Fungal Ecology in a Tertiary Neonatal Intensive Care Unit after 16 Years of Routine Fluconazole Prophylaxis: No Emergence of Native Fluconazole-Resistant Strains
25. Juni 2019 (online)
Objective We analyzed the fungal ecology of a neonatal intensive care unit (NICU) over a period of 20 consecutive years following the introduction of routine fluconazole prophylaxis for all very low birth weight (VLBW; <1,500 g at birth) preterm babies. The aim was to detect the possible appearance of any ecological shifts toward the emergence of native fluconazole-resistant (NFR) fungal species.
Study Design This was a retrospective analysis of clinical and microbiological data of VLBW preterm neonates admitted to a large tertiary NICU in Italy from 1997 to 2016 and surviving more than 3 days. Colonization and infection incidence rates, both for fluconazole-sensitive Candida spp and NFR Candida spp, were calculated for each year. We compared the first 4-year period without prophylaxis (1997–2000) with the last 16-year period with use of routine fluconazole prophylaxis (2000–2016).
Results Overall, the incidence of fungal colonization significantly decreased after the introduction of prophylaxis (from 43.4% to 16.5%) as well as the systemic fungal infection incidence (from 16% to 3.7%). The proportion of colonization and infection by NFR Candida spp, on the other hand, did not increase, remaining stable throughout the 16 years of exposure to fluconazole. During the prophylaxis period, 42 of 1,172 VLBW neonates were colonized by NFR species (3.6%), and of them 11 developed a systemic infection (0.9%). During the preprophylaxis period, colonization by these particular species affected 11 of 285 VLBW neonates (3.8%), and a systemic infection involved 4 neonates (1.4%).
Conclusion Fluconazole prophylaxis is effective in decreasing Candida colonization and systemic infections in preterm neonates in NICU and did not cause emergence or shifts toward NFR Candida spp over a 16-year surveillance period.
- 1 Fridkin SK, Kaufman D, Edwards JR, Shetty S, Horan T. Changing incidence of Candida bloodstream infections among NICU patients in the United States: 1995-2004. Pediatrics 2006; 117 (05) 1680-1687
- 2 Benjamin Jr DK, Stoll BJ, Gantz MG. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics 2010; 126 (04) e865-e873
- 3 Stoll BJ, Hansen N, Fanaroff AA. , 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
- 4 Manzoni P, Pedicino R, Stolfi I. , et al; Task Force per le infezioni fungine neonatali del GSIN; Socieà Italiana di Neonatologia. Criteria for the diagnosis of systemic fungal infections in newborns: a report from the Task Force on neonatal fungal infections of the GSIN [in Italian]. Pediatr Med Chir 2004; 26 (02) 89-95
- 5 Benjamin Jr DK, Stoll BJ, Fanaroff AA. , et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006; 117 (01) 84-92
- 6 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; 107 (02) 293-298
- 7 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 (23) 1660-1666
- 8 Manzoni P, Stolfi I, Pugni L. , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med 2007; 356 (24) 2483-2495
- 9 Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E. European survey on the use of prophylactic fluconazole in neonatal intensive care units. Eur J Pediatr 2012; 171 (03) 439-445
- 10 Manzoni P, Leonessa M, Galletto P. , et al. Routine use of fluconazole prophylaxis in a neonatal intensive care unit does not select natively fluconazole-resistant Candida subspecies. Pediatr Infect Dis J 2008; 27 (08) 731-737
- 11 Benjamin Jr DK, Ross K, McKinney Jr RE, Benjamin DK, Auten R, Fisher RG. When to suspect fungal infection in neonates: a clinical comparison of Candida albicans and Candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia. Pediatrics 2000; 106 (04) 712-718
- 12 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004; 17 (03) 638-680
- 13 National Committee for Clinical Laboratory Standards. Approved Standard M27-A: Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. Wayne, PA: National Committee for Clinical Laboratory Standards; 1997
- 14 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 (04) 703-710
- 15 Autmizguine J, Smith PB. Prather et al. Effect of fluconazole prophylaxis on candida fluconazole susceptibility in premature infants. J Antimicrob Chemother 2018; 73: 3482-3487
- 16 Sarvikivi E, Lyytikäinen O, Soll DR. , et al. Emergence of fluconazole resistance in a Candida parapsilosis strain that caused infections in a neonatal intensive care unit. J Clin Microbiol 2005; 43 (06) 2729-2735
- 17 Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000; 181 (01) 309-316
- 18 Safran DB, Dawson E. The effect of empiric and prophylactic treatment with fluconazole on yeast isolates in a surgical trauma intensive care unit. Arch Surg 1997; 132 (11) 1184-1188
- 19 Husain S, Tollemar J, Dominguez EA. , et al. Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients: prospective, multicenter, case-controlled study. Transplantation 2003; 75 (12) 2023-2029
- 20 Fan X, Xiao M, Liao K. , et al. Notable increasing trend in azole non-susceptible Candida tropicalis causing invasive candidiasis in China (August 2009 to July 2014): molecular epidemiology and clinical azole consumption. Front Microbiol 2017; 8: 464
- 21 Marins TA, Marra AR, Edmond MB. , et al. Evaluation of Candida bloodstream infection and antifungal utilization in a tertiary care hospital. BMC Infect Dis 2018; 18 (01) 187
- 22 Yoder BA, Sutton DA, Winter V, Coalson JJ. Resistant Candida parapsilosis associated with long term fluconazole prophylaxis in an animal model. Pediatr Infect Dis J 2004; 23 (07) 687-688
- 23 Autmizguine J, Smith PB, Prather K. , et al; Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on Candida fluconazole susceptibility in premature infants. J Antimicrob Chemother 2018; 73 (12) 3482-3487