Successful resolution of cardiac mycetomas by combined liposomal Amphotericin B with Fluconazole treatment in premature neonates
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- Karatza, A.A., Dimitriou, G., Marangos, M. et al. Eur J Pediatr (2008) 167: 1021. doi:10.1007/s00431-007-0634-5
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This manuscript reports on two very low birth weight premature infants with respiratory distress, receiving parenteral nutrition and broad-spectrum antibiotics for about 3 weeks, who developed Candida albicans sepsis associated with fungal mycoses and endocarditis, despite treatment with Amphotericin B and Caspofungin. On days 40 and 47, respectively, antifungal therapy was modified to liposomal Amphotericin B combined with Fluconazole 6 mg/kg/day for 4 weeks, resulting in complete resolution of the mycetomas. Our observations suggest that the combination of liposomal Amphotericin B with Fluconazole is able to result in complete resolution of cardiac mycetomas in preterm infants.
KeywordsNeonatal Candida endocarditisCombination antifungal therapyLiposomal Amphotericin BCaspofunginFluconazole
Neonatal fungal endocarditis is a relatively rare infection associated with unfavourable prognosis . The optimal therapeutic approach remains to be defined. Current treatment options include medical therapy and surgical intervention. Unfortunately, surgical strategies to deal with fungal endocarditis in low birth weight infants are often limited by technical issues. A recent review of the English literature since 1980 yielded comparable outcome in neonates treated with combined medical and surgical treatment and those managed with antifungal therapy alone .
Here, we present two premature infants with invasive candidiasis complicated by endocarditis, whose infection remained uncontrolled, despite Amphotericin B and concomitant Caspofungin therapy. Eradication of the infection was achieved by combined liposomal Amphotericin B and IV Fluconazole therapy for another 4 weeks.
Case 1 is a female neonate weighing 1,270 g born at 28 weeks of gestation. The baby was intubated in the delivery room, required three doses of surfactant therapy and remained ventilated for a total of 54 days. Total parenteral nutrition was started on the second day of life and oral feeds were postponed up to day 22, due to haemodynamic instability. On admission, the baby was commenced on IV Ampicillin and Gentamicin for 10 days, after which, antibiotics were switched to IV Meropenem and Teicoplanin for another 10 days, due to recurrent clinical signs suggestive of sepsis.
Case 2 is a male neonate weighing 1,280 g delivered at 29 weeks of gestation. The baby was intubated immediately after birth, received two doses of surfactant therapy and required mechanical ventilation for 36 hours. Total parenteral nutrition was started on day 2 and trophic feeds were commenced on day 5 with preterm formula. On admission, IV Ampicillin and Gentamicin were given for 10 days and then the baby had IV Meropenem and Teicoplanin for another 10 days due to Staphylococcus epidermidis infection.
On day 18, Candida albicans was isolated from blood culture and therapy with liposomal Amphotericin B (5 mg/kg/day) was started. The minimal inhibitory concentration of Candida albicans was 0.016 μg/ml for Amphotericin, 0.190 μg/ml for Fluconazole and 0.125 μg/ml for Caspofungin. Caspofungin (1 mg/kg/day for the first 2 days and then 2 mg/kg/day thereafter) was added on day 23, due to the persistent growth of Candida albicans in serial blood cultures.
Transthoracic echocardiography performed on day 34 showed a vegetation attached to the anterior leaflet of the mitral valve (Fig. 1c), as well an echodense mass in the inferior caval vein extending well into the body of the right atrium.
On day 47, due to the persistence of candidaemia and abnormal echocardiographic findings, antifungal therapy was modified to liposomal Amphotericin B and IV Fluconazole (6 mg/kg/day). All blood cultures taken 5 days after the initiation of the new therapeutic regimen were sterile and complete resolution of both the atrial mycetoma and the vegetation of the mitral valve were confirmed after 31 days of combined Amphotericin B and Fluconazole therapy.
Candida is the third most common pathogen responsible for nosocomial infections in extremely low birth weight neonates, resulting in substantial mortality and morbidity in this population . Risk factors for neonatal candidiasis include lack of enteral feedings, early use of third-generation cephalosporins and a birth weight of less than 750 g, which is also a strong negative predictor of clinical and microbiologic response to invasive Candida infection . Colonisation with fungi is considered as a risk factor for invasive candidiasis, as well as invasive neonatal supportive care . The use of institutional empiric therapeutic guidelines based on well identified risk factors for invasive Candida infection is important for achieving the early diagnosis of fungal infection and, potentially, reducing morbidity and mortality . An alternative approach is the prophylactic use of Fluconazole from birth, a strategy that reduces the incidence of colonisation and invasive Candida infection in extremely low birth weight infants, although the emergence of resistant Candida species after a long period of Fluconazole prophylactic use cannot be excluded. .
Endocarditis is a well recognised complication of neonatal candidiasis, having a variable reported incidence . Involvement of the heart can occur in the absence of significant risk factors or prolonged fungaemia and, therefore, cardiac evaluation is probably indicated in all cases of neonatal candidiasis [3, 8].
The first-line treatment of fungal endocarditis in infants and children is usually Amphotericin B. As Amphotericin B may not penetrate fungal vegetations effectively, the concomitant use of a second agent, such as Flucytocine, that acts synergistically may potentiate the resolution of fungal vegetations .
Caspofungin is the first of a new class of antifungal agents known as echinocandins, currently listed as an option for the treatment of Candida endocarditis, including preterm infants . Experience in its use in young infants is extremely limited and no pharmacokinetic data are available in this age group .
Fluconazole, a fungistatic agent, although less toxic than Amphotericin B, is considered to be less efficacious and serves as a second-line drug in the treatment of fungal endocarditis .
The combination of antifungal agents may be associated with a better clinical response compared to monotherapy in fungal endocarditis. Amphotericin plus Fluconazole has been previously reported to be effective in both native and prosthetic valve Candida endocarditis . Data on the combined or sequential use of Amphotericin B and Caspofungin in Candida endocarditis are sparse and experience has been limited to case reports or preclinical studies.
According to our findings, the combination of Amphotericin B and IV Fluconazole antifungal chemotherapy may be effective and well tolerated in premature infants with prolonged candidaemia complicated by endocardial infection. Our observations appear to support the use of combined Amphotericin B and Fluconazole as an alternative treatment for neonatal Candida endocarditis, unresponsive to first-line antifungal therapy. Further experience with Caspofungin use in neonates is expected to define its role in fungal endocarditis.