Fluconazole Effectiveness in Preventing Invasive Fungal Infection in Very Low Birth Weight Infants: Systematic Review and Meta-analysis

systematic review and meta-analysis

  • Fonny Cokro Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
  • Lorensia Yolanda Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
  • Shelly Caroline Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
DOI: https://doi.org/10.35814/jifi.v20i1.1035

Abstract

Fungal infections in neonates, especially in Very Low Birth Weight (VLBW) infants, are mostly caused by Candida species and may lead to morbidity and mortality. A systematic review and a meta-analysis were conducted to determine the extent to which fluconazole, an antifungal prophylactic, was effective and safe to use in VLBW or premature infants in preventing Invasive Fungal Infection (IFI), by including Randomized Controlled Trials (RCTs) carried out worldwide. The investigation started with searching process through publication databases: MEDLINE, Cochrane, ScienceDirect, and Garuda, for Randomized Controlled Trials (RCTs) that compared the prophylactic effects of fluconazole and placebo on IFI in VLBW infants. The selected eight RCT studies indicated that, compared to placebo, fluconazole accounted for 68% risk reduction of overall fungal colonization (RR=0.32; 95% confidence interval [CI]=0.24-0.42, p=0.00001, I-square=0%) and 60% risk reduction of IFI (RR=0.40; 95%[CI]=0.22-0.72, I-square=56%, p=0.002). However, fluconazole did not significantly reduce mortality in VLBW infants (RR=0.79; 95%[CI]=0.60-1.03; p=0.08, I-square=0%). Also, regarding its safety, fluconazole prophylaxis did not result in significant elevations of SGOT/SGPT levels (RR=1.22; 95%[CI]=0.50-3.00, p=0.66, I-square=0%) nor cause intestinal perforation (RR=0.96; 95%[CI]=0.25-3.68, p=0.96, I-square=59%). Fluconazole is an effective prophylaxis agent against invasive fungal infection when given to preterm infants with birth weight <1500, but not proven in reducing the mortality incidence in VLBW infants.

References

1. Agarwal V, Tomer P, Gupta P, Upadhyay A. Epidemiology, Clinical Spectrum and Outcomes of Fungal Sepsis in Neonates in Neonatal Intensive Care Unit:AProspective Observational Study. 2018;5(1):5.

2. Nobile CJ, Johnson AD. Candida albicans Biofilms and Human Disease. Annu Rev Microbiol. 2015 Oct 15;69(1):71–92.

3. Yoo JR, Shin BR, Jo S, Heo ST. Evaluation of the early fluconazole treatment of candidemia protocol with automated short message service alerts: a before-and-after study. Korean J Intern Med [Internet]. 2020 Jul 9 [cited 2020 Dec 22]; Available from: http://kjim.org/journal/view.php?doi=10.3904/kjim.2019.259

4. Cleminson J, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2015 Oct 24;(10):CD003850.

5. Austin N, Cleminson J, Darlow BA, McGuire W. Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Neonatal Group, editor. Cochrane Database Syst Rev [Internet]. 2015 Oct 24 [cited 2020 Dec 17]; Available from: http://doi.wiley.com/10.1002/14651858.CD003478.pub5

6. Ericson JE, Kaufman DA, Kicklighter SD, Bhatia J, Testoni D, Gao J, et al. Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data. Clin Infect Dis. 2016 Sep 1;63(5):604–10.

7. McGuire W, Clerihew L. The effect of fluconazole prophylaxis in very low birthweight infants is overestimated by before-after studies. Arch Dis Child - Fetal Neonatal Ed. 2010 May 1;95(3):F182–7.

8. Kirpal H, Gathwala G, Chaudhary U, Sharma D. Prophylactic fluconazole in very low birth weight infants admitted to neonatal intensive care unit: randomized controlled trial. J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2016;29(4):624–8.

9. Benjamin DK, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742–9.

10. Aydemir C, Oguz SS, Dizdar EA, Akar M, Sarikabadayi YU, Saygan S, et al. Randomised controlled trial of prophylactic fluconazole versus nystatin for the prevention of fungal colonisation and invasive fungal infection in very low birth weight infants. Arch Dis Child - Fetal Neonatal Ed. 2011 May 1;96(3):F164–8.

11. Parikh TB, Nanavati RN, Patankar CV, Rao S, Bisure K, Udani RH, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007 Nov;44(11):830–7.

12. Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007 Jun 14;356(24):2483–95.

13. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med. 2001 Dec 6;345(23):1660–6.

14. Kicklighter SD, Springer SC, Cox T, Hulsey TC, Turner RB. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics. 2001 Feb;107(2):293–8.

15. Cabrera et al. AAP-Section on Perinatal Pediatrics. J Perinatol. 2002 Oct;22(7):594–622.

16. Berkow E, Lockhart S. Fluconazole resistance in Candida species: a current perspective. Infect Drug Resist. 2017 Jul;Volume 10:237–45.

17. Kaufman DA, Cuff AL, Wamstad JB, Boyle R, Gurka MJ, Grossman LB, et al. Fluconazole Prophylaxis in Extremely Low Birth Weight Infants and Neurodevelopmental Outcomes and Quality of Life at 8 to 10 Years of Age. J Pediatr. 2011 May;158(5):759-765.e1.

18. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis for prevention of invasive Candida infection in high-risk infants of <1000 grams birth weight. J Pediatr. 2005 Aug;147(2):172–9.

19. Manzoni P, Mostert M, Latino MA, Pugni L, Stolfi I, Decembrino L, et al. Clinical characteristics and response to prophylactic fluconazole of preterm VLBW neonates with baseline and acquired fungal colonisation in NICU: data from a multicentre RCT. Early Hum Dev. 2012 May;88 Suppl 2:S60-6.
Published
2022-04-25
How to Cite
COKRO, Fonny; YOLANDA, Lorensia; CAROLINE, Shelly. Fluconazole Effectiveness in Preventing Invasive Fungal Infection in Very Low Birth Weight Infants: Systematic Review and Meta-analysis. JURNAL ILMU KEFARMASIAN INDONESIA, [S.l.], v. 20, n. 1, p. 14-22, apr. 2022. ISSN 2614-6495. Available at: <http://jifi.farmasi.univpancasila.ac.id/index.php/jifi/article/view/1035>. Date accessed: 26 apr. 2024. doi: https://doi.org/10.35814/jifi.v20i1.1035.
Citation Formats
Issue
Vol 20 No 1 (2022): JIFI
Section
Articles
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Licencing
All articles in Jurnal Ilmu Kefarmasian Indonesia are an open-access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which permits unrestricted non-commercial used, distribution and reproduction in any medium.

This licence applies to Author(s) and Public Reader means that the users mays :

  • SHARE:
    copy and redistribute the article in any medium or format
  • ADAPT:
    remix, transform, and build upon the article (eg.: to produce a new research work and, possibly, a new publication)
  • ALIKE:
    If you remix, transform, or build upon the article, you must distribute your contributions under the same license as the original.
  • NO ADDITIONAL RESTRICTIONS:
    You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

It does however mean that when you use it you must:

  • ATTRIBUTION: You must give appropriate credit to both the Author(s) and the journal, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.

You may not:

  • NONCOMMERCIAL: You may not use the article for commercial purposes.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.