Neonatal Intensive Care Drug Manual

There are no adequately powered comparative trials of different antifungal therapies for invasive fungal infection in the neonatal setting.^10,11 One small study (24 newborn infants) that compared conventional (not liposomal) amphotericin B with fluconazole found fluconazole to have fewer side effects.¹²

Australian 2014 consensus guidelines⁶ on antifungal therapy for systemic fungal infections state that (1) the incidence of candidaemia in Australia (2001–2004) was about 1.81 cases per 100 000 population. Candida albicans accounted for approximately 50% of invasive Candida isolates, followed by C. parapsilosis (20%), C. glabrata (15%), C. tropicalis (5%), C. krusei (4%) and C. dubliniensis (2%). In the NICU, C. albicans and C. parapsilosis predominate, (2) all major Candida species are usually susceptible to Amphotericin B; C. glabrata and C. parapsilosis have reduced susceptibility to fluconazole compared to C. albicans, however, fluconazole can usually be used successfully if higher doses are used i.e. 10–12 mg/kg/day. Pichia kudriavzevii (formerly C. krusei) is intrinsically resistant to fluconazole, (3) primary resistance of Cryptococcus to antifungal drugs in Australia is uncommon. Amphotericin B is used in combination therapy during the induction phase, (4) there are no prospective data on the optimal duration of therapy for invasive fungal infections and recommendations are largely based on expert opinion. For candidaemia with deep-tissue infection, treatment with systemic antifungal agents for 14 days following the last, positive, sterile-site culture and resolution of clinical features of infection is recommended (LOEIII, GOR C). Similar duration is recommended for peritonitis, but 6 weeks or longer for difficult-to-treat deep foci such as endocarditis, endophthalmitis, mediastinitis or osteomyelitis (GOR D).
Dosage

Australian 2014 Consensus recommendations on Amphotericin B - Liposomal: 3 mg/kg/dose daily.⁶

In a retrospective study¹³, Weitkamp et al collected data on 21 very low birth weight (VLBW) infants who received liposomal amphotericin B [median dose 2.6 mg/kg/day (range 1–5 mg/kg/day) and median duration: 28 days]. All patients treated with liposomal amphotericin B eradicated fungi and recovered clinically. There was no nephrotoxicity noted. Liposomal amphotericin B (2.5–7 mg/kg/day) was used in 24 VLBW infants with systemic candidiasis in a prospective study.¹⁴ Fungal eradication was achieved in 92% of the episodes with a mean duration of therapy until the eradication being 9 days. Four of the infants died and in 2 of these, the cause of death was directly attributed to systemic candidiasis.

With amphotericin B treatment, drug monitoring is not done as no therapeutic range has been recommended.¹⁸

Liposomal amphotericin B is less nephrotoxic and has fewer infusion related reactions than conventional amphotericin B (LOEI, GOR A).¹⁵ However, the finding of reduced nephrotoxicity with liposomal amphotericin B needs to be interpreted with caution as significant heterogeneity was observed (I² = 59%).¹¹ In a retrospective cohort study,¹⁶ authors noted higher mortality in infants receiving amphotericin B lipid products as compared to conventional amphotericin B. The study, however, lacked clinical data regarding underlying illnesses though there were no significant differences in the mean gestation, birth-weight, age at onset of infection or serum creatinine. Authors discuss that they were unable to determine whether more critically ill infants with higher serum creatinine were selected for amphotericin B lipid products as only 17% of the infants had serum creatinine reported within 1 day of starting treatment. It is also interesting to note that in this study, while the overall mortality is higher for the group receiving amphotericin B lipid products, the 7-day, 14-day and 30-day mortality figures seem to be no different (mortality for conventional amphotericin B and amphotericin B lipid products respectively; 7-day: 7 and 6%, 14-day: 11 and 8%, 30-day: 14 and 13%).