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

  • Konstantinos Vazouras
  • Romain Basmaci
  • Julia Bielicki
  • Laura Folgori
  • Theoklis Zaoutis
  • Mike Sharland
  • Yingfen Hsia
Systematic Review
  • 40 Downloads

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.

Notes

Authors 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.

Compliance with Ethical Standards

Funding

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.

Ethical approval

Not required.

Supplementary material

40265_2018_988_MOESM1_ESM.docx (126 kb)
Supplementary material 1 (DOCX 126 kb)

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 6.
    WHO. Antimicrobial Resistance. Global report on surveillance. 2014. http://www.who.int/drugresistance/documents/surveillancereport/en/ Accessed 29 Jan 2018.
  7. 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.CrossRefGoogle Scholar
  8. 8.
    Logan LK. Carbapenem-resistant Enterobacteriaceae: an emerging problem in children. Clin Infect Dis. 2012;55(6):852–9.CrossRefGoogle Scholar
  9. 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.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Falagas ME, Karageorgopoulos DE, Nordmann P. Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiol. 2011;6(6):653–66.CrossRefGoogle Scholar
  11. 11.
    Hsu AJ, Tamma PD. Treatment of multidrug-resistant Gram-negative infections in children. Clin Infect Dis. 2014;58(10):1439–48.CrossRefGoogle Scholar
  12. 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. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 17.
    Freeman MFT, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat. 1950;21:607–11.CrossRefGoogle Scholar
  18. 18.
    Miller JJ. Inverse of Freeman-Tukey double arcsine transformation. Am Stat. 1978;32(4):138.Google Scholar
  19. 19.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.Google Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.Google Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 45.
    Vigano A, Principi N. Aminoglycosides in paediatric infections: the role of isepamicin. [Italian]. Clin Drug Investig. 1996;12(SUPPL. 1):37–46.Google Scholar
  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.CrossRefGoogle Scholar
  47. 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.Google Scholar
  48. 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.Google Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 53.
    Morello W, La Scola C, Alberici I, Montini G. Acute pyelonephritis in children. Pediatr Nephrol. 2016;31(8):1253–65.CrossRefGoogle Scholar
  54. 54.
    Larcombe J. Urinary tract infection in children. BMJ. 1999;319(7218):1173–5.CrossRefGoogle Scholar
  55. 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.CrossRefGoogle Scholar
  56. 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.CrossRefGoogle Scholar
  57. 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.CrossRefGoogle Scholar
  58. 58.
    Finnell SME. Urinary tract infection in children: an update. Open Urol Nephrol J. 2015;8(Suppl 3: M2):92–5.Google Scholar
  59. 59.
    Strohmeier Y, Hodson EM, Willis NS, Webster AC, Craig JC. Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2014;7:CD003772.Google Scholar
  60. 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.CrossRefGoogle Scholar
  61. 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.CrossRefGoogle Scholar
  62. 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.CrossRefGoogle Scholar
  63. 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.CrossRefGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.CrossRefGoogle Scholar
  66. 66.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.CrossRefGoogle Scholar
  67. 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.CrossRefGoogle Scholar
  68. 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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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Paediatric Infectious Diseases Research Group, Institute for Infection and ImmunitySt George’s University of LondonLondonUK
  2. 2.The Stavros Niarchos Foundation, Collaborative Center for Clinical Epidemiology and Outcomes Research (CLEO)University of AthensAthensGreece
  3. 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 CitéParisFrance
  4. 4.Service de Pédiatrie-Urgences, Hôpital Louis-Mourier, Assistance Publique, Hôpitaux de ParisColombesFrance
  5. 5.Paediatric PharmacologyUniversity Children’s Hospital BaselBaselSwitzerland
  6. 6.Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital of PhiladelphiaUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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