Fluconazole prophylaxis in preterm infants: a systematic review

Juliana Ferreira da Silva Rios Paulo Augusto Moreira Camargos Luísa Petri Corrêa Roberta Maia de Castro Romanelli About the authors

ABSTRACT

Objective:

This article aims to review the use of antifungal prophylaxis with intravenous fluconazole in premature newborns and the occurrence of Invasive Candidiasis.

Methods:

This is a systematic review with search at databases: PubMed, Capes Portal, Virtual Health Library (BVS - Biblioteca Virtual em Saúde)/Lilacs, Scopus and Cochrane. The keywords used were: "Antifungal", "Candida" "Fluconazole prophylaxis" and "Preterm infants".

Results:

Invasive Candidiasis was evaluated in all the twelve items. In eleven of them, there was a statistically significant difference between the groups receiving prophylactic fluconazole, with lower frequency of Invasive Candidiasis, compared to placebo or no prophylaxis group. Colonization by Candida species was also evaluated in five studies; four of them presented statistically lower proportion of colonization in patients with Fluconazole prophylaxis, compared to placebo or no drugs. In one study, there was a significant difference, favoring the use of fluconazole, and reduction of death.

Conclusion:

Studies indicate the effectiveness of prophylaxis with fluconazole, with reduction in the incidence of colonization and invasive fungal disease. The benefits of prophylaxis should be evaluated considering the incidence of candidiasis in the unit, the mortality associated with candidiasis, the safety and toxicity of short and long-term medication, and the potential for development of resistant pathogens.

Keywords:
Antifungal; Candida; Fluconazole prophylaxis; Preterm infants

Introduction

The incidence of invasive fungal infection ranges from 2% to 4% in infants with very low birth weight (VLBW < 1500 g)11 McCrossan BA, McHenry E, O'Neill F, Ong G, Sweet DG. Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection. Arch Dis Child Fetal Neonatal Ed. 2007;92:F454-8. and may affect 4% to 16% of extreme-low birth weight newborns (EBPN < 1000 g).22 Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics. 2006;118:2359-64.

3 Greenberg RG, Benjamin DK. Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect. 2014;69(Suppl. 1):S19-22.
-44 Kelly MS, Benjamin DK, Smith PB. The epidemiology and diagnosis of invasive candidiasis among premature infants. Clin Perinatol. 2015;42:105-17. Candida species have a higher incidence of invasive candidiasis (IC) in newborns and it is one of the most important causes of morbidity and mortality in the neonatal population.55 Pinhat EC, Borba MG, Ferreira ML, et al. Fungal colonization in newborn babies of very low birth weight: a cohort study. J Pediatr (Rio J). 2012;88:211-6.,66 Benjamin DK, Stoll BJ, Gantz MG, et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126:e865-73.

The immaturity of the immune system and the use of invasive devices, such as mechanical ventilation and central venous catheter, are considered important risk factors for IC.77 Ghazal P, Dickinson P, Smith CL. Early life response to infection. Curr Opin Infect Dis. 2013;26:213-8.

8 Brady MT. Health care-associated infections in the neonatal intensive care unit. Am J Infect Control. 2005;33:268-75.
-99 Izquierdo G, Santolaya ME. Invasive candidiasis in newborns: diagnosis, treatment and prophylaxis. Rev Chilena Infectol. 2014;31:73-3. Prior colonization by Candida sp., delivery route, and cross transmission by the hands of health professionals are also considered predisposing factors. Exposure to broad-spectrum antimicrobial drugs favors the selection of microbiome and the use of post-natal steroids and H2 inhibitors is a factor that favors translocation in the colonized patient to invasive infection.55 Pinhat EC, Borba MG, Ferreira ML, et al. Fungal colonization in newborn babies of very low birth weight: a cohort study. J Pediatr (Rio J). 2012;88:211-6.,88 Brady MT. Health care-associated infections in the neonatal intensive care unit. Am J Infect Control. 2005;33:268-75.,99 Izquierdo G, Santolaya ME. Invasive candidiasis in newborns: diagnosis, treatment and prophylaxis. Rev Chilena Infectol. 2014;31:73-3.

Besides bloodstream infection (Candidemia) Candida may affect other organs, especially heart, urinary tract, retina, and central nervous system (CNS).99 Izquierdo G, Santolaya ME. Invasive candidiasis in newborns: diagnosis, treatment and prophylaxis. Rev Chilena Infectol. 2014;31:73-3. CNS involvement may occur in around 50% of newborns with IC,1010 Wynn JL, Benjamin DK, Benjamin DK, Cohen-Wolkowiez M, Clark RH, Smith PB. Very late onset infections in the neonatal intensive care unit. Early Hum Dev. 2012;88:217-25.,1111 Benjamin DK, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117:84-92. and impaired neurological development after infection affects up to 60% of survivors.1212 Adams-Chapman I, Bann CM, Das A, et al. Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. J Pediatr. 2013;163, 961–967.e3. The mortality rate reported in some studies is around 20%,1111 Benjamin DK, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117:84-92.,1313 Blyth CC, Chen SC, Slavin MA, et al. Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients. Pediatrics. 2009;123:1360-8. but it can reach up to 40%.1414 Santolaya ME, Alvarado T, Queiroz-Telles F, et al. Active surveillance of candidemia in children from Latin America: a key requirement for improving disease outcome. Pediatr Infect Dis J. 2014;33:e40-4.

Despite evidences and recommendations favoring the use of intravenous fluconazole for prevention of invasive fungal infections (IFI) in neonates,1515 Hope WW, Castagnola E, Groll AH, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.. Clin Microbiol Infect. 2012;18(Suppl. 7):38-52.

16 Santolaya ME, Alvarado Matute T, de Queiroz Telles F, et al. Recommendations for the management of candidemia in neonates in Latin America. Grupo Proyecto Epico. Rev Iberoam Micol. 2013;30(Suppl. 1):158-70.
-1717 Figueras C, Diaz de Heredia C, Garcia JJ, et al. The Spanish Society of Paediatric Infectious Diseases (SEIP) recommendations on the diagnosis and management of invasive candidiasis. An Pediatr (Barc). 2011;74, 337.e1–e17. universal use of antifungal prophylaxis is controversial in the literature. Currently, it is recommended in Neonatal Intensive Care Units (NICU) with fungal infections rates higher than 5%.1818 Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of Candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1-50.,1919 Kimberlin DW, editor. Red Book - Report of the Committee on Infectious Diseases. 2015.

Thus, this study aimed to conduct a systematic review on the use of antifungal prophylaxis with intravenous fluconazole in premature newborns and the occurrence of IC (Fig. 1).

Fig. 1
Flowchart.

Methods

This was a systematic review which included virtual libraries: PubMed, EmBase, Portal Capes, Virtual Health Library (BVS - Biblioteca Virtual em Saúde)/Lilacs, Scopus, and Cochrane databases, without language restriction, with publications until February 2016 without previous date limit considering the first study was in 2001. It also included forward citation tracking. The keywords were "Antifungal", "Candida", "Fluconazole prophylaxis" and "Preterm infants" or "very low birth weight". The search was performed in duplicate by two researchers.

PICO strategy2020 Murad MH, Montori VM, Ioannidis JPA, et al. How to read a systematic review and meta-analysis and apply the results to patient care. Users' guides to the medical literature. JAMA. 2014;312:171-9. was performed considering: Population (P) - infants with birth weight lower than 1500 g; Intervention (I): use of antifungal prophylaxis with fluconazole; Comparison (C): no antifungal prophylaxis or use of placebo; Outcome (O): occurrence of Invasive Candidiasis; Study type (S): comparative studies of case-control, cohort, or clinical trials.

A total of 168 articles were found: 54 PubMed articles, 52 Portal Capes articles, 31 BVS articles, 20 Scopus articles, 10 Cochrane articles, and a comparative study obtained in references cited in review articles. Of them, 85 were duplicates among the databases and 83 were chosen for the first selection.

Seventy one studies were excluded. Of them, 33 were reviews and five were experts' commentaries on articles published in journals indexed in the databases. Eight studies addressed the treatment of fungal infections, two included treatment of resistant Candida species and one was about diagnostic methods. Four were studies on the prevalence of fungal colonization in neonates and other four reports of infection by other fungal species. Three publications focused on epidemiological surveillance studies of invasive fungal infections. Four other studies evaluated prophylaxis of IC with a different antifungal and four addressed a pharmacokinetic evaluation of antifungal agents. In addition, one article examined the occurrence of side-effects with the use of Fluconazole. Furthermore, one article evaluated the adhesion of neonatologists to prophylactic fluconazole use protocol in NICU and one compared different doses of fluconazole.

Twelve studies were eligible for comparative and qualitative analysis, including four randomized clinical trials (RCT), five comparative studies, two case-control studies, and one cohort study.

Results

We selected 12 original articles which referred to the prophylaxis of IFI with intravenous use of fluconazole in premature infants, eight observational studies (comparative, cohort and case-control), and four clinical trials published between 2001 and 2014 that evaluated 11,405 newborns, from whom 7416 received prophylactic fluconazole and 3989 received placebo or no prophylactic drugs. The studies varied in birth weight (BW) and inclusion criteria ranged from 750 g to 1550 g.

Table 1 shows the summary of the articles, considering year of publication, study population, type of intervention, and occurrence of the event of interest (IC).

Table 1
Original articles selected for systematic review of use of prophylactic Fluconazole in newborns.

Five studies were only described as comparative, considering pre- and post-exposure periods.2121 Uko S, Soghier LM, Vega M, et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics. 2006;117:1243-52.

22 Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics. 2006;117:e22-32.

23 Weitkamp JH, Ozdas A, LaFleur B, Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure. J Perinatol. 2008;28:405-11.

24 Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole resistant Candida species. Pediatrics. 2008;121:703-10.
-2525 Rueda K, Moreno MT, Espinosa M, Saez-Llorens X. Impact of routine fluconazole prophylaxis for premature infants with birth weights of less than 1250 grams in a developing country. Pediatr Infect Dis J. 2010;29:1050-2. Studies defined as case-control and cohort2626 Kaufman DA, Morris A, Gurka MJ, Kapik B, Hetherington S. Fluconazole prophylaxis in preterm infants: a multicenter case-controlled analysis of efficacy and safety. Early Hum Dev. 2014;90(Suppl. 1):S87-90.

27 Rolnitsky A, Levy I, Sirota L, Shalit I, Klinger G. Targeted fluconazole prophylaxis for high-risk very low birth weight infants. Eur J Pediatr. 2012;171:1481-7.
-2828 Cetinkaya M, Ercan TE, Saglam OK, Buyukkale G, Kavuncuoglu S, Mete F. Efficacy of prophylactic fluconazole therapy in decreasing the incidence of Candida infections in extremely low birth weight preterm infants. Am J Perinatol. 2014;31:1043-8. were based on historical controls, comparing neonates who were admitted to the NICU in periods before and after implementation of prophylaxis with fluconazole for IC.

Of four clinical trials, three used a fixed dose of fluconazole with a placebo group2929 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;345:1660-6.

30 Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7.
-3131 Benjamin DK, Hudak ML, Duara S, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014;311:1742-9. and one evaluated two distinct doses of Fluconazole (6 mg/kg and 3 mg/kg) compared to placebo.3232 Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95.

The event IC was examined in all the 12 studies. In 11 of them, there was a statistically significant difference, with lower rates in groups receiving prophylactic fluconazole for IC, compared to placebo or no drug groups. The randomized, double-blind placebo-controlled study conducted by Parikh et al., 2007,3030 Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7. found no difference between the incidence of IC between intervention and placebo groups.

The outcome colonization by Candida species in several body sites (skin, nasopharynx, periumbilical region, perineum, gastric aspirate, endotracheal secretion) was evaluated in five studies. Three randomized clinical trials2929 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;345:1660-6.,3030 Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7.,3232 Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95. and a comparative study2222 Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics. 2006;117:e22-32. found a statistically significant difference between colonization in at least one site searched among the groups, with lower incidence of Candida colonization in the Fluconazole group.

Overall mortality and mortality associated to IC were assessed as an endpoint in six studies: four comparative studies with pre-prophylaxis period and fluconazole prophylaxis period,2121 Uko S, Soghier LM, Vega M, et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics. 2006;117:1243-52.,2222 Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics. 2006;117:e22-32.,2424 Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole resistant Candida species. Pediatrics. 2008;121:703-10.,2525 Rueda K, Moreno MT, Espinosa M, Saez-Llorens X. Impact of routine fluconazole prophylaxis for premature infants with birth weights of less than 1250 grams in a developing country. Pediatr Infect Dis J. 2010;29:1050-2. and two trials comparing Fluconazole to placebo.2929 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;345:1660-6.,3131 Benjamin DK, Hudak ML, Duara S, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014;311:1742-9. In only one these studies,2424 Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole resistant Candida species. Pediatrics. 2008;121:703-10. there was a significant reduction in deaths associated to IC, with 21% mortality in the pre-prophylaxis group versus no deaths in the post-prophylaxis group. Only one clinical trial3131 Benjamin DK, Hudak ML, Duara S, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014;311:1742-9. conducted by Benjamin et al. evaluated neurodevelopment at 18-22 months of age in the infants who were randomized to use prophylactic fluconazole or placebo. The authors concluded that the use of Fluconazole did not impair the neurodevelopment of these neonates.

Discussion

The incidence of IC in different studies and literature reports varies widely ranging between 2 and 4% in neonates with birth weight lower than 1500 g (VLBW) to 10-16% in those below 1000 g (ELBW).11 McCrossan BA, McHenry E, O'Neill F, Ong G, Sweet DG. Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection. Arch Dis Child Fetal Neonatal Ed. 2007;92:F454-8.,22 Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics. 2006;118:2359-64.,3333 Greenberg RG, Benjamin DK. Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect. 2014;69(Suppl. 1):S19-22. However, some studies showed higher incidences of IC: two studies included VLBW newborns and found an incidence rate of 13.2%3232 Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95. and 16.7%2222 Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics. 2006;117:e22-32. before the prophylactic intervention with fluconazole. Two other studies with ELBW (<1000 g) newborns showed an incidence around 20% of IC in groups without prophylaxis.2323 Weitkamp JH, Ozdas A, LaFleur B, Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure. J Perinatol. 2008;28:405-11.,2929 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;345:1660-6.

Two trials were performed at a single center and the number of neonates randomized in each group was small, with 50 or 60 neonates allocated in each group.2929 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;345:1660-6.,3030 Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7. But there was no significant difference in baseline characteristics of the groups, and this did not cause selection bias in the statistical analysis.

Some studies did not show effect measures in their results, not describing relative risks, odds ratio or confidence interval between intervention and placebo or control groups.2323 Weitkamp JH, Ozdas A, LaFleur B, Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure. J Perinatol. 2008;28:405-11.,2424 Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole resistant Candida species. Pediatrics. 2008;121:703-10.,2626 Kaufman DA, Morris A, Gurka MJ, Kapik B, Hetherington S. Fluconazole prophylaxis in preterm infants: a multicenter case-controlled analysis of efficacy and safety. Early Hum Dev. 2014;90(Suppl. 1):S87-90.,2828 Cetinkaya M, Ercan TE, Saglam OK, Buyukkale G, Kavuncuoglu S, Mete F. Efficacy of prophylactic fluconazole therapy in decreasing the incidence of Candida infections in extremely low birth weight preterm infants. Am J Perinatol. 2014;31:1043-8.,3030 Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7. However, four of them presented statistical significance in reducing IC.

The studies have limitations that should be taken into account when evaluating and generalizing their results. However, the high incidence of complications associated with IC in premature infants, including neurodevelopmental impairment, supports the importance of preventive measures, including the use of prophylactic fluconazole.1616 Santolaya ME, Alvarado Matute T, de Queiroz Telles F, et al. Recommendations for the management of candidemia in neonates in Latin America. Grupo Proyecto Epico. Rev Iberoam Micol. 2013;30(Suppl. 1):158-70.

Another study not included in this review evaluated different intervals of fluconazole doses. Kaufman et al.3434 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;147:172-9. evaluated 3 mg/kg of fluconazole administered daily or twice a week. The author found no difference in the incidence of IFD between daily and twice a week dose groups.

The Infectious Diseases Society of America (IDSA)3535 Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;62:e1-50. states that prophylaxis for IC with fluconazole can be considered to VLBW newborns in NICU with rates of candidiasis higher than 10% (AI), based on placebo controlled randomized trials.2929 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;345:1660-6.,3232 Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95. It is also recommended that resistance to antifungal agents, toxicity associated to fluconazole, and assessments of neurological development of newborns should be observed (A-III), since there are no studies that have adequately assessed the effects of long-term use of prophylactic fluconazole. Authors do not specify how long such monitoring should be.1919 Kimberlin DW, editor. Red Book - Report of the Committee on Infectious Diseases. 2015.,3535 Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;62:e1-50.

In Europe, the Spanish Society of Pediatric Infectious Diseases recommends the use of prophylactic fluconazole at a dose of 3 mg/kg, twice a week, throughout the period of risk in preterm infants of VLBW in NICU with incidence of IC greater than 10%,1717 Figueras C, Diaz de Heredia C, Garcia JJ, et al. The Spanish Society of Paediatric Infectious Diseases (SEIP) recommendations on the diagnosis and management of invasive candidiasis. An Pediatr (Barc). 2011;74, 337.e1–e17. based on randomized clinical trials3232 Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95. and recommendations of Concise Reviews of Pediatric Infectious Diseases.3636 Healy CM, Baker CJ. Fluconazole prophylaxis in the neonatal intensive care unit. Pediatr Infect Dis J. 2009;28:49-52.

Subsequently, the European Society of Clinical Microbiology Infectious Diseases1515 Hope WW, Castagnola E, Groll AH, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.. Clin Microbiol Infect. 2012;18(Suppl. 7):38-52. recommended antifungal prophylaxis in neonates as AI evidence, considering risk stratification strategy: (a) in NICU with high frequency IC (>5%), fluconazole 3-6 mg/kg twice a week, intravenous or orally, is indicated to all infants with birth weight lower than 1000 g, based on six systematic reviews and meta-analyses;3737 Austin N, Darlow BA, McGuire W. Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Database Syst Rev. 2009:CD003478.

38 Clerihew L, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2007:CD003850.

39 Clerihew L, Austin N, McGuire W. Systemic antifungal prophylaxis for very low birthweight infants: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2008;93:F198-200.

40 McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2004:CD003850.

41 Mohan P, Eddama O, Weisman LE. Patient isolation measures for infants with candida colonization or infection for preventing or reducing transmission of candida in neonatal units. Cochrane Database Syst Rev. 2007:CD006068.

42 Zhang JP, Chen C. Meta-analysis of the efficacy and safety of fluconazole in prophylaxis of fungal infection in very low birth weight infants. Zhonghua Er Ke Za Zhi. 2009;47:743-891.
-4343 Tripathi N, Watt K, Benjanin DK. Treatment and prophylaxis of invasive candidiasis. Semin Perinatol. 2012;36:416-23. (b) in NICU with incidence rate lower than 2%, the decision to use prophylaxis with fluconazole should be made individually (e.g. infants < 1000 g, with risk factors for IC as central venous catheter, use of third-generation cephalosporins and carbapenems) as evidence B-II.

Although none of the studies examined in this review has been carried out in Latin America, the recommendations of Latin America Invasive Mycosis Network,1616 Santolaya ME, Alvarado Matute T, de Queiroz Telles F, et al. Recommendations for the management of candidemia in neonates in Latin America. Grupo Proyecto Epico. Rev Iberoam Micol. 2013;30(Suppl. 1):158-70. published in 2013, indicate prophylaxis with fluconazole 3 mg/kg, twice a week, for six weeks, in neonates of ELBW (<1000 g) who are in NICU with high incidence of IC (greater than or equal to 5%). When the incidence is lower than 5%, the use of prophylactic fluconazole may be considered, according to the risk factors of each newborn.

Conclusion

The studies included in this review present the effectiveness of prophylaxis of IC with fluconazole, with significant reduction in the incidence of colonization by Candida species and IC. The potential benefits of antifungal prophylaxis should be evaluated considering cost-effectiveness, efficacy of prophylaxis, and incidence of candidiasis and mortality associated with candidiasis at the NICU. Safety and toxicity of the drug at short and long-term and the potential for development of resistant pathogens should also be taken into account.

  • Funding
    Universidade Federal de Minas Gerais (UFMG)/Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Hospital Sofia Feldman - Belo Horizonte/MG - Brasil.

References

  • 1
    McCrossan BA, McHenry E, O'Neill F, Ong G, Sweet DG. Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection. Arch Dis Child Fetal Neonatal Ed. 2007;92:F454-8.
  • 2
    Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics. 2006;118:2359-64.
  • 3
    Greenberg RG, Benjamin DK. Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect. 2014;69(Suppl. 1):S19-22.
  • 4
    Kelly MS, Benjamin DK, Smith PB. The epidemiology and diagnosis of invasive candidiasis among premature infants. Clin Perinatol. 2015;42:105-17.
  • 5
    Pinhat EC, Borba MG, Ferreira ML, et al. Fungal colonization in newborn babies of very low birth weight: a cohort study. J Pediatr (Rio J). 2012;88:211-6.
  • 6
    Benjamin DK, Stoll BJ, Gantz MG, et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126:e865-73.
  • 7
    Ghazal P, Dickinson P, Smith CL. Early life response to infection. Curr Opin Infect Dis. 2013;26:213-8.
  • 8
    Brady MT. Health care-associated infections in the neonatal intensive care unit. Am J Infect Control. 2005;33:268-75.
  • 9
    Izquierdo G, Santolaya ME. Invasive candidiasis in newborns: diagnosis, treatment and prophylaxis. Rev Chilena Infectol. 2014;31:73-3.
  • 10
    Wynn JL, Benjamin DK, Benjamin DK, Cohen-Wolkowiez M, Clark RH, Smith PB. Very late onset infections in the neonatal intensive care unit. Early Hum Dev. 2012;88:217-25.
  • 11
    Benjamin DK, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117:84-92.
  • 12
    Adams-Chapman I, Bann CM, Das A, et al. Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. J Pediatr. 2013;163, 961–967.e3.
  • 13
    Blyth CC, Chen SC, Slavin MA, et al. Not just little adults: candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients. Pediatrics. 2009;123:1360-8.
  • 14
    Santolaya ME, Alvarado T, Queiroz-Telles F, et al. Active surveillance of candidemia in children from Latin America: a key requirement for improving disease outcome. Pediatr Infect Dis J. 2014;33:e40-4.
  • 15
    Hope WW, Castagnola E, Groll AH, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.. Clin Microbiol Infect. 2012;18(Suppl. 7):38-52.
  • 16
    Santolaya ME, Alvarado Matute T, de Queiroz Telles F, et al. Recommendations for the management of candidemia in neonates in Latin America. Grupo Proyecto Epico. Rev Iberoam Micol. 2013;30(Suppl. 1):158-70.
  • 17
    Figueras C, Diaz de Heredia C, Garcia JJ, et al. The Spanish Society of Paediatric Infectious Diseases (SEIP) recommendations on the diagnosis and management of invasive candidiasis. An Pediatr (Barc). 2011;74, 337.e1–e17.
  • 18
    Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of Candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1-50.
  • 19
    Kimberlin DW, editor. Red Book - Report of the Committee on Infectious Diseases. 2015.
  • 20
    Murad MH, Montori VM, Ioannidis JPA, et al. How to read a systematic review and meta-analysis and apply the results to patient care. Users' guides to the medical literature. JAMA. 2014;312:171-9.
  • 21
    Uko S, Soghier LM, Vega M, et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics. 2006;117:1243-52.
  • 22
    Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics. 2006;117:e22-32.
  • 23
    Weitkamp JH, Ozdas A, LaFleur B, Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure. J Perinatol. 2008;28:405-11.
  • 24
    Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole resistant Candida species. Pediatrics. 2008;121:703-10.
  • 25
    Rueda K, Moreno MT, Espinosa M, Saez-Llorens X. Impact of routine fluconazole prophylaxis for premature infants with birth weights of less than 1250 grams in a developing country. Pediatr Infect Dis J. 2010;29:1050-2.
  • 26
    Kaufman DA, Morris A, Gurka MJ, Kapik B, Hetherington S. Fluconazole prophylaxis in preterm infants: a multicenter case-controlled analysis of efficacy and safety. Early Hum Dev. 2014;90(Suppl. 1):S87-90.
  • 27
    Rolnitsky A, Levy I, Sirota L, Shalit I, Klinger G. Targeted fluconazole prophylaxis for high-risk very low birth weight infants. Eur J Pediatr. 2012;171:1481-7.
  • 28
    Cetinkaya M, Ercan TE, Saglam OK, Buyukkale G, Kavuncuoglu S, Mete F. Efficacy of prophylactic fluconazole therapy in decreasing the incidence of Candida infections in extremely low birth weight preterm infants. Am J Perinatol. 2014;31:1043-8.
  • 29
    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;345:1660-6.
  • 30
    Parikh TB, Nanavati RN, Patankar CV, et al. Fluconazole prophylaxis against fungal colonization and invasive fungal infection in very low birth weight infants. Indian Pediatr. 2007;44:830-7.
  • 31
    Benjamin DK, Hudak ML, Duara S, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014;311:1742-9.
  • 32
    Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-95.
  • 33
    Greenberg RG, Benjamin DK. Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect. 2014;69(Suppl. 1):S19-22.
  • 34
    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;147:172-9.
  • 35
    Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2015;62:e1-50.
  • 36
    Healy CM, Baker CJ. Fluconazole prophylaxis in the neonatal intensive care unit. Pediatr Infect Dis J. 2009;28:49-52.
  • 37
    Austin N, Darlow BA, McGuire W. Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Database Syst Rev. 2009:CD003478.
  • 38
    Clerihew L, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2007:CD003850.
  • 39
    Clerihew L, Austin N, McGuire W. Systemic antifungal prophylaxis for very low birthweight infants: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2008;93:F198-200.
  • 40
    McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2004:CD003850.
  • 41
    Mohan P, Eddama O, Weisman LE. Patient isolation measures for infants with candida colonization or infection for preventing or reducing transmission of candida in neonatal units. Cochrane Database Syst Rev. 2007:CD006068.
  • 42
    Zhang JP, Chen C. Meta-analysis of the efficacy and safety of fluconazole in prophylaxis of fungal infection in very low birth weight infants. Zhonghua Er Ke Za Zhi. 2009;47:743-891.
  • 43
    Tripathi N, Watt K, Benjanin DK. Treatment and prophylaxis of invasive candidiasis. Semin Perinatol. 2012;36:416-23.

Publication Dates

  • Publication in this collection
    May-Jun 2017

History

  • Received
    14 Nov 2016
  • Accepted
    23 Jan 2017
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