Invasive Candidiasis in Very Premature Neonates: Tiny Tots With Big Problems
Year: 2017
Type: article
Abstract: (See the Major Article by Barton, et al on pages 921-7) Survival of neonates with extremely low birth weight (ELBW, <1000 g) is a miracle of modern medicine. Management is fraught with numerous complications, including intraventricular hemorrhage, necrotizing enterocolitis, chronic lung disease, patent ductus arteriosus requiring surgery, severe retinopathy, periventricular leukomalacia, and neurodevelopmental impairment, including deafness and decreased cognitive ability. The immature immune system and intense interventional care required to sustain life combine to make sepsis a frequent complication, including invasive candidiasis (IC) [1]. Administration of third-generation cephalosporins or carbapenems also increases the risk of IC [2]. This infection currently occurs in about 3% of ELBW neonates [3, 4] and contributes to mortality, prolonged hospitalization, and neurodevelopmental impairment [2, 5, 6]. Presentation of IC is nonspecific and is often detected by a positive culture of blood (78%), cerebrospinal fluid (CSF; 8%), or other normally sterile fluid [4]. Pneumonia, meningitis, and urinary tract infection are frequent [7]. Antifungal therapy fails in a fourth of infants [8]. The morbidity of IC is so great that intravenous (IV) fluconazole prophylaxis has been advocated for ELBW neonates, based on 11 randomized clinical trials [9, 10]. The declining incidence of IC in ELBW neonates has led some authorities to recommend prophylaxis only in neonatal intensive care units (NICUs) with a high incidence of IC [3, 11]. Other measures advocated for the reduction in the incidence of IC in NICUs include rigorous infection control measures in order to block transmission from mothers or staff to the neonate, stewardship in the use of third-generation cephalosporins and corticosteroids, and meticulous care of IV catheters. Still, “getting to zero” has not been simple [9]. There is, however, progress. One analysis of 709325 neonates in 322 NICUs between 1997 and 2010 found a decreasing incidence of IC, most notable in ELBW neonates. The rate of episodes per 1000 patients fell from 24.2 to 11.6 for neonates 750–999 g and from 82.7 to 23.8 episodes for neonates <750 g [12]. There was a concomitant rise in use of fluconazole prophylaxis and less use of broad-spectrum antibiotics over this period [12]. Our understanding of IC in ELBW neonates has been substantially enhanced by collaborative efforts spanning multiple NICUs. One such group is the Pediatric Investigators Network of Infections in Canada, the group responsible for a report in this issue of Clinical Infectious Diseases [5]. A group of 13 Canadian neonatal ICUs pooled their experience with IC during the period 2001–2003, following 49 neonates with IC and birth weight <1500 g and 90 matched controls. Their 2014 report provided some of our best data on the incidence and morbidity of IC in LBW neonates [13]. The current report from this same study drills down on the differences between the 14 ELBW neonates who had onset of IC in the first 7 days of life (early onset disease [EOD]) and the 31 with later onset (LOD) [5]. Mortality was found to be higher in EOD neonates with IC (71%) than in LOD neonates (32%) or matched controls (15%). Searching for predictors of EOD in ELBW neonates, the authors found that EOD was significantly more common in ELBW neonates who had vaginal delivery, birth weight <750 g, gestational age <25 weeks, or mothers with chorioamnionitis. This interesting analysis raises the question whether most of these 14 neonates were infected during prolonged rupture of the membranes or during passage through the vaginal canal. The Canadian collaborative study was done at a time when none of the neonatal ICUs were using fluconazole prophylaxis. This regimen is given as 3 or 6 mg/kg IV on day 1 and then twice weekly. We don’t know if this would be an optimal regimen to prevent EOD or whether a more aggressive antifungal prophylaxis would benefit a subset of high-risk ELBW neonates. Fluconazole has an admirable safety record in neonates and penetrates well into the CSF and urine, both sites commonly infected in ELBW neonates [3]. To date, azole resistance does not appear to be a problem in NICUs that use fluconazole prophylaxis [3, 9]. Amphotericin B deoxycholate 1 mg/kg IV daily has also been recommended for IC in ELBW neonates, with echinocandins reserved for special situations [10, 11]. Although empirical therapy might seem to be an option, we don’t know which ELBW neonates might benefit. Also, there is the likelihood that starting antifungal drugs once clinical signs are already obvious may be too late to influence outcome [14]. The case fatality rate of 71% in EOD neonates makes it clear that there is plenty of room for improvement [5]. Acknowledgement. This work was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases. Potential conflicts of interest. The author reports no conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/cix007
Author: John E. Bennett
Institution: National Institutes of Health
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2591129665