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Volume 28, Issue 2 (Spring 2022)                   Intern Med Today 2022, 28(2): 160-169 | Back to browse issues page


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Soleimani G, Shafighi Shahri E, Ansari H, Azizi S M. Comparison of the Effect of Azithromycin and Cefixime on Dysentery in Children Referred to Zahedan University Medical Centers. Intern Med Today 2022; 28 (2) :160-169
URL: http://imtj.gmu.ac.ir/article-1-3561-en.html
1- Department of Children's, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran. , Soleimanimd@yahoo.com
2- Department of Children's, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
3- Department of Epidemiology and Biostatistics, Faculty of Health, Zahedan University of Medical Sciences, Zahedan, Iran.
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Introduction
Diarrheal diseases are still considered one of the serious health problems and among the vital causes of mortality of children under 5 years old, especially in developing countries [123]. The most important cause of death caused by diarrhea is the excretion of high amounts of water and electrolytes in the body. Diarrhea is also a major cause of delayed physical development in children, malnutrition, and susceptibility to other diseases [4, 5, 6]. The disease may occur in the form of dysentery. Bloody diarrhea is an inflammatory bowel disease, especially in the colon, which is associated with diarrhea, blood, and mucus in the stool, fever, abdominal pain, and constipation. The general principles of disease management are based on water and electrolyte compensation and the treatment of the cause of dysentery [7]. Bloody diarrhea is often caused by infectious agents (bacterial and parasitic), especially Shigella or Entamoeba species, and causes high mortality, especially in children [8, 9, 10]. 
However, the disease may have non-infectious causes including inflammatory bowel disease (Crohn's disease and ulcerative colitis) and celiac disease, which can cause diarrhea. Allergic reactions to cow's milk, polyps and lumps, Meckel's diverticulum, anal fissure, prolapse, hemorrhoids, and gastrointestinal trauma are other non-infectious causes of dysentery in children [11, 12, 13].
There are some reasons to convince us to conduct a study on pediatric dysentery in Zahedan to compare the effect of azithromycin and cefixime in the treatment of pediatric dysentery to reduce additional financial and drug costs by the correct treatment as well as antibiotics resistances following incorrect treatments. The reasons were as follows: Dysentery is prevalent in Zahedan in all seasons, there is no vaccination to prevent it, and the use of antibiotics in its treatment has side effects and causes drug resistance in individuals and strains resistant to the treatment. Also, since several factors such as geographical area can affect the results of these studies and the pattern of antibiotic resistance in each region is different from another region, especially in Sistan and Balochistan, the therapeutic response of dysentery to various antibiotics has not been studied despite the high prevalence of dysentery. Finally, in sources such as Nelson in the topic of shigellosis, both azithromycin and cefixime are proposed in the treatment of dysentery in children. 
Materials and Methods 
The patients in the present study were 116 children aged 6 months to 5 years referred to Zahedan University of Medical Sciences Centres who were diagnosed with dysentery by pediatricians with blood reported in their diarrhea stools. Dysentery was considered diarrhea with blood or diarrhea confirmed by stool tests. Children with malabsorption, previous history of prolonged diarrhea, intestinal polyps, malnutrition, immunodeficiency, history of probiotic use, inflammatory bowel disease, chronic small bowel disease, and history of antibiotic use in the past month, other illnesses during treatment, and dissatisfaction with parents to continue cooperation were excluded from the study. At the beginning of the study, the names and contact numbers of the patients were obtained from the patient’s families in the clinic. The blocking method with quadruple blocks was used for random allocation. The patients in the two groups, A and B, included 58 patients in each group. Group A received azithromycin for five days, 12 mg/kg on the first day and 6 mg/kg on the next four days. Also, group B received cefixime at 8 mg/kg daily for five days. Additionally, the prescribed drugs (azithromycin and cefixime) were only from one pharmaceutical company.
It should be noted that at the beginning of the study, written consent was obtained from the parents of all participants and the objectives of the project were explained to them. Names and contact numbers were taken from families. Then, on the fifth and tenth days after the start of treatment (days after referral), they were called to investigate the cases. The above information for each patient was entered separately in the information form and analyzed by SPSS software, version 21. 
A Chi-square test was used to compare quantitative data. The significance level of the test was considered 0.05. 
Results
In each of the two groups treated with azithromycin and cefixime, four clinical signs were evaluated. The following questions were answered: How long after the treatment did the fever stop? How long after the treatment did blood in the stool stop? How long after the treatment, did the abdominal pain stop? and finally, how long after the treatment did diarrhea stop? Then, in both categories, these four cases were compared. As can be seen in Table 1, none of the studied parameters such as mean fever stop time (P=0.887), mean blood stop time in the stool (P=0.101), mean abdominal stop time (P=0.133), and the mean diarrhea stop time (P=0.189) had significant difference between the two study groups. 


Regarding demographic studies, there was no significant difference between age and gender. Therefore, the Mean±SD in the cefixime group was 1.46±3.08 regarding age, 1.32±2.89 in the azithromycin group, and 1.39±2.99 in total with (P=0.466). Regarding gender, 44.8% were male and 55.2% were female in the cefixime group, 60.3% were male and 39.7% were female in the azithromycin group (P=0.094). 
Discussion 
In this study, we attempted to compare the effects of azithromycin and cefixime in the treatment of pediatric shigellosis in the native geographical area of Zahedan to reach a statistically significant level, and through this, to achieve a clinical guide of preferred treatment to prevent wastage of drug resources and antibiotic resistance. 
Our study of the four parameters showed that the fever stop time, bleeding stop time, abdominal pain stop time, and diarrhea stop time were not significantly different in any of the two comparisons. In general, the results indicated that there was no significant difference in the improvement of symptoms in patients receiving azithromycin and cefixime. We review and compare the present study with other studies.
In a study conducted by Mahbubur in 2007 on evaluating the resistance of Shigella strains to various antibiotics, it was concluded that the overall bacterial resistance of all Shigella strains to azithromycin was greater than the resistance of these strains to cefixime/ceftriaxone [14]. The present study is not consistent with our study. 
In a study conducted by Basualdo et al. in 2003 on a randomized comparison of the treatment of cefixime and azithromycin in pediatric shigellosis, the results showed that high levels of eradication of Shigella with azithromycin could have significant epidemiological consequences. Treatment of Shigella diarrhea with azithromycin can reduce infection. Also, the clinical efficacy of azithromycin is higher than cefixime [15]. The results are not consistent with our study.
In a study conducted by Sadeghabadi in 2014 on examining antibiotic resistance of E. coli and Shigella, it was concluded that the susceptibility of cefixime and azithromycin to S. sonnei and S.flexneri was 0 % and 66.7% for cefixime and 0% and 33.3% for azithromycin, respectively [16]. Our study is not consistent with this study.
Regarding the previous research, there was no similar local sample of the study with the mentioned characters; therefore, this study could provide a solution for the treatment of shigellosis in children by comparing the two medicines of azithromycin and cefixime. The final statistical analysis did not show a significant difference in the prescription of these two drugs in the treatment of pediatric shigellosis. 
However, Shigella antibiotic treatment, along with the self-limiting course of the disease reduces the course and severity of dysentery, and can also prevent the conflicts potentially leading to fatality. Shigella species can easily become resistant to antibiotics [17].
Studies indicated that the rate of antibiotic resistance in Shigella bacteria is increasing, so this bacterium showed high resistance to cotrimoxazole, tetracycline, and ampicillin. However, fluoroquinolones, macrolides, carbapenems, and third-generation cephalosporin drugs have a very good effect on this organism and are used in the treatment of infections caused by Shigella. Irregular use of drugs and horizontal gene transfer lead to Shigella species becoming resistant to commonly used antibiotics. The pattern of antibiotic resistance is influenced by geographical location, year of isolation, classes of antimicrobial agents, and pressure caused by antibiotic use. [18] Shigella strains have progressively become resistant to the most widely used antimicrobials over the past decades such as ampicillin, chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole [192021]. Antimicrobial compounds that are still effective against Shigella include ciprofloxacin and other fluoroquinolones, ceftriaxone, and erythromycin [222324]. Differences in the pattern of antibiotic resistance in different locations can be due to the emergence and spread of antimicrobial resistance clones. Monitoring programs on antimicrobial resistance should not only focus on identifying pathogenic bacterial species by reporting information such as serotyping, the prevalence of microorganisms, and susceptibility to current antimicrobial agents used for treatment, but also apply programs to control their spread. Since humans are the most known host for pathogenic Shigella and there is no effective vaccine to prevent Shigellosis, Shigella control methods should be applied to remove organisms from their reservoir. These methods include [25] industrial control of water, food and milk, proper disposal of wastewater, control of insects [26], isolation of patients and disinfection of their excrement [27], identification of clinical cases and carriers, especially those involved in food preparation, and [28] treatment of infected persons using antibiotics.
It should be noted that according to Shigellosis treatment guidelines, World Health Organization (WHO) states that fluoroquinolones should be used as the first line and beta-lactams and cephalosporins as the second line of Shigella treatment. Also, it is possible to use Azithromycin in areas where there is resistance to ciprofloxacin. While cefixime is a good alternative, the drug resistance to this drug should be considered [29].  
In the end, we believe that other studies can have different results compared to what we obtained, even in comparing similar shigellosis treatments based on azithromycin and cefixime. The bigger patient sample size will be one of these parameters; Also, a longer period of time can have other consequences. Even changes in the geographical area can make such a difference, and these are all suggestions for further similar studies to provide a country map pattern with regional and provincial differences from the best antibiotic treatment for important pediatric shigellosis to prevent the loss of antibiotics and drug resistance in the country as much as possible. Another important point was the limitation of trust in the accurate response of caregivers of children with the disease at home, since our study was based on outpatient treatment, it was almost impossible to track the time of removing patients’ quadruple symptoms in other ways. If there was no limit to the space and conditions of the hospital, the treatment in the form of hospitalization and monitoring of the patient and the registration of clinical symptoms by the medical staff on a daily and accurate basis could obtain other results. Comparison of hospital injectable drugs such as ceftriaxone in the process of improving and reducing the symptoms of shigellosis by accurately recording the time of removing symptoms or recording possible complications by medical staff is certainly very effective in monitoring the patient and improving study conditions for future reference. 
Conclusion
In general, there was no clear clinical difference in the use of cefixime and azithromycin in the clinical recovery of children with dysentery. As a result, according to the patient’s conditions, the extent, and the severity of the disease, it is recommended to base the correct choice of these drugs on the clinical experience of physicians and the patient’s conditions. 

Ethical Considerations
Compliance with ethical guidelines

This article is a part of the research project related to the children's doctorate thesis with code Ir.zaums.rec.1398.086 dated 2.9.1398 in Zahedan University of Medical Sciences and Health Services.

Funding
This project has been approved and implemented by Zahedan University of Medical Sciences as a free dissertation. 

Authors' contributions
Corresponding author and the first guide of the project: Gholamreza Soleimani; Collection of samples and the second guide of the project: Elham Shafighi Shahri; Consulting and implementation of statistical discussions: Hossein Ansari; Summary of project components: Seyed Mohammad Azizi. 

Conflicts of interest
The research project did not have a conflict of interest. 

Acknowledgements
This article is the result of a research project related to the pediatric doctoral dissertation at Zahedan University of Medical Sciences. Hereby, the authors of the article appreciate their gratitude for the assistance of the Deputy for Research of the University and the Department of Children of Zahedan University of Medical Sciences in conducting this project. 


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Type of Study: Original | Subject: Pediatrics
Received: 2020/07/30 | Accepted: 2022/03/5 | Published: 2022/04/1

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