Recommendations on off-label use of intravenous azithromycin in children
Pengxiang Zhou
Department of Pharmacy, Peking University Third Hospital, Beijing, China
Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
Search for more papers by this authorXiaoling Wang
National Center for Children’s Health, Beijing, China
Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorXianglin Zhang
Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
Search for more papers by this authorBaoping Xu
National Center for Children’s Health, Beijing, China
Department of Respiration, Beijing Children’s Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Respiratory Disease, Beijing, China
Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, Beijing, China
Search for more papers by this authorXiaomei Tong
Department of Pediatrics, Peking University Third Hospital, Beijing, China
Search for more papers by this authorWei Zhou
Department of Pediatrics, Peking University Third Hospital, Beijing, China
Search for more papers by this authorCorresponding Author
Kunling Shen
National Center for Children’s Health, Beijing, China
Department of Respiration, Beijing Children’s Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Respiratory Disease, Beijing, China
Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, Beijing, China
Correspondence
Kunling Shen, Department of Respiration, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, National Clinical Research Center for Respiratory Disease, Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, No.56 South Lishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Suodi Zhai, Department of Pharmacy, Peking University Third Hospital, Institute for Drug Evaluation, Peking University Health Science Center, No.49 North Garden Road, Haidian District, Beijing 100191, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Suodi Zhai
Department of Pharmacy, Peking University Third Hospital, Beijing, China
Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
Correspondence
Kunling Shen, Department of Respiration, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, National Clinical Research Center for Respiratory Disease, Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, No.56 South Lishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Suodi Zhai, Department of Pharmacy, Peking University Third Hospital, Institute for Drug Evaluation, Peking University Health Science Center, No.49 North Garden Road, Haidian District, Beijing 100191, China.
Email: [email protected]
Search for more papers by this authorPengxiang Zhou
Department of Pharmacy, Peking University Third Hospital, Beijing, China
Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
Search for more papers by this authorXiaoling Wang
National Center for Children’s Health, Beijing, China
Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorXianglin Zhang
Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
Search for more papers by this authorBaoping Xu
National Center for Children’s Health, Beijing, China
Department of Respiration, Beijing Children’s Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Respiratory Disease, Beijing, China
Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, Beijing, China
Search for more papers by this authorXiaomei Tong
Department of Pediatrics, Peking University Third Hospital, Beijing, China
Search for more papers by this authorWei Zhou
Department of Pediatrics, Peking University Third Hospital, Beijing, China
Search for more papers by this authorCorresponding Author
Kunling Shen
National Center for Children’s Health, Beijing, China
Department of Respiration, Beijing Children’s Hospital, Capital Medical University, Beijing, China
National Clinical Research Center for Respiratory Disease, Beijing, China
Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, Beijing, China
Correspondence
Kunling Shen, Department of Respiration, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, National Clinical Research Center for Respiratory Disease, Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, No.56 South Lishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Suodi Zhai, Department of Pharmacy, Peking University Third Hospital, Institute for Drug Evaluation, Peking University Health Science Center, No.49 North Garden Road, Haidian District, Beijing 100191, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Suodi Zhai
Department of Pharmacy, Peking University Third Hospital, Beijing, China
Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
Correspondence
Kunling Shen, Department of Respiration, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, National Clinical Research Center for Respiratory Disease, Respiratory Branch of Chinese Pediatric Society of Chinese Medical Association, No.56 South Lishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Suodi Zhai, Department of Pharmacy, Peking University Third Hospital, Institute for Drug Evaluation, Peking University Health Science Center, No.49 North Garden Road, Haidian District, Beijing 100191, China.
Email: [email protected]
Search for more papers by this authorAbstract
Objective
Intravenous azithromycin (AZM) has been widely used in children worldwide, but there still remains much concern regarding its off-label use, which urgently needs to be regulated. Therefore, we developed a rapid advice guideline in China to give recommendations of rational use of intravenous AZM in children.
Methods
This guideline focuses on antimicrobial therapy with intravenous AZM in children. The Delphi research method was used to select questions. A systematic literature review was also conducted. Data were pooled and ranked according to the GRADE system. Recommendations were developed based on expert clinical experience, patients’ values and preferences, and evidence availability. After an external review, the recommendations were revised and approved.
Results
This guideline included eighteen recommendations that covered four domains: (a) Indications: the treatment of pneumonia caused by atypical but common pathogens, such as Mycoplasma pneumoniae, Chlamydia trachomatis or Chlamydophila pneumoniae and Legionella pneumophila, more typical bacteria as well as the treatment of bronchitis of presumed bacterial aetiologies; (b) Usage and dosage: administration route, infusion concentrations, treatment duration, course of sequential treatment, and dosage stratified by age; (c) Adverse reactions and treatment: the management of gastrointestinal reactions, arrhythmias, pain or phlebitis at the infusion site, and anaphylaxis; and (d) Special population: children with renal or liver dysfunction, congenital heart disease, and obesity. This guideline will hopefully help promote a rational use of intravenous AZM in children worldwide.
Conclusion
This guideline has summarised the evidence and has developed recommendations on the use of intravenous AZM in children worldwide. Further attention and well-designed researches should be conducted on the off-label use of intravenous AZM in children.
Open Research
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are available from articles in the References and Supplementary Materials, except that the unpublished values and preferences investigation data of patients’ families are available from the corresponding authors upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijcp14010-sup-0001-TableS1-S9.docxWord document, 159.9 KB | Table S1-S9 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Li W, Hui-Yan C. Pediatric Clinical Pharmacology. Beijing: People's Medical Publishing House Co., Ltd; 2015.
- 2Ovetchkine P, Rieder MJ. Azithromycin use in paediatrics: a practical overview. Paediatr Child Health. 2013; 18(6): 311–316.
- 3 ZITHROMAX (azithromycin) for IV infusion only [package insert]. New York, NY: Pfizer Inc.; 2017. (Ed.).
- 4 Trustworthy IOMU, Guidelines CP. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011.
- 5 World Health Organization. WHO Handbook for Guideline Development. Switzeland: WHO Press; 2014.
- 6Wang X, Chen Y, Yang N, et al. Rapid advice guideline and its methodology: an introduction. Chinese J Eviden Based Med. 2015; 15(09): 1103–1105.
- 7Zhou P, Liang S, Zhai S. A protocol introduction of rapid advice guideline for intravenous azithromycin in children. China Pharm. 2018; 29(04): 436–440.
- 8 WHO and Rapid Advice Guidelines: History and Future Directions. http://www.g-i-n.net/conference/past-conferences/10thconference/monday/10-00-am-to-1-00-pm/norris-62.pdf. Accessed March 24, 2020.
- 9Garritty CM, Norris SL, Moher D. Developing WHO rapid advice guidelines in the setting of a public health emergency. J Clin Epidemiol. 2017; 82: 47–60.
- 10Kowalski SC, Morgan RL, Falavigna M, et al. Development of rapid guidelines: 1. Systematic survey of current practices and methods. Health Res Policy Syst. 2018; 16(1): 61.
- 11Cunha A. Transparent development of WHO rapid advice guidelines: a useful approach. Plos Med. 2007; 4(7): e245.
- 12 International Practice Guidelines Registry Platform. http://www.guidelines-registry.org. Accessed March 24, 2020.
- 13Zhou P, Meng Y, Chen Y, Wang X, Zhai S. Investigation and analysis of clinical questions and outcomes of Rapid Advice Guideline for intravenous Azithromycin in Children. China J Hospital Pharm. 2018; 38(23): 2387–2391.
- 14Zhou P, Xue Y, Chen Y, Zhai S. Using Delphi method to determine the questions and outcomes included in the Rapid Advice Guideline for Intravenous Azithromycin in Children. China J Hospital Pharm. 2018; 38(03): 285–288.
- 15Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358:j4008.
- 16 Higgins JPT ADSJ. Chapter 8: assessing risk of bias in included studies. In: JPT Higgins, S Green eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. www.cochrane-handbook.org. (Ed.).
- 17Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650): 924–926.
- 18Nc D. An experimental study of group opinion the Delphi method. Exp Study Group Opin. 1969; P408–P426.
- 19Zhou P, Lin Q, Chen Y, Xue Y, Zhai S. Using Delphi method to develop the recommendations included in the Rapid Advice Guideline for Intravenous Azithromycin in Children. China J Hospital Pharm. 2018; 38(12): 1273–1276.
- 20Jaeschke R, Guyatt GH, Dellinger P, et al. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ. 2008; 337:a744.
- 21Zhou P, Chen Y, Xu B, Zhai S. Rapid advice Guideline for Intravenous Azithromycin in Children: recommendations external review. China J Hospital Pharm. 2018; 38(17): 1773–1776.
- 22Brouwers MC, Kerkvliet K, Spithoff K. The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines. BMJ. 2016; 352: i1152.
- 23Chen Y, Yang K, Marusic A, et al. A reporting tool for practice guidelines in health care: the RIGHT Statement. Ann Intern Med. 2017; 166(2): 128–132.
- 24Lin Q, Zhou P, Zhai S, Zhao R. Efficacy of azithromycin for injection in the treatment of Mycoplasma pneumoniae pneumonia in children: a systematic review. China Pharmacy. 2018; 29(22): 3146–3152.
- 25Bradley JS, Byington CL, Shah SS, Alverson B. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of America. Clin Infect Dis. 2011; 7(53): e25–e76.
- 26Korppi M, Heiskanen-Kosma T, Kleemola M. Incidence of community-acquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population-based study in primary health care. Respirology. 2004; 9(1): 109–114.
- 27Association RBOC. Community acquired pneumonia management guidelines in chilren (2013 revision) I. Chinese J Pediatr. 2013; 51(10): 745–752.
- 28 Association RBOC. Expert consensus on diagnosis and treatment of Mycoplasma Pneumoniae pneumonia in children (2015 edition). Chinese J Appl Clin Pediatr. 2015, 30(17), 1304-1308.
- 29Harris M, Clark J, Coote N, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011; 66(Suppl 2): i1–i23.
- 30Zhang J, Song H. Clinical analysis of 52 cases of neonatal chlamydial pneumonia. J Clin Rational Drug Use. 2014; 7(5): 87–88.
- 31He R, Liu C, Wan H, Zou Y, Fu R. Using azithromycin sequentially for the treatment of Chlamydia pneumonia. Clin Med J. 2007; 27(12): 47–48.
- 32Sun Y, Gao X, Chen Y. Comparison of therapeutic effects of 64 cases of Chlamydia trachomatis pneumonia in infants. Matern Child Health Care China. 2007; 22: 4845–4846.
- 33Geisler WM. Management of uncomplicated Chlamydia trachomatis infections in adolescents and adults: evidence reviewed for the 2006 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines. Clin Infect Dis. 2007; 44(Suppl 3): S77–S83.
- 34Wang H, Wang G, Huang L. Observation on application effect of azithromycin in Legionella pneumonia in children. Matern Child Health Care China. 2014; 29(25): 4094–4096.
- 35Chen R. Treatment of 60 cases of Legionella pneumonia in children with azithromycin. Contemp Med. 2015; 21(20): 131–132.
- 36Amsden GW. Treatment of Legionnaires' disease. Drugs. 2005; 65(5): 605–614.
- 37Luisa PM, Yu VL. Treatment strategies for Legionella infection. Expert Opin Pharmaco. 2009; 10(7): 1109–1121.
- 38Rodrigues C, Groves H. Community-acquired pneumonia in children: the challenges of microbiological diagnosis. J Clin Microbiol. 2018; 56(3):e01318-17.
- 39Peyrani P, Mandell L, Torres A, Tillotson GS. The burden of community-acquired bacterial pneumonia in the era of antibiotic resistance. Expert Rev Respir Med. 2019; 13(2): 139–152.
- 40Tapiainen T, Aittoniemi J, Immonen J, et al. Finnish guidelines for the treatment of community-acquired pneumonia and pertussis in children. Acta Paediatr. 2016; 105(1): 39–43.
- 41 American Academy of Pediatrics. Pertussis (Whooping Cough) In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Disease. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015: 611.
- 42Farley R, Spurling GK, Eriksson L, Del Mar CB Antibiotics for bronchiolitis in children under two years of age. Cochrane Db Syst Rev. 2014;(10): CD005189.
- 43Contopoulos-Ioannidis DG, Ioannidis JP, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for lower respiratory tract infections. J Antimicrob Chemother. 2001; 48(5): 691–703.
- 44Li X, Yu H, Guo J. A comparative study of azithromycin dry suspension and sequential for the treatment of mycoplasma pneumonia in children. Shaanxi Med J. 2015; 44(9): 1541–1543.
- 45 WHO. Programme for the Control of Acute Respiratory Infections. Technical basis for the WHO recommendations on the management of pneumonia in children at first level health facilities. Geneva, Switzerland: World Health Organization, 1991. (Ed.).
- 46Zar HJ, Jeena P, Argent A, Gie R, Madhi SA. Diagnosis and management of community-acquired pneumonia in childhood–South African Thoracic Society Guidelines. S Afr Med J. 2005; 95(12 Pt 2): 977–981, 984–990.
- 47Zhou P, Chen Y, Zhai S. Azithromycin sequential antimicrobial therapy in the treatment of Mycoplasma pneumoniae pneumonia in children: a systematic review and Meta-analysis. China J Hospital Pharm. 2018; 38(15): 1633–1638.
- 48Al-Eidan FA, McElnay JC, Scott MG, Kearney MP, Troughton KE, Jenkins J. Sequential antimicrobial therapy: treatment of severe lower respiratory tract infections in children. J Antimicrob Chemother. 1999; 44(5): 709–715.
- 49Wei S, Zeng J, Li L, Liu X. Influence of azithromycin with different intravenous infusion durations on therapeutic efficacy and compliance in children with Mycoplasma pneumoniae pneumonia. Guangxi Med J. 2016; 38(11): 1541–1543.
- 50Smith C, Egunsola O, Choonara I, Kotecha S, Jacqz-Aigrain E, Sammons H. Use and safety of azithromycin in neonates: a systematic review. BMJ Open. 2015; 5(12):e8194.
- 51Thomas E. Y. NEOFAX. Thomson Reuters, 2011.
- 52Sanford JP. The sanford guide to antimicrobial therapy. Beijing: Peking Union Medical College Press; 2017.
- 53Periti P, Mazzei T, Mini E, Novelli A. Adverse effects of macrolide antibacterials. Drug Saf. 1993; 9(5): 346–364.
- 54Lenehan PJ, Schramm CM, Collins MS. An evaluation strategy for potential QTc prolongation with chronic azithromycin therapy in cystic fibrosis. J Cyst Fibros. 2016; 15(2): 192–195.
- 55Kuehn BM. Cardiovascular death risk linked to azithromycin use. JAMA. 2012; 307(22):2361.
- 56Moreno M, Espadas D, Castillo S, Moreno C, Martinez E, Escribano A. Longterm treatment with azithromycin is not associated with heart rhythm or QT interval disorders in children. Eur Respir J. 2014; 44: P807.
- 57Jie G, Yong-Fu H, Cheng X, Xiao-Xian Z. Supraventricular tachycardia in a child induced by intravenous infusion of azithromycin. Adver Drug Reac J. 2014; 16(02): 125–126.
- 58Benn K, Salman S, Page-Sharp M, Davis T, Buttery JP. Bradycardia and Hypothermia complicating azithromycin treatment. Am J Case Rep. 2017; 18: 883–886.
- 59Xu L, Zhu Y, Yu J, Deng M, Zhu X. Nursing care of a boy seriously infected with Steven-Johnson syndrome after treatment with azithromycin: a case report and literature review. Medicine (Baltimore). 2018; 97(1):e9112.
- 60Nappe TM, Goren-Garcia SL, Jacoby JL. Stevens-Johnson syndrome after treatment with azithromycin: an uncommon culprit. Am J Emerg Med. 2016; 34(3): 671–676.
- 61Ruuskanen O. Safety and tolerability of azithromycin in pediatric infectious diseases: 2003 update. Pediatr Infect Dis J. 2004; 23(2 Suppl): S135–S139.
- 62Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J. 2015; 8(1): 32.
- 63Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014; 69(8): 1026–1045.
- 64Ferrajolo C, Verhamme KM, Trifiro G, et al. Antibiotic-induced liver Injury in paediatric outpatients: a case-control study in primary care databases. Drug Saf. 2017; 40(4): 305–315.
- 65Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015; 148(7): 1340–1352.
- 66Hoffler D, Koeppe P, Paeske B. Pharmacokinetics of azithromycin in normal and impaired renal function. Infection. 1995; 23(6): 356–361.
- 67Singlas E. Clinical pharmacokinetics of azithromycin. Pathol Biol (Paris). 1995; 43(6): 505–511.
- 68Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012; 366(20): 1881–1890.
- 69Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004; 350(10): 1013–1022.
- 70Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003; 289(16): 2120–2127.
- 71Trinkley KE, Page RN, Lien H, Yamanouye K, Tisdale JE. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin. 2013; 29(12): 1719–1726.
- 72Gade C, Christensen HR, Dalhoff KP, Holm JC, Holst H. Inconsistencies in dosage practice in children with overweight or obesity: a retrospective cohort study. Pharmacol Res Perspect. 2018; 6(3): e398.
- 73Balan S, Hassali MA, Mak VS. Awareness, knowledge and views of off-label prescribing in children: a systematic review. Br J Clin Pharmacol. 2015; 80(6): 1269–1280.
- 74Frattarelli DA, Galinkin JL, Green TP, et al. Off-label use of drugs in children. Pediatrics. 2014; 133(3): 563–567.
- 75Chen Y, Wang C, Shang H, Yang K, Norris SL. Clinical practice guidelines in China. BMJ. 2018; 360:j5158.
- 76Abdellatif M, Ghozy S, Kamel MG, et al. Association between exposure to macrolides and the development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis. Eur J Pediatr. 2019; 178(3): 301–314.
- 77Morrison W. Infantile hypertrophic pyloric stenosis in infants treated with azithromycin. Pediatr Infect Dis J. 2007; 26(2): 186–188.
- 78Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics. 2015; 135(3): 483–488.
- 79Chen J. Pediatric clinical practice guidelines in China: still a long way to go. World J Pediatr. 2018; 14(5): 417–418.
