Twice Weekly Fluconazole Prophylaxis for Prevention of Invasive Candida Infection in High-risk Infants of <1000 Grams Birth Weight

doi:10.1016/j.jpeds.2005.03.036

The Journal of Pediatrics

Volume 147, Issue 2, August 2005, Pages 172-179

https://doi.org/10.1016/j.jpeds.2005.03.036 Get rights and content

Objectives

We tested the hypothesis that twice weekly prophylactic dosing of fluconazole prevents invasive candidiasis without promoting resistant Candida species in high-risk, preterm infants.

Study design

We compared our previous dosing schedule (Group A) to a less frequent dosing schedule of twice a week (Group B) of fluconazole prophylaxis for up to 6 weeks in a prospective, randomized, double-blind clinical trial in preterm infants weighing <1000 grams at birth and with an endotracheal tube and/or central vascular catheter over a 24-month period. Weekly surveillance cultures were obtained on study patients.

Results

Candida colonization was documented in 5 (12%) of 41 Group A and in 4 (10%) of 40 Group B infants. Candida sepsis developed in two (5%) of Group A and one (3%) of Group B infants (risk difference, −0.02; 95% confidence interval, −0.14-0.10; P = .68). All fungal isolates remained sensitive to fluconazole, and no drug side effects were documented.

Conclusions

Twice weekly dosing of prophylactic fluconazole can decrease Candida colonization and invasive infection, cost, and patient exposure in high-risk, preterm infants weighing <1000 grams at birth. We speculate that lower and less frequent dosing may delay or prevent the emergence of antifungal resistance.

Section snippets

Study Design

We conducted a prospective, randomized, double-blind clinical trial to evaluate the efficacy of twice weekly intravenous fluconazole prophylaxis to prevent Candida colonization and invasive infection. Twice weekly fluconazole prophylaxis was compared with the dosing schedule used in our previous study (Table I). Invasive Candida infection was defined as isolation of Candida species from the blood (venipuncture), urine (≥10⁵ or more colony forming units/mL from sterile bladder catheterization or

Study Participants

Forty-one infants were randomized to Group A and 40 infants were randomized to Group B over the 24-month period between July 23, 2001, and July 4, 2003. Infants were born during the study period at our institution or transferred from another facility. Ninety-eight patients were born weighing <1000 grams. Nine of these patients did not require a central vascular catheter or endotracheal tube and thus were ineligible for study enrollment. A total of 89 infants met enrollment criteria during the

Discussion

This pilot study demonstrates that twice weekly dosing of fluconazole prophylaxis is similar in efficacy compared with the more frequent dosing of our earlier study in high-risk, preterm infants. The incidence of Candida colonization and invasive infection was similar for both regimens, and neither was associated with the emergence of resistant Candida or other fungal species. Twice weekly dosing, when compared with our previous study regimen, reduces the total number of fluconazole doses per

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The introduction of antifungal triazoles in the 1990s was a major breakthrough in antifungal chemotherapy and has revolutionized prevention and treatment over the ensuing decades: Fluconazole and itraconazole were the first viable alternatives to standard treatment with amphotericin B deoxycholate and assumed an important role in systemic antifungal prophylaxis in high-risk patient populations. A decade later, voriconazole became the first-line option for treatment of invasive aspergillosis, yielding improved response rates and overall survival relative to amphotericin B deoxycholate. Around the same time, posaconazole was developed as a highly effective prophylactic agent, reducing invasive fungal infections in comparison to fluconazole or itraconazole, and improving overall outcome of treated patients. Finally, the recent introduction of isavuconazole has provided an equally effective alternative to voriconazole in treatment of invasive aspergillosis with an additional indication for treatment of mucormycosis.
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Adjunctive testing to identify fungi have a role in high-risk patients, but due to the prevalence of ICI and cost of testing, it does not have utility with all sepsis evaluations. Polymerase chain reaction (PCR) and cell wall polysaccharides such as (1-3)-beta-D-glucan (BDG) and mannan are helpful in high-risk patients in determining the need for empiric antifungal therapy and detecting infections that are not in the bloodstream. A higher cutoff for BDG >125 pg/mL for neonates may be helpful, as BDG can be elevated with bacteremia, colonization, and blood transfusions. BDG levels decrease with treatment. Mannan has been used to identify high-risk patients who may benefit from preemptive antifungal treatment.
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Original ArticleTwice Weekly Fluconazole Prophylaxis for Prevention of Invasive Candida Infection in High-risk Infants of <1000 Grams Birth Weight

Objectives

Study design

Results

Conclusions

Section snippets

Study Design

Study Participants

Discussion

Fluconazole prophylaxis against fungal colonization and infection in preterm infants

N Engl J Med

Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus

Antimicrob Agents Chemother

The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans

Antimicrob Agents Chemother

Stable azole drug resistance associated with a substrain of Candida albicans from an HIV-infected patient

Oral Dis

Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus-positive patients: persistence of Candida albicans strains with the same genotype

J Clin Microbiol

Mechanisms of fungal resistance: an overview

Drugs

Clinical, cellular, and molecular factors that contribute to antifungal drug resistance

Clin Microbiol Rev

Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life

Clin Pharmacol Ther

Pharmacokinetics of fluconazole in pediatric patients

Eur J Clin Microbiol Infect Dis

Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis

N Engl J Med

Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis

N Engl J Med

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

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

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

Original Article
Twice Weekly Fluconazole Prophylaxis for Prevention of Invasive Candida Infection in High-risk Infants of <1000 Grams Birth Weight