Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection

Objectives

To evaluate the impact of selective fluconazole prophylaxis on incidence of invasive fungal infection and emergence of fluconazole resistance in neonatal intensive care.

Design

Retrospective study of very low birthweight (VLBW) babies (<1500 g birth weight) admitted to a neonatal intensive care unit (NICU) in the period 1 year before and after the implementation of an antifungal prophylaxis guideline.

Patients

VLBW babies with an additional risk factor: colonisation of Candida species from surface sites with a central venous catheter; third generation cephalosporin treatment; or total duration of antibiotic treatment >10 days.

Fluconazole protocol

Fluconazole 6 mg/kg for 3 weeks. Dose interval is every 72 h during the first 2 weeks of life. Thereafter, dose interval is reduced to every 48 h until 3 weeks old when daily fluconazole is given. Fluconazole is administered orally when enteral feeding achieved.

Results

121 and 107 VLBW babies were admitted to the NICU in the year before and after the guideline was implemented, respectively. Data were available in 110 and 102 charts. 33/110 and 31/102 babies were eligible for fluconazole prophylaxis in the period before and after guideline implementation. 6/33 babies eligible for prophylaxis developed culture proven Candida sepsis before compared with no (0/31) babies after the guideline was implemented (p = 0.03). One baby (1/31) did develop probable Candida sepsis in the post guideline implementation period. During both study periods all Candida isolates remained fully susceptible to fluconazole.

Conclusions

Selective antifungal prophylaxis has reduced invasive fungal sepsis in one NICU without evidence of fluconazole resistance emerging.Invasive fungal infection, most commonly due to Candida species, is increasingly common in preterm babies in neonatal intensive care.1,2,3,4,5,6 The estimated incidence in very low birthweight (VLBW) babies is between 2% and 4%, but it may be as high as 10% in extremely low birthweight (ELBW) babies. Fungal sepsis has much higher mortality, 21–32%, than bacteraemia, and it is also associated with markedly higher rates of adverse neurodevelopmental outcomes.6,7,8,9,10Fluconazole prophylaxis reduces the incidence and mortality from invasive fungal infection,11,12,13,14,15,16,17,18,19 but widespread use of antifungals might increase the emergence of resistance.3,10,20,21,22,23 Studies to date are too short to fully assess the potential for fluconazole resistance and there remain reservations about treating all babies to protect a few.12 Fluconazole seems to be well tolerated in prophylactic doses,11,12,13,14,15,16,17,18,19 but there are associations with rise in liver transaminases, cholestasis, toxic epidermal necrolysis and Steven–Johnson syndrome, and interactions with other medications.2,13,24,25,26 Selective use of antifungal prophylaxis in the subset of VLBW babies at very high risk of fungaemia may be preferable to minimise the risk of adverse effects.2,12 Although comparatively little data are available on selective antifungal prophylaxis, two recent studies reported reductions in invasive fungal infection with a fluconazole prophylaxis policy targeting VLBW babies with additional risk factors.16,17 Recognised additional risk factors for acquiring fungal sepsis in preterm infants include third generation cephalosporin use, fungal colonisation, prolonged broad spectrum antibiotic use, parenteral nutrition with lipids, endotracheal intubation, male gender, central venous catheter use and number of days in situ, previous bacterial blood stream infections, postnatal steroids, gastrointestinal pathology, H₂‐receptor antagonists, shock and coagulopathy.2,25,27,28,29,30In October 2003, the neonatal intensive care unit (NICU) at the Royal Maternity Hospital, Belfast, developed a guideline for antifungal prophylaxis in VLBW babies with additional risk factors for fungal sepsis. We conducted this retrospective study to determine if the use of selective fluconazole prophylaxis was effective in reducing invasive fungal infection in high‐risk babies. We also wanted to establish if there has been an increase in fluconazole resistance.