1ORIGINAL ARTICLEUse of Azithromycin in Uncomplicated Enteric Fever asFirst Line AntibioticWAQAR HUSSAIN, AHSAN AHMAD, ANI...
2Organization), the overall incidence of typhoid           This is a case series study conducted in thefever is 412 cases ...
3serious drug reaction, patient was taken off from                       51 (61.44%) patients were male while 32(38.55%)th...
4                                      N            %                N            %           N            %Fever         ...
5--------------------------------------------------------------------------------       9.   Bhutta ZA. Current concepts i...
619. Frenck RW Jr, Mansour A, Nakhla I, et al. Short-       23. Ansari I, Adhikari N, Pande R, et al. Enteric    course az...
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use of azithromycin in enteric fever in children as af first line antibiotic

  1. 1. 1ORIGINAL ARTICLEUse of Azithromycin in Uncomplicated Enteric Fever asFirst Line AntibioticWAQAR HUSSAIN, AHSAN AHMAD, ANITA LAMICHHANE, Asfand Tariq, Muhammad Aslam Khan------------------------------------------------------------------ Pak Paed J 2012; 36(2): ABSTRACT Introduction: Enteric fever is a systemic infection caused by the bacteria, Salmonella enterica serovara Typhi (S.typhi) and Salmonella entericaAuthor’s affiliations serovara Paratyphi (S. paratyphi A, B and C). Disease burden is more in the developing countries. There is day by day increase in the multidrug------------------------------------------- resistant strains.Correspondence to: Objectives: This study was conducted to assess the efficacy of azithromycin as a first line antibiotic in the treatment of uncomplicatedWaqar Hussain, enteric fever.Department of PaediatricsShaikh Zayed Hospital, Methods: This case series study was conducted in 83 children betweenLahore. Pakistan 2-12 years of age in Shaikh Zayed Hospital, Lahore, Pakistan. Those patients who were Typhidot and/or blood culture positive included in thisE-mail: study and treated with azithromycin 20mg/kg/ single dose daily for 7gwaq_122@hotmail.com days. Results: Out of the 83 children enrolled, 75(90.36%) completed the study as the eight children lost to follow up. Male to female ratio was 1.6:1 with common age group between 8-12 years. S.typhi was isolated in 5(6.67%) cases and all achieve bacteriological cure by day 7. Mean (SD) duration of fever at presentation was 5±3.07 days. Clinical cure was seen in 71 (94.6%) subjects. Mean day of response was 4 days. There was no death in the study. No serious adverse event was observed in the study. Conclusion: Azithromycin was found to be safe and efficacious for the management of uncomplicated typhoid fever in a dose of 20 mg/kg/day per oral once a day for seven days. Keywords: Enteric fever, Azithromycin, Salmonella typhi.INTRODUCTION The global estimate of incidence of enteric fever caused by S.typhi is 21 million cases causingTyphoid fever is a systemic infection caused by 7,00,000 deaths each year3. Pakistan is a highthe bacterium Salmonella enteric serotype typhi, burden country with an annual incidence ofa member of the family Enterobacteriaceae. This 413/100,000 person/year2. Up to 93% of globalorganism is an important cause of febrile illness in episodes occur in Asia, where Southeast Asia hascrowded and impoverished populations with an estimated incidence of 110 cases/1,00,000inadequate sanitation that are exposed to populations4. S.typhi has no non-human vectors.unsafe water and food1,2. Salmonella is human An inoculum as small as 1,00,000 organismsrestricted pathogen and transmission is feco-oral. causes infection in more than 50% of healthy volunteers5. According to WHO (World Health
  2. 2. 2Organization), the overall incidence of typhoid This is a case series study conducted in thefever is 412 cases per 100,000 population per year department of Pediatrics, Shaikh Zayed Federalin Pakistan6,7. Post Graduate Medical Institute, Lahore, Pakistan from 1st May to 31st December 2011 with the priorBecause of the ready availability of the over-the approval of the study protocol from the Ethicalcounter antibiotics and subsequent resistance to Committee of the Institutional Review Board ofthese drugs in areas of endemicity, enteric fever the concerned hospital. All the children betweenis harder to treat6. Previously chloramphenicol 2-12 years of age who had typhidot IgM and/orwas used to treat this infection but in 1980 blood culture positive and diagnosed asemergence of resistance limited its use8. This was uncomplicated enteric fever were included infollowed by emergence of multidrug resistant the study. All those children who fulfilled the(MDR) strains (combined resistance to following criteria were excluded from the study:chloramphenicol, ampicillin and cotrimoxazole)initially reported from India, Pakistan and Middle 1. Any child who was already taking otherEast and then from all over the world. There is antibiotics for more than 48 hoursemergence of resistance to first line drugs like 2. Any child with poor oral intake.chloramphenicol, ampicillin, cephalosporins8-10also. 3. Any child with life threatening complication of enteric fever(perforation, shock or seizures)On the other hand, widespread use offluroquinolones led to the emergence of 4. Any patient with congenital or acquiredSalmonella Enterica serovar Typhi and Paratyphi immunodeficiencystrains with reduced susceptibility to Written consent was obtained fromfluoroquinolones11. Widespread emergence of parents/guardians of all children. On day ofmultidrug resistant S. typhi has necessitated the recruitment a complete medical, treatment andsearch for other therapeutic options for typhoid vaccination history was recorded. Completefever12,13. physical examination was carried out. All theAzalides are another class of antibiotics which children between 2-12 years of age whohave shown promise in the treatment of typhoid presented with the signs and symptoms of entericfever. Azithromycin is the first drug of this class fever and not taking antibiotics for more than 48and studies comparing the efficacy of hours before presentation were startedazithromycin with cefixime in adults and children Azithromycin (20 mg/kg/day) dispersiblewith typhoid fever have reported it to be safe tablet/suspension for seven days in a single dailyand efficacious14-16. In these circumstances, dose after sending CBC, blood culture andrecent clinical trials suggest that azithromycin sensitivity and typhidot IgM. After getting thetreatment (20 mg/kg/day upto a maximum of reports of blood culture and sensitivity and1000 mg/day for 7 days in children) is useful for typhidot IgM, only those patients having bloodthe management of uncomplicated typhoid culture or/and Typhidot IgM positive werefever17. included. Study medication was dispensed and monitoring instruction provided to each patient.Azithromycin has excellent penetration into most Children were treated at their home andtissues and achievement in macrophages and reassessed in the out-patient department on dayneutrophils that are >100 fold higher than 4, day 7 and day 30 after the start of theconcentrations in serum. These together with treatment. On day 4 and day 7 temperatureazithromycin’s long half life of 72 hours, show charts and symptom diary was evaluated with apotential in the therapeutic management of complete physical examination. Drugenteric intracellular pathogens18. Few studies are compliance was assessed by history andexclusively reported in children19-20. collecting the empty wrappers/bottles.We conducted this case series study to assess the Children who were blood culture positive weresafety and efficacy of single daily dose of evaluated on day 7 also for repeat blood culture.azithromycin for uncomplicated typhoid fever in If the temperature increased or the clinicalchildren. condition of the patient worsened or there was aMATERIAL AND METHODS
  3. 3. 3serious drug reaction, patient was taken off from 51 (61.44%) patients were male while 32(38.55%)the study and treated with intravenous were female. 55(66.27%) belonged to middleCeftriaxone (75 mg/kg/day). All follow ups were class family while 28(33.73%) were from the lowercarried out in the out-patient department of the low socioeconomic background. Only 26(31.33%)hospital. children had received antibiotics before presentation. None of the patients had receivedTypes of outcome measures prior typhoid vaccination. There was no mortalityClinical Response: Resolution of symptoms and amongst the patients included in this study.fever clearance (axillary temperature less than Various clinical presentations of the patients at380C for >72 hours) was considered sustained the time of inclusion in this study are shown in theafter 7 days of treatment. table 2 while the clinical findings of the patientsMicrobiiological Response: Was considered when are shown in table 1.the blood culture became negative for TABLE 1: Physical Examinationsalmonella typhi or para typhi after 7 days oftreatment. Clinical findings No. of patients % age Coated tongue 67 89.30Clinical Failure: Lack of resolution of symptoms by Hepatomegaly 52 69.30day 7 or development of a major complication of Abdominal tenderness 20 26.67typhoid fever (intestinal perforation, shock or Splenomegaly 15 20.00seizures). Rose spots 05 06.67Microbiological Failure: Blood culture positive on 8(9.6%) patients left the study. Out of these eightday 7 for S.typhi or S. Paratyphi. patients, 5 did not come at day 4 for visit and 3 did not come for visit on day 7. So the data fromRelapse: Recurrence of fever along with signs and these 8 patients could not be collectedsymptoms of typhoid fever within 4 weeks of completely. Only 75 patients completed thecompletion of therapy, along with isolation of the study. 37(49.33%) patients had temperatureorganism in blood culture. between 101-1020F followed by 31(41.33%) patients with 100-1010F while 7(9.33%) had temperature between 103-1040F. Fever clearanceRESULTS time (FCT) was 96 hours (4 days) in 62(82.66%)We enrolled 83 children aged 2-12 years who patients. Fever settled at day 5 in 4(5.33%)fulfilled the inclusion criteria. Mean age at the patients while on day 6 in 2(2.67%). 3(4%) patientstime of presentation was 7.7±3.07 years. Fig-1 had settlement of fever on day 7 while in 4(5.33%)shows the age distribution of the patients. patients fever took more than 7 days to settle. In 5(6.67%) patients relapse was documented. 50.00% Blood culture was positive in five (6.67%) patients. 45.00% All of these patients achieved bacteriological 40.00% cure at 7th day. All the 75 patients had typhidot 35.00% 30.00% positive. 25.00% Treatment failure was observed in 4(5.3%) 20.00% 15.00% children. These children were started on 10.00% intravenous antibiotic (Ceftriaxone) and all 5.00% improved by day 12-15. 0.00% 2-5 yrs 5-8 yrs 8-12yrs Clinical features at the time of presentation and at the time of follow-ups are given in table-2.Fig 1: Frequency of age distributionTABLE 2: Clinical characteristics of study children at baseline and follow up.Clinical findings Visit 1 (Day 0) Visit 2 (Day 4) Visit 3 (Day 7)
  4. 4. 4 N % N % N %Fever 75 100.00 13 17.33 4 5.33Headache 23 30.70 5 6.67 0 0Constipation 6 8.00 2 2.67 0 0Diarrhea 15 20.00 3 4.00 0 0Anorexia 16 21.00 10 13.33 3 4.00Pain abdomen 27 36.00 4 5.33 1 1.33Hepatomegaly 52 69.30 32 42.67 10 13.33Splenomegaly 15 20.00 10 13.33 4 5.33Coated tongue 67 89.30 50 66.67 10 13.33DISCUSSION In our study, males had higher incidence of the disease (male to female ratio of 1.6:1). This is inEnteric fever is one of the commonest cause of accordance with the study done by Ansari et alfebrile illness and is the major reason for seeking 200223 and Bhattarai et al 200324.This study alsohealth service by the common people21. showed that fever was present in all the patientsDue to the emergence of multidrug resistance to followed by abdominal pain, headache anddrugs (Chloramphenicol, Ampicilin, Cotrimoxa- anorexia at the time of presentation which iszole), the need of newer drugs for the treatment similar to other studies25,26.of enteric fever is necessitated; the results with The emergence of the resistant strains of S.typhimacrolides like Azithromycin is promising. In our has become an area of concern for decades.study, a 7 day course of oral Azithromycin was Various trials have focused the mechanisms byfound to be highly effective, showing efficacy of which resistance to the first line drugs used in the94.6%. The efficacy of Azithromycin has also been therapeutic management of enteric feverestablished by other studies. Frenck et al 2004 develop. Hence the search for new drugs forshowed a similar comparable high percentage which S.typhi shows evidence of clinicalof clinical response to azithromycin at an response.average rate which supports the present study19. Failure rate was found to be 6.67% while theIn this study, the most common age group relapse rate was 5.33%. This has been observed inaffected was 8-12 years (45.33%), which is earlier studies on azithromycin11.different from the study of Prajapati et al 2008where result showed that common age group The limitation of this study was that it was notwas 1-5 years22. comparative and no data is available from Pakistan on the role of Azithromycin in theThe fever clearance time was 96 hours (4days) in treatment of uncomplicated enteric fever to62(82.66%) patients which is also comparable compare the results on this study.with the study done by Frenck et al 2004 19, wherefever clearance time was 4.5 days. This study was a case series; however other studies where comparison of Azithromycin wasThe bacteriological cure was seen in all the seven done with intravenous ceftriaxone, the resultspatients in our study. Similar response was were comparable. So, we suggest more studiesobserved by the study done by Frenck et al of Azithromycin in comparison with other drugs in200419, where bacteriological cure with our country so that the efficacy and safety ofAzithromycin was also 100%. In the present study, Azithromycin can be established.Azithromycin was tolerated well. In only fewpatients, abdominal symptoms like diarrhoea andnausea was observed on 1st and 2nd day of CONCLUSIONtreatment. But these symptoms did not requireany therapy and settled by themselves although As there is rise in the emergence of multidrugthis cannot be proven, it is likely that many of the resistant strains, azithromycin may be consideredgastrointestinal tract symptoms were associated in uncomplicated enteric fever in a dosage of 20with the underlying disease and not with the mg/kg/day per oral once a day for 7 days(maxtreatment. 1000mg/day).
  5. 5. 5-------------------------------------------------------------------------------- 9. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ 2006;Author’s affiliations 333 (7558): 78-82.Waqar Hussain, Ahsan Ahmad, Anita Lamichhane, 10. Gupta SK, Madalla F, Omondi MW, et al.Asfand Tariq, Muhammad Aslam Khan Laboratory based surveillance of parathyroidDepartment of Paediatrics, Shaikh Zayed Hospital, fever is the United States: travel andLahore, Pakistan. antimicrobial resistance. Clin Infect Dis 2008; 46(11): 1656-63.REFERENCES 11. Parry CM, Thretfall EJ. Antimicrobial resistance in typhoidal and non-typhoidal salmonellae.1. White taker JA, Franco-Pardes C, Dell RC, et Curr Opin Infec Dis 2009; 21(5): 531-38. al. Rethinking Typhoid vaccines: implications 12. Yanagi D, de Vries GC, Rahardjo D, et al. for travelers and people living in highly Emergence of fluoroquinolone resistant strains endemic areas. J Travel Med 2009; 16(1): of Salmonella enterica in Surabaya, 46-52. Indonesia. Diagn Microbiol Infect Dis. 2009;2. Crump JA, Mintz ED. Global trends in typhoid 64(4): 422-26. and paratyphoid Fever. Clin Infec Dis 2010; 13. Aggarwal A, Ghosh A, Gomber S, et al. 50(2): 241-46. Efficacy and safety of azithromycin for3. Karkey A, Arjyal A, Anders KL, et al. The uncomplicated typhoid fever: an open label burden and characteristics of enteric fever at non-comparative study. Indian Pediatr 2011; a healthcare facility in a densely populated 48(11). 553-6. area of Kathmandu. PLoS One. 2010; 5(11): 14. Capoor MR, Rawat D, Nair D, et al. In vitro e13988. Available from: activity of azithromycin, newer quinolones http://www.plosone.org/article/info%3Adoi and cephalosporins in ciprofloxacin-resistant %2F10.1371%2Fjournal.pone.0013988 Salmonella causing enteric fever. J Med [accessed on 20/02/2012] Microbiol 2007; 56(Pt11):1490-94.4. Siddique FJ, Rabbani F, Hasan R, et al. 15. Dolecek C, Tran TP, Nguyen NR, et al. A multi- Typhoid fever in children: Some center randomized controlled trial of epidemiological considerations from Karachi, gatifloxacin versus azithromycin for the Pakistan. Int J Infect Dis 2006;10(3): 215-22. treatment of uncomplicated typhoid fever in5. Levine MM, Tacket CO, Sztein MB. Host- children and adults in Vietnam. PLoS One. Salmonella infection: human trials. Microbes 2008; 3(5): e2188. Available from: Infect 2001; 3(14-15): 1271-79. http://dx.plos.org/10.1371/journal.pone.00021 88 (accessed on 20/02/2012]6. Hayat AS, Shaikh N, Shah SIA. Typhoid fever. Evaluation of Typhidot (IgM) in early and 16. Parry CM, Ho VA, Phuong le T, et al. rapid diagnosis of Typhoid fever. Professional Randomized controlled comparison of Med J 2011;18(2): 259-64. ofloxacin, azithromycin, and an ofloxacin- azithromycin combination for treatment of7. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, multidrug-resistant and nalidixic acid-resistant et al. A study of typhoid fever in five Asian typhoid fever. Antimicrob Agents Chemother. countries: disease burden and implicated 2007; 51(3): 819-25. and implications for controls. Bull World Health Organ 2008; 86(4): 260-68. 17. Effa EE, Bukiwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid8. Qaiser S, Irfan S, Khan E, et al. In vitro fever(enteric fever). Cochrane Database Syst susceptibility of typhoidal Salmonella against Rev 2008;(4):CD006083. newer antimicrobial agents: A Search for alternate treatment options. J Pak Med Assoc 18. Shah D. Role of Azithromycin in Enteric fever. 2011; 61(5): 462-5. Indian Pediatr 2009; 46(1): 50-52.
  6. 6. 619. Frenck RW Jr, Mansour A, Nakhla I, et al. Short- 23. Ansari I, Adhikari N, Pande R, et al. Enteric course azithromycin for the treatment of fever: is ciprofloxacin failing? J Nepal Pediatr uncomplicated typhoid fever in children and Soc 2002; 20: 6-16. adolescents. Clin Infect Dis 2004; 38(7): 24. Bhatttarai PM, Bista KP, Dhakwa JR, et al. A 951-57. clinical profile of enteric fever at Kanti20. Islam MN, Khaleque MA, Siddika M, et al. Children Hospital . J Nepal Pediatr Soc 2003; Efficacy of azithromycin in the treatment of 21: 50-53. childhood typhoid Fever. Mymensingh Med J 25. Ramaswamy G, Janakiraman L, 2007; 16(2):149-53. Thiruvengadam V, et al. Profile of Typhoid21. Joshi BG, Keyal K, Pandey R, et al. Clinical fever in Children from Tertiary Care hospital in Profile and Sensitivity Pattern of Salmonella Chennai-South India. Indian J Pediatr 2010; Serotypes in Children: A Hospital Based Study. 77(10): 1089-92. J Nepal Pediatr Soc 2011; 31(3):180-83. 26. Neopane A, Singh SB, Bhatta R, et al.22. Prajapati B, Rai GK, Rai SK, et al. Prevalence Changing spectrum of antibiotic sensitivity in of Salmonella typhi and paratyphi infection in enteric fever. KUMJ 2008; 6(1):12-15. Children: a hospital based study. Nepal Med Coll J 2008; 10(4): 238-41.