Comparison of Fluconazole and Nystatin Oral Suspensions for Prophylaxis of Systemic Fungal Infection in Very Low Birthweight Infants

ABSTRACT

We compared the efficacy and safety of fluconazole and nystatin oral suspensions for the prevention of systemic fungal infection (SFI) in very low birthweight infants. A prospective, randomized clinical trial was conducted over a 15-month period, from May 1997 through September 1998, in 80 preterm infants with birthweights <1500 g. The infants were randomly assigned to receive oral fluconazole or nystatin, beginning within the first week of life. Prophylaxis was continued until full oral feedings were attained. Blood and urine cultures were obtained at enrollment and then weekly thereafter. Thirty-eight infants were randomly assigned to receive oral fluconazole (group I), and 42 infants were assigned to receive nystatin (group II). Birthweight, gestational age, and risk factors for fungal colonization and SFI at the time of randomization and during the hospital course were similar in both groups. SFI developed in two infants (5.3%) in group I and six infants (14.3%) in group II. The difference between these two rates was not statistically significant (relative risk, 0.37; 95% confidence interval, 0.08 to 1.72). There were no deaths in group I and six deaths in group II (p = 0.03). Two infants died of neonatal sepsis, and four deaths were related to necrotizing enterocolitis and/or spontaneous intestinal perforation. No deaths were due to SFI. Enrollment was halted before completion and the study did not attain adequate power to detect a hypothesized drop in SFI rate from 15 to 5%. Although the results cannot justify any conclusion about the relative efficacy of fluconazole versus nystatin in prevention of SFI, the significantly higher mortality rate in the nystatin group raises questions about the relative safety of this medication.

KEYWORDS

Fluconazole - nystatin - fungal infections - very low birthweight infants

REFERENCES

• 1 Stoll B J, Hansen N, Fanaroff A A et al.. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network.  Pediatrics. 2002;  110(2 Pt 1) 285-291
• 2 Makhoul I R, Sujov P, Smolkin T, Lusky A, Reichman B. Epidemiological, clinical, and microbiological characteristics of late-onset sepsis among very low birth weight infants in Israel: a national survey.  Pediatrics. 2002;  109(1) 34-39
• 3 Kossoff E H, Buescher E S, Karlowicz M G. Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases.  Pediatr Infect Dis J. 1998;  17(6) 504-508
• 4 Fanaroff A A, Korones S B, Wright L L The National Institute of Child Health and Human Development Neonatal Research Network et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants.  Pediatr Infect Dis J. 1998;  17(7) 593-598
• 5 Benjamin Jr D K, Stoll B J, Fanaroff A A National Institute of Child Health and Human Development Neonatal Research Network 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(1) 84-92
• 6 Saiman L, Ludington E, Pfaller M et al.. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey study group.  Pediatr Infect Dis J. 2000;  19(4) 319-324
• 7 Mittal M, Dhanireddy R, Higgins R D. Candida sepsis and association with retinopathy of prematurity.  Pediatrics. 1998;  101(4 Pt 1) 654-657
• 8 Friedman S, Richardson S E, Jacobs S E, O'Brien K. Systemic Candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome.  Pediatr Infect Dis J. 2000;  19(6) 499-504
• 9 Faix R G, Kovarik S M, Shaw T R, Johnson R V. Mucocutaneous and invasive candidiasis among very low birth weight (less than 1,500 grams) infants in intensive care nurseries: a prospective study.  Pediatrics. 1989;  83(1) 101-107
• 10 Rowen J L, Rench M A, Kozinetz C A, Adams Jr J M, Baker C J. Endotracheal colonization with Candida enhances risk of systemic candidiasis in very low birth weight neonates.  J Pediatr. 1994;  124(5 Pt 1) 789-794
• 11 Austin N C, Darlow B. Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants.  Cochrane Database Syst Rev. 2004;  (1) CD003478
• 12 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;  (1) CD003850
• 13 Sims M E, Yoo Y, You H, Salminen C, Walther F J. Prophylactic oral nystatin and fungal infections in very-low-birthweight infants.  Am J Perinatol. 1988;  5(1) 33-36
• 14 Ozturk M A, Gunes T, Koklu E, Cetin N, Koc N. Oral nystatin prophylaxis to prevent invasive candidiasis in neonatal intensive care unit.  Mycoses. 2006;  49 484-492
• 15 Kaufman D, Boyle R, Hazen K C, Patrie J T, Robinson M, Donowitz L G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.  N Engl J Med. 2001;  345(23) 1660-1666
• 16 Kicklighter S D, Springer S C, Cox T, Hulsey T C, Turner R B. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.  Pediatrics. 2001;  107(2) 293-298
• 17 Manzoni P, Arisio R, Mostert M et al.. Prophylactic fluconazole is effective in preventing fungal systemic infections in preterm neonates: A single-center, 6-year, retrospective cohort study.  Pediatrics. 2006;  117 e22-e32
• 18 Uko S, Soghier L M, Vega M et al.. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants.  Pediatrics. 2006;  117(4) 1243-1252
• 19 Bertini G, Perugi S, Dani C, Filippi L, Prates S, Rubaltelli F F. Fluconazole prophylaxis prevents invasive fungal invasive infection in high-risk, very low birth weight infants.  J Pediatr. 2005;  147 162-165
• 20 Healy C M, Baker C J, Zaccaria E, Campbell J R. Impact of fluconazole prophylaxis on incidence and outcome of invasive candidiasis in a neonatal intensive care unit.  J Pediatr. 2005;  147(2) 166-171
• 21 Burwell L A, Kaufman D, Blakely J, Stoll B J, Fridkin S K. Antifungal prophylaxis to prevent neonatal candidiasis: a survey of perinatal physician practices.  Pediatrics. 2006;  118(4) e1019-e1026
• 22 U.S. Food and Drug Administration .Approval letter, final printed labeling, and chemistry review(s). Nystatin oral suspension USP. Approval date: June 25, 1998. http://Available at www.fda.gov/cder/foi/anda/98/64142.htm Accessed April 14, 2009
• 23 Antifungal agents for common paediatric infections.  Paediatr Child Health. 2007;  12(10) 875-883
• 24 Mutz A E, Obladen M W. Hyperosmolar oral medication and necrotizing enterocolitis.  Pediatrics. 1985;  75(2) 371-372
• 25 Novelli V, Holzel H. Safety and tolerability of fluconazole in children.  Antimicrob Agents Chemother. 1999;  43(8) 1955-1960
• 26 Charlier C, Hart E, Lefort A et al.. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?.  J Antimicrob Chemother. 2006;  57(3) 384-410
• 27 Flynn P M, Cunningham C K, Kerkering T The Multicenter Fluconazole Study Group et al. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.  J Pediatr. 1995;  127(2) 322-328
• 28 Groll A H, Just-Nuebling G, Kurz M et al.. Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer.  J Antimicrob Chemother. 1997;  40(6) 855-862
• 29 Kaufman D, Fairchild K D. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants.  Clin Microbiol Rev. 2004;  17(3) 638-680
• 30 Aghai Z H, Mudduluru M, Nakhla T A et al.. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis.  J Perinatol. 2006;  26(9) 550-555