Correspondence
Fluconazole Prophylaxis against Fungal Infection in Preterm Infants
N Engl J Med 2002; 346:1913-1914June 13, 2002
- Article
To the Editor:
Kaufman et al. (Dec. 6 issue)1 define invasive fungal infections by positive cultures of blood, urine, or cerebrospinal fluid. However, it is difficult to evaluate whether all reported cases of fungal infections represented candida sepsis rather than candida colonization. The authors do not specify whether blood samples were obtained from central catheters or from peripheral vessels; it is difficult to distinguish systemic fungemia from a positive culture due to a contaminated catheter.2 Two isolated episodes of candiduria were considered to represent invasive infections, but isolated candiduria may reflect transient colonization in a patient receiving antibiotic therapy.2 The method of urine sampling was not specified; individual urine samples from bladder catheterization or sterile urine bags can easily be contaminated by perineal candidiasis.
In contrast to the report by Kaufman et al., another recent study found that fluconazole was not effective in preventing candida sepsis in 103 very-low-birth-weight infants.3 We wonder whether misclassification of fungal colonization as invasive fungal infection in the study by Kaufman et al. may explain the apparent efficacy of fluconazole in preventing invasive fungal infections.
3 ReferencesCarlo Dani, M.D.
Giovanna Bertini, M.D.
Marco Pezzati, M.D.
Careggi University Hospital of Florence, 50134 Florence, Italy
cdani@unifi.it 1
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;345:1660-1666
Full Text | Web of Science | Medline2
Khoory BJ ,Vino L ,Dall'Agnola A ,Fanos V . Candida infections in newborns: a review. J Chemother 1999;11:367-378
Web of Science | Medline3
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;107:293-298
CrossRef | Web of Science | Medline
To the Editor:
The reduction of colonization associated with fluconazole use is no better than that attained with the use of oral nystatin in infants weighing less than 1250 g who are receiving mechanical ventilation. In a randomized, controlled trial, nystatin (1 ml every eight hours until one week after extubation) reduced the rate of candida colonization from 44 percent to 6 percent.1 In the study by Kaufman et al., fluconazole led to a reduction from 60 percent to 22 percent in the rate of colonization.
The 20 percent incidence of invasive fungal disease involving all candida species in the study by Kaufman et al. is markedly higher than that in previous reports. The authors refer to a report stating that 9 percent of cases of late-onset sepsis in infants weighing less than 1500 g are related to fungal infections.2 Other reports estimate that the incidence of systemic candidiasis is approximately 3 to 5 percent in infants weighing less than 1500 g.3
There is little doubt that systemic fungal infections impose a heavy burden in extremely-low-birth-weight neonates, but the use of intravenous fluconazole does not seem to carry any significant advantage over the use of oral nystatin in preventing colonization or invasive fungal disease. In rare cases, fluconazole is associated with skin eruptions, hepatotoxic effects, and decreases in the platelet count, whereas oral nystatin is safe, effective in reducing colonization, and cheap.
3 ReferencesDan Casalaz, F.R.A.C.P., M.R.C.P.C.H.
Mercy Hospital for Women, East Melbourne 3002, Australia
dcasalaz@mercy.com. au 1
Sims ME ,Yoo Y ,You H ,Salminen C ,Walther FJ . Prophylactic oral nystatin and fungal infections in very-low-birthweight infants. Am J Perinatol 1988;5:33-36
CrossRef | Web of Science | Medline2
Stoll BJ ,Gordon T ,Korones SB , et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63-71
CrossRef | Web of Science | Medline3
McDonnell M ,Isaacs D . Neonatal systemic candidiasis. J Paediatr Child Health 1995;3:490-492
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: Dani and colleagues ask about the diagnosis of invasive fungal infection. All blood cultures were obtained from peripheral sites — none from vascular lines. Urinary tract infections were defined by the growth of more than 10,000 fungal organisms in two or more cultures of urine obtained by sterile bladder catheterization or suprapubic aspiration. Fungal urinary tract infections require intravenous antifungal therapy and can lead to candidemia and renal involvement in preterm infants.1
The study by Kicklighter et al. was designed to evaluate whether prophylactic fluconazole would reduce fungal colonization in preterm infants weighing less than 1500 g, and treatment was associated with a decrease in the rate of rectal colonization (from 46 percent to 15.1 percent, P=0.005).2 Because the incidence of fungal sepsis in preterm infants weighing less than 1500 g is low, the study was not designed to show a difference in the incidence of fungal sepsis; indeed, only one patient had fungal sepsis during the treatment period.
When comparing our results with those of other studies, it is important to consider the populations of patients. We studied preterm infants weighing less than 1000 g who had additional risk factors for invasive fungal infection, including the presence of an endotracheal tube or a central vascular line.3 Preterm infants weighing less than 1000 g have a much higher incidence of invasive fungal infection and associated mortality than do preterm infants weighing less than 1500 g. In a series of 6911 preterm infants, the incidence of fungal sepsis was 3.2 percent among those weighing less than 1500 g,3 as compared with 9.9 percent among infants weighing less than 1000 g.4
Dr. Casalaz states that oral nystatin is as effective as fluconazole in reducing fungal colonization. Sims et al. studied prophylaxis with oral (nonabsorbable) nystatin for decontamination of the gastrointestinal tract in 67 preterm infants weighing less than 1250 g and found a significant difference between the groups only in the incidence of fungal urinary tract infections (6 percent in the nystatin group [2 patients] vs. 29 percent in the control group [10 patients]).5 Fungal sepsis occurred in none of the patients who were treated with oral nystatin, as compared with two of the control patients (6 percent). Preterm infants weighing less than 1000 g often cannot tolerate this oral therapy or do not receive the therapy because of clinical instability.6
The dose of fluconazole in our study was 3 mg per kilogram of body weight — half the standard dose — and it was given less frequently than is standard for the treatment of documented invasive fungal infection (5 to 10 mg per kilogram per day). These factors may be responsible for the low rate of adverse outcomes we observed, as compared with that found with the usual dosing regimens used to treat invasive fungal infection in neonates.
6 ReferencesDavid Kaufman, M.D.
Robert Boyle, M.D.
Leigh B. Donowitz Grossman, M.D.
University of Virginia Health System, Charlottesville, VA 22908
dak4r@virginia.edu 1
Phillips JR ,Karlowicz MG . Prevalence of Candida species in hospital-acquired urinary tract infections in a neonatal intensive care unit. Pediatr Infect Dis J 1997;16:190-194
CrossRef | Web of Science | Medline2
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;107:293-298
CrossRef | Web of Science | Medline3
Stoll BJ ,Gordon T ,Korones SB , et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63-71
CrossRef | Web of Science | Medline4
Kossoff EH ,Buescher ES ,Karlowicz MG . Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases. Pediatr Infect Dis J 1998;17:504-508
CrossRef | Web of Science | Medline5
Sims ME ,Yoo Y ,You H ,Salminen C ,Walther FJ . Prophylactic oral nystatin and fungal infections in very-low-birthweight infants. Am J Perinatol 1988;5:33-36
CrossRef | Web of Science | Medline6
Damjanovic V ,Connolly CM ,van Saene HK , et al. Selective decontamination with nystatin for control of a Candida outbreak in a neonatal intensive care unit. J Hosp Infect 1993;24:245-259
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
W McGuire, L Clerihew, N Austin, William McGuire. 2004. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants. .
CrossRef
