Does fluconazole prophylaxis reduce the incidence of death or invasive candida infection in extremely preterm infants?

MANUSCRIPT CITATION:

Benjamin DK Jr, Hudak ML, Duara S, et al. Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742-9 doi: 10.1001/jama.2014.2624. PMID 24794367

REVIEWED BY:

Ravi Mangal Patel MD, MSc
Assistant Professor of Pediatrics, Division of Neonatology
Emory University School of Medicine, Atlanta, GA

TYPE OF INVESTIGATION:

Prevention

QUESTION:

In infants weighing <750 grams at birth, does prophylactic use of fluconazole at a dose of 6mg/kg administered twice weekly for 42 days reduce the incidence of either death or invasive candidiasis by 49 days of postnatal age when compared to placebo?

METHODS:

  • Design: Randomized clinical trial
  • Allocation: Interactive voice recognition system used to randomize infants in fixed block sizes of 4, stratified by site. Siblings assigned to the same treatment group.
  • Blinding: Treatment group was blinded from site investigators, parents, and clinicians ascertaining the secondary neurodevelopmental outcome at 18 to 22 months. Site pharmacists preparing the study drug, who were unblinded, mixed the placebo to be the same consistency and color as fluconazole.
  • Follow-up period: Primary outcome: 49 days after randomization (1 week after completion of study drug). Secondary outcomes: Evaluated at hospital discharge and 18 to 22 months corrected age.
  • Setting: 32 neonatal intensive care units in the United States
  • Patients: Infants with a birthweight of <750 grams who were less than 120 hours old were eligible for enrollment. Infants receiving systemic antifungal therapy, diagnosed with a congenital anomaly or invasive candidiasis, or with abnormal liver or kidney function (aspartate transaminase (AST) or alanine transaminase (ALT) levels greater than 250 U/L or creatinine greater than 2mg/dL) were excluded.
  • Intervention: Randomization to either experimental group (fluconazole at a dose of 6mg/kg) or control (normal saline) administered twice weekly for 42 days. Study drug was administered intravenously, unless there was no intravenous access, in which case the study drug was administered by feeding tube.
  • Outcomes:
    • Primary outcome: The primary outcome was a composite of death or definite or probable invasive candidiasis prior to study day 49.
      • Definite candidiasis was defined as a positive Candida culture from a normally sterile site such as blood, cerebrospinal fluid, peritoneal fluid or urine (obtained by suprapubic or one-time urethral catheterization).
      • Probable invasive candidiasis was defined as the receipt of > 5 days of consecutive antifungal therapy and both thrombocytopenia (<150,000/103 μL) and a positive Candida culture from a non-sterile site such as urine obtained from a bag specimen.
    • Secondary outcomes: A number of secondary and safety outcomes were evaluated. These included individual components of the composite primary outcome as well as neurodevelopmental impairment determined by either a Bayley-III cognition composite score < 70, blindness, deafness, or diagnosis of cerebral palsy.
  • Analysis and Sample Size: Based on prior published studies, the authors estimated the incidence of death or candidiasis among infants with a birthweight <750g to be 30%. The trial had a power of 92%, assuming a type I error of 0.05, to detect a decrease in the incidence of death or candidiasis from 30% (control) to 15% (experimental group) for a risk difference of 15%. The full analysis data set was defined as all randomized infants who received at least 1 dose of study drug (modified intention to treat). The authors accounted for correlation from multiple births that were randomized to the same study arm using generalized estimating equations. Missing outcome data was evaluated in sensitivity analyses. No adjustment was made for an increased type I error from multiple testing of secondary outcomes.
  • Patient follow-up: Of 2153 screened infants, 362 were randomized (189 received fluconazole and 173 received placebo). Of the 362 randomized, 361 received the study drug and were analyzed for the primary outcome in a modified intention to treat analysis. Although overall completion of follow-up at 18-22 months was low (62% of randomized), there was non-differential loss to follow-up: a total of 118 (63%) of infants randomized to fluconazole and 107 (62%) infants randomized to placebo completed 18-22 month neurodevelopmental follow-up assessment.

MAIN RESULTS:

Primary outcome
Outcome Fluconazole

(n = 188)

Placebo

(n=173)

Treatment difference (95%CI) P value
Death or candidiasis before day 49, n (%) 31/188 (16) 37/173 (21) -5 (-13 to 3) 0.24
Secondary outcomes
Death before day 49, n (%) 27/188 (14) 25/173 (14) 0 (-7 to 7) 0.98
Invasive candidiasis, n (%) 6/188 (3) 16/173 (9) -6 (-11 to -1) 0.02
Neurodevelopmental impairment, n (%) 27/87 (31) 23/84 (27) 4 (-10 to 17) 0.60

Fluconazole treatment, compared to placebo, did not have an effect on the incidence of the composite primary outcome of death or invasive candidiasis before day 49. Similarly, there was no effect when this same endpoint was evaluated before hospital discharge. Treatment with fluconazole, compared to placebo, did reduce the incidence of invasive candidiasis, which was a component of the composite outcome (P=0.02). There was no difference in a number of safety end points between fluconazole and placebo groups, including increases in liver enzymes, conjugated bilirubin or infection. Of note, spontaneous intestinal perforation was more common in the fluconazole group compared to the placebo group when initially measured by the sites (treatment difference 7; 95% CI 1 to 13; P=0.03), but this difference was no longer present after central adjudication of cases (treatment difference 3; 95% CI -2 to 8; P=0.22).

CONCLUSION:

The authors conclude that among infants weighing < 750 g at birth, fluconazole prophylaxis, compared to placebo, did not decrease the incidence of the composite outcome of death or invasive candidiasis. The authors go on to conclude that their findings do not support the universal use of prophylactic fluconazole in extremely low birth weight infants.

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COMMENTARY:

Invasive candida infection in preterm infants is associated with a case-fatality rate of approximately 30%1 and long-term neurodevelopmental impairment is common among survivors2. Prior studies, including two randomized trials by Manzoni et al.3 and Kaufman et al.4, have identified fluconazole prophylaxis as an effective strategy to reduce the incidence of invasive candidiasis, particularly among preterm infants weighing <1000g a birth5. Indeed, the use of fluconazole prophylaxis is likely to have accounted for some of the temporal decreases in invasive candidiasis in preterm infants observed from 1997 to 2010 in a cohort of US neonatal intensive care units6. However, concerns regarding short- and long-term safety of antifungal prophylaxis and lack of a clear benefit on mortality have remained unresolved5, and some studies have suggested an increased risk of cholestasis related to fluconazole prophylaxis7.

This randomized trial8 evaluates the efficacy and safety of fluconazole prophylaxis among the most immature preterm infants, those weighing <750g at birth. The study shows no effect of fluconazole prophylaxis on the composite outcome of death or invasive candidiasis. However, fluconazole prophylaxis does decrease the incidence of invasive candidiasis. How are we to explain the lack of effect of mortality despite a significant reduction in invasive fungal disease? It is possible, as the authors explain, that fluconazole prophylaxis does not have an effect on mortality, despite the high case-fatality rate associated with infection. Infants with invasive candidiasis may also suffer from other co-morbid complications of prematurity that have an effect on mortality that would not be expected to be modified by fluconazole prophylaxis. Alternatively, the effect of fluconazole prophylaxis on death from invasive candidiasis may be too small to be detected by this study. Assuming a reduction in the absolute risk of invasive candidiasis of 7% in this study and a 30% case-fatality rate1, the risk difference in candida-related mortality would be expected to be around 2%, a difference this study was not powered to detect.

The authors’ selection of their composite primary outcome of death or invasive candidiasis in the trial is reasonable, both because of hypothesized effect of fluconazole on reducing mortality from invasive candidiasis as well as a method to account for mortality as a competing event in this high-risk population9. In addition, the authors are correct to focus their conclusion that “these findings do not support the universal use of prophylactic fluconazole” based on the results of the primary composite outcome, rather than the individual components. Although long-term follow-up rates were low, there was no differential-loss to follow-up between treatment groups. The lack of an effect of fluconazole prophylaxis on improved long-term neurocognitive outcomes in this study is consistent with prior studies10, despite the known adverse effects of invasive candida infection on neurodevelopment2.

What is less clear is how this study will influence the use of fluconazole prophylaxis in clinical practice. Taking into account the other prior randomized trials, we can confidently conclude that fluconazole prophylaxis effectively reduces invasive candidiasis. This trial also supports its favorable safety profile for use among this population. However, until further studies and updated meta-analyses are completed, this therapy cannot be recommended to clinicians seeking to improve survival without neurodevelopmental impairment among their most immature infants.

REFERENCES

1. 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;110:285-91.
2. Adams-Chapman I, Bann CM, Das A, et al. Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. The Journal of pediatrics 2013;163:961-7 e3.
3. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. The New England journal of medicine 2007;356:2483-95.
4. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. The New England journal of medicine 2001;345:1660-6.
5. Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. The Cochrane database of systematic reviews 2013;4:CD003850.
6. Aliaga S, Clark RH, Laughon M, et al. Changes in the incidence of candidiasis in neonatal intensive care units. Pediatrics 2014;133:236-42.
7. Aghai ZH, Mudduluru M, Nakhla TA, et al. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis. Journal of perinatology : official journal of the California Perinatal Association 2006;26:550-5.
8. Benjamin DK, Jr., Hudak ML, Duara S, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. Jama 2014;311:1742-9.
9. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? Jama 2003;289:2554-9.
10. Kaufman DA, Cuff AL, Wamstad JB, et al. Fluconazole prophylaxis in extremely low birth weight infants and neurodevelopmental outcomes and quality of life at 8 to 10 years of age. The Journal of pediatrics 2011;158:759-65 e1.