Fluconazole prophylaxis: Can we eliminate invasive Candida infections in the neonatal ICU?

Current Opinion in Pediatrics

Volumn 20, Issue 3, 2008, Pages 332-340

  Kaufman, David A ^a,b  

^a UNIVERSITY OF VIRGINIA   (United States)

^b UNIVERSITY OF VIRGINIA HEALTH SYSTEM   (United States)

Author keywords

Antifungal prophylaxis; Candida; Fluconazole; Neonatal candidiasis; Preterm infant

Indexed keywords

AMPHOTERICIN B DEOXYCHOLATE; FLUCONAZOLE; NYSTATIN;

BACTERIAL INFECTION; CANDIDA; CANDIDA GLABATA; CANDIDA PARAPSILOSIS; CANDIDIASIS; CENTRAL VENOUS CATHETER; CHOLESTASIS; CLINICAL TRIAL; CONFIDENCE INTERVAL; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG MEGADOSE; ERADICATION THERAPY; FUNGAL COLONIZATION; GESTATIONAL AGE; HOSPITAL COST; HOSPITALIZATION; HUMAN; INCIDENCE; LOW DRUG DOSE; MORTALITY; NECROTIZING ENTEROCOLITIS; NEUROLOGIC DISEASE; NEWBORN INTENSIVE CARE; NOTE; PREMATURITY; PRIORITY JOURNAL; PROPHYLAXIS; RETROSPECTIVE STUDY; RISK; SEPSIS; URINARY TRACT INFECTION;

ANTIFUNGAL AGENTS; CANDIDIASIS; FLUCONAZOLE; HUMANS; INFANT; INFANT, NEWBORN; MULTICENTER STUDIES AS TOPIC; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 43449117784     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/MOP.0b013e3282f79c48     Document Type: Note

References (49)

1. Fridkin SK, Kaufman D, Edwards JR, et al. Changing incidence of Candida bloodstream infections among NICU patients in the United States: 1995-2004. Pediatrics 2006; 117:1680-1687. Largest multicenter data analysis of Candida BSIs, data from the NNIS from 1995 to 2004 from 132 NICUs and 130 523 neonates. For infants <1000 g, >50% of NICUs had fungal BSI rates of 7.5% and 25% had rates >13.5%. There was variation between NICUs ranging from 3 to 23% for the 10th and 90th percentiles. Limited in only reporting BSIs and not all ICI.
2. Cotten CM, McDonald S, Stoll B, et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006; 118:717-722. This study reported an incidence of Candida BSIs or meningitis of 7.7% in infants <1000g. Center candidiasis incidence ranged from 2.4 to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant.
3. Kaufman D, Boyle R, Hazen KC, et al. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001; 345:1660-1666.
4. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial on prophylactic fluconazole in preterm neonates. N Engl J Med 2007; 356:2483-2495. First multicenter RCT of fluconazole prophylaxis. This study demonstrates efficacy, safety and no emergence or change in resistance in all infants <1500 g, and subgroup analysis of both infants <27 weeks gestation and <1000 g.
5. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38:161-189.
6. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96:2055-2061.
7. 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; 181:309-316.
8. Kicklighter SD, Springer SC, Cox T, et al. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics 2001; 107:293-298.
9. 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 2003; 1:CD003850.
10. American Academy of Pediatrics. Candidiasis. In: Pickering L, Baker CJ, Long SS, McMillian JA, editors. Red book: 2006 report of the Committee on Infectious Diseases. Elk Grove Village: American Academy of Pediatrics; 2006. pp. 242-246.
11. Burwell LA, Kaufman D, Blakely J, et al. Antifungal prophylaxis to prevent neonatal candidiasis: a survey of perinatal physician practices. Pediatrics 2006; 118:e1019-e1026.
12. Walsh TJ, Gonzalez CE, Piscitelli S, et al. Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis. J Clin Microbiol 2000; 38:2369-2373.
13. Vaden SL, Heit MC, Hawkins EC, et al. Fluconazole in cats: pharmacokinetics following intravenous and oral administration and penetration into cerebrospinal fluid, aqueous humour and pulmonary epithelial lining fluid. J Vet Pharmacol Ther 1997; 20:181-186.
14. Koks CH, Crommentuyn KM, Hoetelmans RM, et al. Can fluconazole concentrations in saliva be used for therapeutic drug monitoring? Ther Drug Monit 2001; 23:449-453.
15. Schuman P, Capps L, Peng G, et al. Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. Ann Intern Med 1997; 126:689-696.
16. Houang ET, Chappatte O, Byrne D, et al. Fluconazole levels in plasma and vaginal secretions of patients after a 150-milligram single oral dose and rate of eradication of infection in vaginal candidiasis. Antimicrob Agents Chemother 1990; 34:909-910.
17. Kojic EM, Darouiche RO. Candida infections of medical devices. Clin Microbiol Rev 2004; 17:255-267.
18. Ellepola AN, Samaranayake LP. Adhesion of oral C. albicans to human buccal epithelial cells following limited exposure to antifungal agents. J Oral Pathol Med 1998; 27:325-332.
19. Hazen KC, Coleman E, Wu G. Influence of fluconazole at subinhibitory concentrations on cell surface hydrophobicity and phagocytosis of Candida albicans. FEMS Microbiol Lett 2000; 183:89-94.
20. Ghannoum MA, Filler SG, Ibrahim AS, et al. Modulation of interactions of Candida albicans and endothelial cells by fluconazole and amphotericin B. Antimicrobial Agents Chemother 1992; 36:2239-2244.
21. Faergemann J, Laufen H. Levels of fluconazole in serum, stratum corneum, epidermis-dermis (without stratum corneum) and eccrine sweat. Clin Exp Dermatol 1993; 18:102-106.
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-e32.
23. Manzoni P, Farina D, Galletto P, et al. Type and number of sites colonized by fungi and risk of progression to invasive fungal infection in preterm neonates in neonatal intensive care unit. J Perinat Med 2007; 35:220-226. High-grade (colonization of three or more sites) and high-risk colonization (urine, catheter tip, drains, surgical devices) (P=0.001 for both), birth weight (P=0.02) and presence of CVC (P=0.04) remained independent predictors of invasive fungal infections.
24. Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics 2006; 118:2359-2364. Fungal colonization of the CVC and colonization in multiple sites remained significantly associated with invasive fungal infection.
25. Kaufman DA, Gurka MJ, Hazen KC, et al. Patterns of fungal colonization in preterm infants weighing less than 1000 g at birth. Pediatr Infect Dis J 2006; 25:733-737. Fungal colonization occurs on the skin and gastrointestinal tract before the respiratory tract. In addition, C. albicans is more likely than C. parapsilosis to colonize multiple sites.
26. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998; 11:382-402.
27. Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004; 351:876-883.
28. Schelonka RL, Chai MK, Yoder BA, et al. Volume of blood required to detect common neonatal pathogens. J Pediatr 1996; 129:275-278.
29. Sarkar S, Bhagat I, DeCristofaro JD, et al. A study of the role of multiple site blood cultures in the evaluation of neonatal sepsis. J Perinatol 2006; 26:18-22.
30. Kaufman D, Boyle R, Hazen KC, et al. Twice weekly fluconazole prophylaxis for prevention of invasive candida infection in high-risk infants of <1000 g birth weight. J Pediatr 2005; 147:172-179.
31. Sarvikivi E, Lyytikainen 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; 43:2729-2735.
32. Bertini G, Perugi S, Dani C, et al. Fluconazole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infants. J Pediatr 2005; 147:162-165.
33. Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on incidence and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005; 147:166-171.
34. 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; 117:1243-1252. Retrospective study of fluconazole prophylaxis in infants <1500 g when receiving >3 days of antibiotic treatment; 80% of infants <1000 g and 40% infants 1000-1500 g received prophylaxis. Needs confirmation in RCT.
35. Aghai ZH, Mudduluru M, Nakhla TA, et al. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis. J Perinatol 2006; 26:550-555. Retrospective study of fluconazole prophylaxis in infants <1000 g. Major effect in infants <750 g. Cholestasis was more common in infants during fluconazole prophylaxis time period, but not different at the time of discharge between groups.
36. Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004; 17:638-680.
37. Manzoni P, Mostert M, Latino MA, et al. Routinary use of fluconazole prophylaxis in a neonatal intensive care unit does not select natively fluconazole-resistant Candida subspecies. Pediatr Infect Dis J 2008; Epub ahead of print. There was no emergence or increase in the incidence of colonization or infection due to C. glabrata or C. krusei reported in this single center over 10 years (4 years prior to and 6 years post fluconazole prophylaxis). For these species, colonization and invasive fungal infection remained stable around 4 and 1%, respectively.
38. 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; 23:687-688.
39. Safdar A, Chaturvedi V, Cross EW, et al. Prospective study of Candida species in patients at a comprehensive cancer center. Antimicrob Agents Chemother 2001; 45:2129-2133.
40. Saxen H, Hoppu K, Pohjavuori M. Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life. Clin Pharmacol Ther 1993; 54:269-277.
41. Sims ME, Yoo Y, You H, et al. Prophylactic oral nystatin and fungal infections in very-low-birthweight infants. Am J Perinatol 1988; 5:33-36.
42. Ozturk MA, Gunes T, Koklu E, et al. Oral nystatin prophylaxis to prevent invasive candidiasis in neonatal intensive care unit. Mycoses 2006; 49:484-492. Prospective study demonstrating efficacy of nystatin prophylaxis. Most effective in infants <1500 g when started in first 2 days of life. Not as effective when started after colonization was detected.
43. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292:2357-2365.
44. Benjamin DK Jr, 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. Neurodevelopmental outcome in infants <1000 g with Candida BSI or meningitis was 57 vs. 36% in infants with or without other infections during the hospitalization. Empiric and prompt therapy did not affect outcomes. Delayed catheter removal or replacement was associated with increased mortality. Limitation: only 30% of patients had CVC removal at time of diagnosis and some patients only had their catheter replaced, which would not be the optimal management of Candida BSIs. This may have affected outcomes.
45. Smith PB, Morgan J, Benjamin JD, et al. Excess costs of hospital care associated with neonatal candidemia. Pediatr Infect Dis J 2007; 26:197-200. Candida BSI was associated with increased median hospital costs of $28 446 and length of stay of 9 days. Hospital costs were significantly higher in infants >750 g and length of stay in infants >1000 g. Study limitation: used ICD-9 codes which may or may not have been chosen for ICIs.
46. Zaoutis TE, Heydon K, Localio R, et al. Outcomes attributable to neonatal candidiasis. Clin Infect Dis 2007; 44:1187-1193. ICIs increased costs by >$39 045 in infants <1000 g and by $122 302 in infants ≥1000 g with an additional length of stay of 16 days. Overall morality rate of 26% with attributable mortality of 11.9% due to invasive candidiasis. At one center the ICD-9 code was only used in 70% of the cases. Study limitation: used ICD-9 codes which may or may not have been chosen for ICIs.
47. Makhoul IR, Bental Y, Weisbrod M, et al. Candidal versus bacterial late-onset sepsis in very low birthweight infants in Israel: a national survey. J Hosp Infect 2007; 65:237-243. Candidal sepsis, compared with bacterial sepsis, was associated with decreasing gestational age and bronchopulmonary dysplasia (BPD). BPD only (OR1.84; 95% CI 1.03-3.23) and BPD with postnatal steroid therapy (OR 2.66; 95% CI 1.59-4.46) were independently associated with an increased risk for candidal sepsis.
48. Johnsson H, Ewald U. The rate of candidaemia in preterm infants born at a gestational age of 23-28 weeks is inversely correlated to gestational age. Acta Paediatr 2004; 93:954-958.
49. Feja KN, Wu F, Roberts K, et al. Risk factors for candidemia in critically ill infants: a matched case-control study. J Pediatr 2005; 147:156-161.