A multicenter, randomized trial of prophylactic fluconazole in preterm neonates.

BACKGROUND: Invasive candida infections are a major cause of morbidity and mortality in preterm infants. We performed a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of fungal colonization and infection in very-low-birth-weight neonates. METHODS: During a 15-month period, all neonates weighing less than 1500 g at birth from eight tertiary Italian neonatal intensive care units (322 infants) were randomly assigned to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). We performed weekly surveillance cultures and systematic fungal susceptibility testing. RESULTS: Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P<0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P=0.005 for the 6-mg group and P=0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect. CONCLUSIONS: Prophylactic fluconazole reduces the incidence of colonization and invasive candida infection in neonates weighing less than 1500 g at birth. The benefit of treating candida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869 [controlled-trials.com]).

Type and number of sites colonized by fungi and risk of progression to invasive fungal infection in preterm neonates in neonatal intensive care unit.

AIMS: Retrospective cohort study to assess if different patterns of Candida colonization determine different risks of progression to invasive fungal infection (IFI) in preterm neonates in NICU. METHODS: Weekly surveillance cultures from all neonates weighing at birth <1500 g admitted over a 6-year period were reviewed. Infants with available results from at least 3 cultures/week and from at least 4 different sites were enrolled and identified by the number of sites involved [1-2 (low-grade), 3 or more (high-grade)] and type (low-risk, if colonization was recovered from skin, stool, ear canal swab, gastric aspirate, nasopharynx secretions, endotracheal tube; high-risk, from urine, catheter tip, drains, surgical devices). Progression rates from colonization to IFI were calculated for each subgroup. Univariate analysis was performed looking for significant associations between IFI and a number of risk factors, including the different subgroups of colonization. Multiple logistic regression assessed all significantly (P<0.05) associated risk factors. MAIN RESULTS: In the 405 eligible infants, overall colonization rate was 42.9%, IFI rate 9.9%, overall progression rate to IFI 0.23, the latter being significantly higher in high-grade or high-risk than in low-grade or low-risk colonized infants (0.59 vs. 0.18, P=0.001; 0.44 vs. 0.11, P<0.001, respectively). Infants with concomitant high-grade + high-risk colonization had 4-fold higher risk of progression than any other colonized infant, and 7-fold higher risk than infants concomitantly low-grade + low-risk colonized (P<0.001). At multivariate analysis, high-grade and high-risk colonization (P=0.001 for both), birth weight (P=0.02) and presence of central venous line (P=0.04) remained independent predictors of IFI. CONCLUSIONS: Density and severity of fungal colonization condition the progression to IFI in preterm infants in NICU, and certain patterns of colonization are independent predictors of IFI. Increased culture surveillance and prophylactic measures should be addressed to preterm colonized infants in NICU featuring the most risky colonization patterns.

Early-onset neutropenia is a risk factor for Candida colonization in very low-birth-weight neonates.

Neutropenia is a major risk factor for bacterial colonization and sepsis in preterm neonates in the neonatal intensive care unit (NICU), but little is known about its relationships with candidal colonization (CC) in these settings. We performed a case-control study on neonates with birth weight of <1500 g admitted to our NICU during a 7-year period (1996-2003, N = 585). Through database search, infants with early-onset neutropenia (EON) (n = 68, group A) were identified and 1:1 matched with controls without EON (n = 68, group B). Microbiologic data from weekly surveillance cultures were examined to determine the presence and intensity of CC. Groups A and B were similar clinically and demographically. All group A neonates recovered from EON before the 8th day of life. Incidence of CC in the 1st month of life (at least 1 site) was significantly higher in group A (61.8% versus 35.3%, P = 0.002) and was not modified by treatment with recombinant granulocyte colony-stimulating factor. The same was true of CC intensity, expressed as the number of sites affected (P = 0.002). Incidence of candidal sepsis, mortality rates, and relative frequencies of the various subspecies of Candida among the isolates did not significantly differ between the 2 groups. In conclusion, EON in preterm neonates is a significant, independent risk factor for CC. Larger, prospective, adequately powered studies should verify whether increased CC related to neutropenia may translate into a similar increased occurrence of candidal sepsis in these settings.

Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization.

OBJECTIVE: Colonization by Candida spp is a major risk factor for development of fungal sepsis, but little is known about the variables associated with progression to invasive disease in already colonized neonates. We investigated such variables in a large number of colonized preterm neonates in an NICU. SETTING: This study was conducted in the Department of Neonatology and the NICU at Sant'Anna Hospital in Torino, Italy. DESIGN AND PATIENTS: A database search of clinical charts and weekly surveillance cultures was used to identify all neonates with birth weights < 1500 g (very low birth weight) who were admitted to our NICU during 1998-2005 and were colonized (> or = 1 site) by Candida spp during their stay, as well as infants with invasive fungal infection. The association between a number of factors with progression to invasive fungal infection was evaluated. Those shown to be significantly associated by univariate analysis were cross-checked by logistic regression. RESULTS: Colonization occurred in 201 infants (32.1% of very low birth weight admitted neonates), and invasive fungal infection occurred in 51 (8.1%) of them, with an overall progression rate of 0.25. At univariate analysis, 10 factors (namely low birth weight, low gestational age, use of third-generation cephalosporins, endotracheal intubation, duration of stay in the NICU, bacterial sepsis, colonization of central venous catheter, of endotracheal tube, of gastric aspirate, or in > or = 3 [multiple] sites) were associated with an increased risk of progression, whereas prophylaxis with fluconazole was associated to a decreased risk. After logistic regression, only colonization of central venous catheter and colonization in multiple sites remained significantly associated with invasive fungal infection. Fluconazole prophylaxis remained an independent protective factor. CONCLUSIONS: Central venous catheter colonization and multiple-site colonization are independent risk factors and predictors of progression to fungal sepsis in preterm very low birth weight neonates colonized by Candida spp during their stay in the NICU. Fluconazole prophylaxis is an independent protective factor. These findings can be used to improve the surveillance, prophylaxis, or preemptive measures in neonates at high risk.

Hyperglycaemia as a possible marker of invasive fungal infection in preterm neonates.

AIM: The incidence of invasive fungal infection in preterm newborns is rising steadily. Early recognition and treatment are imperative, but diagnosis is difficult as data from microbiological investigations are often poor, and clinical and laboratory signs do not help in differentiating bacterial from fungal infections. We evaluated whether glucose intolerance could represent a possible surrogate marker predictor of invasive fungal infection in preterm neonates. METHODS: We performed a case-control study on neonates with birthweight less than 1250 g admitted to our tertiary-level unit during the years 1998-2004 (n = 383), comparing those with invasive fungal infection (n = 45, group A) to matched controls with late-onset sepsis caused by bacterial agents (n = 46, group B). We investigated in both groups the occurrence of hyperglycaemia (serum glycaemia > 215 mg/dl, i.e. 12 mmol/l) in the first month of life, and its temporal relationship with the episodes of sepsis. RESULTS: Hyperglycaemia occurred significantly more often in group A (21/45, 46.6%) than in group B neonates (11/46, 23.9%) (OR 1.95, 95% CI 1.235-4.432, p = 0.008). Moreover, in 19 of 21 (90.4%) neonates with hyperglycaemia in group A, the carbohydrate intolerance episode typically occurred 72 h prior to the onset of invasive fungal infection; in contrast, no temporal relationship was found in neonates with bacterial sepsis (p = 0.002). Correction of hyperglycaemia was successfully achieved in all neonates of both groups, with no significant differences in the number of days of insulin treatment needed to normalize glycaemia (p = 0.15). CONCLUSIONS: Hyperglycaemia is significantly more frequent in neonates who subsequently develop fungal rather than bacterial late-onset sepsis, with a typical 3-d interval. We suggest that a preterm neonate whose birthweight is less than 1250 g in its first month of life should be carefully evaluated for systemic fungal infection whenever signs of carbohydrate intolerance occur.

Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study.

OBJECTIVE: Despite the promising preliminary results observed in extremely low birth weight (ELBW) populations, the use of fluconazole to prevent fungal colonization and infection in preterm neonates in the NICU is still an open question and not yet recommended as a standard of care. We have reviewed our 6-year series to assess the effectiveness and safety of this form of prophylaxis. METHODS: This retrospective study consisted of 465 neonates who weighed < 1500 g at birth and were admitted to our NICU in the period 1998-2003. Those who were born between 1998 and 2000 and did not receive fluconazole prophylaxis (group A, n = 240) were compared with those who were born between 2001 and 2003 and treated with fluconazole until the 30th day of life (45th for neonates < 1000 g at birth; group B, n = 225). Weekly surveillance cultures were obtained from all patients. Incidence of fungal colonization, incidence of systemic fungal infection (SFI), rate of progression from colonization to infection, and mortality rates attributable to fungi were calculated for both groups and separately for neonates who were < 1000 g (ELBW) and were 1001 to 1500 g (NE-VLBW) at birth. RESULTS: Overall fungal colonization was significantly lower in group B (24.0%) than in group A (43.8%; relative risk [RR]: 0.406; 95% confidence interval [CI]: 0.273-0.605). The same was true of neonates with colonization in multiple sites (2.6% vs 5.8%) and of those with colonization from high-risk sites (5.8% vs 19.2%). SFI incidence was significantly lower in group B (10 of 225 cases; 4.4%) than in group A (40 of 240 cases; 16.7%; RR: 0.233; 95% CI: 0.113-0.447). Reduction of both colonization and SFI in group B was greater in the ELBW neonates and also significant in the NE-VLBW neonates. Rate of progression from colonization to infection was significantly lower in group B (0.17 vs 0.38; RR: 0.369; 95% CI: 0.159-0.815). Crude mortality rate attributable to Candida species was 1.7% (4 of 240) in group A vs 0% (0 of 225) in group B. Overall mortality rate (any cause before hospital discharge) was similar in the two groups (11.2% vs 10.6%), but in colonized infants (n = 159), it was significantly lower in group B (3.7% vs 18.1%; RR: 0.174; 95% CI: 0.039-0.778). The incidence of natively fluconazole-resistant fungal species did not increase over the years, and patterns of sensitivity to fluconazole remained the same. No adverse reaction related to fluconazole occurred. CONCLUSIONS: Prophylactic fluconazole significantly reduces the incidence of colonization and systemic infection by Candida species in both ELBW and NE-VLBW neonates and decreases the rates of progression from initial colonization to massive colonization and to systemic infection. All VLBW neonates may benefit from fluconazole prophylaxis.