MJSBH vol12 Issue1 final.indd M J S B H J a n u a r y - J u n e 2 0 1 3 | Vo l 1 2 | I s s u e 1 M e d i c a l J o u r n a l o f S h r e e B i r e n d r a H o s p i t a l 37 Original Article Ceftriaxone, ofl oxacin or both in the treatment of enteric fever. Rishi Khatri1, Rajeeb Kumar Deo1, Binod Karki1, Arun Sharma1. 1Department of Medicine, Shree Birendra Hospital. INTRODUCTION Enteric fever is characterized by systemic illness with fever and abdominal pain1.The incidence of enteric fever has declined greatly with the provision of clean water and good sewage systems in Europe and the USA since the early 20th century2 but the disease remains a serious public- health problem in developing countries3.Enteric fever is common diagnosis in day to day practice in Kathmandu which can be attributed to poor personal hygiene, poor sanitation, and poor quality of water supply. The treatment of enteric fever at the outset may look straightforward with various classes of effective antibiotics available for use but the emerging resistance is a big problem. The problem may be choice of too many and choosing appropriate antibiotic can be a challenge at times. Treatment of enteric fever has been complicated by the development and rapid dissemination of typhoidal organisms resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. In recent years, development of resistance to fl uoroquinolones as well as some extent to cephalosporins has resulted in more challenges4-5. ABSTRACT Introduction: Enteric fever is a common diagnosis in febrile patients admitting to the hospital of Nepal. ! e treatment of enteric fever, though looks straightforward, in recent times has been complicated by emerging resistance to various antibiotics including " uoroquinolones and cephalosporins. Methods: ! is was a randomized clinical study done at Shree Birendra Hospital from January 2011 to December 2011.Patients with with high grade fever ,headache, relative bradycardia, abdominal pain, diarrhoea or constipation with normal to low leukocyte count were clinically diagnosed as Enteric fever and were randomized to either o" oxacin or ce# riaxone group, both well accepted $ rst line treatment for enteric fever and observed for at least $ ve days before the addition of the second drug that is ce# riaxone in o" oxacin group and o" oxacin in ce# riaxonegroup and the response to the drug was noted in terms of defervescence of fever. Results: Total 50 patients were enrolled, 25 in each treatment group. A# er $ ve days, six patients in Ce# riaxone group needed addition of O" oxacin and two patients in O" oxacin group needed Ce# riaxone. ! e average fever defervescence time in Ce# riaxone group was 3.88 days and in O" oxacin group was 3.04 days. All patients were afebrile by 9 days of antibiotics. Conclusions: Fever defervescence time with O" oxacin was lesser than ce# riaxone group and need of supplementary antibiotic is lesser in o" oxacine group. So, o" oxacin can be recommended as 1st line drug for enteric fever. Keywords: ce# riaxone; enteric fever; fever defervescence; o" oxacin ....................................................................................... Correspondence: Col. Dr. Rishi Khatri Department of Medicine, Shree Birendra Hospital, Kathmandu Nepal Email: khatririshi@ymail.com M e d i c a l J o u r n a l o f S h r e e B i r e n d r a H o s p i t a l38 M J S B H J a n u a r y - J u n e 2 0 1 3 | Vo l 1 2 | I s s u e 1 In this setting, it is really challenging to decide which antibiotics to initiate and how long to wait before adding the second drug for the treatment. In our study, we have tried to fi nd the effi cacy of ofl oxacin and ceftriaxone alone or in combination for the treatment of enteric fever. METHODS The randomized clinical study was conducted at Shree Birendra Hospital for a period of one year from January 2011 to July 2011, which comprised of fi fty consecutive patients admitted with clinical diagnosis of Enteric fever as suggested by high grade fever, headache, relative bradycardia, abdominal pain, diarrhoea orconstipation with normal to low leukocyte count. Blood culture was sent from each patient. All patients above 15 years old with the abovementioned clinical features were included in the study and any patient already taking antibiotics from outside setting was excluded. The permission was taken from the hospital administration and consent obtained from the patients. They were randomly divided in two groups to receive either intravenous Ceftriaxone 2 g per day or intravenous ofl oxacin 400 mgper day, which are both, approved fi rst line therapy for enteric fever. Patients were observed for at least fi ve days for the fever defervescence before adding on the second antibiotic (intravenousOfl oxacin in patients receiving Ceftriaxone and intravenous Ceftriaxone in a patients receiving Ofl oxacin). Once the patient became afebrile for about 48 hours they were switched to oral ofl oxacin 800 mg per day or oral Cefi xime 800 mg per day from their respective iv preparations. All patients were planned for total of 14 days of therapy. The patients were discharged after 14 days and asked to follow up after one week in medical OPD.The data were tabulated and analysed using chi-sqaire and t test as indicated using SPSS 17.1 software. RESULTS There were 25 patients in Ceftriaxone group and 25 patients in Ofl oxacin group.The baseline characteristics in both the treatment arm were comparable in the study (Table 1).The mean age of the patient in the ofl oxacin group was 28.92 and that of the ceftriaxone grop was 31.36 which was not statistically signifi cant (p=0.45).The distribution of Sex (male), duration of Fever (days), and symptoms like Headache, Abdominal pain, diarrhoea, Constipation, Cough and Blood culture positivity were not different in both the group indicating that both the groups were comparable (Figure 1). The fever duration at the time of presentation to hospital for patients in Ceftriaxone group and Ofl oxacin group was 8.6 days and 6.04 days respectively. Six patients in Ceftriaxone group needed addition of Ofl oxacin after fi ve days and two patients in Ofl oxacin group needed addition of Ceftriaxone after fi ve days (Table 2). The average fever defervescence time in Ceftriaxone group was 3.88 days and in Ofl oxacin group was 3.04 days.All patients were afebrile by 9 days of antibiotics. Average duration of hospital stay for patients on Ceftriaxone group was 6.64 days and on Ofl oxacin group was 5.28 days. There were no complications and all patients were discharged from the hospital in stable condition. DISCUSSION Enteric fever also known as enteric feveris a systemic illness characterized by high grade fever and abdominal symptoms and it makes a major portion of hospital admission diagnosis for febrile patients in our hospital. Though enteric feveris usually treated with a single antibacterial drug, the optimal choice of drug and duration of therapy is uncertain and the selection of antibiotics depend upon local resistance patterns, patient age, whether oral medications are feasible, the clinical setting, and available resources6-8. The current recommendation for the treatment is with either fl uoroquinolone such as ciprofl oxacin or ofl axacin or with third generationcephalosporins such as ceftraxone9. The emergence of multi drug resistance (MDR) strains have caused numerous outbreaks in the Indian subcontinent, Southeast Asia, Mexico, the Arabian Gulf, and Africa4,10. There are concerns with the resistance even with ofl oxacin and ceftriaxone4-5. In this study, we tried to see the response of enteric fever in terms of fever defervescene with Ofl oxacin, Cefriaxone or both. The common presenting symptoms of enteric fever which are fever, abdominal pain, headache, cough, diarrhea and constipation were consistent with other previous studies. In a study conducted M J S B H J a n u a r y - J u n e 2 0 1 3 | Vo l 1 2 | I s s u e 1 M e d i c a l J o u r n a l o f S h r e e B i r e n d r a H o s p i t a l 39 by David et al11 in CIWEC clinic of Nepal and by Sharma et al12 in Dhulikhel have shown the similar clinical features of typhoid fever. In view of poor result from the blood culture, which was only 5 % of total cases, we had to depend mostly on the clinical features of typhoid fever. The low yield of culture may be due to inappropriate use of antibiotics by the primary care health worker before the patient presents to the hospital and the delay in incubating the media after the blood withdrawal. Figure 1. Comparison of clinical features in the patients. Table 1: Baseline characteristics of the two treatment groups Variables Ceftriaxone group (n=25) Ofl oxacin group (n=25) p value Mean age 28.92 31.36 0.45 Sex (male) 24(96%) 21(84%) 0.34 Fever duration at presentation (days) 8.6 6.04 0.70 Headache 14(56%) 15(60%) 1.00 Abdominal pain 12(48%) 9(36%) 0.56 Diarrhoea 20(80%) 17(68%) 0.52 Constipation 1(4%) 3(12%) 0.62 Cough 2(8%) 2(8%) 1.00 Blood culture positivity 2(8%) 3(12%) 1.00 M e d i c a l J o u r n a l o f S h r e e B i r e n d r a H o s p i t a l40 M J S B H J a n u a r y - J u n e 2 0 1 3 | Vo l 1 2 | I s s u e 1 The average fever defervescence time in Ceftriaxone group was 3.88 days and in Ofl oxacin group was 3.04 days which was also consistent with the similar studies of enteric fever done in Kathmandu12. In our study, six of the patients receiving ceftriaxone and two of those receiving ofl oxacin needed the addition of the second drug which was ofl oxacin in ceftriaxone group and vice versa. The study done by Sharma et al12 in Dhulikhel hospital had shown 100% sensitivity to the ceftriaxone however the present fi nding of our study showed different result. Smith et al had shown in his study when comparing the treatment with oral ofl oxacin with intravenous ceftriaxone in Vietnamese patients, that short-course treatment with oral ofl oxacin was signifi cantly better than that withceftriaxone13. The low number of sample size and the lack of correlation whether the non responder were having resistant to the treatment drug in vitro also have been the limitation of our study. However it does provide a new area of research for the emerging resistance pattern of the salmonella species in our part of the world. It also raises the concern whether multi drug therapy may be better than monotherapy in order to avoid treatment failure or drug resistance. CONCLUSION Fever defervescence time with Ofl oxacin was lesser than ceftriaxone group and need of supplementary antibiotic is lesser in ofl oxacine group. So, ofl oxacin can be recommended as 1st line drug for enteric fever. Further large randomised trials are needed to substantiate the fi ndings. REFERENCES 1. Parry CM, Hien TT, Dougan G, et al. Typhoid fever. N Engl J Med 2002; 347:1770. 2. Osler W. The principles and practice of medicine: designed for the use of practitioners and students of medicine. 8th edn. New York:D Appleton, 1912: 1–46. 3. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever.Bull World Health Organ 2004; 82: 346–53. 4. Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmo- nella typhi:a worldwide epidemic. Clin Infect Dis 1997; 24 (suppl 1): S106–09. 5. Saha SK, Talukder SY, Islam M, Saha S. A highly ceftriaxone resistant Salmonella typhiin Bangladesh. Pediatr Infect Dis J 1999;18: 387. 6. Wain, J, Hoa, NT, Chinh, NT. Quinolone-resistant Salmonella typhi in Viet Nam: Molecular basis of resistance and clini- cal response to treatment. Clin Infect Dis 1997; 25:1404. 7. Limson, BM. Short course quinolone therapy of enteric feverin developing countries. Drugs 1995; 49 S2:136. 8. Thaver, D, Zaidi, A, Critchley, J, et al. Fluoroquinolones for treating typhoid and paraenteric fever(enteric fever). Cochrane Database Syst Rev 2005; :CD004530. 9. Longo DL, Kasper DL, Jameson LJ, Fauci AS, Hauser LS, Los- calzo J. Harrison’s Principles of Internal Medicine. 18th ed. New York:McGrawHill; 2012:1274-81. 10. RastegarLari A, Validi N, Ghaffarzadeh K, Shamshiri AR. In vitro activity of cefi xime versus ceftizoxime against Salmo- nella typhi. PatholBiol (Paris) 1997; 45:415. 11. David R. Shlim,Eli Schwartz,Molly Eaton.Clinical Importance of Salmonella Paratyphi A Infection to Enteric Fever in Nepal.Journal of Travel Medicine.1995;2(3):165-68 12. Sharma N, Koju R, Karmacharya B, Tamang MD, Makaju R, Nepali N, Shrestha P, Adhikari D.Typhoid fever in Dhu- likhel hospital, Nepal.Kathmandu Univ Med J (KUMJ). 2004 Jul-Sep;2(3):188-92. 13. Smith MD,DuongNM,HoaNTT,WainJ,HaHD,Diep TS et al. Comparison of Ofl oxacin and Ceftriaxone for Short- CourseTreatment of Enteric Fever. Antimiocrobs agents chemother.1994; 38(8):1716-20 Table 2. cross tabulation between treatment group and addition of second drug Treatment Group Second drug added Total No Yes 25 Ceftriaxone 19 6 25 Ofl oxacin 23 2 50 Total 42 8