Prophylactic fluconazole decreases incidence of invasive candidiasis in preterm infants

Article Outline

• Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al for the Italian Task Force for the Study and Prevention of Neonatal Fungal Infections and Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med 2007;356:2483-95
  • Question
  • Design
  • Setting
  • Participants
  • Intervention
  • Outcomes
  • Results
  • Conclusions
  • Commentary
• Copyright

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Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al for the Italian Task Force for the Study and Prevention of Neonatal Fungal Infections and Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med 2007;356:2483-95 

Question 

In very low birth weight (VLBW) infants, does fluconazole prevent fungal colonization and infection?

Design 

Multicenter, randomized, controlled trial.

Setting 

Eight tertiary Italian neonatal intensive care units.

Participants 

All neonates weighing <1500 g at birth (n = 322).

Intervention 

Infants were randomly assigned to receive either fluconazole (either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth).

Outcomes 

Incidence of colonization and incidence of invasive fungal infection.

Results 

In infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P < .001 for both fluconazole groups versus the placebo group, number needed to treat [NNT] = 6 for the 6 mg dose and 5 for the 3 mg dose). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P = .005 for the 6-mg group, NNT = 10, and P = .02 for the 3-mg group versus the placebo group, NNT = 11). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect.

Conclusions 

Prophylactic fluconazole reduces the incidence of colonization (NNT = 5-6) and invasive candida infection (NNT = 10-11) in neonates weighing <1500 g at birth. The benefit of treating candida colonization is unclear.

Commentary 

This study offers the strongest support for fluconazole prophylaxis of invasive candidiasis in preterm neonates to date. Despite these apparently encouraging findings, caution remains warranted before embracing this strategy as standard for care. It took 15 months for the 8 participating Italian neonatal intensive care units to identify 363 VLBW infants (although 27 were excluded from enrollment and another 14 from analysis) and enroll 141 extremely low birth weight (ELBW; birth weight ≤1000 grams) infants. This suggests that each neonatal intensive care unit admitted slightly >3 VLBW and 1 ELBW infant per month, totals much lower than would be seen in most neonatal intensive care units in the United States. This may be an important factor, because development of antimicrobial resistance in a discrete care unit (such as an intensive care unit) is often dependent on the frequency and intensity of exposure of flora to the antimicrobial agent in question. The larger the number of VLBWs and ELBWs present in a neonatal intensive care unit and receiving a specific antimicrobial agent, the greater is the likelihood that resistance to that agent will develop (although the speed at which such a development occurs varies with the family of antimicrobial). The absence of induced fluconazole resistance in this study may reflect the relatively short duration of the study and the apparently limited exposure to the agent within each neonatal intensive care unit.

The reported lack of improvement in overall mortality and duration of neonatal intensive care unit hospitalization in this study are disappointing, but not necessarily surprising, because of the relatively small number of infected infants and VLBW and ELBW infants frequently encountering numerous other challenges that determine the duration and outcome of their hospitalization. Because the outcome for neonatal intensive care unit graduates of most interest is long-term survival without (or at least without severe) neurodevelopmental morbidity, it would be of considerable interest to learn whether there is any appreciable difference between the study groups at 18 months corrected age or later. The well-known occurrence of invasive candidiasis found at autopsy despite negative antemortem culture results also makes it worthwhile to know how many of the 28 infants who died underwent autopsy. Of those who apparently died of other causes, what were the causes and is there any possible relationship of fluconazole or fungal infection to those causes? Despite these reasons for caution, it is notable that most of the accumulating evidence about fluconazole prophylaxis in premature infants so far suggests that benefits outweigh risks. Neonatal intensive care units that have a critical frequency of invasive candidiasis may wish to give this intervention serious consideration for selected high-risk infants. Further data remain warranted and desirable.