The Association Between Seizures and Quinolone Antibiotics in Children: a Systematic Review of Adverse Events (Online Supplementary File)

The Association Between Seizures and Quinolone Antibiotics in Children: A Systematic Review of Adverse Events (Online Supplementary File)

Search Strategy

CENTRAL search strategy "quinolones":ti,ab,kw or "quinolone":ti,ab,kw or "ciprofloxacin":ti,ab,kw or "levofloxacin":ti,ab,kw (Word variations have been searched) AND "safety":ti,ab,kw or "adverse effect":ti,ab,kw or "adverse drug effect":ti,ab,kw or "adverse drug reaction":ti,ab,kw (Word variations have been searched) AND "pediatric":ti,ab,kw or "paediatric":ti,ab,kw or "infant":ti,ab,kw or "baby":ti,ab,kw or "neonate":ti,ab,kw (Word variations have been searched) EMBASE search strategy "(exp *CIPROFLOXACIN/ OR exp *OFLOXACIN/ OR exp *LEVOFLOXACIN/ OR exp *GATIFLOXACIN/ OR exp *MOXIFLOXACIN/) AND (exp *INFANT/ OR (exp *JUVENILE/ OR exp *CHILD/) OR exp *"PRESCHOOL CHILD"/ OR exp *ADOLESCENT/)"

MEDLINE search strategy "(exp *CIPROFLOXACIN/ OR exp *OFLOXACIN/ OR exp *LEVOFLOXACIN/ OR exp *GATIFLOXACIN/ OR exp *MOXIFLOXACIN/) AND (exp *INFANT/ OR (exp *JUVENILE/ OR exp *CHILD/) OR exp *"PRESCHOOL CHILD"/ OR exp *ADOLESCENT/)"

PUBMED search strategy ("adverse effects"[All Fields] OR "safety"[All Fields]) AND (((((((child[Title/Abstract] OR children[Title/Abstract]) OR infant[Title/Abstract]) OR pediatric[Title/Abstract]) OR paediatric[Title/Abstract]) OR pediatrics[Title/Abstract]) OR paediatrics[Title/Abstract]) AND ((("quinolones"[Title/Abstract] OR "fluroquinolones"[Title/Abstract]) OR "ciprofloxacin"[Title/Abstract]) OR "levofloxacin"[Title/Abstract]))

List of References for Studies Included in Analysis 1. Abu-Arja RF, Gonzalez BE, Jacobs MR, et al. Disseminated Bacillus Calmette-Guerin (BCG) infection following allogeneic hematopoietic stem cell transplant in a patient with Bare Lymphocyte Syndrome type II. Transplant infectious disease : an official journal of the Transplantation Society. 2014;16(5):830-837. 2. Adler-Shohet FC, Low J, Carson M, Girma H, Singh J. Management of latent tuberculosis infection in child contacts of multidrug-resistant tuberculosis. The Pediatric infectious disease journal. 2014;33(6):664-666. 3. Ahmed AS, Khan NZ, Saha SK, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh: lack of effects on growth and development. The Pediatric infectious disease journal. 2006;25(12):1137-1141.

4. Alam M, Haq S, Das K, et al. Efficacy of ciprofloxacin in enteric fever: comparison of treatment duration in sensitive and multidrug-resistant Salmonella. The American journal of tropical medicine and hygiene. 1995;53(3):306-311. 5. Angel CA, Green J, Swischuk L, Patel J. Severe ciprofloxacin-associated pseudomembranous colitis in an eight-year-old child. J Pediatr Surg. 2004;39(10):1590-1592. 6. Aquino VM, Herrera L, Sandler ES, Buchanan GR. Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer. Cancer. 2000;88(7):1710-1714. 7. Arguedas A, Sher L, Lopez E, et al. Open label, multicenter study of gatifloxacin treatment of recurrent otitis media and acute otitis media treatment failure. The Pediatric infectious disease journal. 2003;22(11):949-955. 8. Arguedas A, Dagan R, Pichichero M, et al. An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media. The Pediatric infectious disease journal. 2006;25(12):1102-1109. 9. Arora R, Gupta A, Joshi N, Kataria V, Lall P, Anand A. Multidrug resistant typhoid fever: study of an outbreak in Calcutta. Cough. 1992;39:37.38. 10. Atasoy H, Erdem G, Ceyhan M, Ecevit Z, Kanra G. Hypertension associated with ciprofloxacin use in an infant. The Annals of pharmacotherapy. 1995;29(10):1049. 11. Bannon M, Stutchfield P, Weindling A, Damjanovic V. Ciprofloxacin in neonatal Enterobacter cloacae septicaemia. Archives of disease in childhood. 1989;64(10 Spec No):1388-1391. 12. Belet N, Haciömeroğlu P, Küçüködük Ş. Ciprofloxacin Treatment in Newborns with Multi- Drug-Resistant Nosocomial PseudomonasInfections. Neonatology. 2004;85(4):263-268. 13. Bendig J, Kyle P, Giangrande P, Samson D, Azadian B. Two neutropenic patients with multiple resistant Pseudomonas aeruginosa septicaemia treated with ciprofloxacin. Journal of the Royal Society of Medicine. 1987;80(5):316. 14. Bethell DB, Hien TT, Phi LT, et al. Effects on growth of single short courses of fluoroquinolones. Archives of disease in childhood. 1996;74(1):44-46. 15. Bhutta ZA, Farooqui BJ, Sturm AW. Eradication of a multiple drug resistant Salmonella paratyphi A causing meningitis with ciprofloxacin. Journal of Infection. 1992;25(2):215-219. 16. Black A, Redmond AO, Steen HJ, Oborska IT. Tolerance and safety of ciprofloxacin in paediatric patients. The Journal of antimicrobial chemotherapy. 1990;26 Suppl F:25-29. 17. Brack E, Bodmer N, Simon A, et al. First-day step-down to oral outpatient treatment versus continued standard treatment in children with cancer and low-risk fever in neutropenia. A randomized controlled trial within the multicenter SPOG 2003 FN study. Pediatric blood & cancer. 2012;59(3):423-430. 18. Bradley JS, Arguedas A, Blumer JL, Saez-Llorens X, Melkote R, Noel GJ. Comparative study of levofloxacin in the treatment of children with community-acquired pneumonia. The Pediatric infectious disease journal. 2007;26(10):868-878. 19. Brown N, Körner R, Zollman C, Martin R, Millar M. Ciprofloxacin treatment of bacterial endocarditis involving prosthetic material after cardiac surgery. Archives of disease in childhood. 1997;76(1):68-69. 20. Cannon PS, Mc Keag D, Radford R, Ataullah S, Leatherbarrow B. Our experience using primary oral antibiotics in the management of orbital cellulitis in a tertiary referral centre. Eye (London, England). 2009;23(3):612-615. 21. Chalumeau M, Tonnelier S, D’Athis P, et al. Pediatric Fluoroquinolone Safety Study Investigators: Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111(6 pt 1). 22. Chauny JV, Lorrot M, Prot-Labarthe S, et al. Treatment of tuberculosis with levofloxacin or moxifloxacin: report of 6 pediatric cases. The Pediatric infectious disease journal. 2012;31(12):1309-1311.

23. Chien S, Wells TG, Blumer JL, et al. Levofloxacin pharmacokinetics in children. Journal of clinical pharmacology. 2005;45(2):153-160. 24. Choeyprasert W, Hongeng S, Anurathapan U, Pakakasama S. Bacteremia during neutropenic episodes in children undergoing hematopoietic stem cell transplantation with ciprofloxacin and penicillin prophylaxis. International journal of hematology. 2017;105(2):213-220. 25. Chotigeat U, Khorana M, Waranawat N. Successful treatment of late onset infection due to multi-drug resistant Acinetobacter Lwoffii in a low birth weight neonate using ciprofloxacin. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2001;84(6):910- 913. 26. Church DA, Kanga JF, Kuhn RJ, et al. Sequential ciprofloxacin therapy in pediatric cystic fibrosis: comparative study vs. ceftazidime/tobramycin in the treatment of acute pulmonary exacerbations. The Cystic Fibrosis Study Group. The Pediatric infectious disease journal. 1997;16(1):97-105; discussion 123-106. 27. Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 1991;19(4):289-296. 28. Connett GJ, Pike KC, Legg JP, et al. Ciprofloxacin during upper respiratory tract infections to reduce Pseudomonas aeruginosa infection in paediatric cystic fibrosis: a pilot study. Therapeutic advances in respiratory disease. 2015;9(6):272-280. 29. Cuevas LE, Kazembe P, Mughogho GK, Tillotson GS, Hart CA. Eradication of nasopharyngeal carriage of Neisseria meningitidis in children and adults in rural Africa: a comparison of ciprofloxacin and rifampicin. The Journal of infectious diseases. 1995;171(3):728-731. 30. Dalle JH, Auvrignon A, Vassal G, Leverger G. Interaction between methotrexate and ciprofloxacin. Journal of pediatric hematology/oncology. 2002;24(4):321-322. 31. Davis H, McGoodwin E, Reed TG. Anaphylactoid reactions reported after treatment with ciprofloxacin. Annals of internal medicine. 1989;111(12):1041-1043. 32. Dey S. Nightmare due to ciprofloxacin in young patients. Indian pediatrics. 1995;32:918-918. 33. Doherty CP, Saha SK, Cutting WA. Typhoid fever, ciprofloxacin and growth in young children. Annals of tropical paediatrics. 2000;20(4):297-303. 34. Dolecek C, Tran TP, Nguyen NR, et al. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PloS one. 2008;3(5):e2188. 35. Drossou-Agakidou V, Roilides E, Papakyriakidou-Koliouska P, et al. Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year. The Pediatric infectious disease journal. 2004;23(4):346-349. 36. Dutta P, Rasaily R, Saha M, et al. Ciprofloxacin for treatment of severe typhoid fever in children. Antimicrobial agents and chemotherapy. 1993;37(5):1197-1199. 37. Dutta S, Chowdhary G, Kumar P, Mukhopadhay K, Narang A. Ciprofloxacin administration to very low birth weight babies has no effect on linear growth in infancy. Journal of tropical pediatrics. 2006;52(2):103-106. 38. Esposito S, Tagliabue C, Bosis S, Principi N. Levofloxacin for the treatment of Mycoplasma pneumoniae-associated meningoencephalitis in childhood. International journal of antimicrobial agents. 2011;37(5):472-475. 39. Garazzino S, Scolfaro C, Raffaldi I, Barbui AM, Luccoli L, Tovo PA. Moxifloxacin for the treatment of pulmonary tuberculosis in children: a single center experience. Pediatr Pulmonol. 2014;49(4):372-376. 40. Gendrel D, Raymond J, Legall MA, Bergeret M, Badoual J. Use of pefloxacin after failure of initial antibiotic treatment in children with severe salmonellosis. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 1993;12(3):209-211.

41. Ghosh G, Chakraborty S, Ray J, Mukherjee S. Parenteral ciprofloxacin in persistent diarrhoea in children. Journal of the Indian Medical Association. 1995;93(10):382, 384-382, 384. 42. Grady R. Safety profile of quinolone antibiotics in the pediatric population. The Pediatric infectious disease journal. 2003;22(12):1128-1132. 43. Green SD, Ilunga F, Cheesbrough JS, Tillotson GS, Hichens M, Felmingham D. The treatment of neonatal meningitis due to Gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid. Journal of Infection. 1993;26(3):253- 256. 44. Gupta A, Swaroop C, Agarwala S, Pandey RM, Bakhshi S. Randomized control trial comparing oral amoxicillin-clavulanate and ofloxacin with intravenous ceftriaxone and amikacin as outpatient therapy in pediatric low-risk febrile neutropenia. Journal of pediatric hematology/oncology. 2009;31(9):635-641. 45. Gürpinar A, Balkan E, Kilic N, Kiriştioǧlu I, Doǧruyol H. The effects of a fluoroquinolone on the growth and development of infants. Journal of international medical research. 1997;25(5):302-306. 46. Hacimustafaoğlu M, Cil E, Nacarküçük E. Unusual adverse effects of ciprofloxacin: purpuric eruptions and local venospasm. The Pediatric infectious disease journal. 1995;14(6):551-552. 47. Hafez HA, Yousif D, Abbassi M, Elborai Y, Elhaddad A. Prophylactic levofloxacin in pediatric neutropenic patients during autologous hematopoietic stem cell transplantation. Clinical transplantation. 2015;29(12):1112-1118. 48. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report. The Pediatric infectious disease journal. 1997;16(1):127-129; discussion 160-122. 49. Hata A, Honda Y, Asada K, Sasaki Y, Kenri T, Hata D. Mycoplasma hominis meningitis in a neonate: case report and review. Journal of Infection. 2008;57(4):338-343. 50. Hoppe J, Dopfer R, Huber S, Niethammer D. Eradication of Salmonella dublin in an immunodeficient child by combined use of ceftriaxone and ciprofloxacin after failure of either agent alone. Infection. 1989;17(6):399-400. 51. Hussey G, Kibel M, Parker N. Ciprofloxacin treatment of multiply drug-resistant extrapulmonary tuberculosis in a child. The Pediatric infectious disease journal. 1992;11(5):408-409. 52. Isaacs D, Slack M, Wilkinson A, Westwood A. Successful treatment of Pseudomonas ventriculitis with ciprofloxacin. Journal of Antimicrobial Chemotherapy. 1986;17(4):535-538. 53. Inaba H, Gaur AH, Cao X, et al. Feasibility, efficacy, and adverse effects of outpatient antibacterial prophylaxis in children with acute myeloid leukemia. Cancer. 2014;120(13):1985-1992. 54. Jawad A. Cystic fibrosis and drug-induced arthropathy. British journal of rheumatology. 1989;28(2):179-180. 55. Jick S. Ciprofloxacin safety in a pediatric population. The Pediatric infectious disease journal. 1997;16(1):130-133; discussion 133-134, 160-132. 56. Johansson A, Berglund L, Gothefors L, Sjostedt A, Tarnvik A. Ciprofloxacin for treatment of tularemia in children. The Pediatric infectious disease journal. 2000;19(5):449-453. 57. Karaaslan A, Cagan E, Kadayifci EK, et al. Intravenous Colistin Use for Multidrug-Resistant Gram-Negative Infections in Pediatric Patients. Balkan medical journal. 2016;33(6):627-632. 58. Karande S, Kshirsagar NA. Ciprofloxacin use: acute arthropathy and long-term follow up. Indian pediatrics. 1996;33(11):910-916. 59. Khan DM, Bhutta ZA. Ciprofloxacin in multi-resistant infections in childhood: an audit. JPMA The Journal of the Pakistan Medical Association. 1995;45(6):147-150. 60. Khaneja M, Naprawa J, Kumar A, Piecuch S. Successful treatment of late-onset infection due to resistant Klebsiella pneumoniae in an extremely low birth weight infant using ciprofloxacin. J Perinatol. 1999;19(4):311-314.

61. Knorr JP, Moshfeghi M, Sokoloski MC. Ciprofloxacin-induced Q-T interval prolongation. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2008;65(6):547-551. 62. Kuruvilla KA, James V, Subramani M, Mathew B. Adverse drug reactions associated with ciprofloxacin in neonates. Archives of disease in childhood. 2012;97. 63. van der Laan LE, Schaaf HS, Solomons R, et al. Probable Levofloxacin-associated Secondary Intracranial Hypertension in a Child With Multidrug-resistant Tuberculosis. The Pediatric infectious disease journal. 2016;35(6):706-708. 64. Lang R, Goshen S, Raas-Rothschild A, et al. Oral ciprofloxacin in the management of chronic suppurative otitis media without cholesteatoma in children: preliminary experience in 21 children. The Pediatric infectious disease journal. 1992;11(11):925-929. 65. Laoprasopwattana K, Khwanna T, Suwankeeree P, Sujjanunt T, Tunyapanit W, Chelae S. Ciprofloxacin reduces occurrence of fever in children with acute leukemia who develop neutropenia during chemotherapy. The Pediatric infectious disease journal. 2013;32(3):e94- 98. 66. Leibovitz E, Janco J, Piglansky L, et al. Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children. The Pediatric infectious disease journal. 2000;19(11):1060-1067. 67. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic and clinical efficacy of oral gatifloxacin for the treatment of recurrent/nonresponsive acute otitis media: an open label, noncomparative, double tympanocentesis study. The Pediatric infectious disease journal. 2003;22(11):943-949. 68. Lillquist YP, Cho E, Davidson AG. Economic effects of an eradication protocol for first appearance of Pseudomonas aeruginosa in cystic fibrosis patients: 1995 vs. 2009. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2011;10(3):175-180. 69. Lipman J, Gous AG, Mathivha LR, et al. Ciprofloxacin pharmacokinetic profiles in paediatric sepsis: how much ciprofloxacin is enough? Intensive care medicine. 2002;28(4):493-500. 70. Lo W-T, Wang C-C, Lee C-M, Chu M-L. Successful treatment of multi-resistant Stenotrophomonas maltophilia meningitis with ciprofloxacin in a pre-term infant. European journal of pediatrics. 2002;161(12):680-682. 71. Lolekha S, Vibulbandhitkit S, Poonyarit P. Response to antimicrobial therapy for shigellosis in Thailand. Reviews of infectious diseases. 1991;13 Suppl 4:S342-346. 72. Lotti T, Mirone V, Imbimbo C, Russo A. Ciprofloxacin in the treatment of urinary tract infections. Journal of international medical research. 1987;15(4):240-244. 73. Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible adverse effect on the teeth. The Pediatric infectious disease journal. 1991;10(8):619. 74. Malik I. Out-patient management of febrile neutropenia in indigent paediatric patients. Annals of the Academy of Medicine, Singapore. 1997;26(6):742-746. 75. Martell M, de Ben S, Weinberger M, Beltrami G. Growth and development in preterm infants receiving fluoroquinolones. Journal of Perinatal Medicine-Official Journal of the WAPM. 1996;24(3):287-291. 76. Mian AN, Farney AC, Mendley SR. Mycoplasma hominis septic arthritis in a pediatric renal transplant recipient: case report and review of the literature. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2005;5(1):183-188. 77. Miller MS, Pharm B, Gaido F, Rourk Jr MH, Spock A. Anaphylactoid reactions to ciprofloxacin in cystic fibrosis patients. The Pediatric infectious disease journal. 1991;10(2):164. 78. Mishra A, Mishra S, Jaganath G, Mittal RK, Gupta P, Patra D. Acinetobacter sepsis in newborns. Indian pediatrics. 1998;35:27-32.

79. Moffett BS, Rosenstein BJ, Mogayzel PJ, Jr. Ciprofloxacin-induced renal insufficiency in cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2003;2(3):152-154. 80. Moffett BS, Kim S, Bomgaars LR. Readmissions for warfarin-related bleeding in pediatric patients after hospital discharge. Pediatric blood & cancer. 2013;60(9):1503-1506. 81. Mullen CA, Petropoulos D, Rytting M, et al. Acute reversible arthropathy in a pediatric patient with cancer treated with a short course of ciprofloxacin for febrile neutropenia. Journal of pediatric hematology/oncology. 1998;20(5):516-517. 82. Mullen CA, Petropoulos D, Roberts WM, et al. Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Cancer. 1999;86(1):126-134. 83. Naccari F, Salpietro DC, De Sarro A, Masaracchio A, Barberi I. Tolerance and pharmacokinetics of ciprofloxacin in the chick. Preliminary experience in subjects of pediatric age with urinary tract infections (UTI). Research communications in molecular pathology and pharmacology. 1998;99(2):187-192. 84. Nallammai A, Vasundara K, Subramanian V. Comparison of efficacy and tolerability of ofloxacin and ceftriaxone in the management of acute enteric fever in children. Indian Journal of Pharmacology. 2013;45. 85. Noel GJ, Blumer JL, Pichichero ME, et al. A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media. The Pediatric infectious disease journal. 2008;27(6):483-489. 86. Noel GJ, Bradley JS, Kauffman RE, et al. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. The Pediatric infectious disease journal. 2007;26(10):879-891. 87. Nuutinen M, Turtinen J, Uhari M. Growth and joint symptoms in children treated with nalidixic acid. The Pediatric infectious disease journal. 1994;13(9):798-800. 88. Nydert P, Lindemalm S, Nemeth A. Off-label drug use evaluation in paediatrics--applied to ciprofloxacin when used as treatment of cholangitis. Pharmacoepidemiol Drug Saf. 2011;20(4):393-398. 89. Orenstein DM, Pattishall EN, Noyes BE, Kurland G, Hartigan ER, Yu VL. Safety of ciprofloxacin in children with cystic fibrosis. Clinical pediatrics. 1993;32(8):504-506. 90. Ozsurekci Y, Aykac K, Cengiz AB, et al. Is colistin effective in the treatment of infections caused by multidrug-resistant (MDR) or extremely drug-resistant (XDR) gram-negative microorganisms in children? Diagnostic microbiology and infectious disease. 2016;85(2):233- 238. 91. Paganini H, Rodriguez-Brieshcke T, Zubizarreta P, et al. Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia. Cancer. 2001;91(8):1563-1567. 92. Paganini H, Gomez S, Ruvinsky S, et al. Outpatient, sequential, parenteral-oral antibiotic therapy for lower risk febrile neutropenia in children with malignant disease: a single-center, randomized, controlled trial in Argentina. Cancer. 2003;97(7):1775-1780. 93. Pandit A, Arjyal A, Day JN, et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PloS one. 2007;2(6):e542. 94. Park JR, Coughlin J, Hawkins D, Friedman DL, Burns JL, Pendergrass T. Ciprofloxacin and amoxicillin as continuation treatment of febrile neutropenia in pediatric cancer patients. Pediatric blood & cancer. 2003;40(2):93-98. 95. Parry CM, Ho VA, Bay PVB, et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug- resistant and nalidixic acid-resistant typhoid fever. Antimicrobial agents and chemotherapy. 2007;51(3):819-825. 96. Peltola H, Ukkonen P, Saxen H, Stass H. Single-dose and steady-state pharmacokinetics of a new oral suspension of ciprofloxacin in children. Pediatrics. 1998;101(4 Pt 1):658-662.

97. Petrilli AS, Dantas LS, Campos MC, Tanaka C, Ginani VC, Seber A. Oral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: randomized prospective trial. Medical and pediatric oncology. 2000;34(2):87-91. 98. Petrilli A, Altruda Carlesse F, Alberto Pires Pereira C. Oral gatifloxacin in the outpatient treatment of children with cancer fever and neutropenia. Pediatric blood & cancer. 2007;49(5):682-686. 99. Phuong CXT, Kneen R, Anh NT, et al. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Pediatric infectious disease journal. 1999;18(3):245-248. 100. Pillay T, Pillay D, Adhikari M, Pillay A, Sturm A. An outbreak of neonatal infection with Acinetobacter linked to contaminated suction catheters. Journal of Hospital Infection. 1999;43(4):299-304. 101. Pradhan KM, Arora NK, Jena A, Susheela AK, Bhan MK. Safety of ciprofloxacin therapy in children: magnetic resonance images, body fluid levels of fluoride and linear growth. Acta paediatrica (Oslo, Norway : 1992). 1995;84(5):555-560. 102. Redmond A, Sweeney L, MacFarland M, Mitchell M, Daggett S, Kubin R. Oral ciprofloxacin in the treatment of pseudomonas exacerbations of paediatric cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance image scanning. The Journal of international medical research. 1998;26(6):304-312. 103. Redmond AO. Risk-benefit experience of ciprofloxacin use in pediatric patients in the United Kingdom. The Pediatric infectious disease journal. 1997;16(1):147-149; discussion 160-142. 104. Rfidah EI, Findlay CA, Beattie TJ. Reversible encephalopathy after intravenous ciprofloxacin therapy. Pediatric Nephrology. 1995;9(2):250-251. 105. Richard DA, Nousia-Arvanitakis S, Sollich V, Hampel BJ, Sommerauer B, Schaad UB. Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic Fibrosis Study Group. The Pediatric infectious disease journal. 1997;16(6):572-578. 106. Rizvi Q. Effectiveness of anti-typhoid drugs currently used in Pakistan. Pakistan J Surg. 2007;23:57-64. 107. Rubio TT. Ciprofloxacin in the treatment of Pseudomonas infection in children with cystic fibrosis. Diagnostic microbiology and infectious disease. 1990;13(2):153-155. 108. Rubio TT, Miles MV, Lettieri JT, Kuhn RJ, Echols RM, Church DA. Pharmacokinetic disposition of sequential intravenous/oral ciprofloxacin in pediatric cystic fibrosis patients with acute pulmonary exacerbation. The Pediatric infectious disease journal. 1997;16(1):112-117; discussion 123-116. 109. Saez-Llorens X, Mccoig C, Feris JM, et al. Quinolone treatment for pediatric bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin. The Pediatric infectious disease journal. 2002;21(1):14-22. 110. Sáez-Llorens X, Rodriguez A, Arguedas A, et al. Randomized, investigator-blinded, multicenter study of gatifloxacin versus amoxicillin/clavulanate treatment of recurrent and nonresponsive otitis media in children. The Pediatric infectious disease journal. 2005;24(4):293-300. 111. Saha D, Khan WA, Karim MM, Chowdhury HR, Salam MA, Bennish ML. Single-dose ciprofloxacin versus 12-dose erythromycin for childhood cholera: a randomised controlled trial. The Lancet. 2005;366(9491):1085-1093. 112. Salam MA, Dhar U, Khan WA, Bennish ML. Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis. Lancet (London, England). 1998;352(9127):522-527.

113. Sarkar S, Singh M, Narang A. Successful treatment of hospital acquired Klebsiella pneumoniae meningitis in a neonate with ciprofloxacin. 1993. 114. Sato M, Kubota N, Katsuyama Y, et al. Case report of a 6-year-old girl with Mycoplasma hominis ventriculoperitoneal shunt infection. J Neurosurg Pediatr. 2017;19(5):620-624. 115. Schaad U, Wedgwood-Krucko J, Guenin K, Buehlmann U, Kraemer R. Antipseudomonal therapy in cystic fibrosis: aztreonam and amikacin versus ceftazidime and amikacin administered intravenously followed by oral ciprofloxacin. European Journal of Clinical Microbiology and Infectious Diseases. 1989;8(10):858-865. 116. Schaad UB, Stoupis C, Wedgwood J, Tschaeppeler H, Vock P. Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. The Pediatric infectious disease journal. 1991;10(10):723-729. 117. Schaad UB, Wedgwood J, Ruedeberg A, Kraemer R, Hampel B. Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis. The Pediatric infectious disease journal. 1997;16(1):106-111; discussion 123-106. 118. Sen S, Goyal R, Dev R. Ciprofloxacin in the management of multiple drug resistant typhoid fever. Indian pediatrics. 1991;28(4):417-419. 119. Sideri G, Kafetzis DA, Vouloumanou EK, Papadatos JH, Papadimitriou M, Falagas ME. Ciprofloxacin in critically ill children. Anaesthesia and intensive care. 2011;39(4):635-639. 120. Simpson J, Watson A, Mellersh A, Nelson C, Dodd K. Typhoid fever, ciprofloxacin, and renal failure. Archives of disease in childhood. 1991;66(9):1083. 121. Singh UK, Sinha RK, Prasad B, Chakrabarti B, Sharma SK. Ciprofloxacin in children: is arthropathy a limitation? Indian journal of pediatrics. 2000;67(5):386-387. 122. Taccetti G, Bianchini E, Cariani L, et al. Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study comparing two different protocols. Thorax. 2012:thoraxjnl-2011-200832. 123. Thee S, Garcia-Prats AJ, Draper HR, et al. Pharmacokinetics and safety of moxifloxacin in children with multidrug-resistant tuberculosis. Clinical Infectious Diseases. 2015;60(4):549- 556. 124. Thomsen LL, Paerregaard A. Treatment with ciprofloxacin in children with typhoid fever. Scandinavian journal of infectious diseases. 1998;30(4):355-357. 125. Tramper-Stranders GA, Wolfs TF, van Haren Noman S, et al. Controlled trial of cycled antibiotic prophylaxis to prevent initial Pseudomonas aeruginosa infection in children with cystic fibrosis. Thorax. 2010;65(10):915-920. 126. Trautmann M, Held T, Ruhnke M, Schnoy N. A case of rhinoscleroma cured with ciprofloxacin. Infection. 1993;21(6):403-406. 127. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Archives of pediatrics & adolescent medicine. 2011;165(9):847-856. 128. Uppal R, Jhaj R, Malhotra S. Adverse drug reactions to fluoroquinolones at a tertiary care hospital in northern India. The Journal of the Association of Physicians of India. 1998;46(11):946-947. 129. Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. The Lancet. 1991;338(8769):725-726. 130. van den Oever HL, Versteegh FG, Thewessen EA, van den Anker JN, Mouton JW, Neijens HJ. Ciprofloxacin in preterm neonates: case report and review of the literature. European journal of pediatrics. 1998;157(10):843-845. 131. Vinh H, Anh VT, Anh ND, et al. A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children. PLoS neglected tropical diseases. 2011;5(8):e1264.

132. Winrow A, Supramaniam G. Benign intracranial hypertension after ciprofloxacin administration. Archives of disease in childhood. 1990;65(10):1165-1166. 133. Wlazlowski J, Krzyzanska-Oberbek A, Sikora JP, Chlebna-Sokol D. Use of the quinolones in treatment of severe bacterial infections in premature infants. Acta poloniae pharmaceutica. 2000;57 Suppl:28-31. 134. Workman MR, Price EH, Bullock P. Salmonella meningitis and multiple cerebral abscesses in an infant. International journal of antimicrobial agents. 1999;13(2):131-132. 135. Yeh TC, Liu HC, Hou JY, et al. Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer. 2014;120(8):1255-1262. 136. Yildirim P. Association patterns in open data to explore ciprofloxacin adverse events. Applied clinical informatics. 2015;6(04):728-747. 137. Yousef AA, Fryer CJ, Chedid FD, Abbas AA, Felimban SK, Khattab TM. A pilot study of prophylactic ciprofloxacin during delayed intensification in children with acute lymphoblastic leukemia. Pediatric blood & cancer. 2004;43(6):637-643. 138. Zaman RA, Ettenger RB, Cheam H, Malekzadeh MH, Tsai EW. A novel treatment regimen for BK viremia. Transplantation. 2014;97(11):1166-1171. 139. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. The Pediatric infectious disease journal. 2002;21(12):1136-1141. 140. Zhao W, Hill H, Le Guellec C, et al. Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age. Fundamental and Clinical Pharmacology. 2015;29:22.

Studies Excluded Following Review of Full Text Excluded References Reasons for Exclusion A reappraisal of quinolone tolerability. The experience of their musculoskeletal adverse effects 1

Review article Adverse reactions and interactions of fluoroquinolones 2

Non-English Language Antibiotics in the management of shigellosis in children: what role for the quinolones? 3

Review article Clinical features and management of adverse effects of quinolone antibacterials 4

Review article Clinical toxicological aspects of fluoroquinolones 5

Review article Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis 6

Inhaled

Eradication of early Pseudomonas aeruginosa infection 7

Review article Fluoroquinolone toxicity profiles: a review focusing on newer agents 8

Review article Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) 9

Review article Fluoroquinolones in the treatment of cystic fibrosis 10

Review article Fluoroquinolones. Adverse reactions during clinical trials and postmarketing surveillance 11

Review article National Institute for Health and Clinical Excellence: Guidance 12

Review article Outpatient parenteral antibiotic therapy for bone and joint infections: an italian multicenter study 13

not able to separate data from children Quinolone arthropathy in animals versus children 14

Review article Safety profile of the fluoroquinolones: focus on levofloxacin

Review article Safety profile of the quinolones 15

Review article Side-effects of quinolones: comparisons between quinolones and other antibiotics 16

Review article Single-agent, broad-spectrum fluoroquinolones 17for the outpatient treatment of low-risk febrile neutropenia

Review article Quinolones in the pediatric patient 18

Review article The use of quinolones in pediatric patients 19

Review article Ciprolfloxacin: The current status in pediatric practice 20

Review article Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care 21

Not administered quinolones Adverse drug reaction monitoring of ciprofloxacin in pediatric practice 22

Duplicate Data

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis 23

Review article Antibiotics for preventing lower respiratory tract infections in high-risk children aged 12 years and under 24

Review article Appropriate use of fluoroquinolones in children 25

Review article Assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin 26

Duplicate Data Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk? 27

Review Article Ciprofloxacin in treatment of fever and neutropenia in pediatric cancer patients 28

Review Article Ciprofloxacin in typhoid fever 29 Duplicate Data Ciprofloxacin safety in paediatrics: a systematic review 30

Review Article Clinical use of fluoroquinolones in children 31 Review Article Comparative tolerability of the newer fluoroquinolone antibacterials 32

Review Article Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs 33

Quinolones not administered Critical risk/benefit analysis of pefloxacine use in children under 15 years--the problem of arthralgias 34 Review Article Dangers of empiric oral ciprofloxacin in the treatment of acute inflammatory diarrhea in children 35

Review Article Dramatic decrease in fluoroquinolones in the pediatric population in Korea 36

No reporting of AEs Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study' 37

Duplicate Data Fluoroquinolone antibiotics. Microbiology, pharmacokinetics and clinical use 38

Review article Fluoroquinolone toxicities. An update 39 Review article Fluoroquinolones for the treatment of tuberculosis in children 40

Review article

Fluoroquinolones in children with fever and neutropenia: a systematic review of prospective trials 41

Review article Fluoroquinolones in children: poorly defined risk of joint damage 42

Review article Fluoroquinolones in children: update of the literature 43 Review article Fluoroquinolones in paediatrics 25 Review article Fluoroquinolones in paediatrics: a risk for the patient or for the community? 44

Review article Fluoroquinolones in pediatrics: review of hospital prescription use over 2 years 45

No AE reporting Fluoroquinolones in the treatment of cystic fibrosis: a critical appraisal 46

Review article Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomized controlled trial47

Data for children not reported separately Gram-negative bacteraemia (GNB) after 428 unrelated donor bone marrow transplants (UD-BMT): risk factors, prophylaxis, therapy and outcome 48

No AE reporting Invasive pneumococcal infection and drug-resistant Streptococcus pneumoniae in Thai children 49

No AE reporting Management of infection in children with bone marrow failure 50

Review article Overview of fluoroquinolone 51safety Review article Pediatric use of quinolones 52 Review Article Pediatric uses of fluoroquinolone antibiotics 53

Review article Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns 54

Review article Pharmacodynamically Guided Levofloxacin Dosing for Pediatric Community-Acquired Pneumonia 55

Not administered quinolones

Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: A randomized, multicenter, double-blind trial 56

Not administered quinolones (line locks only) Quinolone use in the developing world 57: state of the art

Review article Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data 58

Review article Quinolones in children. Are concerns over arthropathy justified? 59

Review article Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery 60

Intratympanic Review of ciprofloxacin use in children 61

Review article Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones 62

Review article Risk of medication error administering ciprofloxacin oral suspension in children 63

Describing administration error not AE Risk-benefit experience of ciprofloxacin use in pediatric patients in the United Kingdom 64

Review article Risks associated with the therapeutic use of fluoroquinolones 65

Review article Role of the new quinolones in pediatric practice 66

Review article Safety and efficacy of ciprofloxacin in paediatric patients--review 67

Review article Safety profile of quinolone antibiotics in the pediatric population 68

Review article

Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis 69

No AE reporting Symposium on antimicrobial agents. The 70quinolones

Review article Systemic quinolone antibiotics in children: a review of the use and safety 71

Review article The use of systemic fluoroquinolones 72

Review article Toxicity of quinolones 73

Review article Trovafloxacin: a new fluoroquinolone 74

Review article Use of ciprofloxacin in developing countries 75

Review article Use of quinolones in pediatric patients 76

Review article Use of quinolones in pediatrics 77

Review article Use of the new quinolones in pediatrics 78 Review article Safety of ciprofloxacin in neonates with 79sepsis.

Review article Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight 80newborns with severe infections. Not administered quinolones Pharmacokinetics of moxifloxacin in an infant with mycoplasma hominis meningitis 81

No AE reporting Therapeutic drug monitoring of levofloxacin in an obese adolescent with intra-abdominal infection 82

No AE reporting A randomized double-blind, placebo controlled trial of ciprofloxacin in the treatment of upper respiratory tract infections in children with cystic fibrosis 83 No AE reporting European network on evaluation of anti-infective agents for the treatment of preterm and term neonates 84 Duplicate Data Population pharmacokinetics of levofloxacin in children treated for, or exposed to, multidrug resistant tuberculosis in the federated states of micronesia and republic of Marshall Islands 85 No AE reporting Efficacy of prophylactic oral levofloxacin in preventing infection during high dose methotrexate chemotherapy of acute lymphoblastic leukemia in children 86 No AE reporting Pharmacokinetics studies of levofloxacin in children treated for, or exposed to, multidrug-resistant tuberculosis-united states affiliated pacific islands,2010-2011 87 No AE reporting Enteric fever in Cambodian children is dominated by multidrug resistant H58 Salmonella enterica serovar Typhi with decreased susceptibility to ciprofloxacin 88 No AE reporting

Levofloxacin pharmacokinetics (PK) after administration of MP-376 (Levofloxacin inhalation solution; Aeroquin) in children with cystic fibrosis (CF) 89 Inhalation

1. Hayem G, Carbon C. A reappraisal of quinolone tolerability. The experience of their musculoskeletal adverse effects. Drug safety 1995; 13(6): 338-42. 2. Ball P. Adverse reactions and interactions of fluoroquinolones. Clinical and investigative medicine Medecine clinique et experimentale 1989; 12(1): 28-34. 3. Fontaine O. Antibiotics in the management of shigellosis in children: what role for the quinolones? Reviews of infectious diseases 1989; 11 Suppl 5: S1145-50. 4. Paton JH, Reeves DS. Clinical features and management of adverse effects of quinolone antibacterials. Drug safety 1991; 6(1): 8-27. 5. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicology letters 2002; 127(1-3): 269-77. 6. Stockmann C, Sherwin CM, Ampofo K, Spigarelli MG. Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis. Therapeutic advances in respiratory disease 2014; 8(1): 13-21. 7. Hoiby N, Frederiksen B, Pressler T. Eradication of early Pseudomonas aeruginosa infection. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2005; 4 Suppl 2: 49- 54. 8. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1999; 28(2): 352-64. 9. Effa EE, Lassi ZS, Critchley JA, et al. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev 2011; (10): Cd004530. 10. Høiby N, Pedersen S, Jensen T, Valerius N, Koch C. Fluoroquinolones in the treatment of cystic fibrosis. Drugs 1993; 45(3): 98-101. 11. Janknegt R. Fluoroquinolones. Adverse reactions during clinical trials and postmarketing surveillance. Pharmaceutisch weekblad Scientific edition 1989; 11(4): 124-7. 12. National Clinical Guideline C. National Institute for Health and Clinical Excellence: Guidance. Drug Allergy: Diagnosis and Management of Drug Allergy in Adults, Children and Young People. London: National Institute for Health and Care Excellence (UK) Copyright (c) National Clinical Guideline Centre, 2014.; 2014. 13. Esposito S, Leone S, Noviello S, et al. Outpatient parenteral antibiotic therapy for bone and joint infections: an italian multicenter study. Journal of chemotherapy (Florence, Italy) 2007; 19(4): 417-22. 14. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1997; 25(5): 1196-204. 15. Stahlmann R. Safety profile of the quinolones. The Journal of antimicrobial chemotherapy 1990; 26 Suppl D: 31-44. 16. Norrby SR. Side-effects of quinolones: comparisons between quinolones and other antibiotics. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 1991; 10(4): 378-83. 17. Cooper MR, Durand CR, Beaulac MT, Steinberg M. Single-agent, broad-spectrum fluoroquinolones for the outpatient treatment of low-risk febrile neutropenia. The Annals of pharmacotherapy 2011; 45(9): 1094-102. 18. Poole MD. Quinolones in the pediatric patient. Ear, nose, & throat journal 1993; 72(2): 162. 19. Bender WJ. The use of quinolones in pediatric patients. South Dakota journal of medicine 1999; 52(9): 351-2.

20. Gulati S, Marwaha RK. Ciprolfloxacin: The current status in pediatric practice [1]. Indian pediatrics 1991; 28(12): 1530-1. 21. Novak PH, Ekins-Daukes S, Simpson CR, Milne RM, Helms P, McLay JS. Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care. British journal of clinical pharmacology 2005; 59(6): 712-7. 22. Karande SC, Kshirsagar NA. Adverse drug reaction monitoring of ciprofloxacin in pediatric practice. Indian pediatrics 1992; 29(2): 181-8. 23. Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2017; 4: Cd004197. 24. Onakpoya IJ, Hayward G, Heneghan CJ. Antibiotics for preventing lower respiratory tract infections in high-risk children aged 12 years and under. Cochrane Database Syst Rev 2015; (9): Cd011530. 25. Principi N, Esposito S. Appropriate use of fluoroquinolones in children. International journal of antimicrobial agents 2015; 45(4): 341-6. 26. Bradley JS, Kauffman RE, Balis DA, et al. Assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin. Pediatrics 2014; 134(1): e146-53. 27. Burstein GR, Berman SM, Blumer JL, Moran JS. Ciprofloxacin for the treatment of uncomplicated gonorrhea infection in adolescents: does the benefit outweigh the risk? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2002; 35(Suppl 2): S191-9. 28. Mullen CA. Ciprofloxacin in treatment of fever and neutropenia in pediatric cancer patients. The Pediatric infectious disease journal 2003; 22(12): 1138-42. 29. Bavdekar A, Chaudhari M, Bhave S, Pandit A. Ciprofloxacin in typhoid fever. Indian journal of pediatrics 1991; 58(3): 335-9. 30. Adefurin A, Sammons H, Jacqz-Aigrain E, Choonara I. Ciprofloxacin safety in paediatrics: a systematic review. Archives of disease in childhood 2011; 96(9): 874-80. 31. Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. The Annals of pharmacotherapy 2000; 34(3): 347-59; quiz 413-4. 32. Ball P, Mandell L, Niki Y, Tillotson G. Comparative tolerability of the newer fluoroquinolone antibacterials. Drug safety 1999; 21(5): 407-21. 33. Gandhi SV, Rodriguez W, Khan M, Polli JE. Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs. AAPS PharmSciTech 2014; 15(3): 601-11. 34. Chevais M, Reinert P, Rondeau MC, et al. Critical risk/benefit analysis of pefloxacine use in children under 15 years--the problem of arthralgias. International journal of clinical pharmacology, therapy, and toxicology 1987; 25(6): 306-9. 35. Acheson DW, Sears CL. Dangers of empiric oral ciprofloxacin in the treatment of acute inflammatory diarrhea in children. The Pediatric infectious disease journal 2001; 20(8): 817-8. 36. Shin JY, Kim MH, Shin SM, Lee SH, Park BJ. Dramatic decrease in fluoroquinolones in the pediatric population in Korea. Pharmacoepidemiol Drug Saf 2014; 23(12): 1320-4. 37. Treggiari MM, Rosenfeld M, Mayer-Hamblett N, et al. Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'. Contemporary clinical trials 2009; 30(3): 256-68. 38. Paton JH, Reeves DS. Fluoroquinolone antibiotics. Microbiology, pharmacokinetics and clinical use. Drugs 1988; 36(2): 193-228. 39. Lietman PS. Fluoroquinolone toxicities. An update. Drugs 1995; 49 Suppl 2: 159-63. 40. Thee S, Garcia-Prats AJ, Donald PR, Hesseling AC, Schaaf HS. Fluoroquinolones for the treatment of tuberculosis in children. Tuberculosis (Edinburgh, Scotland) 2015; 95(3): 229-45. 41. Sung L, Manji A, Beyene J, et al. Fluoroquinolones in children with fever and neutropenia: a systematic review of prospective trials. The Pediatric infectious disease journal 2012; 31(5): 431-5. 42. Fluoroquinolones in children: poorly defined risk of joint damage. Prescrire international 2004; 13(73): 184-6.

43. Bacci C, Galli L, de Martino M, Chiappini E. Fluoroquinolones in children: update of the literature. Journal of chemotherapy (Florence, Italy) 2015; 27(5): 257-65. 44. Gendrel D, Chalumeau M, Moulin F, Raymond J. Fluoroquinolones in paediatrics: a risk for the patient or for the community? The Lancet Infectious diseases 2003; 3(9): 537-46. 45. Genuini M, Prot-Labarthe S, Bourdon O, et al. Fluoroquinolones in pediatrics: review of hospital prescription use over 2 years. International journal of clinical pharmacology and therapeutics 2014; 52(11): 940-7. 46. LeBel M. Fluoroquinolones in the treatment of cystic fibrosis: a critical appraisal. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 1991; 10(4): 316-24. 47. Arjyal A, Basnyat B, Nhan HT, et al. Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial. The Lancet Infectious diseases 2016; 16(5): 535-45. 48. Mitchell AE, Derrington P, Turner P, Hunt LP, Oakhill A, Marks DI. Gram-negative bacteraemia (GNB) after 428 unrelated donor bone marrow transplants (UD-BMT): risk factors, prophylaxis, therapy and outcome. Bone marrow transplantation 2004; 33(3): 303-10. 49. Pancharoen C, Chongthaleong A, Reinprayoon S, Thisyakorn U. Invasive pneumococcal infection and drug-resistant Streptococcus pneumoniae in Thai children. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 2001; 84(9): 1246-50. 50. Hann IM. Management of infection in children with bone marrow failure. Bailliere's best practice & research Clinical haematology 2000; 13(3): 441-56. 51. Wolfson JS, Hooper DC. Overview of fluoroquinolone safety. The American journal of medicine 1991; 91(6a): 153s-61s. 52. Schaad UB. Pediatric use of quinolones. The Pediatric infectious disease journal 1999; 18(5): 469-70. 53. Murray TS, Baltimore RS. Pediatric uses of fluoroquinolone antibiotics. Pediatric annals 2007; 36(6): 336-42. 54. Gao CH, Yu LS, Zeng S, Huang YW, Zhou Q. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns. Therapeutics and clinical risk management 2014; 10: 217-27. 55. Courter JD, Nichols KR, Kazazian C, Girotto JE. Pharmacodynamically Guided Levofloxacin Dosing for Pediatric Community-Acquired Pneumonia. Journal of the Pediatric Infectious Diseases Society 2017; 6(2): 118-22. 56. Henrickson KJ, Axtell RA, Hoover SM, et al. Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: A randomized, multicenter, double-blind trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2000; 18(6): 1269-78. 57. Tupasi TE. Quinolone use in the developing world: state of the art. Drugs 1999; 58 Suppl 2: 55-9. 58. Sendzik J, Lode H, Stahlmann R. Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data. International journal of antimicrobial agents 2009; 33(3): 194-200. 59. Stahlmann R, Forster C, Van Sickle D. Quinolones in children. Are concerns over arthropathy justified? Drug safety 1993; 9(6): 397-403. 60. Mair EA, Moss JR, Dohar JE, Antonelli PJ, Bear M, LeBel C. Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery. The Annals of otology, rhinology, and laryngology 2016; 125(2): 105-14. 61. Okoye NV, Oyawole MR, Uzochukwu PU, Oyetunde OO. Review of ciprofloxacin use in children. Nigerian quarterly journal of hospital medicine 2013; 23(1): 43-7. 62. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. The Pediatric infectious disease journal 1997; 16(1): 118-22; discussion 23-6.

63. Lajoinie A, Valla FV, Kassai B. Risk of medication error administering ciprofloxacin oral suspension in children. European journal of clinical pharmacology 2015; 71(6): 769-70. 64. Redmond AO. Risk-benefit experience of ciprofloxacin use in pediatric patients in the United Kingdom. The Pediatric infectious disease journal 1997; 16(1): 147-9; discussion 60-2. 65. Stahlmann R, Lode HM. Risks associated with the therapeutic use of fluoroquinolones. Expert opinion on drug safety 2013; 12(4): 497-505. 66. Schaad UB. Role of the new quinolones in pediatric practice. The Pediatric infectious disease journal 1992; 11(12): 1043-6. 67. Kubin R. Safety and efficacy of ciprofloxacin in paediatric patients--review. Infection 1993; 21(6): 413-21. 68. Grady R. Safety profile of quinolone antibiotics in the pediatric population. The Pediatric infectious disease journal 2003; 22(12): 1128-32. 69. Yeh TC, Liu HC, Hou JY, et al. Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer 2014; 120(8): 1255-62. 70. Walker RC, Wright AJ. Symposium on antimicrobial agents. The quinolones. Mayo Clinic proceedings 1987; 62(11): 1007-12. 71. Grady RW. Systemic quinolone antibiotics in children: a review of the use and safety. Expert opinion on drug safety 2005; 4(4): 623-30. 72. The use of systemic fluoroquinolones. Pediatrics 2006; 118(3): 1287-92. 73. Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999; 58 Suppl 2: 37-42. 74. Alghasham AA, Nahata MC. Trovafloxacin: a new fluoroquinolone. The Annals of pharmacotherapy 1999; 33(1): 48-60. 75. Green S, Tillotson G. Use of ciprofloxacin in developing countries. The Pediatric infectious disease journal 1997; 16(1): 150-9; discussion 60-2. 76. Adam D. Use of quinolones in pediatric patients. Reviews of infectious diseases 1989; 11 Suppl 5: S1113-6. 77. Schaad UB. Use of the quinolones in paediatrics. Drugs 1993; 45 Suppl 3: 37-41. 78. Schaad UB. Use of the new quinolones in pediatrics. Israel journal of medical sciences 1994; 30(5-6): 463-8. 79. Bonati M, Pandolfini C, Kaguelidou F, Jacqz-Aigrain E, Turner M, Choonara I. Safety of ciprofloxacin in neonates with sepsis. Adverse Drug Reaction Bulletin 2010; (265): 1019-22. 80. Pandolfini C, Kaguelidou F, Sequi M, et al. Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight newborns with severe infections. European journal of clinical pharmacology 2013; 69(4): 1031-6. 81. Watt KM, Massaro MM, Smith B, Cohen-Wolkowiez M, Benjamin Jr DK, Laughon MM. Pharmacokinetics of moxifloxacin in an infant with mycoplasma hominis meningitis. The Pediatric infectious disease journal 2011. 82. Cies J, Moore W, Parker J, Shea P, Chopra A. Therapeutic drug monitoring of levofloxacin in an obese adolescent with intra-abdominal infection. Critical Care Medicine 2015; 43(12): 309. 83. Legg J, Cathie K, Harris A, et al. A randomized double-blind, placebo controlled trial of ciprofloxacin in the treatment of upper respiratory tract infections in children with cystic fibrosis. Pediatric Pulmonology 2014; 49: 333. 84. Legrand F, Jacqz-Aigrain E, Matrot B, et al. European network on evaluation of anti-infective agents for the treatment of preterm and term neonates. Fundamental and Clinical Pharmacology 2014; 28: 69. 85. Gonzalez D, Peloquin C, Mase S, et al. Population pharmacokinetics of levofloxacin in children treated for, or exposed to, multidrug resistant tuberculosis in the federated states of micronesia and republic of Marshall Islands. Journal of Pharmacokinetics and Pharmacodynamics 2013; 40(1).

86. Rahman M, Islam A. Efficacy of prophylactic oral levofloxacin in preventing infection during high dose methotrexate chemotherapy of acute lymphoblastic leukemia in children. Pediatric Blood and Cancer 2013; 60: 61. 87. Mase SR, Jereb J, Brostrom R, et al. Pharmacokinetics studies of levofloxacin in children treated for, or exposed to, multidrug-resistant tuberculosis-united states affiliated pacific islands,2010-2011. American Journal of Respiratory and Critical Care Medicine 2012; 185. 88. Ngoun C, Khun PA, Soeng S, et al. Enteric fever in Cambodian children is dominated by multidrug resistant H58 Salmonella enterica serovar Typhi with decreased susceptibility to ciprofloxacin. International Journal of Infectious Diseases 2012; 16. 89. Kearns GL, Rubino CM, Forrest A, et al. Levofloxacin pharmacokinetics (PK) after administration of MP-376 (Levofloxacin inhalation solution; Aeroquin) in children with cystic fibrosis (CF). Journal of Cystic Fibrosis 2011; 10.

Reported on Section/topic # Checklist item page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility 4 criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 5 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, 5-6 comparisons, outcomes, and study design (PICOS). METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, 6 provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years 6 considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 6 additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be Online repeated. supplementary file, 1 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if 6 applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any 7,8 processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions 7,8 and simplifications made.

Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this 7 studies was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 7 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of 7 consistency (e.g., I2) for each meta-analysis.

Page 1 of 2 Reported on Section/topic # Checklist item page # Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective 7 reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, 7 indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for 8 exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) 8, online and provide the citations. supplementary file Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11, online supplementary file Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each 9,10 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. N/A Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). N/A Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 11 16]). DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their 11,12 relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval 12,13 of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future 13 research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for 1 the systematic review.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Review s and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097