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ABSTRACT

OBJECTIVE: To determine the efficacy of oral azithromycin and intravenous ceftriaxone for treatment of uncomplicated enteric fever and the frequency of relapse in both groups.STUDY DESIGN: A randomized controlled trial PLACE AND DURATION: Study was conducted at Pediatric Medicine Ward and Emergency Department of Sir Ganga Ram Hospital from

st st1 May 2013 to 31 Oct 2013. METHODOLOGY: Using Non probability purposive sampling, 100 patients with uncomplicated enteric fever were taken who were fulfilling the inclusion criteria. Patient was randomly divided in 2 groups using random numbers, Group "A" and Group "B", with 50 patients in each group. Group A was given ceftriaxone for 7 days. Group B was given azithromycin once a day for 7 days. A culture was repeated at day 4 of therapy. Both groups were compared for efficacy and relapse. RESULTS: Efficacy achieved by oral azithromycin as well as intravenous ceftriaxone in treatment of uncomplicated enteric fever was statistically same. There were 11 patients in Ceftriaxone group (A) with relapse. There were 3 patients in Azithromycin group with relapse. The rate of relapse was different statistically in both groups. CONCLUSION: Efficacy achieved by both the oral azithromycin and intravenous ceftriaxone in treatment of uncomplicated enteric fever was satisfactory and statistically same. However, higher rate of relapse was observed in group treated by intravenous ceftriaxone compared to oral azithromycin.KEY WORDS: Typhoid fever, Ceftriaxone, Azithromycin, Children.

ORIGINAL ARTICLE ISRA MEDICAL JOURNAL | Volume 8 - Issue 4 | Oct - Dec 2016

INTRODUCTION

Enteric fever (also known as typhoid fever), a systemic infection caused by Salmonella enterica serovars (S. typhi& S. paratyphi) always remains a major public health issue especially in

1,2developing countries. According to a study, WHO reported that there are about 21 million cases of typhoid fever in the world and it has swallowed more than six hundred thousand

3people worldwide. Typhoid fever leads to nearly 22 million 4cases and 216,500 deaths annually, primarily in Asia, and case

5fatality rate is 1% to 4%. The prevalence of enteric fever is high 6 in developing countries like Pakistan. Developing nations suffer

more from this fatal disease because of increase in population size, growing trend of urbanization, limited availability of safe

7 water for drinking and unsatisfactory systems of health. Enteric fever starts usually 7-14 days after exposure to virulent bacteria

S typhi.The most predominant feature of uncomplicated enteric fever is fever which is high grade and gradually increases in intensity over several days. Patients can also have abdominal

pain, anorexia, headaches, diarrhea, cough, rose colored spots o n n e c k , c h e s t a n d a b d o m e n , m a l a i s e a n d

8hepatosplenomegaly. Unusual presentation of enteric fever could be in form of severe headache that is easily confused with

9 meningitis, lung consolidation, isolated arthralgia, arthritis,dysuria or burning micturition, poly serositis and cholestatic

10 hepatitis. Complications of typhoid fever usually occur in those patients who have not been given adequate treatment in form of antibiotics. Complications are seen in about 1 in 10 patients, which are usually seen in third week of infection.

11 Complications most commonly seen are perforation of bowel and hemorrhages in intestine that can lead to shock,

inflammation of pancreas, pneumonia, myocarditis, meningitis, 12Osteomyelitis, abscesses anywhere in body and rare

13 neurological complications like Guillain Barre syndrome. The gold standard of diagnosis for enteric fever is Bone marrow culture but as it is an invasive procedure the mainstay of

st 14,15 diagnosis in 1 week of illness is positive blood culture. The bacterium that causes typhoid fever spreads to humans through fecal oral route and endemic in countries with poor

.16sanitation and lack of availability of clean drinking water Patients of uncomplicated typhoid fever are given home treatment of 7-14 days. Patients with complications are admitted in hospital. Around 1 in 20 children who are treated for typhoid fever suffer from relapse, in which symptoms reappear. Symptoms usually reappear about a week after the treatment with antibiotics has finished. The relapse is usually milder, but it is recommended to treat the patient with antibiotics. The timely appropriate management of typhoid fever can considerably reduce both morbidity and mortality.With the development of multidrug resistance (resistance to ampicillin, chloramphenicol, and co-trimoxazole) in enteric

17fever, ciprofloxacin was introduced as first line therapy.

COMPARISON OF EFFICACY OF ORAL AZITHROMYCIN WITHINTRAVENOUS CEFTRIAXONE FOR THE TREATMENT

OF UNCOMPLICATED ENTERIC FEVERBUSHRA SAEED, TOOBA RIAZ

1. Senior Registrar of Pediatric2. Assistant Professor of Pediatric University College of Medicine and Dentistry, University of Lahore, Pakistan

Correspondence to:Tooba RiazAssistant Professor of PediatricUniversity College of Medicine and Dentistry, University of Lahore, Pakistan Email: drtoobafjog@yahoo.com

Received for Publication: 24-04-16Accepted for Publication: 08-08-16

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ward of Sir Ganga Ram Hospital through OPD or emergency were enrolled. Informed consent regarding inclusion in study was taken from parents or guardians and risk benefit ratio was discussed. The attendants were ensured that appropriate measures were taken promptly in case of adverse effects. Consent from ethical committee was taken. Patient was randomly divided in 2 groups using random numbers, Group "A" and Group "B", with 50 patients in each group. Group A was given ceftriaxone (75m/kg/day) X OD for 7 days. Group B was given azithromycin (10mg/kg /day) OD for 7 days. Patients were followed closely with vital records 8 hourly, daily examination for resolution of sign and symptoms. A culture was repeated at day 4 of therapy. Both groups were compared for efficacy and relapse. All this was entered in the Proforma.Data analysis: Data was analyzed using SPSS version12. For numerical variables e.g. age, mean and standard deviation was calculated. Gender, efficacy& relapse were calculated by calculating frequency & percentage. Two groups were compared for efficacy & relapse. Chi-square test was used to determine significant differences of efficacy & relapse between 2 groups, with p value of <0.05 was considered significant.

RESULTS

The mean age of the patients was 6.68±2.77 years for group A and 7.47±2.93 years for group B. The minimum age of patients in group A was 1 year and maximum age was 12 years similarly the minimum age of the patients in group B was 3 years and maximum age was 12 years. (Table-I) Number of patients in different age groups is shown in table. (Table-II) There were 27(54%) males and 23(46%) females in group A and 27(54%) males and 23(46%) females in group B out of total 100 patients. (Table-II) There were 43(86%) patients in Ceftriaxone group (A) with efficacy and 7(14%) patients with no efficacy. There were 40(80%) patients in Azithromycin group (B) with efficacy and 10(20%) patients with no efficacy. Efficacy achieved by oral azithromycin as well as intravenous ceftriaxone in treatment of uncomplicated enteric fever was statistically same (p-value= 0.424). (Table-III) There were 11(22%) patients in Ceftriaxone group (A) with relapse and 39(78%) patients with no relapse. There were 3(6%) patients in Azithromycin group with relapse and 47(94%) patients with no relapse. The rate of relapse was different statistically in both groups (p-value= 0.021) (Table-IV)

However strains with decreased susceptibility to ciprofloxacin resulting in treatment failure have been endemic in several countries in Indian subcontinent and High level ciprofloxacin

18,19resistance has evolved in Asian countries. Fluoroquinolones then were mostly recommended as drug of choice for the treatment of typhoid fever. But sadly, few strains of S. typhi have

20 developed some resistance to flouroquinolones so the therapeutics of ciprofloxacin and flouroquinonones resistant enteric fever narrows down to third & fourth generation

21Cephalosporins and azithromycin.One of the members of macrolide group of antibiotics, Azithromycin, is now increasingly used as an alternate drug for

22treatment of Typhoid fever because of its properties of achieving low intravascular levels, good penetration into the tissues and long half-life. Absorption of this drug from gut is rapid and if used orally it is well tolerated by the body. These properties of Azithromycin make it eligible for once daily dose

23and a shorter duration of treatment is required.Considering the hazards of intravenous therapy i.e. transmission of infections, local complications and discomfort to the child, it was worthwhile to compare oral azithromycin with intravenous ceftriaxone in patients with enteric fever. Oral therapy with azithromycin was cost effective, avoids hospital stay and will avoid hazards of intravenous therapy and will also give the benefit of shorter duration of treatment. It is also worthwhile that previous studies have been done using small number of patients so study including increased number of patients should be done.

METHODOLOGY

This randomized controlled trial was conducted in Pediatric Medicine Ward and Emergency of Sir Ganga Ram Hospital,

st stLahore over a period of six months from 1 May 2013 to 31 Oct 2013. Inclusion criteria were age 3 to 12 years, gender: both male and female, history of fever for at least 4 days and blood culture positive for S.typhi or S.paratyphi. Exclusion Criteria were documented hypersensitivity to ceftriaxone or azithromycin (or to any other macrolide), significant underlying illness (e.g. heart disease, asthma requiring chronic medications, or immunodeficiency) documented by previous medical record and those patients who had treatment with in past 4 days with either study medicine or with ampicillin, co- trimoxazole or chloramphenicol. Patients fulfilling the inclusion criteria, admitted in Pediatric

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children. The author of the study has therefore focused on the importance of school vaccination instead of infant vaccination

25to reduce the incidence of enteric fever.Another study showed the most critical age range of children at

26risk of enteric fever to be 3-10 years, much similar to our study.In Our study Efficacy achieved by oral azithromycin as well as intravenous ceftriaxone in treatment of uncomplicated enteric fever was statistically same (p-value= 0.424). The rate of relapse was different statistically in both groups (p-value= 0.021) and Azithromycin was found to be superior in reducing relapses as compared to Ceftriaxone.The results in our study were compatible to another similar study which was done in 2011 by Effa EE in which he compared the efficacy of Azithromycin with other antibiotics including Ceftriaxone. He also concluded that Ceftriaxone was similar in curing enteric fever with Azithromycin but Azithromycin significantly reduced the relapse rate as compared to

27ceftriaxone. In a meta-analysis, Triyedi NA studied the safety and efficacy of Azithromycin with other antibiotics including ceftriaxone. He concluded that Ceftriaxone was similar to Azithromycin in preventing clinical failure in enteric fever but Azithromycin was

DISCUSSION

Typhoid fever is one of the commonest diseases in children as well as adults. Particularly, in south central and South East Asia, this problem continues to be a major cause of illness and mortality. This is because of high prevalence of poor sanitary system, hazardous food and poor water condition in these

24countries. Various treatment options are opted for treatment of this problem that mainly constitutes the medications for children. However the efficacy of each drug has its own advantages and disadvantages, and need to be chosen according to individual case. Our study henceforth, focused on the efficacy of oral azithromycin with intravenous ceftriaxone for treatment of uncomplicated enteric fever. Also, the frequency of relapse was studied in both the groups. In our study, out of total 100 patients, maximum number (39%) was from age group of 4-6years. These results were compatible with a number of international studies in which school going children have been reported to be at more risk of disease. One international study showed the global burden of typhoid and paratyphoid fever in India and found very narrow age ranges with high incidence of disease in under five and school going

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2014;63(39):855-60. 5. Basnyat B. Tackle Nepal's typhoid problem now. Nature.

2015;524(7565):267.6. Sahastrabuddhe S, Carbis R, Wierzba TF, Ochiai RL.

Increasing rates of Salmonella Paratyphi A and the current status of its vaccine development. Expert Rev Vaccines. 2013;12(9):1021- 31.

7. Andualem G, Abebe T, Kebede N, Gebre-Selassie S, Mihret A, Alemayehu H et al. A comparative study of Widal test with blood culture in the diagnosis of typhoid fever in febrile patients. BMC research notes. 2014;17(7):653.

8. Azmatullah A, Qamar FN, Thaver D, Zaidi AK, Bhutta ZA . Systematic review of the global epidemiology, clinical and laboratory profile of enteric fever. J of Global Health. 2015;5(2):020407.

9. Dhakad U, Das SK, Srivastva D, Nolkha N. Arthritis and adult respiratory distress syndrome: unusual presentations of typhoid fever. BMJ Case Reports. 2014;21:2014.

10. Thandassery RB, Sharma M, Abdelmola A, Derbala MF, Al Kaabi SR. Un common gastrointestinal complications of enteric fever in a non-endemic country. Qatar Med J 2014;2014(1):46-49.

11. Talabi AO, Etonyeaku AC, Sowande OA, Olowookere SA, Adejuyigbe O. Predictors of mortality in children with typhoid ileal perforation in a Nigerian tertiary hospital. Pediatric Surg Intern. 2014;30(11):1121-27.

12. McAnearney S, McCall D. Salmonella Osteomyelitis. The Ulster Med J. 2015;84(3):171-72.

13. Kapoor K, Jain S, Jajoo M, Talukdar B. A rare neurological complication of typhoid fever: Guillain-Barre' syndrome. J of Paed Neur. 2014;9(2):148-49.

14. Tennant SM, Toema D, Qamar F, Iqbal N, Boyd MA, Marshall JM, et al. Detection of Typhoidal and Paratyphoidal Salmonella in Blood by Real-time Polymerase Chain Reaction. Clinc Infect Dis. 2015;61 Suppl 4:S241-50.

15. Andrews JR, Ryan ET. Diagnostics for invasive Salmonella infections: Current challenges and future directions. Vaccine. 2015;33 Suppl 3:C8-15.

16. Dave J, Sefton A. Enteric fever and its impact on returning travellers. Int Health. 2015;7(3):163-68.

17. Bula-Rudas FJ, Rathore MH, Maraqa NF. Salmonella Infections in Childhood. Adv Pediatr. 2015 ;62(1):29-58.

18. Capoor MR, Nair D, Deb M. Enteric fever perspective in India: emergence of high-level ciprofloxacin resistance and rising MIC to cephalosporins. J of Med Micr. 2007;56(8):1131-32.

19. Capoor MR, Rawat D, Nair D, Hasan AS, Deb M, Aggarwal P, et al. In vitro activity of azithromycin, newer quinolones and cephalosporins in ciprofloxacin-resistant Salmonella causing enteric fever. J of Med Micr. 2007;56(11):1490-94.

20. Harish BN, Menezes GA. Determination of antimicrobial resistance in Salmonella spp. Methods Mol Biol. 2015;1225:47-61.

21. Dave J, Sefton A. Enteric fever and its impact on returning travellers. Int Health. 2015;7(3):163-68.

22. Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, Clinical Presentation, Laboratory Diagnosis,

seen to reduce significantly the chance of relapse with RR 0.1 (95% CI 0.01- 0.76). No significant adverse effects were seen in any of the trials. These results were similar to our study but here author has also enforced the importance of large clinical trials in

28pediatric age group to reach a final conclusion.Now a day the biggest concern is the worldwide appearance of multidrug resistant strains. Work is being made to increase our understanding of the molecular pathogenesis. New areas of targets in diagnosis and treatment are being explored by genomic studies. The importance of availability of safe water for

29drinking, good sanitary measures, and immunization in the 30presence of increasing resistance of antibiotics is cardinal. Also

the growing importance of Salmonella enterica serotype 31,32Paratyphi A in Asia is also a concerning fact. Large studies

should be done for Calculation of the incidence of typhoid fever during preschool and school years so that the optimum age of immunization for public-health programs in developing countries can be estimated. Also, need of the time is to conduct large control based trials to reach a final conclusion regarding treatment of uncomplicated typhoid fever with a safe drug with minimum adverse effects, clinical failure and relapse rate.

CONCLUSION

Efficacy achieved by both the oral azithromycin and intravenous ceftriaxone in treatment of uncomplicated enteric fever was satisfactory and statistically same. However, higher rate of relapse was observed in group treated by intravenous ceftriaxone compared to oral azithromycin.

Contribution of Author:Bushra Saeed: Conception and design, Collection and assembly of data, Analysis and interpretation of the data, Statistical expertiseTooba Riaz: Drafting of the article, Critical revision of the article for important intellectual content, Final approval and guarantor of the article

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