The effect of antibiotics on post-adenotonsillectomy morbidity in tanzanian children: study protocol for a randomized double-blind placebo-controlled trial.

The effect of antibiotics on post-adenotonsillectomy morbidity in tanzanian children: study protocol for a randomized double-blind placebo-controlled trial. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol The effect of antibiotics on post-adenotonsillectomy morbidity in tanzanian children: study protocol for a randomized double-blind placebo-controlled trial. Denis Robert Katundu, Peter Stephen Shija, Baltazari Nyombi, Hadija Semvua, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.12518/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Dec, 2019 Read the published version in Trials → Version 2 posted 3 You are reading this latest preprint version Show more versions Abstract Background: Adenotonsillectomy is the most frequently performed operation in children worldwide. For decades prophylactic antibiotics have been prescribed to limit postoperative complications. In a Cochrane review the effect of this antibiotic use has been refuted. However, all reviewed studied were done in developed countries. In Tanzania, like many other developing countries with limited resources and a high burden of infectious diseases, postoperative antibiotic prescription is still very common to decrease the supposed higher postoperative morbidity. However, as a consequence of this widespread use of postoperative antibiotics cross-resistance and risk of allergic side effects rise. Well designed randomised controlled trials are needed to limit unnecessary antibiotic prescription and secondary antibiotic resistance. Aim: The aim of this study is to analyse the prophylactic role of postoperative antibiotic on the morbidity following adenotonsillectomy in children in Tanzania. Design: A double blinded randomised placebo controlled trial set in northern Tanzania. Participating centres are the department of otolaryngology at Kilimanjaro Christian Medical Centre (KCMC) in Moshi and the department of paediatric surgery at the Arusha Lutheran Medical Centre (ALMC) in Arusha. Methods: Around 270 children aged 2 to 14 years, all scheduled for elective (adeno)tonsillectomy, will be included and assigned to receive either a standard regimen of 5 days antibiotic prophylaxis or placebo after surgery. The primary outcomes are postoperative haemorrhage, fever and pain. Secondary outcomes are the time until normal diet is resumed, the time until normal activities are resumed, occurrence of adverse events and microbial recolonization of the tonsillar beds. Discussion: This study will enhance increase of proper antimicrobial prescription in Tanzanian institutions as well as other resource-limited countries where prescription of antibiotics is still very common. In addition, it might augment current knowledge about surface and core tonsillar micro-organisms and sensitivity patterns. Internal Medicine Integrative & Complementary Medicine Translational Medicine Adenotonsillectomy tonsillectomy postoperative morbidity amoxicillin RCT antimicrobial resistance AMR Figures Figure 1 Figure 2 Background Adenotonsillectomy (ATE) is one of the most frequently performed operations in children worldwide and the most frequently performed otolaryngological operation in children. Indications for adenotonsillectomy are, amongst others, adenotonsillar hypertrophy, recurrent adenotonsillitis and obstructive sleep apnea syndrome[1, 2]. This also applies to Tanzania, where both pediatric sleep apnea as well as upper respiratory tract infections due to chronic adenotonsillar hypertrophy are very common problems. At Kilimanjaro Christian Medical Center (KCMC) alone, a large referral hospital in Northern Tanzania, over 1000 adenotonsillectomies performed yearly. Different surgical techniques can be used to remove the tonsils and adenoid but regardless of the surgical technique, the pharyngeal wall embedding the tonsillar fossa is left open for secondary wound healing intention at the end of the procedure. Subsequently the wound bed is contaminated by commensal flora present in the oropharyngeal mucosa. It has been argued that, because of this, people are predisposed to inflammatory response and infection. This contributes to postoperative morbidity such as pain and the consequent need for analgesics, postoperative haemorrhage and the inability to resume normal diet. For this reason, several studies have recommended the prophylactic use of antibiotics to reduce the morbidity [2-5]. However, in a Cochrane review published in 2012, involving 10 trials with a pooled population of 1035 patients, the use of postoperative antibiotics did not show a clinically relevant effect on the haemorrhage rates, the time to resume a normal diet, pain and consequent need for analgesics[5]. Little evidence suggested that prophylactic use of postoperative antibiotics reduced fever. With the existing set of evidence, Dhiwakar and colleagues advocated against the routine prescription of antibiotics to patients undergoing adenotonsillectomy. However, they did highlight the need for further trials including subgroups of patients who might be in need of selective administration[5]. None of the studies reviewed in this Cochrane review had been conducted in resource-limited settings. Despite the lack of high level evidence for postoperative antibiotics, in Tanzania all children receive postoperative antibiotics after adenotonsillectomy based on the assumption that there is a higher risk of postoperative morbidity due to limited resources and a higher burden of infectious diseases. On the other hand, the widespread use of (postoperative) antibiotics is not without risks. There is the individual risk of gastrointestinal and allergic side effects, ranging from vomiting, diarrhoea and rash to severe anaphylaxis. And there is the risk of antimicrobial resistance. While global concern for antimicrobial resistances rises, there is still a significant gap of knowledge on this topic in resource-limited settings, like Tanzania. In developing countries, amoxicillin is one of the most misused and wrongly prescribed drugs. The majority of young children suffering from acute respiratory infection symptoms is treated inappropriately with this antibiotic. A cross-sectional research from 2018, performed in Moshi Tanzania, found that 92.3% of retailers dispensed antibiotics without prescriptions [6]. This practice disadvantages most inhabitants of these areas in particular. Cross-resistance and cost in obtaining superior antimicrobial agents become a big challenge. Summarizing the above, the widespread use of postoperative antibiotics after (adeno)tonsillectomy in children in Tanzania may have more negative effects than benefits, if there are any benefits at all. To limit unnecessary antibiotic prescription and secondary antibiotic resistance, well-designed randomized controlled trials are needed. This randomized double-blind placebo-controlled trial studies the prophylactic effect of antibiotics on morbidity after adenotonsillectomy in children in Tanzania. Method Design This study is a two centre, double-blind, randomized controlled trial. Patients will be randomly allocated to receive either 50mg/kg body weight of placebo or amoxicillin 5 days after surgery as standard prophylaxis regime. Study setting Participating centres are the department of otolaryngology at Kilimanjaro Christian Medical Centre (KCMC) in Moshi and the department of paediatric surgery at the Arusha Lutheran Medical Centre (ALMC) in Arusha, being the only settings with established Ear, Nose and Throat (ENT) services in northern Tanzania. Study population All Children from 2 to 14 years of age who will undergo an elective (adeno)tonsillectomy will be approached. Elective surgery is indicated in case of recurrent chronic tonsillitis, as defined by 5 or more episodes of tonsillitis yearly for at least 2 consecutive years, or in case of obstructive sleep apnoea due to adenotonsillar hypertrophy with inadequate response to pharmacotherapy. Inclusion will be done after written informed consent. Inclusion of patients started January 2019. Patients will be excluded from participation if they meet any of the following criteria. The patient is scheduled for unilateral tonsillectomy, tonsillar biopsy, tonsillectomy for a known carcinoma. The (adeno)tonsillectomy is combined with any other type of surgery. The patient has an acute tonsillar infection or peritonsillar abscess at the time of surgery. The patient is known to have a cardiac co-morbidity, with or without current treatment or follow-up by a cardiologist. The patient has a condition which results in weakness or failure of the host defence mechanism, like leukemia, acquired immune deficiency syndrome or current use of immunosuppressive medication. The patient has a syndromal disorder or a craniofacial malformation. The patient has a reported allergy to any antibiotic, ibuprofen or paracetamol. The patient was treated with antibiotics during or less than 1 week prior to surgery. Patients on any other concomitant medications at the point of enrolment. Study objective To compare the postoperative morbidity following elective (adeno)tonsillectomy in children treated with postoperative amoxicillin or a placebo in Northern Tanzania. We hypothesize that placebo is noninferior to amoxicillin in preventing postoperative morbidities following a (adeno)tonsillectomy in children in northern Tanzania. Primary outcomes The primary outcome is post-(adeno)tonsillectomy morbidity, however morbidity cannot be measured as a single parameter. Postoperative haemorrhage and infection are the most important postoperative complications contributing to post-(adeno)tonsillectomy morbidity. Post-(adeno)tonsillectomy infection is difficult to define since the tonsillar beds are left to heal by secondary intention after surgery in a bacterial, mucosal environment. Typical symptoms of surgical site infection are therefore absent. Clinically worsening pain and raised temperature are thus considered features of infection. For this reason, postoperative haemorrhage, raised temperature (fever) and pain are the primary outcomes in this research. Postoperative haemorrhage as defined using two parameters (major as if warranting re‐admission, blood transfusion or return to theatre for haemostasis and minor as any recorded postoperative blood loss i.e. Spitting of blood saliva 24 hours post-operative). Fever (temperature greater than 38°C on 2 consecutive post-operative days or greater than 39°C on any postoperative day), Post-operative pain score (Wong-Baker FACES® Pain Rating Score). Temperature will be taken daily by the research nurse while admitted and thereafter by the parent/caretaker with an axillary thermometer until the seventh postoperative day. The Wong-Baker FACES® Pain Rating Scale will be used to assess children's pain perception postoperatively. Written permission has been granted from Wong-Baker FACES Foundation for using both the English (while in hospital) and Swahili (while at home) Wong-Baker FACES® Pain Rating Scale in this study. The consequent need for analgesics will be documented by the prescribing physician. Secondary outcomes These includes time until normal diet is resumed, time until normal activities are resumed and adverse events (rash, vomiting, diarrhea and anaphylaxis) and microbial recolonization of the tonsillar niche. Study sample Post-operative bleeding, fever and pain were used as primary outcomes. We calculated power for all primary outcomes and only took the outcome with the largest number of participants. Based on the latest Cochrane review, titled “Antibiotics to reduce post-tonsillectomy morbidity”, 2,5% of all patients who undergo an elective tonsillectomy have a significant postoperative haemorrhage. With this haemorrhage rate, a significance level (α) of 0.05, a power(π) of 0.80, and a non-inferiority margin of 5%, we calculated the number of patients in our intervention group. The group treated with antibiotics should include 121 patients, giving a total of 242 patients necessary for analysis. To allow for some loss to follow-up, the aim is to include 270 children. Randomization Baseline characteristics of the subjects will be compiled at informed consent. Subjects will be randomly divided into an intervention and a control arm on the day of admission, with the aid of a computer-based randomization module in a 1:1 ratio. Stratified randomization is accomplished using gender, age group (2-4 years, 5-8 years and 9-14 years), residence (rural or urban) and research centre (KCMC or ALMC) as strata. Randomization is performed by the KCMC’s research pharmacist who will then prepare medication (either the antibiotics or a placebo capsules or solution, depending on the age of the child). Both placebo capsules as well as solutions have the same taste and appearance as the amoxicillin capsules and solution. Labelled with only the study protocol number and patients’ details the medication will be distributed by one of the research nurses. Thus, blinding all health professionals involved in the trial process. Surgery All (adeno)tonsillectomies will be carried out under general anaesthesia with the use of orotracheal intubation. Surgery will be performed by all grades of doctors, from residents to specialists. The tonsils are removed using either routine dissection, Sluders technique or electrodissection [7]. Which technique is chosen depends on the surgeon’s experience and preference. Previous studies have shown that the technique does not affect the outcome or the postoperative morbidity [7, 8]. In all patients the adenoid is removed using Beckmann adenoid curette. Microbial isolates During surgery just before dissection of the tonsils, a swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the tonsillar surface for culture and sensitivity. After the operation is completed, one dissected tonsil will be submerged in iodopovidone for around 30 seconds. Subsequently the tonsil will be rinsed using sterilized normal saline and divided into two parts with a new sterile blade. Another swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the core of the tonsil. For patients operated at KCMC both swabs will be maintained at a temperature between 2 and 8 degrees Celsius dispatched within 30 minutes to the microbiology research laboratory. Samples from ALMC will be stored at a temperature between 2 and 8 degrees Celsius and transported on the same day to the microbiology research laboratory. At the microbiology research laboratory all swabs will be incubated at 37 degrees Celsius for 24 hours. After incubation is completed, subcultures from growing microorganism will be prepared on agar plates. The isolated bacteria will then be gram stained and microscopically investigated. Only pathogenic organisms will be worked up, no workups for normal flora will be done. Microbiological workup will entirely adhere to the Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing. Antibiotic sensitivity testing will be done for all pathogenic, cultured microorganisms using the disc diffusion test [9]. Discs of the most common antibiotics will be used. Postoperative management After surgery all patients will be kept at the ward for at least one night. Based on their clinical condition patients will be discharged. On the ward, patients will receive their labelled medication with either 50 milligrams per kilogram amoxicillin or the placebo. Medication will be taken eight hourly for five consecutive days. Parents and caretakers are given instructions about the importance of continuing the medication after discharge from the hospital. All patients will be given paracetamol three times a day and ibuprofen twice a day based on their weight for 10 days. Any additional analgesics or other treatment will be started whenever necessary at the discretion of the treating physician. Follow-up During discharge, a questionnaire will be provided to persons legally responsible for the participating child. It will be filled out daily and will be presented to the investigator at follow-up visits. The questionnaire is translated, adopted and modified from the standardized Linden et al post tonsillectomy follow-up questionnaire. On day 7, the wound bed and the general health status will be inspected by the study doctor at the department of otolaryngology at KCMC and ALMC respectively. On day 14, a third swab (Copan ESwab, Copan Italia SPA, Brescia Italy) of the surgical site will be taken and sent to the microbiology research laboratory for culture and sensitivity analysis, as described above. During both visits detailed information will be obtained by the study doctor. The entire process from patients allocation up to follow-up is displayed in figure 1 and well described on SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) in figure 2. Statistical analysis Continuous variables will be presented as means and standard deviation or median and interquartile range (IQR) if not normally distributed. Categorical data will be presented as a number with percentage. All analysis will be done according to an intention-to-treat protocol. Differences between the observed risks of events (for primary outcomes bleeding, and fever) between placebo and antibiotics group will be calculated along with their 95% confidence intervals. Absolute risks will also be presented as it is important to be aware of the underlying risk of events. Differences in pain score between the two treatment arms will be calculated as mean differences with 95% CIs, using Student’s tests. Secondary outcomes will be analysed using Chi squared tests for categorical data (return to normal activities and microbial recolonization) or Wilcoxon rank sum tests (days to return to normal diet) for continuous data. P-values < 0.05 will be considered statistically significant. All data will be coded to maximize confidentiality. Collected data will be entered into a database and analysed using IBM® SPSS® Statistics version 24. Data and safety monitoring Data and safety monitoring will be done by the independent data and safety monitoring committee of Kilimanjaro Christian Research Institute (KCRI). They will perform interim analyses every six months as long as patient inclusion and data collection is ongoing. Ethics approval and consent to participate This clinical trial has been approved by the Kilimanjaro Christian Medical College Research Ethics and Review Committee (CRERC), the Tanzanian Food and Drug Authority (TFDA) and the Tanzanian National Institute for Medical Research (NIMR). Prior to randomization, written informed consent will be obtained from the parents/caretakers of each participant. Discussion Study strengths Our study aims to evaluate the effect of antibiotic prophylaxis on postoperative morbidity following (adeno)tonsillectomy in Tanzania. This research could add to generalization and increase in proper antimicrobial prescription in institutions in Tanzania as well as in the whole of Africa. Furthermore, it might enhance current knowledge about surface and core tonsillar micro-organisms. A young age, a poor nutritional status and either very low or very high body weight, are likely contributing factors to worse outcomes after (adeno)tonsillectomy. Moreover, in a developing country like Tanzania, there is significant inequality in living conditions and overall health status between the general public and the upper class. Children raised in a low social economical environment are prone to higher morbidity rates regardless of the postoperative management. Through the use of randomisation in this study design, we aim at limiting these confounders. Furthermore, we use double blinding to prevent information bias by both subjects and researchers. Study limitations Children coming from distant areas surrounding the hospital might not return for follow-ups and therefore the loss to follow-up rate might be higher than estimated. This in turn could result in inadequate sample sizes. We will try to reduce the amount of subjects lost to follow up by implementing reimbursement of travel expenses. Different surgical techniques will be used in performing an(adeno)tonsillectomy. This can be routine dissection, Sluder technique or electrodissection, according to the preference and custom of the surgeon performing the operation. As a consequence of this, the use of coagulation may differ within subjects. This, in turn, could result in differences in prevalence of pain and infection post-operatively. Still, up to now there is insufficient data to prove that one method of tonsillectomy is superior to the others[8]. In Tanzania, it is a custom that relatives oversee patients’ medication supply and intake. Though all patients are prescribed the same amount of analgesics, it is not regular practice that nurses supervise the medication intake. This could influence the patients’ perception of pain. Moreover, flushing of the wound bed with water post-operatively might decrease the infection risk following (adeno)tonsillectomy. This, however, is a management factor which is difficult to standardise and could therefore influence the outcomes. Trial status This is protocol version 9 October 2019, v12_2019. Page 11. At the time of manuscript submission, the researchers have started recruiting and including patients. Anticipating date of last recruitment to be 27/02/2020. List of Abbreviations ALMC - Arusha Lutheran Medical Centre CRERC - Kilimanjaro Christian Medical College Research Ethics and Review Committee ENT- Ear, Nose and Throat IQR - interquartile range KCMC - Kilimanjaro Christian Medical Centre NIMR - Tanzanian National Institute for Medical Research PACTR - Pan African Clinical Trials Registry SPIRIT- Standard Protocol Items: Recommendations for Interventional Trials TFDA - Tanzanian Food and Drug Authority Declarations Ethics approval and consent to participate Informed Consent to participate in the study will be obtain from all parents and persons legally responsible for the participant. This research has been awarded a clearance certificate, numbered 2373, by the Kilimanjaro Christian Medical College Clinical Research Ethics and Review Committee (KCMUCo-CRERC). The trial is registered by the National institute for Medical Research (NIMR) and the Tanzanian Food and Drug Authority (TFDA) also Trial registered to Pan African Clinical Trials Registry (PACTR) with Trial registration number PACTR201905466349317, registered Retrospectively on 15 May 2019 with trial registry record https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=8119 . The trial committee will monitor progress of this trial. Information obtained in this study period will only be used for study purposes. Consent for publication Not applicable Competing Interests No competing interests. Funding This study is non-industry funded. All costs are covered by a grant from the RadboudUMC Revolving Research Fund, i.e. a scholarship program for PhD candidates from low-middle income countries. Tanzania Ministry of Health Community Development Gender Elderly and Children (MoHCDEC) together with Training Health Researchers into Vocational Excellence (THRiVE) as Secondary Sponsors are responsible for funding postgraduate research activities including local related fees and publication related costs respectively. All these monetary bodies are purely not associated and engaged with study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. Authors contribution DK and NvH designed the study and drafted the manuscript. DK performs inclusion and follow-up of all patients and participates in surgical procedures. PS is local supervisor and participates in surgical procedures. BN and HS are responsible for microbiology and trial medication respectively. PS, BN, HS and FO coauthored the manuscript. All authors have read and approved the final version of the manuscript. Acknowledgements Participating parents/caretakers will be provided with a thermometer for temperature measurements and reimbursed for travel expenses. References Ingram, D.G. and N.R. Friedman, Toward Adenotonsillectomy in Children: A Review for the General Pediatrician. JAMA Pediatr, 2015. 169 (12): p. 1155-61. Oburra, H.O. and M. Idenya, Frequency of adenotonsillectomy in some Nairobi hospitals. East Afr Med J, 2001. 78 (7): p. 338-42. Rohlfing, M.L., et al., Investigation of Postoperative Oral Fluid Intake as a Predictor of Postoperative Emergency Department Visits After Pediatric TonsillectomyOral Fluid Intake and Adverse Outcomes After Pediatric TonsillectomyOral Fluid Intake and Adverse Outcomes After Pediatric Tonsillectomy. JAMA Otolaryngology–Head & Neck Surgery, 2016. 142 (4): p. 357-363. Egeli, E., et al., Can post-adenotonsillectomy morbidity be reduced by intravenous 24 h hydration in pediatric patients following adenotonsillectomy? Int J Pediatr Otorhinolaryngol, 2004. 68 (8): p. 1047-51. Dhiwakar, M., et al., Antibiotics to reduce post-tonsillectomy morbidity. Cochrane Database Syst Rev, 2012. 12 : p. Cd005607. Horumpende, P.G., et al., Prescription and non-prescription antibiotic dispensing practices in part I and part II pharmacies in Moshi Municipality, Kilimanjaro Region in Tanzania: A simulated clients approach. PLOS ONE, 2018. 13 (11): p. e0207465. Pynnonen, M., et al., Coblation versus other surgical techniques for tonsillectomy. Cochrane Database of Systematic Reviews, 2017(8). Pinder, D.K., H. Wilson, and M.P. Hilton, Dissection versus diathermy for tonsillectomy. Cochrane Database of Systematic Reviews, 2011(3). Bauer, A.W., et al., Antibiotic Susceptibility Testing by a Standardized Single Disk Method. American Journal of Clinical Pathology, 1966. 45 (4_ts): p. 493-496. Supplementary Files unmarkedSPIRITChecklistv9October2019v122019.pdf Cite Share Download PDF Status: Published Journal Publication published 09 Dec, 2019 Read the published version in Trials → Version 2 posted Editorial decision: Accept 22 Oct, 2019 Editor assigned by journal 19 Oct, 2019 Submission checks completed at journal 18 Oct, 2019 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3274","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":195002,"identity":"53e57598-efb4-4e94-9902-b772a03a35e1","order_by":1,"name":"Denis Robert 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placebo-controlled trial.\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eAdenotonsillectomy (ATE) is one of the most frequently performed operations in children worldwide and the most frequently performed otolaryngological operation in children. Indications for adenotonsillectomy are, amongst others, adenotonsillar hypertrophy, recurrent adenotonsillitis and obstructive sleep apnea syndrome[1, 2]. This also applies to Tanzania, where both pediatric sleep apnea as well as upper respiratory tract infections due to chronic adenotonsillar hypertrophy are very common problems. At Kilimanjaro Christian Medical Center (KCMC) alone, a large referral hospital in Northern Tanzania, over 1000 adenotonsillectomies performed yearly.\u003c/p\u003e\n\u003cp\u003eDifferent surgical techniques can be used to remove the tonsils and adenoid but regardless of the surgical technique, the pharyngeal wall embedding the tonsillar fossa is left open for secondary wound healing intention at the end of the procedure. Subsequently the wound bed is contaminated by commensal flora present in the oropharyngeal mucosa. It has been argued that, because of this, people are predisposed to inflammatory response and infection. This contributes to postoperative morbidity such as pain and the consequent need for analgesics, postoperative haemorrhage and the inability to resume normal diet. For this reason, several studies have recommended the prophylactic use of antibiotics to reduce the morbidity [2-5].\u003c/p\u003e\n\u003cp\u003eHowever, in a Cochrane review published in 2012, involving 10 trials with a pooled population of 1035 patients, the use of postoperative antibiotics did not show a clinically relevant effect on the haemorrhage rates, the time to resume a normal diet, pain and consequent need for analgesics[5]. Little evidence suggested that prophylactic use of postoperative antibiotics reduced fever. With the existing set of evidence, Dhiwakar and colleagues advocated against the routine prescription of antibiotics to patients undergoing adenotonsillectomy. However, they did highlight the need for further trials including subgroups of patients who might be in need of selective administration[5]. None of the studies reviewed in this Cochrane review had been conducted in resource-limited settings. Despite the lack of high level evidence for postoperative antibiotics, in Tanzania all children receive postoperative antibiotics after adenotonsillectomy based on the assumption that there is a higher risk of postoperative morbidity due to limited resources and a higher burden of infectious diseases. On the other hand, the widespread use of (postoperative) antibiotics is not without risks. There is the individual risk of gastrointestinal and allergic side effects, ranging from vomiting, diarrhoea and rash to severe anaphylaxis. And there is the risk of antimicrobial resistance. While global concern for antimicrobial resistances rises, there is still a significant gap of knowledge on this topic in resource-limited settings, like Tanzania. In developing countries, amoxicillin is one of the most misused and wrongly prescribed drugs. The majority of young children suffering from acute respiratory infection symptoms is treated inappropriately with this antibiotic. A cross-sectional research from 2018, performed in Moshi Tanzania, found that 92.3% of retailers dispensed antibiotics without prescriptions [6]. This practice disadvantages most inhabitants of these areas in particular. Cross-resistance and cost in obtaining superior antimicrobial agents become a big challenge.\u003c/p\u003e\n\u003cp\u003eSummarizing the above, the widespread use of postoperative antibiotics after (adeno)tonsillectomy in children in Tanzania may have more negative effects than benefits, if there are any benefits at all. To limit unnecessary antibiotic prescription and secondary antibiotic resistance, well-designed randomized controlled trials are needed. This randomized double-blind placebo-controlled trial studies the prophylactic effect of antibiotics on morbidity after adenotonsillectomy in children in Tanzania.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e\u003cstrong\u003eDesign \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a two centre, double-blind, randomized controlled trial. Patients will be randomly allocated to receive either 50mg/kg body weight of placebo or amoxicillin 5 days after surgery as standard prophylaxis regime.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipating centres are the department of otolaryngology at Kilimanjaro Christian Medical Centre (KCMC) in Moshi and the department of paediatric surgery at the Arusha Lutheran Medical Centre (ALMC) in Arusha, being the only settings with established Ear, Nose and Throat (ENT) services in northern Tanzania.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll Children from 2 to 14 years of age who will undergo an elective (adeno)tonsillectomy will be approached. Elective surgery is indicated in case of recurrent chronic tonsillitis, as defined by 5 or more episodes of tonsillitis yearly for at least 2 consecutive years, or in case of obstructive sleep apnoea due to adenotonsillar hypertrophy with inadequate response to pharmacotherapy. Inclusion will be done after written informed consent. Inclusion of patients started January 2019.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients will be excluded from participation if they meet any of the following criteria.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient is scheduled for unilateral tonsillectomy, tonsillar biopsy, tonsillectomy for a known carcinoma.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe (adeno)tonsillectomy is combined with any other type of surgery.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient has an acute tonsillar infection or peritonsillar abscess at the time of surgery.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient is known to have a cardiac co-morbidity, with or without current treatment or follow-up by a cardiologist.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient has a condition which results in weakness or failure of the host defence mechanism, like leukemia, acquired immune deficiency syndrome or current use of immunosuppressive medication.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient has a syndromal disorder or a craniofacial malformation.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient has a reported allergy to any antibiotic, ibuprofen or paracetamol.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eThe patient was treated with antibiotics during or less than 1 week prior to surgery.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePatients on any other concomitant medications at the point of enrolment.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eStudy objective \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo compare the postoperative morbidity following elective (adeno)tonsillectomy in children treated with postoperative amoxicillin or a placebo in Northern Tanzania. We hypothesize that placebo is noninferior to amoxicillin in preventing postoperative morbidities following a (adeno)tonsillectomy in children in northern Tanzania.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcomes \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome is post-(adeno)tonsillectomy morbidity, however morbidity cannot be measured as a single parameter. Postoperative haemorrhage and infection are the most important postoperative complications contributing to post-(adeno)tonsillectomy morbidity. Post-(adeno)tonsillectomy infection is difficult to define since the tonsillar beds are left to heal by secondary intention after surgery in a bacterial, mucosal environment. Typical symptoms of surgical site infection are therefore absent. Clinically worsening pain and raised temperature are thus considered features of infection. For this reason, postoperative haemorrhage, raised temperature (fever) and pain are the primary outcomes in this research.\u003c/p\u003e\n\u003cp\u003ePostoperative haemorrhage as defined using two parameters (major as if warranting re‐admission, blood transfusion or return to theatre for haemostasis and minor as any recorded postoperative blood loss i.e. Spitting of blood saliva 24 hours post-operative). Fever (temperature greater than 38\u0026deg;C on 2 consecutive post-operative days or greater than 39\u0026deg;C on any postoperative day), Post-operative pain score (Wong-Baker FACES\u0026reg; Pain Rating Score).\u003c/p\u003e\n\u003cp\u003eTemperature will be taken daily by the research nurse while admitted and thereafter by the parent/caretaker with an axillary thermometer until the seventh postoperative day. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Wong-Baker FACES\u0026reg; Pain Rating Scale will be used to assess children's pain perception postoperatively. Written permission has been granted from Wong-Baker FACES Foundation for using both the English (while in hospital) and Swahili (while at home) Wong-Baker FACES\u0026reg; Pain Rating Scale in this study. The consequent need for analgesics will be documented by the prescribing physician.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese includes time until normal diet is resumed, time until normal activities are resumed and adverse events (rash, vomiting, diarrhea and anaphylaxis) and microbial recolonization of the tonsillar niche.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy sample\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost-operative bleeding, fever and pain were used as primary outcomes. We calculated power for all primary outcomes and only took the outcome with the largest number of participants. Based on the latest Cochrane review, titled \u0026ldquo;Antibiotics to reduce post-tonsillectomy morbidity\u0026rdquo;, 2,5% of all patients who undergo an elective tonsillectomy have a significant postoperative haemorrhage. With this haemorrhage rate, a significance level (\u0026alpha;) of 0.05, a power(\u0026pi;) of 0.80, and a non-inferiority margin of 5%, we calculated the number of patients in our intervention group. The group treated with antibiotics should include 121 patients, giving a total of 242 patients necessary for analysis. To allow for some loss to follow-up, the aim is to include 270 children.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline characteristics of the subjects will be compiled at informed consent. Subjects will be randomly divided into an intervention and a control arm on the day of admission, with the aid of a computer-based randomization module in a 1:1 ratio. Stratified randomization is accomplished using gender, age group (2-4 years, 5-8 years and 9-14 years), residence (rural or urban) and research centre (KCMC or ALMC) as strata. Randomization is performed by the KCMC\u0026rsquo;s research pharmacist who will then prepare medication (either the antibiotics or a placebo capsules or solution, depending on the age of the child). Both placebo capsules as well as solutions have the same taste and appearance as the amoxicillin capsules and solution. Labelled with only the study protocol number and patients\u0026rsquo; details the medication will be distributed by one of the research nurses. Thus, blinding all health professionals involved in the trial process. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll (adeno)tonsillectomies will be carried out under general anaesthesia with the use of orotracheal intubation. Surgery will be performed by all grades of doctors, from residents to specialists. The tonsils are removed using either routine dissection, Sluders technique or electrodissection [7]. Which technique is chosen depends on the surgeon\u0026rsquo;s experience and preference. Previous studies have shown that the technique does not affect the outcome or the postoperative morbidity [7, 8]. In all patients the adenoid is removed using Beckmann adenoid curette.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eMicrobial isolates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring surgery just before dissection of the tonsils, a swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the tonsillar surface for culture and sensitivity. After the operation is completed, one dissected tonsil will be submerged in iodopovidone for around 30 seconds. Subsequently the tonsil will be rinsed using sterilized normal saline and divided into two parts with a new sterile blade. Another swab (Copan ESwab, Copan Italia SPA, Brescia Italy) will be taken from the core of the tonsil.\u003c/p\u003e\n\u003cp\u003eFor patients operated at KCMC both swabs will be maintained at a temperature between 2 and 8 degrees Celsius dispatched within 30 minutes to the microbiology research laboratory. Samples from ALMC will be stored at a temperature between 2 and 8 degrees Celsius and transported on the same day to the microbiology research laboratory. At the microbiology research laboratory all swabs will be incubated at 37 degrees Celsius for 24 hours. After incubation is completed, subcultures from growing microorganism will be prepared on agar plates. The isolated bacteria will then be gram stained and microscopically investigated. Only pathogenic organisms will be worked up, no workups for normal flora will be done. Microbiological workup will entirely adhere to the Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing. Antibiotic sensitivity testing will be done for all pathogenic, cultured microorganisms using the disc diffusion test [9]. Discs of the most common antibiotics will be used.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter surgery all patients will be kept at the ward for at least one night. Based on their clinical condition patients will be discharged. On the ward, patients will receive their labelled medication with either 50 milligrams per kilogram amoxicillin or the placebo. Medication will be taken eight hourly for five consecutive days. Parents and caretakers are given instructions about the importance of continuing the medication after discharge from the hospital.\u003c/p\u003e\n\u003cp\u003eAll patients will be given paracetamol three times a day and ibuprofen twice a day based on their weight for 10 days. Any additional analgesics or other treatment will be started whenever necessary at the discretion of the treating physician.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring discharge, a questionnaire will be provided to persons legally responsible for the participating child. It will be filled out daily and will be presented to the investigator at follow-up visits. The questionnaire is translated, adopted and modified from the standardized Linden et al post tonsillectomy follow-up questionnaire.\u003c/p\u003e\n\u003cp\u003eOn day 7, the wound bed and the general health status will be inspected by the study doctor at the department of otolaryngology at KCMC and ALMC respectively. On day 14, a third swab (Copan ESwab, Copan Italia SPA, Brescia Italy) of the surgical site will be taken and sent to the microbiology research laboratory for culture and sensitivity analysis, as described above. During both visits detailed information will be obtained by the study doctor. The entire process from patients allocation up to follow-up is displayed in figure 1 and well described on SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) in figure 2.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables will be presented as means and standard deviation or median and interquartile range (IQR) if not normally distributed. Categorical data will be presented as a number with percentage. All analysis will be done according to an intention-to-treat protocol.\u003c/p\u003e\n\u003cp\u003eDifferences between the observed risks of events (for primary outcomes bleeding, and fever) between placebo and antibiotics group will be calculated along with their 95% confidence intervals. Absolute risks will also be presented as it is important to be aware of the underlying risk of events. Differences in pain score between the two treatment arms will be calculated as mean differences with 95% CIs, using Student\u0026rsquo;s tests. Secondary outcomes will be analysed using Chi squared tests for categorical data (return to normal activities and microbial recolonization) or Wilcoxon rank sum tests (days to return to normal diet) for continuous data. P-values \u0026lt; 0.05 will be considered statistically significant. All data will be coded to maximize confidentiality. Collected data will be entered into a database and analysed using IBM\u0026reg; SPSS\u0026reg; Statistics version 24.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and safety monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData and safety monitoring will be done by the independent data and safety monitoring committee of Kilimanjaro Christian Research Institute (KCRI). They will perform interim analyses every six months as long as patient inclusion and data collection is ongoing.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical trial has been approved by the Kilimanjaro Christian Medical College Research Ethics and Review Committee (CRERC), the Tanzanian Food and Drug Authority (TFDA) and the Tanzanian National Institute for Medical Research (NIMR). Prior to randomization, written informed consent will be obtained from the parents/caretakers of each participant.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eStudy strengths\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study aims to evaluate the effect of antibiotic prophylaxis on postoperative morbidity following (adeno)tonsillectomy in Tanzania. This research could add to generalization and increase in proper antimicrobial prescription in institutions in Tanzania as well as in the whole of Africa. Furthermore, it might enhance current knowledge about surface and core tonsillar micro-organisms.\u003c/p\u003e\n\u003cp\u003eA young age, a poor nutritional status and either very low or very high body weight, are likely contributing factors to worse outcomes after (adeno)tonsillectomy. Moreover, in a developing country like Tanzania, there is significant inequality in living conditions and overall health status between the general public and the upper class. Children raised in a low social economical environment are prone to higher morbidity rates regardless of the postoperative management.\u003c/p\u003e\n\u003cp\u003eThrough the use of randomisation in this study design, we aim at limiting these confounders. Furthermore, we use double blinding to prevent information bias by both subjects and researchers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChildren coming from distant areas surrounding the hospital might not return for follow-ups and therefore the loss to follow-up rate might be higher than estimated. This in turn could result in inadequate sample sizes. We will try to reduce the amount of subjects lost to follow up by implementing reimbursement of travel expenses.\u003c/p\u003e\n\u003cp\u003eDifferent surgical techniques will be used in performing an(adeno)tonsillectomy. This can be routine dissection, Sluder technique or electrodissection, according to the preference and custom of the surgeon performing the operation. As a consequence of this, the use of coagulation may differ within subjects. This, in turn, could result in differences in prevalence of pain and infection post-operatively. Still, up to now there is insufficient data to prove that one method of tonsillectomy is superior to the others[8].\u003c/p\u003e\n\u003cp\u003eIn Tanzania, it is a custom that relatives oversee patients\u0026rsquo; medication supply and intake. Though all patients are prescribed the same amount of analgesics, it is not regular practice that nurses supervise the medication intake. This could influence the patients\u0026rsquo; perception of pain. Moreover, flushing of the wound bed with water post-operatively might decrease the infection risk following (adeno)tonsillectomy. This, however, is a management factor which is difficult to standardise and could therefore influence the outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is protocol version 9 October 2019, v12_2019. Page 11. At the time of manuscript submission, the researchers have started recruiting and including patients. Anticipating date of last recruitment to be 27/02/2020.\u003c/p\u003e"},{"header":"List of Abbreviations","content":"\u003cp\u003eALMC - Arusha Lutheran Medical Centre\u003c/p\u003e\n\u003cp\u003eCRERC - Kilimanjaro Christian Medical College Research Ethics and Review Committee\u003c/p\u003e\n\u003cp\u003eENT- Ear, Nose and Throat\u003c/p\u003e\n\u003cp\u003eIQR - interquartile range\u003c/p\u003e\n\u003cp\u003eKCMC - Kilimanjaro Christian Medical Centre\u003c/p\u003e\n\u003cp\u003eNIMR - Tanzanian National Institute for Medical Research\u003c/p\u003e\n\u003cp\u003ePACTR - Pan African Clinical Trials Registry\u003c/p\u003e\n\u003cp\u003eSPIRIT- Standard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\n\u003cp\u003eTFDA - Tanzanian Food and Drug Authority\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed Consent to participate in the study will be obtain from all parents and persons legally responsible for the participant. This research has been awarded a clearance certificate, numbered 2373, by the Kilimanjaro Christian Medical College Clinical Research Ethics and Review Committee (KCMUCo-CRERC). The trial is registered by the National institute for Medical Research (NIMR) and the Tanzanian Food and Drug Authority (TFDA) also Trial registered to Pan African Clinical Trials Registry (PACTR) with Trial registration number PACTR201905466349317, registered Retrospectively on 15 May 2019 with\u0026nbsp; trial registry record \u003ca href=\"https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=8119\"\u003ehttps://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=8119\u003c/a\u003e. The trial committee will monitor progress of this trial. Information obtained in this study period will only be used for study purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is non-industry funded. All costs are covered by a grant from the RadboudUMC Revolving Research Fund, i.e. a scholarship program for PhD\u0026nbsp;candidates from low-middle income countries.\u003c/p\u003e\n\u003cp\u003eTanzania Ministry of Health Community Development Gender Elderly and Children (MoHCDEC) together with Training Health Researchers into Vocational Excellence (THRiVE) as Secondary Sponsors are responsible for funding postgraduate research activities including local related fees and publication related costs respectively. All these monetary bodies are purely not associated and engaged with study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDK and NvH designed the study and drafted the manuscript. DK performs inclusion and follow-up of all patients and participates in surgical procedures. PS is local supervisor and participates in surgical procedures. BN and HS are responsible for microbiology and trial medication respectively. PS, BN, HS and FO coauthored the manuscript. All authors have read and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipating parents/caretakers will be provided with a thermometer for temperature measurements and reimbursed for travel expenses.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIngram, D.G. and N.R. Friedman, \u003cem\u003eToward Adenotonsillectomy in Children: A Review for the General Pediatrician.\u003c/em\u003e JAMA Pediatr, 2015. \u003cstrong\u003e169\u003c/strong\u003e(12): p. 1155-61.\u003c/li\u003e\n\u003cli\u003eOburra, H.O. and M. Idenya, \u003cem\u003eFrequency of adenotonsillectomy in some Nairobi hospitals.\u003c/em\u003e East Afr Med J, 2001. \u003cstrong\u003e78\u003c/strong\u003e(7): p. 338-42.\u003c/li\u003e\n\u003cli\u003eRohlfing, M.L., et al., \u003cem\u003eInvestigation of Postoperative Oral Fluid Intake as a Predictor of Postoperative Emergency Department Visits After Pediatric TonsillectomyOral Fluid Intake and Adverse Outcomes After Pediatric TonsillectomyOral Fluid Intake and Adverse Outcomes After Pediatric Tonsillectomy.\u003c/em\u003e JAMA Otolaryngology\u0026ndash;Head \u0026amp; Neck Surgery, 2016. \u003cstrong\u003e142\u003c/strong\u003e(4): p. 357-363.\u003c/li\u003e\n\u003cli\u003eEgeli, E., et al., \u003cem\u003eCan post-adenotonsillectomy morbidity be reduced by intravenous 24 h hydration in pediatric patients following adenotonsillectomy?\u003c/em\u003e Int J Pediatr Otorhinolaryngol, 2004. \u003cstrong\u003e68\u003c/strong\u003e(8): p. 1047-51.\u003c/li\u003e\n\u003cli\u003eDhiwakar, M., et al., \u003cem\u003eAntibiotics to reduce post-tonsillectomy morbidity.\u003c/em\u003e Cochrane Database Syst Rev, 2012. \u003cstrong\u003e12\u003c/strong\u003e: p. Cd005607.\u003c/li\u003e\n\u003cli\u003eHorumpende, P.G., et al., \u003cem\u003ePrescription and non-prescription antibiotic dispensing practices in part I and part II pharmacies in Moshi Municipality, Kilimanjaro Region in Tanzania: A simulated clients approach.\u003c/em\u003e PLOS ONE, 2018. \u003cstrong\u003e13\u003c/strong\u003e(11): p. e0207465.\u003c/li\u003e\n\u003cli\u003ePynnonen, M., et al., \u003cem\u003eCoblation versus other surgical techniques for tonsillectomy.\u003c/em\u003e Cochrane Database of Systematic Reviews, 2017(8).\u003c/li\u003e\n\u003cli\u003ePinder, D.K., H. Wilson, and M.P. Hilton, \u003cem\u003eDissection versus diathermy for tonsillectomy.\u003c/em\u003e Cochrane Database of Systematic Reviews, 2011(3).\u003c/li\u003e\n\u003cli\u003eBauer, A.W., et al., \u003cem\u003eAntibiotic Susceptibility Testing by a Standardized Single Disk Method.\u003c/em\u003e American Journal of Clinical Pathology, 1966. \u003cstrong\u003e45\u003c/strong\u003e(4_ts): p. 493-496.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Adenotonsillectomy, tonsillectomy, postoperative morbidity, amoxicillin, RCT, antimicrobial resistance, AMR","lastPublishedDoi":"10.21203/rs.2.12518/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.12518/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Adenotonsillectomy is the most frequently performed operation in children worldwide. For decades prophylactic antibiotics have been prescribed to limit postoperative complications. In a Cochrane review the effect of this antibiotic use has been refuted. However, all reviewed studied were done in developed countries. In Tanzania, like many other developing countries with limited resources and a high burden of infectious diseases, postoperative antibiotic prescription is still very common to decrease the supposed higher postoperative morbidity. However, as a consequence of this widespread use of postoperative antibiotics cross-resistance and risk of allergic side effects rise. Well designed randomised controlled trials are needed to limit unnecessary antibiotic prescription and secondary antibiotic resistance. \nAim: The aim of this study is to analyse the prophylactic role of postoperative antibiotic on the morbidity following adenotonsillectomy in children in Tanzania.\nDesign: A double blinded randomised placebo controlled trial set in northern Tanzania. Participating centres are the department of otolaryngology at Kilimanjaro Christian Medical Centre (KCMC) in Moshi and the department of paediatric surgery at the Arusha Lutheran Medical Centre (ALMC) in Arusha. \nMethods: Around 270 children aged 2 to 14 years, all scheduled for elective (adeno)tonsillectomy, will be included and assigned to receive either a standard regimen of 5 days antibiotic prophylaxis or placebo after surgery. The primary outcomes are postoperative haemorrhage, fever and pain. Secondary outcomes are the time until normal diet is resumed, the time until normal activities are resumed, occurrence of adverse events and microbial recolonization of the tonsillar beds. \nDiscussion: This study will enhance increase of proper antimicrobial prescription in Tanzanian institutions as well as other resource-limited countries where prescription of antibiotics is still very common. In addition, it might augment current knowledge about surface and core tonsillar micro-organisms and sensitivity patterns.","manuscriptTitle":"The effect of antibiotics on post-adenotonsillectomy morbidity in tanzanian children: study protocol for a randomized double-blind placebo-controlled trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-10-23 16:58:00","doi":"10.21203/rs.2.12518/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2019-10-22T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-10-19T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-10-18T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-08-09 01:42:31","doi":"10.21203/rs.2.12518/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2019-09-22T12:00:00+00:00","index":1,"fulltext":"Form responses:\n---\n* Quality of written English\nPlease indicate the quality of language in the manuscript:\tAcceptable: **Quality of figures\nAll images and figures within the manuscript should be genuine i.e. without evidence of manipulation. No specific feature within an image may be enhanced, obscured, moved, removed, or introduced. If you have concerns about the veracity of the figures you should choose the first option below.\tAcceptable**\n"},{"type":"decision","content":"Major revision","date":"2019-09-22T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-08-31T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-08-28T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-08-13T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-08-02T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-08-02T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fffeb27d-e326-4472-aa64-2160e31d0434","owner":[],"postedDate":"October 23rd, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":20266,"name":"Internal Medicine"},{"id":20267,"name":"Integrative \u0026 Complementary Medicine"},{"id":20268,"name":"Translational Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":{"articleIdentity":"rs-3274","link":"https://doi.org/10.1186/s13063-019-3830-5","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2019-12-09 12:00:00","publishedOnDateReadable":"December 9th, 2019"},"versionCreatedAt":"2019-10-23 16:58:00","video":"","vorDoi":"10.1186/s13063-019-3830-5","vorDoiUrl":"https://doi.org/10.1186/s13063-019-3830-5","workflowStages":[]},"version":"v2","identity":"rs-3274","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-3274","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}