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Antibiotics and Cure Rates in Childhood Febrile Urinary Tract Infections in Clinical Trials: A Systematic Review and Meta-analysis

Drugs volume 78, pages 1593–1604 (2018)Cite this article

Abstract

Purpose

Urinary tract infections (UTIs) are common bacterial infections among children.

Objective

To systematically review the antimicrobials used for febrile UTIs in paediatric clinical trials and meta-analyse the observed cure rates and reasons for treatment failure.

Materials and Methods

We searched Medline, Embase and Cochrane central databases between January 1, 1990, and November 24, 2016, combining MeSH and free-text terms for: “urinary tract infections”, AND “therapeutics”, AND “clinical trials” in children (age range 0–18 years). Two independent reviewers assessed study quality and performed data extraction. The major outcome measures were clinical and microbiological cure rates according to different antibiotics.

Results

We identified 2762 published studies and included 30 clinical trials investigating 3913 cases of paediatric febrile urinary tract infections. Children with no underlying condition were the main population included in the trials (n = 2602; 66.5%). Cephalosporins were the most frequent antibiotics studied in trials (22/30, 73.3%). Only a few antibiotics active against resistant UTIs have been tested in randomised clinical trials, mainly aminoglycosides. The average point cure rate of all investigational drugs was estimated to 95.3% (95% CI 93.5–96.9%). Among 3002 patients for whom cure and failure rates were reported, only 3.9% (3.9%; 118/3002) were considered clinically to have treatment failure, while 135 (4.5%; 135/3002) had microbiological failure.

Conclusions

We observed high treatment cure rates, regardless of the investigational drug chosen, the route of administration, duration and dosing. This suggests that future research should prioritise observational studies and clinical trials on children with multi-drug-resistant infections.

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References

  1. Watt K, Waddle E, Jhaveri R. Changing epidemiology of serious bacterial infections in febrile infants without localizing signs. PLoS One. 2010;5(8):e12448.

    Article  Google Scholar 

  2. Cheng CH, Tsai MH, Su LH, Wang CR, Lo WC, Tsau YK, et al. Renal abscess in children: a 10-year clinical and radiologic experience in a tertiary medical center. Pediatr Infect Dis J. 2008;27(11):1025–7.

    Article  Google Scholar 

  3. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med. 2003;348(3):195–202.

    Article  Google Scholar 

  4. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics. 2010;126(6):1084–91.

    Article  Google Scholar 

  5. Shaikh N, Mattoo TK, Keren R, Ivanova A, Cui G, Moxey-Mims M, et al. Early antibiotic treatment for pediatric febrile urinary tract infection and renal scarring. JAMA Pediatr. 2016;170(9):848–54.

    Article  Google Scholar 

  6. WHO. Antimicrobial Resistance. Global report on surveillance. 2014. http://www.who.int/drugresistance/documents/surveillancereport/en/ Accessed 29 Jan 2018.

  7. Logan LK, Hujer AM, Marshall SH, Domitrovic TN, Rudin SD, Zheng X, et al. Analysis of beta-lactamase resistance determinants in enterobacteriaceae from chicago children: a multicenter survey. Antimicrob Agents Chemother. 2016;60(6):3462–9.

    CAS  Article  Google Scholar 

  8. Logan LK. Carbapenem-resistant Enterobacteriaceae: an emerging problem in children. Clin Infect Dis. 2012;55(6):852–9.

    CAS  Article  Google Scholar 

  9. Lukac PJ, Bonomo RA, Logan LK. Extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: old foe, emerging threat. Clin Infect Dis. 2015;60(9):1389–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Falagas ME, Karageorgopoulos DE, Nordmann P. Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiol. 2011;6(6):653–66.

    CAS  Article  Google Scholar 

  11. Hsu AJ, Tamma PD. Treatment of multidrug-resistant Gram-negative infections in children. Clin Infect Dis. 2014;58(10):1439–48.

    Article  Google Scholar 

  12. FDA. FDA Drug Safety Podcast: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. 2013. https://www.fda.gov/drugs/drugsafety/ucm369580.htm Accessed 29 Jan 2018.

  13. Raman G, Avendano E, Berger S, Menon V. Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis. BMC Infect Dis. 2015;15:395.

    Article  Google Scholar 

  14. Freedman AL, Urologic Diseases in America P. Urologic diseases in North America Project: trends in resource utilization for urinary tract infections in children. J Urol. 2005;173(3):949–54.

  15. Basmaci R, Vazouras K, Bielicki J, Folgori L, Hsia Y, Zaoutis T, et al. Urinary tract infection antibiotic trial study design: a systematic review. Pediatrics. 2017;140(6):e20172209.

    Article  Google Scholar 

  16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS medicine. 2009;6(7):e1000097.

    Article  Google Scholar 

  17. Freeman MFT, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat. 1950;21:607–11.

    Article  Google Scholar 

  18. Miller JJ. Inverse of Freeman-Tukey double arcsine transformation. Am Stat. 1978;32(4):138.

    Google Scholar 

  19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  Google Scholar 

  20. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article  Google Scholar 

  21. Allameh Z, Karimi A, Tabatabaei SR, Sharifian M, Sal2372Tuberculamzadeh J. Effect of n-acetylcysteine on inflammation biomarkers in pediatric acute pyelonephritis: a randomized controlled trial. Iran J Kidney Dis. 2015;9(6):454–62.

  22. Baker PC, Nelson DS, Schunk JE. The addition of ceftriaxone to oral therapy does not improve outcome in febrile children with urinary tract infections. Arch Pediatr Adolesc Med. 2001;155(2):135–9.

    CAS  Article  Google Scholar 

  23. Bakkaloglu A, Saatci U, Soylemezoglu O, Ozen S, Topaloglu R, Besbas N, et al. Comparison of ceftriaxone versus cefotaxime for childhood upper urinary tract infections. J Chemother. 1996;8(1):59–62.

    CAS  Article  Google Scholar 

  24. Begue P, Astruc J, Francois P, Floret D. Comparison of ceftriaxone and cefotaxime in severe pediatric bacterial infection: a multicentric study. [French]. Medecine et Maladies Infectieuses. 1998;28(4):300–6.

  25. Benador D, Neuhaus TJ, Papazyan JP, Willi UV, Engel-Bicik I, Nadal D, et al. Randomised controlled trial of three day versus 10 day intravenous antibiotics in acute pyelonephritis: effect on renal scarring. Arch Dis Child. 2001;84(3):241–6.

    CAS  Article  Google Scholar 

  26. Bocquet N, Sergent Alaoui A, Jais JP, Gajdos V, Guigonis V, Lacour B et al. Randomized trial of oral versus sequential intravenous/oral antibiotic for acute pyelonephritis in children. [French, English]. Pediatrics. 2012;129(2):e269–e75.

  27. Carapetis JR, Jaquiery AL, Buttery JP, Starr M, Cranswick NE, Kohn S, et al. Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections. Pediatr Infect Dis J. 2001;20(3):240–6.

    CAS  Article  Google Scholar 

  28. Cheng CH, Tsau YK, Lin TY. Effective duration of antimicrobial therapy for the treatment of acute lobar nephronia. Pediatrics. 2006;117(1):e84–9.

    Article  Google Scholar 

  29. Chong CY, Tan ASL, Ng W, Tan-Kendrick A, Balakrishnan A, Chao SM. Treatment of urinary tract infection with gentamicin once or three times daily. Acta Paediatr Int J Paediatr. 2003;92(3):291–6.

    CAS  Article  Google Scholar 

  30. Dagan R, Einhorn M, Lang R, Pomeranz A, Wolach B, Miron D, et al. Once daily cefixime compared with twice daily trimethoprim/sulfamethoxazole for treatment of urinary tract infection in infants and children. Pediatr Infect Dis J. 1992;11(3):198–203.

    CAS  Article  Google Scholar 

  31. Francois P, Bensman A, Begue P, Artaz MA, Coudeville L, Lebrun T et al. Assessment of the efficacy and cost efficiency of two strategies in the treatment of acute pyelonephritis in children: oral cefixime or parenteral ceftriaxone after an initial IV combination therapy. [French]. Medecine et Maladies Infectieuses. 1997;27(SPEC. ISS. JUNE):667–73.

  32. Gok F, Duzova A, Baskin E, Ozen S, Besbas N, Bakkaloglu A. Comparative study of cefixime alone versus intramuscular ceftizoxime followed by cefixime in the treatment of urinary tract infections in children. J Chemother. 2001;13(3):277–80.

    CAS  Article  Google Scholar 

  33. Huang YY, Chen MJ, Chiu NT, Chou HH, Lin KY, Chiou YY. Adjunctive oral methylprednisolone in pediatric acute pyelonephritis alleviates renal scarring. Pediatrics. 2011;128(3):2010.

    Google Scholar 

  34. Kafetzis DA, Maltezou HC, Mavrikou M, Siafas C, Paraskakis I, Delis D, et al. Isepamicin versus amikacin for the treatment of acute pyelonephritis in children. Int J Antimicrob Agents. 2000;14(1):51–5.

    CAS  Article  Google Scholar 

  35. Levtchenko E, Lahy C, Levy J, Ham H, Piepsz A. Treatment of children with acute pyelonephritis: a prospective randomized study. Pediatr Nephrol. 2001;16(11):878–84.

    CAS  Article  Google Scholar 

  36. Marild S, Jodal U, Sandberg T. Ceftibuten versus trimethoprim-sulfamethoxazole for oral treatment of febrile urinary tract infection in children. Pediatr Nephrol. 2009;24(3):521–6.

    Article  Google Scholar 

  37. Montini G, Toffolo A, Zucchetta P, Dall’Amico R, Gobber D, Calderan A, et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ. 2007;335(7616):386–8.

    CAS  Article  Google Scholar 

  38. Neuhaus TJ, Berger C, Buechner K, Parvex P, Bischoff G, Goetschel P, et al. Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis. Eur J Pediatr. 2008;167(9):1037–47.

    CAS  Article  Google Scholar 

  39. Noorbakhsh S, Lari AR, Masjedian F, Mostafavi H, Alaghehbandan R. Comparison of intravenous aminoglycoside therapy with switch therapy to cefixime in urinary tract infections. Saudi Med J. 2004;25(10):1513–5.

    PubMed  Google Scholar 

  40. Pena DA, Viviani ST, le Corre PN, Morales MV, Montecinos BC, Gajardo SC. Treatment of urinary tract infections in febrile infants: Experience of outpatient intravenous antibiotic treatment. [Spanish]. Revista Chilena de Infectologia. 2009;26(4):350–4.

  41. Schaad UB, Eskola J, Kafetzis D, Fishbach M, Ashkenazi S, Syriopoulou V et al. Cefepime vs. ceftazidime treatment of pyelonephritis: a European, randomized, controlled study of 300 pediatric cases. Pediatr Infect Dis J. 1998;17(7):639–44.

  42. Sobouti B, Hooman N, Movahed M. The effect of vitamin E or vitamin A on the prevention of renal scarring in children with acute pyelonephritis. Pediatr Nephrol (Berlin, Germany). 2013;28(2):277–83.

    Article  Google Scholar 

  43. Tapaneya-Olarn C, Tapaneya-Olarn W, Pitayamornwong V, Petchthong T, Tangnararatchakit K. Single daily dose of gentamicin in the treatment of pediatric urinary tract infection. J Med Assoc Thai. 1999;82(Suppl 1):S93–7.

    PubMed  Google Scholar 

  44. Toporovski J, Steffens L, Noack M, Kranz A, Burdeska A, Kissling M. Effectiveness of cefetamet pivoxil in the treatment of pyelonephritis in children. J Int Med Res. 1992;20(1):87–93.

    CAS  Article  Google Scholar 

  45. Vigano A, Principi N. Aminoglycosides in paediatric infections: the role of isepamicin. [Italian]. Clin Drug Investig. 1996;12(SUPPL. 1):37–46.

  46. Vigano A, Principi N, Brivio L, Tommasi P, Stasi P, Villa AD. Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children. Antimicrob Agents Chemother. 1992;36(7):1499–503.

    CAS  Article  Google Scholar 

  47. Vilaichone A, Watana D, Chaiwatanarat T. Oral ceftibuten switch therapy for acute pyelonephritis in children. J Med Assoc Thailand Chotmaihet thangphaet. 2001;84;(suppl 1):S61–S67.

  48. Yosefichaijan P, Khabazi M, Pakniyat A, Goudarzi. Therapeutic effect of complementary Vitamin C on pediatrics urinary tract infection. Pediatr Nephrol. 2016;31 (10):1796.

  49. Yousefichaijan P, Kahbazi M, Rasti S, Rafeie M, Sharafkhah M. Vitamin E as adjuvant treatment for urinary tract infection in girls with acute pyelonephritis. Iran J Kidney Dis. 2015;9(2):97–104.

    PubMed  Google Scholar 

  50. Yousefichaijan P, Naziri M, Taherahmadi H, Kahbazi M, Tabaei A. Zinc supplementation in treatment of children with urinary tract infection. Iran J Kidney Dis. 2016;10(4):213–6.

    PubMed  Google Scholar 

  51. Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 I):79–86.

  52. Kaguelidou F, Turner MA, Choonara I, van den Anker J, Manzoni P, Alberti C, et al. Randomized controlled trials of antibiotics for neonatal infections: a systematic review. Br J Clin Pharmacol. 2013;76(1):21–9.

    Article  Google Scholar 

  53. Morello W, La Scola C, Alberici I, Montini G. Acute pyelonephritis in children. Pediatr Nephrol. 2016;31(8):1253–65.

    Article  Google Scholar 

  54. Larcombe J. Urinary tract infection in children. BMJ. 1999;319(7218):1173–5.

    CAS  Article  Google Scholar 

  55. Becknell B, Schober M, Korbel L, Spencer JD. The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Rev Anti Infect Ther. 2015;13(1):81–90.

    CAS  Article  Google Scholar 

  56. Kyriakidou KG, Rafailidis P, Matthaiou DK, Athanasiou S, Falagas ME. Short- versus long-course antibiotic therapy for acute pyelonephritis in adolescents and adults: a meta-analysis of randomized controlled trials. Clin Ther. 2008;30(10):1859–68.

    CAS  Article  Google Scholar 

  57. Folgori L, Bielicki J, Ruiz B, Turner MA, Bradley JS, Benjamin DK Jr, et al. Harmonisation in study design and outcomes in paediatric antibiotic clinical trials: a systematic review. Lancet Infect Dis. 2016;16(9):e178–89.

    Article  Google Scholar 

  58. Finnell SME. Urinary tract infection in children: an update. Open Urol Nephrol J. 2015;8(Suppl 3: M2):92–5.

  59. Strohmeier Y, Hodson EM, Willis NS, Webster AC, Craig JC. Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2014;7:CD003772.

  60. Jeffrey H. Are oral antibiotics equivalent to intravenous antibiotics for the initial management of pyelonephritis in children? Paediatr Child Health. 2010;15(3):150–2.

    Article  Google Scholar 

  61. Vouloumanou EK, Rafailidis PI, Kazantzi MS, Athanasiou S, Falagas ME. Early switch to oral versus intravenous antimicrobial treatment for hospitalized patients with acute pyelonephritis: a systematic review of randomized controlled trials. Curr Med Res Opin. 2008;24(12):3423–34.

    Article  Google Scholar 

  62. Lee B, Kang SY, Kang HM, Yang NR, Kang HG, Ha IS, et al. Outcome of antimicrobial therapy of pediatric urinary tract infections caused by extended-spectrum beta-lactamase-producing enterobacteriaceae. Infect Chemother. 2013;45(4):415–21.

    CAS  Article  Google Scholar 

  63. Dalgic N, Sancar M, Bayraktar B, Dincer E, Pelit S. Ertapenem for the treatment of urinary tract infections caused by extended-spectrum beta-lactamase-producing bacteria in children. Scand J Infect Dis. 2011;43(5):339–43.

    CAS  Article  Google Scholar 

  64. Wu UI, Chen WC, Yang CS, Wang JL, Hu FC, Chang SC, et al. Ertapenem in the treatment of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli: a propensity score analysis. IJID. 2012;16(1):e47–52.

    CAS  PubMed  Google Scholar 

  65. Collins VL, Marchaim D, Pogue JM, Moshos J, Bheemreddy S, Sunkara B, et al. Efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2012;56(4):2173–7.

    CAS  Article  Google Scholar 

  66. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    CAS  Article  Google Scholar 

  67. Singh KP, Li G, Mitrani-Gold FS, Kurtinecz M, Wetherington J, Tomayko JF, et al. Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection. Antimicrob Agents Chemother. 2013;57(11):5284–90.

    CAS  Article  Google Scholar 

  68. US Department of Health and Human Services; Food and Drug Administration. Guidance for industry. Complicated urinary tract infections and pyelonephritis: developing antimicrobial drugs for treatment. Draft guidance. 1998. www.fda.gov/ohrms/dockets/98fr/2559dft.pdf. Accessed 29 Jan 2018.

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Author notes

  1. Konstantinos Vazouras and Romain Basmaci contributed equally to the work and are co-first authors.

Affiliations

  1. Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George’s University of London, Cranmer Terrace, London, SW17 0RE, UK

    Konstantinos Vazouras, Julia Bielicki, Laura Folgori, Mike Sharland & Yingfen Hsia

  2. The Stavros Niarchos Foundation, Collaborative Center for Clinical Epidemiology and Outcomes Research (CLEO), University of Athens, Athens, Greece

    Konstantinos Vazouras & Theoklis Zaoutis

  3. Infection, Antimicrobiens, Modélisation, Evolution, Unité Mixte de Recherche 1137, Institut National de la Santé Et de la Recherche Médicale, Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    Romain Basmaci

  4. Service de Pédiatrie-Urgences, Hôpital Louis-Mourier, Assistance Publique, Hôpitaux de Paris, 92700, Colombes, France

    Romain Basmaci

  5. Paediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland

    Julia Bielicki

  6. Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Theoklis Zaoutis

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  1. Konstantinos Vazouras
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  7. Yingfen Hsia
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Contributions

KV, RB and YH conceptualized and designed the work. KV, RB, JB and LF identified eligible studies. KV, RB and LF appraised study quality; data were extracted, transformed and analysed by KV and RB. Data analysis was guided by YH. MS and TZ contributed substantially to data interpretation. KV and RB drafted the initial manuscript. JB, LF, TZ, MS and YH critically revised the manuscript for important intellectual content. All authors contributed to, reviewed, and approved the final version to be published. All authors received access to all the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. YH is the guarantor.

Corresponding author

Correspondence to Konstantinos Vazouras.

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No external funding for this manuscript.

Conflict of interest

MS reports grants from GlaxoSmithKline, Pfizer and Cubist Pharmaceuticals, outside the submitted work. JB’s husband is senior corporate counsel at Novartis International AG, Basel, Switzerland, and holds Novartis stock and stock options. The other authors have no conflicts of interest to disclose.

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Vazouras, K., Basmaci, R., Bielicki, J. et al. Antibiotics and Cure Rates in Childhood Febrile Urinary Tract Infections in Clinical Trials: A Systematic Review and Meta-analysis. Drugs 78, 1593–1604 (2018). https://doi.org/10.1007/s40265-018-0988-1

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