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Female newborn with a 26 weeks of gestation is born to a 29-year-old multigravida woman via vaginal delivery due to preterm labor. An uneventful antenatal period is noted. The duration of amniotic membrane rupture is six hours before birth. A single course of antenatal corticosteroid therapy is completed at the proper time. Magnesium sulfate is administered to the mother with the aim of neuroprotection before delivery. There is no history of fever, urinary tract infection, chorioamnionitis or antibiotic usage until delivery.
The birth weight of the neonate is 760 g. Apgar scores are 4 and 6 at 1 and 5 minutes respectively. The infant is admitted to the neonatal intensive care unit. Non-invasive respiratory support is started due to mild respiratory distress and extreme prematurity. There is no need for surfactant administration. Penisillin G (100.000 IU/kg) and gentamisin (5mg/kg/48 h) therapy is established due to preterm labor. Parenteral nutrition and minimal trophic breast milk is initiated. Oral nystatin is given at admission based on the protocols of our unit. Umbilical venous catheter is inserted, but the catheter is removed due to leakage in the third day. A peripherally inserted central catheter (PICC) line is fitted afterwards. She improves gradually, oxygen need diminishes in the first postnatal days. On the sixth day of life, her clinical status worsens and develops tachypnea, grunting, tachycardia, abdominal distention with enterorrhagia. Her neurologic examination reveals a normal anterior fontanelle. She is intubated and put on mechanical ventilation. Enteral feeding is ceased. The parameters of sepsis are positive (high white blood cell, C-reactive protein and interleukin-6). A lumbar culture is done, which displays elevated WBC count (70 cell/L) and protein (200 mg/dL) in cerebrospinal fluid. Empirical antibiotic therapy (as vancomycin, amikacin and meropenem) is started due to suspected sepsis with the clinical and laboratory findings. PICC line is removed. The neonate receives blood transfusions owing to severe anemia, thrombocytopenia and coagulopathy. C-reactive protein and interleukin-6 remains high in the 7th day of the antibiotic treatment. Serial cranial ultrasonography imaging reveals widespread, multiple, cystic lesions in the brain. Brain magnetic resonance imaging shows innumerable wide-spread cerebral abscesses (Figure 1).
Candidiasis is a significant reason of nosocomial sepsis in hospitalized neonates, especially for extremely preterm infants (1). Despite routine usage of antifungal prophylaxis in many neonatal intensive care units, non-albicans Candida is appearing in substantial rate and has a paramount role in nosocomial sepsis partly due to better survival of very low birth weight (VLBW) infants (2). The critical point is exact diagnosis and appropriate treatment. A positive blood culture for candida necessitates investigation of different organ systems, especially the central nervous system (CNS), for the spreading of infection (3). CNS disease may be more often than thought. Therefore infected infants should be carefully assessed with both cerebrospinal fluid (CSF) analysis and neuroimaging for accurate diagnosis, treatment and follow-up (3).
Amphotericine B and fluconazole is conferred on the 16th day when there is evidence of C. dubliniensis in the blood culture. The microorganism is isolated many times from consecutive blood and CSF cultures taken on different days. No evidence of vegetation is present in transthoracic echocardiography. Typing of the species reveals C. dubliniensis. Antifungal treatment is modified to voriconasole on day 34 due to the endophtalmitis and ongoing respiratory distress. Her clinical status improves gradually. Antifungal treatment continues for eight weeks until the recovery of brain MRG findings, negative blood and CSF culture results. She is discharged from the hospital in 94th postnatal day. Written informed consent was obtained from the family of the patient for publication of this case report and accompanying images.
Neonatal invasive candidiasis is associated with high mortality and neurodevelopmental morbidity. (1) There are a plenty of risk factors, but immaturity is the foremost due to the underdeveloped immune system. (2) Extremely preterm infants are often exposed to central venous catheters, a long period of parenteral nutrition, delayed enteral feeding and broad-spectrum antibiotic usage which predispose to invasive fungal infection. (2) We deduced that this infection is related with central venous catheter history. Colonization, which is frequent in hospitalized extremely preterm infants, determines the course of the disease. Biofilm formation by candida species on the surface of the catheters interferes with immune system and also diminishes the potency of antifungal therapy. Also, it is still unclear how much treatment is adequate in newborn antifungal sepsis. (3) Currently used antifungal therapy doses are likely insufficient due to the lack of enough data about the dosing regimens. (3) It may be the reason of treatment failure in our patient during the early period. We promptly removed the central line after the knowledge of positive blood culture. Although it is known that catheter elimination reduces mortality and morbidity rates, it is pending whether the efficacy of antifungal therapy is influenced by the removal of the catheter. (4)
There has been a shift toward non-albicans candidemia associated sepsis probably due to wide-spread usage of antifungal prophylaxis and higher rates of immaturity. (5) In our patient, there was growth of C. dubliniensis in both blood and CSF culture. C. dubliniensis, most similar pathogen to albicans, is rarely seen in neonates compared to other non-albicans species. (6) Microbiological differentiation may be troublesome between these two species due to this resemblance. (6) So it may have been underdiagnosed until now, so careful microbiological evaluation is necessary for detection of C. dubliniensis.
Detection of fungi in blood culture should be evaluated carefully due to high risk of life-threatening septicemia in neonates. Suspicion of invasive disease necessitates interpretation of CNS. (7) A simple CSF analysis may be the cornerstone of treatment plan in early period of the suspected sepsis. When the CSF culture is positive for Candida, both neurodevelopmental sequelae and mortality rates raise compared with the culture negative cases. (7) However, there may not be fungal growth in blood culture despite the presence of CNS disease. So, routine brain MRI is recommended despite normal CSF findings due to brain lesions that are rarely seen in cranial ultrasonography. So we performed a lumbar puncture and brain MRI. There was C. dubliniensis production in both blood and CSF cultures. Multiple abscesses with various sizes were seen in MRI.
We have not been able to find a preterm infant with C. dubliniensis associated CNS disease in the previous literature. Invasive CNS disease should be kept in mind in a premature neonate who has a positive blood culture for Candida. Detailed neuroimaging is crucial for exact diagnosis, treatment plan and follow-up of the patient despite normal CSF findings.
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