What is already known on this topic
- Fluconazole prophylaxis reduces the incidence of invasive fungal infection and mortality in very low birthweight babies.
- There are concerns that widespread use may lead to fluconazole resistance in Candida species.
Here we have presented data on antifungal prophylaxis given to a subset of VLBW babies with recognised additional risk factors for fungal sepsis. The results for the entire group of babies eligible for fluconazole prophylaxis are shown, rather than the babies who were selected for treatment, as there were no suitable controls for the selected group. We found a significant reduction in culture proven Candida sepsis in a group of babies at particularly high risk, following the introduction of antifungal prophylaxis to a NICU. The retrospective nature of this study, relatively small numbers of eligible babies and low incidence of invasive Candida infection make this study underpowered to draw firm conclusions about the impact of selective fluconazole prophylaxis. Other limitations were the lack of controls and routine monitoring for adverse effects. However, the reduction in total cases of Candida sepsis (culture proven and probable) from 5% to 1% may be important, given the high morbidity and mortality associated with this condition.
What this study adds
- Fluconazole prophylaxis may reduce the incidence of invasive fungal infection when given to a subgroup of babies at particularly high risk of invasive fungal infection.
A Cochrane meta‐analysis concluded that fluconazole prophylaxis for all VLBW or ELBW babies considerably reduces the incidence of fungal sepsis.11
More recent studies have included additional risk factors. Bertini et al
observed a marked reduction in invasive candidiasis (7.6% to 0%) when fluconazole prophylaxis was given to VLBW babies with central venous catheters in situ (38% of all VLBW babies in the study period).17
Uko et al
reported similar results when a shorter course of lower‐dose fluconazole prophylaxis (3 mg/kg) was given to VLBW babies receiving systemic antibiotics for more than 3 days (51% of all VLBW babies in the study period).18
All of the studies quoted report similar reductions in the incidence of Candida
sepsis; however, none adopted a risk‐based policy as selective as this guideline (14% of all VLBW babies in the study period).
To achieve greater selection of babies at highest risk of fungal sepsis our guideline only included what are considered the most important risk factors: cephalosporin treatment, fungal colonisation, prolonged antibiotic use and the presence of a central venous catheter.11
‐receptor antagonists and postnatal dexamethasone are rarely used in our unit and were not included in the guideline. The guideline was not designed to be prescriptive and a large proportion of eligible babies in our NICU were considered not to require antifungal prophylaxis by the attending neonatologist. For example, two VLBW infants were started on a cephalosporin for suspected necrotising enterocolitis, but this was discontinued after 48 h once the clinical picture made this improbable. Eleven babies were eligible because of prolonged antibiotic use as their only risk factor. None of these babies received prophylaxis. It is difficult to comment on the decisions of individuals in a retrospective study. However, in practice, fluconazole prophylaxis was administered to infants with lower birth weights, with two or more risk factors and, in particular, those receiving a third generation cephalosporin.
It is possible that other factors may have influenced the decrease in invasive fungal infection. Although there was no change in infection control policy in the NICU, an audit of blood stream infections in this unit during the same period showed a modest 26% reduction in laboratory‐confirmed blood stream infections but no reduction in those not confirmed by the laboratory. In addition, prevention of horizontal transmission of Candida
by hand infection control measures has had only limited success in decreasing Candida
colonisation and sepsis in neonates.31
Fluconazole prophylaxis gives rise to concerns that species which are inherently resistant to fluconazole will be selected out, or that there will be a gradual increase in resistance among previously sensitive strains. A strain of C parapsilosis
, less susceptible to fluconazole, has been identified as causing blood stream infections in a NICU where fluconazole prophylaxis has been practised for 10 years.33
Azole resistance in Candida albicans
has also been reported, and Candida
resistance has been found in preterm animals.34
However, similar to most previous studies,11
we found no evidence of the emergence of fluconazole‐resistant strains, and all isolated Candida
remained fully susceptible to fluconazole. As the study period was short it will be necessary to continue surveillance with these issues in mind.
In conclusion, the incidence of Candida sepsis in the NICU noticeably decreased in the 12 months following the introduction of an antifungal prophylaxis guideline, using fluconazole, targeted at a subset of VLBW babies at higher risk of invasive fungal infection. This study highlights the practicalities of implementing a fluconazole prophylaxis policy that attempts to appropriately identify those infants at greatest risk, while not exposing infants at lesser risk to a potentially harmful medication. Our results suggest that this risk‐based approach correctly identifies those infants most likely to benefit from fluconazole prophylaxis. Achieving the correct balance has implications for cost effectiveness, emergence of resistant species and reducing exposure to potentially harmful medications. We are unable to prove any causal relationship due to the lack of power and retrospective nature of this study. However, a multicentre randomised controlled trial would elucidate the importance of particular risk factors in the development of fungal sepsis and the role of antifungal prophylaxis.