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T h e n e w e ng l a n d j o u r na l o f m e dic i n e Prophylactic Fluconazole in Preterm Neonates Paolo Manzoni, M.D., Ilaria Stolfi, M.D., Lorenza Pugni, M.D., Lidia Decembrino, M.D., Cristiana Magnani, M.D., Gennaro Vetrano, M.D., Elisabetta Tridapalli, M.D., Giuseppina Corona, M.D., Chiara Giovannozzi, M.D., Daniele Farina, M.D., Riccardo Arisio, M.D., Franco Merletti, M.D., Ph.D., Milena Maule, M.D., Fabio Mosca, M.D., Ph.D., Roberto Pedicino, M.D., Mauro Stronati, M.D., Michael Mostert, M.D., and Giovanna Gomirato, M.D., for the Italian Task Force for the Study and Prevention of Neonatal Fungal Infections and the Italian Society of Neonatology Background
Invasive candida infections are a major cause of morbidity and mortality in preterm From Sant’Anna Hospital, Turin (P.M., C.G.,
D.F., G.G.); Policlinico Umberto I, Rome infants. We performed a multicenter, randomized, double-blind, placebo-controlled (I.S., R.P.); Mangiagalli Hospital IRCCS, trial of fluconazole for the prevention of fungal colonization and infection in very-low- University of Milan, Milan (L.P., F. Mosca); San Matteo Hospital, Pavia (L.D., M.S.); Arcispedale, Reggio Emilia (C.M.); Fate-benefratelli Hospital, Benevento (G.V.); University of Bologna, Bologna (E.T.); Uni- During a 15-month period, all neonates weighing less than 1500 g at birth from eight versity of Messina, Messina (G.C.); and University of Turin, Turin (R.A., M. Maule, tertiary Italian neonatal intensive care units (322 infants) were randomly assigned F. Merletti, M. Mostert) — all in Italy. Ad- to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body dress reprint requests to Dr. Manzoni at weight) or placebo from birth until day 30 of life (day 45 for neonates weighing the Neonatology and Hospital Neonatal Intensive Care Unit, Sant’Anna Hospital, <1000 g at birth). We performed weekly surveillance cultures and systematic fungal Corso Spezia 60, 10126 Turin, Italy, or at Copyright 2007 Massachusetts Medical Society. 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 can- dida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869).
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Despite efforts to improve the out- tee at each hospital. Parents or guardians pro- comes of preterm infants, systemic fungal vided written informed consent. Pfizer Italia sup- diseases caused mainly by candida species ported the study with a grant and supplied both are an important complication of the care of neo- fluconazole and placebo; the sponsor was not in- nates on the threshold of viability. Candida spe- volved in the study design, in the enrollment of cies colonize up to 60% of very-low-birth-weight patients, or in the collection, analysis, interpreta- neonates (those weighing less than 1500 g) during tion of the data or preparation of the manuscript. their first month in the neonatal intensive care All authors vouch for the completeness and accu- unit (NICU). Such colonization may progress to racy of the data presented.
invasive fungal infection in up to 20% of these The primary objective was to evaluate the ef- infants.1-5 Nonspecific clinical features, poor sen- fectiveness of fluconazole at doses of 3 mg and sitivity of diagnostic tests, and late recognition 6 mg per kilogram of body weight in the preven- mean that at the time of diagnosis invasive fungal tion of candida colonization and infection. Sec- infection is often advanced. Such infections in- ondary objectives were assessment of the incidence crease the rate of death from all causes (28%, vs. of gram-positive and gram-negative sepsis, necro- 7% for infants without such infections3) and death tizing enterocolitis, ligation of patent ductus arte- that is attributable to fungal infection (up to 44% riosus, threshold retinopathy of prematurity requir- of deaths).1-5 Early diagnosis and successful treat- ing surgery, severe intraventricular hemorrhage, ment have not been shown to prevent prolonged bronchopulmonary dysplasia, and alteration of stays in the NICU, high costs, or neurodevelop- liver function at baseline and at the end of pro- Very-low-birth-weight neonates are at risk for Very-low-birth-weight neonates who were ad- invasive fungal infection because of their imma- mitted to the NICU before day 3 of life were eli- ture immune system and the invasive supportive gible for enrollment. Exclusion criteria were a lack care they require.9-14 Prophylaxis with antifungal of parental consent and liver failure (levels of drugs is established in certain select high-risk aspartate aminotransferase and alanine amino- patients, such as adult and pediatric patients with transferase that were three times the upper limit hematologic cancers and immunity defects.15-19 of the range of normal values). The pharmacy at Among such patients, prophylactic fluconazole each center used computer-generated randomiza- has decreased candida-related complications.20,21 tion lists to form three groups in a 1:1:1 ratio and After a single-center, randomized trial suggested prepared the daily drug doses. Infants received similar efficacy in high-risk, extremely-low-birth- either 6 mg or 3 mg of fluconazole (Diflucan, weight neonates (those with birth weights below Pfizer Italia) per kilogram of body weight every 1000 g),22 some NICUs began using fluconazole third day for the first 2 weeks and then every for routine prophylaxis.23-26 Even so, expert opin- other day; the placebo group received 1 ml of nor- ion27-30 and Cochrane reviews31,32 do not recom- mal saline on the same schedule.20,21 Extremely- mend this practice because of the paucity of data low-birth-weight infants received prophylaxis for regarding safety and resistance and the absence 6 weeks; neonates weighing 1000 to 1500 g re- of adequately powered, multicenter trials. This ceived prophylaxis for 4 weeks,20,21,25 unless they study presents the results of such a multicenter, were discharged earlier or required systemic anti- prospective, randomized, double-blind, placebo- fungal therapy for proven or presumed invasive controlled evaluation of fluconazole prophylaxis fungal infection. Administration of the study drug in very-low-birth-weight infants in the NICU.
began on day 3 with one daily dose intravenously, if a catheter was present, or through an orogas- Weekly surveillance of liver function (levels of Patients
serum aspartate aminotransferase, alanine amino- From May 1, 2004, to July 31, 2005, we enrolled transferase, γ-glutamyltransferase, and bilirubin) neonates at eight tertiary Italian NICUs in the was performed for the duration of administration study, which was approved by the ethics commit- of the study drug. Drug interactions with flucon- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. Prophylactic Fluconazole in Preterm Neonates azole were screened. Invasive fungal infection of candida species at autopsy), the presence of was defined as a positive culture from blood (a natively fluconazole-resistant species, secondary peripheral site), urine (collected by sterile supra- outcomes (including those potentially related to pubic puncture or bladder catheterization, with fluconazole), the rate of progression of coloniza- growth of ≥10,000 organisms per milliliter), or tion to invasive fungal infection, and patterns of cerebrospinal fluid. Diagnosis relied on guide- the sensitivity of isolates to fluconazole. Infants lines from international consensus documents33,34 receiving either 6 mg or 3 mg of fluconazole per and recommendations of the Italian Neonatology kilogram were compared separately with those re- Society’s Fungal Infections Task Force.35 Invasive ceiving placebo. Since there were no significant fungal infections were treated with intravenous differences between the 6-mg group and the 3-mg liposomal amphotericin B at the recommended group, a post hoc analysis was performed compar- doses. Investigators remained unaware of study- ing the placebo group with both fluconazole group assignments during such treatment.
groups combined. Proportions and continuous variables were compared with the use of Fisher’s Fungal Isolation and Identification
exact two-tailed test and the t-test, respectively. The following cultures were obtained: at baseline Risk ratios and 95% confidence intervals were and then weekly, we performed surveillance cul- calculated to compare cumulative between-group tures of the ear canal (at birth only), stool, gastric incidences with the use of Stata software. A multi- aspirate, and nasopharynx or endotracheal secre- variate logistic-regression analysis was performed tions while infants were receiving fluconazole or with adjustment for important risk factors possi- placebo; cultures were obtained from surgical de- bly associated with invasive fungal infection. The vices after removal; and clinical cultures were ob- Wald test was used to assess the significance of tained from sites indicated by the physician (e.g., the estimated coefficients.
skin and respiratory secretions). Baseline coloniza- The number of patients needed for each group tion was defined as the isolation of fungi from the was estimated in 82 infants for colonization on ear canal at birth or from any site during days 1 and the basis of a two-sided type I error rate of 0.05 or less and a power of 90% to detect an absolute Specimens were incubated on chromogen cul- difference of at least 66% (a decrease from 30% ture plates (Albicans ID, BioMérieux) to identify to 10%) in the cumulative incidence of fungal Candida albicans colonies as blue stains after 48 colonization between infants in the fluconazole hours at 37°C. Colonies were speciated through a groups and those in the placebo group, given a miniaturized system of biochemical tests (Vitec pretrial incidence of 30%. The number needed for Yeast, BioMérieux). Isolates were tested for sensitiv- each group was also estimated in 89 infants for ity to fluconazole with standardized microbroth invasive fungal infection on the basis of a two- dilution assays (ATB-Fungus-2-Int, BioMérieux) sided type I error rate of 0.05 or less and a power according to recommendations of the National of 80% to detect an absolute difference of at least Committee for Clinical Laboratory Standards 80% (a decrease from 15% to 3%) in the cumula- (NCCLS).36 The interpretative breakpoint of flu- tive incidence of invasive fungal infection between conazole resistance was defined as at least 64 μg infants in the fluconazole groups and those in the per milliliter. A breakpoint of 16 to 32 μg per placebo group, given a pretrial incidence of 15%. milliliter was considered to be indicative of dose- A total of 118 infants would have been needed to reach a power of 90%. Given the low incidence of invasive fungal infection in the two fluconazole Statistical Analysis
groups, the study was underpowered to detect sig- The following variables were analyzed: incidence nificant differences for this outcome between of colonization (at least one site), invasive fungal these groups. Assuming an incidence of 4% in infection, death from all causes before discharge the 3-mg group, 1141 infants would have been from the hospital, candida-related deaths (death needed to reach a power of 80% to detect an ab- within 3 days after the last positive culture from solute difference of 50%, and 424 infants would any site in the absence of other causes or isolation have been needed for a difference of 75%. Power n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e calculations were performed with the use of S-plus Four infants (1.2%) who were incorrectly as- signed to the 6-mg group by investigators in one NICU received a dose of 6 mg per kilogram. Analyses that were repeated without the data from these infants provided no significant changes in Patients
the estimates. A total of 32.2% of fluconazole A total of 363 very-low-birth-weight neonates sur- doses were administered orally, and 90.1% of in- vived for at least 3 days and were potentially eligi- fants received both oral and intravenous admin- ble for the study. Of these infants, 27 were ineli- istration. There were no intergroup differences in gible owing to liver failure at baseline (3 patients), the route of administration. Demographic and a lack of consent (12 patients), and missing or in- neonatal characteristics and major risk factors for correct randomization (12 patients). Another 14 fungal infections are listed in Tables 1 and 2. infants were removed from the analysis owing to There were no significant baseline differences in incomplete data (3 in the 6-mg group, 3 in the most risk factors for colonization and invasive 3-mg group, and 4 in the placebo group), incor- fungal infection between groups. However, accord- rect drug administration (2 in the 6-mg group and ing to univariate analysis, the use of corticoste- 1 in the 3-mg group), or accidental administra- roids and oxygen was significantly increased in tion of five doses of fluconazole instead of placebo the groups receiving fluconazole, as compared (1 in the placebo group). A total of 322 neonates with those receiving placebo (for corticosteroids, were randomly assigned, 112 to the 6-mg group, P<0.001 for the 6-mg group and P = 0.02 for the 104 to the 3-mg group, and 106 to the placebo 3-mg group; for oxygen, P = 0.05 for the 3-mg Fungal Colonization and Invasive Fungal
Infection
Data regarding fungal colonization, invasive fun- gal infection, and distribution of fungal species and colonization sites and infection are shown in Tables 3 and 4. Colonization occurred less fre- 12 Did not provide consent12 Had other reasons quently in the 6-mg group (9.8%) and the 3-mg group (7.7%) than in the placebo group (29.2%; P<0.001 for both comparisons). Also less frequent was invasive fungal infection (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 and P = 0.02, respectively). The 21 episodes of invasive fungal infection were caused by C. albicans (16 pa- tients), C. parapsilosis (2), C. glabrata (2), C. tropicalis (1), and C. guil iermondii (1). One neonate was in- fected with both C. parapsilosis and C. glabrata. Inva- sive fungal infections occurred in 2 of 7 neonates with baseline colonization (28.6%) in the flucona- zole groups combined and in 4 of 14 neonates Fluconazole did not have an effect on the as- sociation between colonization and subsequent progression to invasive fungal infection, which occurred in 27.3% of infants in the 6-mg group and 50.0% in the 3-mg group, as compared with 45.2% in the placebo group (P = 0.47 and P = 1.0, Figure 1. Enrollment and Outcomes.
respectively). Excluding the neonates with coloni- zation at baseline, the adjusted rate of progression n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. AUTHOR, PLEASE NOTE:
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Prophylactic Fluconazole in Preterm Neonates Table 1. Characteristics of the Patients.*
Variable
Fluconazole
P Value†
* Plus–minus values are means ±SD.
† P values were calculated with the use of Fisher’s exact two-tailed test for comparing proportions and the t-test for com- paring continuous variables (e.g., birth weight).
‡ Race was determined by the investigators. Percentage refers to both parents.
§ The Apgar score ranges from 0 to 10, with higher scores indicating better functioning.
from colonization to invasive fungal infection P = 0.17). However, our study was underpowered was 33.0% in the fluconazole groups combined for a cluster analysis of these two subgroups.
and 50.0% in the placebo group (P = 0.30). In a post hoc comparison of the fluconazole groups Mortality
combined versus the placebo group, prophylaxis Overall mortality was similar in the three groups significantly reduced colonization and invasive (8.0% in the 6-mg group [P = 0.81] and 8.7% in fungal infection (P<0.001 and P = 0.001, respective- the 3-mg group [P = 1.0], as compared with 9.4% ly), without modifying the association between in the placebo group). In the fluconazole groups, colonization and subsequent invasive fungal in- no deaths were attributable to candida infection, fection (P = 0.77). Fluconazole at either dose de- as compared with two deaths (1.9%) in the place- creased colonization and invasive fungal infection bo group (P = 0.23 for the 6-mg group and P = 0.50 in extremely-low-birth-weight infants and in those for the 3-mg group) (Table 3).
weighing 1000 to 1500 g (P = 0.001 for coloniza- tion in both groups; P = 0.02 and P = 0.03 for in- Isolates Natively Resistant to Fluconazole
vasive fungal infection, respectively), as well as in There were no significant between-group differ- neonates weighing 750 to 1500 g (P = 0.007 for ences in the incidence of colonization and infec- invasive fungal infection and P<0.001 for coloni- tion with C. krusei, C. glabrata, and C. guil iermondii. zation). A nonsignificant decrease in invasive fun- Overall, three isolates from these species were gal infection was observed in infants weighing less seen in both of the fluconazole groups (C. krusei, than 750 g (16.7% vs. 2.2%, P = 0.07), as well as C. glabrata, and C. guil iermondi ) and two in the pla- in those weighing 750 to 1000 g (12.0% vs. 3.7%, cebo group (both C. glabrata). C. glabrata caused two n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 2. Major Risk Factors for Invasive Fungal Infection and Secondary End Points.*
Variable
Fluconazole
P Value†
Risk factor
Secondary end point
Necrotizing enterocolitis (requiring surgery or defined by pneu- Threshold retinopathy of prematurity (requiring surgery) — % n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. Prophylactic Fluconazole in Preterm Neonates Table 2. (Continued.)
Variable
Fluconazole
P Value†
Severe (grade 3 or 4) intraventricular hemorrhage — % Major surgery (including ligation of PDA) Death from any cause before hospital discharge — no. (%) Multivariate logistic analysis adjusted for the most important risk factors
Third-generation cephalosporins — per day * Plus–minus values are means ±SD. CI denotes confidence interval, PDA patent ductus arteriosus, and NICU neonatal intensive care unit. † P values were calculated with the use of Fisher’s exact two-tailed test for comparing proportions and the t-test for comparing continuous ‡ Odds ratios are for the fluconazole groups versus the placebo group.
nonfatal invasive fungal infections, one each in cause of presumed adverse events, intolerance, or the 6-mg group and the placebo group.
potentially dangerous interactions with other drugs. At 4 weeks of age, infants who received Minimal Inhibitory Concentration
fluconazole had increased levels of aspartate Sensitivity to fluconazole as measured by the min- aminotransferase and alanine aminotransferase. imal inhibitory concentration (MIC) required to For aspartate aminotransferase, the mean (±SD) inhibit the growth of 90% of the isolates (MIC90) levels were 16.8±11.0 U per liter in the flucon- did not vary during the study period, and all iso- azole groups combined and 13.1±10.0 U per liter lates remained sensitive to fluconazole (C. albicans, in the placebo group (P = 0.004); for alanine amino- 0.125 to 2.0; and C. parapsilosis, 0.25 to 2.0). MICs of transferase, the mean levels were 22.8±16.0 U per fluconazole in the isolated strains did not increase liter in the fluconazole groups combined and in any of the neonates at any center during the 19.5±11.0 U per liter in the placebo group (P = 0.06). study period. Satisfactory sensitivity (MIC90: 1 [col- These modifications were not observed at 6 weeks onizing isolates], 2.0 and 8 [infecting isolates]) or at hospital discharge. Elevations in levels of continued for C. glabrata. All infecting and colo- more than two times the range of normal in serum nizing isolates were sensitive to amphotericin B aspartate aminotransferase and alanine amino- and flucytosine (MIC90, 0.125 to 1.0 and 0.125 to transferase were recorded in 4 neonates who re- ceived fluconazole and in no neonates in the placebo group (P = 0.31 for both comparisons); Secondary Outcomes
such increases in γ-glutamyltransferase levels oc- There were no significant differences in secondary curred in 13 neonates who received fluconazole outcomes (Table 5). No serious adverse events or and in 6 who received placebo (P = 1.0). At 6 weeks fluconazole-related toxic effects were recorded. of age, three infants in the fluconazole groups Drug administration was not discontinued be- (none with previous alterations in levels) main- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 3. Rates of Invasive Fungal Infection, Progression from Colonization to Systemic Infection, Previous Colonization, and Mortality.*
Variable
Treatment Group
Invasive fungal infection
Infections caused by natively fluconazole-resistant candida species Progression from colonization to invasive fungal infection
Colonization
Natively fluconazole-resistant candida species tained serum levels that were slightly above nor- colonization and infection by candida species in mal (one for aspartate aminotransferase and two very-low-birth-weight infants. Our findings are for γ-glutamyltransferase), as compared with two similar to those from single-NICU studies21-26 infants (both for γ-glutamyltransferase) in the pla- and to those observed in immunocompromised cebo group. These abnormalities were transient adults and children.15-19 Colonization is consid- and absent at discharge. No infants reached lev- ered a major risk factor for invasive fungal infec- els of more than three times the normal range of tion in the preterm neonate.10,11,14,37 In our study, values or had clinical signs of hepatotoxicity or fluconazole was effective in preventing rather cholestasis, and none required treatment for than treating colonization.
cholestasis. None of the neonates required photo- Exposure of newborns to fungi is a complex therapy to treat hyperbilirubinemia.
problem and results from both horizontal and vertical transmission. Treatment of maternal vag- inal candidiasis and good hand hygiene of health care workers should reduce the risk of “new This prospective, randomized, multicenter study entry” candida in the NICU. Breaking the hori- showed that prophylactic fluconazole prevents zontal NICU transmission cycle of hand coloni- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. Prophylactic Fluconazole in Preterm Neonates 6 mg and 3 mg of Fluconazole vs. Placebo
6 mg of Fluconazole vs. Placebo
3 mg of Fluconazole vs. Placebo
* The exclusion of four infants who were original y assigned to the 3-mg group but actual y received the 6-mg dose of fluconazole yields the fol ow- ing risk ratios (as compared with the placebo group): for colonization, risk ratio, 0.34; 95% confidence interval (CI), 0.18 to 0.67; P<0.001; for in- vasive fungal infection, risk ratio, 0.22; 95% CI, 0.07 to 0.74; P = 0.007. However, the error in assignment does not change the P value for progres- sion from colonization to invasive fungal infection (P = 0.47) and does not change the P value for mortality, since none of the four infants died.
zation from caregivers to neonates and vice lactic regimens with the targeting of prophylaxis versa by fluconazole prophylaxis should reduce to ever-more-selected subgroups of high-risk neo- the risk that preterm infants pose to one an- nates.9,37 Prophylaxis should be adapted to the infection rate in each NICU to optimize the num- Rates of candidemia in the NICU vary greatly ber needed to treat, in line with guidelines rec- among institutions. NICU-related factors (e.g., the ommending antifungal prophylaxis in “carefully average use of broad-spectrum antibiotic per in- selected patients in units with high rates of in- fant5) may be implicated, in addition to the well- vasive candidiasis.”38 In our study, the number known preterm-related factors. Decreasing the needed to treat was eight (five among extremely- incidence of infection would benefit a NICU’s low-birth-weight infants) to prevent invasive fun- present and future preterm infants, a factor that gal infection.
may lead to the adoption of intermittent prophy- Two randomized, placebo-controlled studies n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e cated that approximately 1100 patients would be Table 4. Distribution of Candida Fungal Species and Sites of Colonization
and Infection.
A post hoc analysis was performed to evaluate 6 mg and 3 mg
the effect of at least 3 mg per kilogram of flu- Variable
All Infants
of Fluconazole
conazole by comparing both the 6-mg group and the 3-mg group with the placebo group. This analysis requires cautious interpretation. The high- er dose could be more effective against strains that are dose-susceptible to fluconazole but could Colonization
also be more toxic because of increased drug ex- posure. In this study, at 4 weeks treated infants showed higher levels of alanine aminotransferase and significantly higher levels of aspartate amino- transferase, although the levels remained within the normal reference range. However, at 6 weeks and at discharge, these modifications were not observed, and all treated neonates were discharged without abnormalities possibly caused by flucona- zole. Mild and transient increases of liver enzymes, without clinical implications, are described in Another concern regarding fluconazole pro- phylaxis is the emergence of fungal resistance.18 In this small, brief study, sensitivity of susceptible strains remained unchanged. (MIC90 remained be- low the cutoff of NCCLS guidelines.) Another Invasive fungal infection
concern is the selection of natively resistant can- dida species (e.g., C. glabrata and C. krusei), which are occasionally associated with fluconazole ex- posure.40,41 Consistent with other, short-term stud- ies,19,42 there was no significant change in can- dida ecology among the three groups, and MICs for C. glabrata remained in the susceptible range during the study period. Nevertheless, our study was underpowered to detect a change in fungal ecology because of its short duration. Thus, we were unable to detect shifts in candida species or the establishment of acquired resistance muta- tions. Long-term surveillance of fungal ecology * One infant was infected with both C. parapsilosis and C. glabrata.
will be important for NICUs that adopt a pro- In this multicenter study, fluconazole prophy- of prophylactic fluconazole have been conducted laxis reduced fungal colonization and infection among preterm infants, one in which 3 mg per in preterm neonates. Future studies should fur- kilogram of the drug was administered and the ther refine the identification of neonates who other in which 6 mg per kilogram was adminis- are at highest risk for infection for whom pro- tered.21,22 Our study was underpowered to detect phylaxis would be most optimally suited. Such differences in the outcome of invasive fungal in- trials should also help to define the lowest effec- fection between the two groups, owing to the low tive dose for such prophylaxis and the possible incidence of such infection. Power analysis indi- long-term emergence of fungal resistance.
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. Prophylactic Fluconazole in Preterm Neonates Table 5. Adverse Events.*
Event or Value
Fluconazole
γ-Glutamyltransferase (week 4) — U/liter Elevation of direct bilirubin — no. (%) * Plus–minus values are means ±SD. All P values, which were calculated with the use of Fisher’s exact two-tailed test for comparing propor- tions and the t-test for comparing continuous variables, are for comparisons with the placebo group. Infants with a birth weight of less than 750 g had no notable differences in the incidence of adverse effects, as compared with infants who weighed more than 750 g. AST denotes aspartate aminotransferase, ALT alanine aminotransferase, and ULN upper limit of normal.
† Infants were not among those with previously noted abnormalities.
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on July 27, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e No potential conflict of interest relevant to this article was Some data from this study were presented in preliminary form at reported.
the 46th annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 27–30, 2006.
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