contidence and 80% power Treatment Patients were allocated at random to receive ofloxacin (OflocetTM; Roussel-Uclaf, Paris, France), 15 mg/kg/d for d or 10 mglkgld for d Randomization was in blocks Treatment codes were contained in serially numbered sealed envelopes that were opened at the time a patient entered the study Antipyretics were not given during the study Assessment of patients A complete medical history was obtained and clinical examination performed by a member of the study team All details were recorded on standard forms Axillary temperature and other vital signs were recorded every h Patients were examined daily and symptoms documented Address for correspondence: Dr Tom Solomon, Wellcome Trust Clinical Research Unit, Centre for Tropical Diseases, Cho Quan Hospital, 190 Ben HamTu, Quan 5, Ho Chi Minh City,Viet Nam; phone +84 8353954, fax +84 8353904 Laboratory procedures On admission, blood was taken for haematocrit, examination for malaria parasites, platelet count, differen- Downloaded from http://trstmh.oxfordjournals.org/ at University of East Anglia on July 17, 2015 Abstract Typhoid fever continues to be a major public health problem in tropical countries, exacerbated in recent years by the spread of multi-drug resistant strains of Salmonella typhi Short treatment courses of fluoroquinolones are effective, and have the advantage of reduced cost and increased compliance, but the optimal length of treatment is unknown In an open, randomized comparison, 107 adults with uncomplicated enteric fever (95 of whom had positive blood cultures for S typhi and for S paratypht) were treated with oral ofloxacin, 15 mglkgid for d or 10 mg/kg/d for d Mean fever clearance times were the same in the treatment groups (97 h).There were treatment failures, one in the d group and in the d group (fiO.07) Three of the patients infected with nalidixic acid resistant strains of S typhi had treatment failures, compared with of 90 with nalidixic acid sensitive isolates Cp 168 h Microbiological relapse Duration of admission after 7.6(1.4) starting treatment (d) 53 26 (49%) 24.2 (7.1) 45.0(7.6) 13.2(6.5) 103(11) 13 (25%) 6.9 (3.2) 52 40 97 (44; 15-288) 47 7.8 1.6) aMean (standard deviation in parentheses) bMean (standard deviation and range in parentheses) =One patient with nalidixic acid resistant S typhi had both acute complications and prolonged fever clearance time Microbiology Sixteen of the 95 S typhi isolates (17%) were susceptible to all antimicrobial agents Multiple resistance to chloramphenicol, ampicillin, sulphamethoxazole, trimethopim, and tetracycline oc&rred in 75 isolates (79%) Five of these resistant isolates were also resistant to naiidixic acid (MIC >64 @L) Full details of these and other recently isolated nalidixic acid resistant isolates will be presented elsewhere All isolates were sensitive to ofloxacin, although the 50% MIC of ofloxacin was higher for the nalidixic acid resistant iosolates than for nalidixic acid sensitive isolates-meanz0.25 m/L (range 0.125-l.O), vs mean=0.06 E/L (range 0.015 -0.125) (Z’cO.0005) Response to treatment The mean fever clearance time was the same in both treatment groups: 97 h (SD=33) following treatment for d and 97 h (SD=&) after treatment for d (Table) There was also no significant difference in the fever resolution with survival analysis There were treatment failures: acute failures and one microbiological relapse Six of the failures were in the group treated with ofloxacin for d and one was in the d group (relative risk=5+3, 95% confidence interval [CI] 0.7-43; eO.07) Three of the treatment failures in the d group were associated with nalidixic acid resistant isolates of S typhi Two of these patients were still febrile d after starting treatment: one was successfully retreated with further days ofloxacin (400 mg/d); the other developed lower gastrointestinal bleeding on day and was re-treated with ofloxacin for d (400 mg/d) The third treatment failure had a good initial respinse to treatment, but relapsed weeks later with fever and a positive blood culture for S typhi and was treated with ofloxacin for d (400 mg/d) The other patients in the d group deteriorated clinically on the second day of treatment: one developed abdominal pain and hypotension, one became jaundiced, and the third had gastrointestinal bleeding Ofloxacin 400 mgid was continued for 7-10 d and all were successfully treated No adverse effect of ofloxacin was observed in any patient Fifty patients (50%) were assessed at follow-up Six patients had recurrent fever within months of discharge (4 in the d group and in the d group) but in only one of these (described above) was the blood culture positive The other patients were treated with oral ofloxacin (3-7 d) No follow-up stool culture was positive Three of the patients in this series with nalidixic acid resistant S typhi had treatment failures, compared with of 90 with nalidixic sensitive S typhi (4%) (RO.0001; relative riskz13.5, 95% CI 4.1-45) The majority of patients (89%) were still febrile when treatment stopped (i.e., after or d), but only patients (3%) were still febrile d after starting treatment Excluding those who had already failed treatment, because thev had developed complications, continuing fever d aft& starting treatment-predicted eventual treatment failure with 75% sensitivitv and 83% suecificitv (relative - risk=12.3, 95% CI l+li2) Discussion Over the last 45 years the treatment of typhoid fever has changed as S typhi has developed resistance to the available antimicrobial drugs In the last years, S typhi resistant to all the conventional first-line antibiotics, Downloaded from http://trstmh.oxfordjournals.org/ at University of East Anglia on July 17, 2015 Evaluation of treatment response Patients were considered cured if they became afebrile, symptoms and signs resolved, and th&e was no evidence of relapse Fever clearance time was defined as the time at which fever fell below 375°C for at least 24 h Acute treatment failure was defined as continuing fever and symptoms for d after the start of treatment, or deterioration in clinical condition before d which warranted further treatment Patients were instructed to return to hospital if fever recurred after discharge, and were asked to attend as an out-patient weeks after the end of treatment Those who failed to attend were followed-up at home patient was therefore excluded from the detailed analysis Fourteen of the natients with S tvvahi (15%) and one patient with S pkztyphi A had a G&it& stobi culture One patient with S parutyphi A had a positive urine culture The demographic, clinical and laboratory findings for the 100 culture confirmed cases of typhoid fever are shown in the Table There was no significant difference between the admission characteristics of the treatment groups, nor between the culture positive and culture negative patients (data not shown) 349 OFLOXACINFORENTERICFEVER View publication stats Acknowledgements We are grateful to the Director of the Centre for Tropical Diseases and the manv medical, nursina and laboratorv staff who helped with the stbdy We thank Professor A Bryskier of Roussel-Uclaf for providing the ofloxacin The study was funded by the Wellcome Trust of Great Britain References Achavara G Butler T Ho M Sharma l? R Tiwari M Adiikaii, k K., Khagha, i B.,‘Pokhrel, ‘B & Pathak, c N: (1995) Treatment of typhoid fever: randomized trial of a t‘hree-hay course of ceftiiaxone versus a fourteen-day course of chloramphenicol American Journal of Tropical Medicine and Hygiene, 52, 162-165 Bethell, D B., Hien, T T., Phi, L T., Day, N I? J., Vinh, H., Dung M N., Len N V., Chuone, L V & White, N (199:j.The effects on growth of siniie short courses of flu& roquinolones Archives of Diseases in Childhood, 14,44-46 Butler, T., Linh, N N., Arnold, K & Pollack, M (1973) Chloramuhenicol-resistant tvohoid fever inViet Nam associated with’R-factor Lancet, ii,‘983-985 Butler, T., Rumans, L & Arnold, K (1982) Response of tyohoid fever caused bv chloramohenicol-resistant strains of kalmonella typhi to treatment w;th trimethoprim-sulphamethoxazole Reviews of Infectious Diseases, 4, 55 l-56 Edelman R & Levine, M M (1986) Summarv of an international workshop on typhoid‘fever: Reviews of hfectious Diseases, 8,329-349 Hien, T T., Duong, N M., Ha, H D., Hoa, N T T., Diep, T S., Phi L T & Arnold K (1994) A randomized comnarat&e &dy of fleroxacin add cekriaxone in enteric fever Transactions of the Royal Society of Tropical Medicine and Hygiene, g&464-465 Hien T T., Bethell D B Hoa N T T., Wain, Dien T S Phi, L ?., Cuong, B ‘M., Duong, k M.; “Than&’ I? T.; Walsh, A L., Day, N I? J & White, N J (1995) Short course ofloxacin treatment of multi-drug resistant typhoid Clinical Infectious Diseases, 20,917-923 Hoa, N T.T., Phi, L E., Hien,T T., Smith, M D &White, N J (1992) Antibiotic resistance in Salmonella typhi and S paratyphi A from Viet Nam Abstracts: XIZZth International Congress for Tropical Medicine and Malaria; Pattaya, Thailand, abstract no WeP3-2, p 193 Islam, A., Butler, T., Nath, S K., Alam, N H., Stoeckel, K., Houser H B & Smith A L (1988) Randomized treat\ I ment of patients with typhoid fever by using ceftriaxone or chloramphenicol .yo’ournal of Infectious Diseases, 158, 742-747‘ Jesudason, M V & John,T J (1990) Multiresistant Salmonella qphi in India Lance& 336, 252 Lewin, C S., Nandivada, L S & Aymes, S G B (199 1) Multi-resistant Salmonella and fluoroquinolones Journal of Antimicrobial Chemotheraav 227 147-149 Meskin, S., Jacob, M S., Macaden, R., Keystone, J S., Kozarskv, I? E., Ramachadran, A N & Metchock, B (1992) %&t-co&e treatment oftyphoid fever with cipiofloxacin in south India Transactions of the Royal Society of Tropical Medicine and Hygiene, 86,446-447 Panicker, C K J & Vimala, K N (1972) Transferable chloramphenicol resistance in Salmonella typhi Nature, 239, 109-110 Ramirez, C A J., Bran, L., Mejia, C R & Garcia, J F (1985) Open, prospective study of the clinical efficacy of ciprofloxacin Antimicrobial Agents and Chemotherapy, 28, 128-132 Rowe, B., Ward, L R &Threlfall, E J (1995) Ciprofloxacinresistant Salmonella zvbhi in the UK tancet 346 1302 Smith, M D., Duong, % M., Hoa, N T T.,kain; J., Ha, H D., Diep, T S., Day, N l? J., Hien, T T & White, N J (1994) Comparison of ofloxacin and ceftriaxone for shortcourse treatment of enteric fever Antimicrobial Apenw and Chemotherapy, 38, 17 16-1720 Vinh, H., Wain, J., Hanh, V T N., Nga, C N., Chinh, M T., Bethell,D Hoa.N.T.T DieD.T.S Dune.N.M.&White N J (1 i)96j Two or three days bf o&xacin?or uncomplicated multi-drug resistant typhoid fever in children AnimicrobialAgents and Chemotherapy, 40,958-961 Wallace, M & Yousif, A A (1990) Spread of multiresistant Salmonella typhi Lancet, 336, 1065-1066 Wang, F., Gu, X J., Zhang, M F & Tai, Y T (1989) Treatment of typhoid fever with ofloxacin.Journal ofAntimicrobial Chemotherapy, 23, 785-788 Received October 1996; accepted for publication ber 1996 15 Octo- Downloaded from http://trstmh.oxfordjournals.org/ at University of East Anglia on July 17, 2015 ampicillin, co-trimoxazole and chloramphenicol, has been reported from Central and South America, the Middle East, the Indian sub-continent and south-east Asia These multi-drug resistant infections are emerging at an alarming rate In 1992 less than 2% of S typhi isolates from southern Viet Nam were multi-resistant (HOA et al., 1992) compared with the current study (conducted between 1993 and 1995) which found 79% of strains to be multi-resistant; furthermore, resistance to a quinolone, nalidixic acid, has now developed The fluoroquinolones are an attractive option in the treatment of multi-drug resistant typhoid fever Their excellent activity and tissue penetration result in very high cure rates with a considerably shorter duration of treatment than the 2-3 weeks’ therapy traditionally recommended Despite earlier worries about the effects of quinolones on the cartilage of young animals, follow-up studies of children treated with ofloxacin have shown no deleterious effect (BETHELL et al., 1996) Short courses minimize any risk of side effects and have the advantage of reduced cost, reduced periods in hospital, and increased compliance But how short can the course of treatment be before efficacy is reduced significantly? Ciprofloxacin (500 mg every 12 h) and ofloxacin (300 mg every 12 h) have been effective in courses of 14 and 10 d (RAMIREz et al., 1985; WANG et al., 1989) Ciprofloxacin (750 mg every 12 h) for d (MESKIN et al., 1992), fleroxacin (400 mg daily; HIEN et al., 1994), and ofloxacin (200 mg every 12 h) for d (SMITH et al., 1994) have achieved 100% cure rates Recently, during an epidemic in Viet Nam, ofloxacin 10 mgikg daily for d and 15 mg/kg daily for d were both almost completely effective in treating multi-drug resistant typhoid (HIEN et al., 1995) The present study has shown that ofloxacin treatment for d is as effective as treatment for d in adults with mild or moderate multi-drug resistant typhoid Similar results have been reported recently in children (VINH et al., 1996) There were clinical failures; one in the d group and six in the d group This may be an overestimate, as only one of these was confirmed microbiologically, and clinical deterioration on the second day of treatment (as occurred in patients) does not necessarily reflect a failure of antimicrobial treatment; indeed, when the same drug was continued for longer than d, each case responded Protracted fever is more likely to result from antimicrobial failure There were more such cases in the d group but this reflects the greater incidence of nalidixic acid resistant S typhi in this group Nalidixic acid resistance appears to predict subsequent failure of fluoroquinolone treatment Further testing at this centre has revealed that up to 15% of multi-drug resistant S typhi isolates are nalidixic acid resistant (unpublished observations) Strains of Salmonella which are resistant to nalidixic acid, and have reduced sensitivity to other quinolones, have recently been reported from India (hWIN et al., 199 1; ROWE et al., 1995) To date, there has been no report of any such strain from south-east Asia The emergence of resistant strains in India was thought to be due to the widespread availability of nalidixic acid (IXWIS et al., 199 1) Although nalidixic acid is not widely used in southern Viet Nam, fluoroquinolones are now freely available and can be purchased without prescription and may have provided sufficient drug pressure to induce resistance Who should be treated with very short courses of ofloxacin? This study has shown that a d or d course of ofloxacin will cure 96% of patients infected with a nalidixic acid sensitive S typhi For those patients with nalidixic acid resistant strains, longer courses are needed The persistence of fever for d after starting fluoroquinolone treatment is a valuable predictor of subsequent failure The optimum treatment for patients with nalidixic acid resistant infections is not known, and clearly this requires further study ... of the blood culture confirmed cases of enteric fever Ofloxacin treatment 2d 3d No of patients I&%) No of males 25.3 (8.9) Age (years)a 46.2 (8.7) Weight (kg)a Duration of fever 12.4(5.1) before... recurrent fever within months of discharge (4 in the d group and in the d group) but in only one of these (described above) was the blood culture positive The other patients were treated with oral ofloxacin. .. Comparison of ofloxacin and ceftriaxone for shortcourse treatment of enteric fever Antimicrobial Apenw and Chemotherapy, 38, 17 16-1720 Vinh, H., Wain, J., Hanh, V T N., Nga, C N., Chinh, M T., Bethell,D