Fluconazole Prophylaxis in High-Risk Neonates

Brent N Reed, Kelly E Caudle, and P David Rogers

ate-onset neonatal sepsis (>3 days of age) is a major cause of morbidity and mortality among low-birth-weight infants. Fungal organisms are responsible for over 10% of these cases, as several fac- tors put preterm neonates at higher risk for developing invasive fungal infections.1 Risk factors associated with late-onset infections include invasive devices and procedures (eg, central venous catheters, mechanical ventilation), treatment with broad-spectrum antibiotics and cortico- steroids, low gestational age or birth weight, total parenteral nutrition, and gas- trointestinal pathology including congeni- tal anomalies and necrotizing entero- colitis.2-5 Furthermore, the increased risk in low-birth-weight infants can be attributed to an immature immune system and longer stays in the neonatal intensive care unit (NICU). For the purpose of this paper, the terms very-low-birth-weight (VLBW) and extremely- low-birth-weight (ELBW) are used to denote infants with birth weights of less than 1500 g and less than
1000 g, respectively.
Candida spp. remain one of the most common etiologies of invasive infections in neonates.5 Among infants admitted to the NICU, colonization with Candida spp. appears to be associated with the de- velopment of invasive infections.2,5
These infections increase mortality and contribute to sig- nificant morbidity among survivors, including impaired neu- rodevelopment and end-organ dissemination, a feature

Author information provided at end of text.

unique to this fungal pathogen. As a result, invasive Candida infections also represent a significant financial burden to the health system. The most common isolate in invasive fungal infections is Candida albicans, where mortality rates among VLBW infants may be as high as 44%.1,6 To date, diagnostic and treatment approaches have not demonstrated a signifi-

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cant reduction in length of stay or morbidity among neonates who develop invasive fungal infections.7,8
Because it has been successful at reducing infections in immunocompromised populations, antifungal prophylaxis with fluconazole has been suggested as an approach for preventing fungal colonization and invasive fungal infec- tions in at-risk neonates. Although research in this area has grown over the last decade, concerns remain regarding the risk of the development of fluconazole resistance among clinical isolates, as well as the risk of selecting for flucona- zole resistant strains of Candida such as C. glabrata and
C. krusei. Other concerns include adverse effects of flu- conazole therapy and the lack of data demonstrating its im- pact on long-term morbidity and mortality.

Data Sources
A literature search of MEDLINE (February 2001–Au- gust 2009) using the search terms fluconazole and prophy- laxis with limits for age group (ie, birth–18 y) was con- ducted. Twelve English-language prospective and retro- spective studies were chosen from the search results. Reference citations from identified articles were also re- viewed.

Literature Review
Four prospective, randomized controlled trials have as- sessed the use of fluconazole prophylaxis in high-risk or preterm neonates. The first of these studies was conducted by Kicklighter et al.9 and investigated whether fluconazole prophylaxis in the first 28 days of life would decrease candi- dal colonization in VLBW infants. Infants were randomized to receive intravenous fluconazole 6 mg/kg or placebo every 72 hours until day of life (DOL) 7 and then every 24 hours through DOL 28. Rectal colonization with Candida spp. was reduced in infants receiving fluconazole (8/53, 15.1%) compared to placebo (23/50, 46%; p = 0.0005); however, the investigators noted that the study was not powered to de- tect prevention of candidal infection. Although this study was not designed to detect the emergence of resistant species, no significant increases in minimum inhibitory con- centration (MIC) were seen among fungal isolates. To assess the risk for fluconazole toxicity, hepatic transaminase en- zymes were measured at baseline and once weekly. No clin- ically significant adverse effects of fluconazole prophylaxis were seen. Overall, the authors conclude that fluconazole prophylaxis for the first 28 days of life safely and effectively reduced candidal colonization in VLBW infants.
A prospective, randomized, double-blind clinical trial assessed the safety and efficacy of fluconazole in prevent- ing colonization and invasive infection among ELBW in- fants between May 1998 and October 2000.10 All ELBW infants less than 5 days old admitted to the NICU were in-

cluded in the trial. Only infants with liver failure were ex- cluded. Based on previously reported pharmacokinetic data, the investigators administered fluconazole 3 mg/kg every 72 hours for the first 2 weeks of life, every 48 hours during weeks 3 and 4, and every 24 hours during weeks 5 and 6.11,12 Fungal cultures of the nasopharynx, skin (groin), and stool or rectum were obtained at the day of randomiza- tion and then weekly. Results demonstrated a significant reduction in fungal colonization in the fluconazole group (11/50, 22%) compared to the placebo group (30/50, 60%; p = 0.002). None of the infants receiving fluconazole pro- phylaxis developed an invasive fungal infection compared to 10 infants in the placebo group (20% difference in risk; 95% CI 0.04 to 0.36; p = 0.008). Despite the difference in risk between the 2 groups, the authors could not establish an association between fungal colonization and invasive infection. Additionally, no significant differences in mor- tality were demonstrated between the 2 groups. Minimum inhibitory concentration (MIC) data taken from isolates in- dicated that there were no significant changes in flucona- zole susceptibility by the end of the study. No clinically significant adverse effects were documented, which the au- thors attributed to lower fluconazole doses and intermittent dosing strategies. The investigators concluded that flu- conazole prophylaxis was effective in preventing both fun- gal colonization and invasive disease in ELBW infants.
A prospective, randomized, double-blind clinical trial conducted by the same investigators assessed the efficacy of twice-weekly fluconazole prophylaxis compared to the regimen used in the previous study.13 Additionally, fungal cultures were obtained weekly from study and nonstudy infants in order to assess the emergence of azole-resistant isolates obtained from patients receiving fluconazole pro- phylaxis. When the 2 regimens were compared, no signifi- cant differences were seen in fungal colonization or invasive infection (p = 0.83 and 0.68, respectively); however, the study was not powered to demonstrate equivalence between these groups. As demonstrated in previous studies, no signif- icant differences in morbidity or mortality were seen be- tween the 2 groups. In terms of fluconazole resistance, there was no significant change in MICs from fungal isolates drawn from study and nonstudy infants throughout the trial. After a follow-up investigation, the authors concluded that twice-weekly dosing decreases both costs and fluconazole exposure without loss of efficacy in preventing coloniza- tion and invasive disease.
Manzoni et al.14 conducted a multicenter, randomized
controlled trial to compare the effectiveness of fluconazole 3 or 6 mg/kg versus that of placebo in the prevention of colo- nization and invasive fungal infections in VLBW infants. Fluconazole was administered as either a 3- or 6-mg/kg dose every 72 hours for the first 2 weeks of life and then every 48 hours for 30 days of life. Doses were also administered until day 45 for neonates weighing less than 1000 g at birth. Fun-

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BN Reed et al.
gal colonization was detected in 7.7% of infants in the 3- mg/kg group and in 9.8% of those in the 6-mg/kg group, compared to 29.2% of infants receiving placebo (p < 0.001). Although fluconazole did not demonstrate an appreciable ef- fect on the association between colonization and infection, invasive infections occurred less frequently in patients receiv- ing fluconazole 3 mg/kg (3.8%) and 6 mg/kg (2.7%), com- pared to those receiving placebo (12.2%; p = 0.02 and 0.005, respectively). The study was not powered to detect a differ- ence between the 3- and 6-mg/kg groups and the authors cautioned against comparing subgroups and placebo. As demonstrated in single-center trials, the results obtained by Manzoni et al. did not detect any significant differences in mortality between the fluconazole and placebo groups. Addi- tionally, no significant differences were demonstrated among the ecology or susceptibility of fungal isolates, although the study was not powered to detect these differences. Where the studies conducted by Kaufman et al.10,13 evaluated the prac- tice in a single NICU, Manzoni et al. summarized their inves- tigation by concluding that fluconazole prophylaxis effective- ly reduced both colonization and invasive fungal disease across multiple healthcare centers.
Since 2005, 8 retrospective cohort studies have been published on the topic of fluconazole prophylaxis in neonates. Bertini et al.15 examined fluconazole prophylaxis in VLBW infants with central vascular access, which is one of several risk factors that can predispose infants to in- vasive fungal infections. Investigators compared 3 years of data before and after the implementation of a prophylaxis protocol, where fluconazole was administered for 28 days at 6 mg/kg every 72 hours for the first week of life and then every 24 hours thereafter. While the studies by Kauf- man et al.10,13 discontinued therapy upon removal of central access, Bertini et al. transitioned patients to equivalent dos- es of oral fluconazole therapy Although invasive infection did not occur in any of the infants after implementation of the prophylaxis protocol (7.6%; difference in risk 0.076; 95% CI 0.03 to 0.122; p = 0.003), no significant differ- ences were seen in mortality or secondary outcomes, in- cluding bacterial infections, necrotizing enterocolitis, liga- tion of patent ductus arteriosus, threshold of retinopathy of prematurity, bronchopulmonary dysplasia, or abnormal findings on cranial ultrasonography. Bertini et al. conclud- ed that the implementation of a fluconazole prophylaxis protocol was effective in reducing invasive infections among VLBW infants with central vascular access.
Healy et al.16 evaluated the impact of fluconazole prophy- laxis on ELBW infants by comparing 2 years of data before and after the implementation of a prophylaxis protocol. In- fants were administered fluconazole 3 mg/kg intravenously every 72 hours for 2 weeks, every 48 hours for 2 weeks, and then every 24 hours for 2 weeks. While the protocol estab- lished certain inclusion parameters, including intravenous ac- cess, the decision as to whether or not to initiate prophylaxis

was at the discretion of an attending neonatologist. Of the 215 infants who received prophylaxis, only 70 (33%) com- pleted a full 6-week course. Reasons for discontinuation in- cluded infants for whom intravenous access was no longer needed (n = 117), death due to unrelated causes (n = 17), transfer to another hospital (n = 5), development of transient serum transaminase elevations that resolved upon flucona- zole discontinuation (n = 3), and development of invasive candidiasis (n = 3). Results showed a decrease in invasive candidiasis from 7% (15/206) to 2% (5/240) and candidiasis- related mortality from 2% (4/206) to 0 (p = 0.1 and 0.4, re- spectively). However, infants in the preprotocol group had lower birth weight (mean birth weight 0.650 kg vs 1.105 kg; p = 0.02) and were more premature than those in the postpro- tocol group (gestational age 25 wk vs 28 wk; p = 0.07). A shift in candidiasis infection was demonstrated by a non- significant increase in invasive candidiasis in infants weigh- ing more than 1000 g (0.1– 0.2%; p = 0.6) following initia- tion of the prophylaxis protocol. Susceptibility testing of Candida isolates was not performed; however, the authors stated that no fluconazole-resistant species were isolated in the postprotocol period. Healy et al. concluded that while in- vasive fungal disease was reduced with a fluconazole pro- phylaxis protocol, it was not eliminated and instead shifted to occurring in larger and more mature infants.
A retrospective analysis examined the safety and effica- cy of fluconazole prophylaxis in VLBW infants using data obtained 3 years before and after the implementation of a prophylaxis protocol.17 All eligible neonates received flu- conazole 6 mg/kg administered intravenously every 72 hours for 1 week and every 48 hours until DOL 30 for VLBW in- fants and DOL 45 for ELBW infants. Cultures were obtained weekly from the ear canal, stool, gastric aspiration, and na- sopharynx secretions and at any time from any site indicated by the physician. Fluconazole prophylaxis reduced the rates of overall colonization when compared to historical controls (24.0% vs 43.8%; relative risk [RR] 0.406; 95% CI 0.273 to
0.605; p < 0.0001), invasive infection (4.4% vs 16.7%; RR
0.233; 95% CI 0.113 to 0.447; p < 0.0001), and progression
from colonization to infection (0.17 vs 0.38; RR 0.369; 95% CI 0.159 to 0.815). While overall mortality was similar be- tween the 2 groups, it was significantly lower in infants re- ceiving fluconazole prophylaxis who were colonized with Candida (3.7% vs 18.1%; 95% CI 0.039 to 0.778; p =
0.007). A subgroup analysis demonstrated that this was also true among colonized ELBW but not VLBW infants. In ad- dition to patient-specific parameters, the investigators did not detect any significant changes in the susceptibility of clinical isolates to fluconazole therapy. In their conclusion, the au- thors recommended that fluconazole prophylaxis should be considered for all ELBW infants and for VLBW infants who become colonized during hospitalization.
A retrospective analysis conducted by Uko et al.18 specifically examined the efficacy of targeted fluconazole

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prophylaxis in infants with a gestational age of less than 32 weeks or weight of less than 1500 g receiving more than 3 consecutive days of antibiotic therapy. The investigators also assessed mortality rates, toxicity, and costs associated with the intervention. Between July 2003 and December 2004, fluconazole 3 mg/kg was administered intravenous- ly, using different intervals based on gestational age and continued until antibiotic therapy was discontinued. These data were compared to the historical controls prior to proto- col initiation. Fluconazole prophylaxis reduced the rates of invasive infection from 6.3% (13/206) to 1.1% (2/178; p = 0.007); however, prophylaxis was not associated with changes in late (>3 days) mortality rates (11/206 control pa- tients vs 8 of 178 fluconazole patients; p = 0.644). Summa- rizing their data, Uko et al. concluded that short targeted courses of fluconazole therapy in VLBW and ELBW in- fants during periods of antibiotic therapy more than 3 days may be as effective as longer courses while also being more cost-effective and exposing infants to less drug therapy.
Previous studies focused on the elevation of hepatic
transaminase levels as a measure of potential fluconazole toxicity, whereas Aghai et al.19 were the first to examine changes in conjugated bilirubin levels in ELBW infants re- ceiving fluconazole prophylaxis. ELBW infants were com- pared to historical controls following the implementation of a fluconazole prophylaxis protocol from March 2001 to September 2005, which utilized a design previously re- ported.16 While investigators noted a higher mortality rate among infants born prior to protocol implementation (39.4% vs 25.7%; p = 0.02), there were no significant dif- ferences in morbidities. However, rates of conjugated hy- perbilirubinemia (direct bilirubin >2 mg/dL) were signifi- cantly more frequent in patients receiving fluconazole pro- phylaxis (42.9% vs 8.8%; p < 0.001). While conjugated hyperbilirubinemia was observed for longer durations in patients receiving prophylaxis, there was no significant dif- ference between the 2 groups in the number of patients whose hyperbilirubinemia had resolved by discharge. While Aghai et al. concluded that fluconazole prophylaxis effectively reduced the incidence of invasive disease, they also cautioned its use due to the increased incidence of conjugated hyperbilirubinemia seen in their investigation.
A retrospective study evaluated the impact of selective
fluconazole prophylaxis on the incidence of invasive fun- gal infection and emergence of fluconazole resistance in VLBW infants.20 Infants were eligible to receive antifun- gal prophylaxis only if they met certain criteria associat- ed with risk factors for invasive fungal infections, includ- ing treatment with a third-generation cephalosporin, treatment for more than 10 consecutive days with broad- spectrum antibiotics, fungal colonization from surface sites, or central venous access. Despite defined criteria for inclusion, the decision to use fluconazole prophylaxis was at the discretion of an attending neonatologist. In-

Fluconazole Prophylaxis in High-Risk Neonates
fants who met the above criteria and were enrolled in the study received fluconazole 6 mg/kg for 3 weeks. A sig- nificant reduction in culture-proven candidal sepsis was seen in neonates receiving prophylaxis (0/33) as com- pared to historical controls (6/33; p = 0.03). No evidence of fluconazole resistance was noted. The authors con- cluded that their selective prophylaxis protocol effective- ly prevented invasive fungal disease in VLBW infants at highest risk while avoiding unnecessary fluconazole ex- posure.
Weitkamp et al.21 also performed a retrospective study evaluating selective fluconazole prophylaxis in patients con- sidered at high risk for invasive fungal infection. Neonates less than 26 weeks of age and/or less than 750 g birth weight requiring central vascular access were considered eligible for inclusion and were compared to historical controls. Twice- weekly fluconazole therapy at 3 mg/kg was administered for up to 6 weeks. In the period prior to fluconazole prophylaxis, 9 of 44 (20%) infants developed invasive fungal infections and 5 (11.4%) developed candidemia. No invasive infections were detected in patients receiving fluconazole prophylaxis, which was a statistically significant difference (p = 0.004). Selective therapy reduced the number of infants who re- ceived prophylaxis and the investigators noted that no pre- ventable infections were missed. The authors concluded that a selective twice-weekly prophylaxis protocol was effective in infants considered at highest risk but did not demonstrate an association with conjugated hyperbilirubinemia, as noted by Aghai et al.19
A second retrospective study conducted by Healy et al.22 compared infants receiving fluconazole prophylaxis to his- torical controls in order to evaluate potential impacts on mortality, adverse effects, and susceptibility among Candi- da isolates. Eligibility criteria and study methodology re- flected the design that the investigators used previously16 and the decision to initiate prophylaxis remained at the dis- cretion of the attending neonatologist. Four years after im- plementation of the prophylaxis protocol, the incidence of invasive candidiasis had decreased from 0.6% (19/3012) to 0.3% (22/6393; p = 0.05) and related mortality decreased from 0.1% to 0 (p = 0.004). In ELBW infants, invasive in- fections and infection-related mortality decreased from 7.3% (15/206) to 2% (9/448; p = 0.003) and 2% (4/206) to
0 (p = 0.01), respectively. Nearly one third of patients
(127) who received fluconazole prophylaxis developed cholestasis, although two thirds had other predisposing conditions. No significant changes in the incidence of in- vasive disease caused by fluconazole-resistant Candida spp. were observed after the prophylaxis protocol was im- plemented. Healy et al. concluded that their protocol effec- tively reduced both invasive disease and infection-related mortality without the emergence of fluconazole-resistant isolates.

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Discussion
The Red Book: 2009 Report of the Committee on Infec- tious Diseases recommends considering fluconazole pro- phylaxis for ELBW neonates in nurseries with at least moderate rates of invasive candidiasis.23 The studies re- viewed here demonstrate an ongoing controversy regard- ing the use of fluconazole prophylaxis in neonates at risk for the development of invasive fungal infections. Al- though evidence for the benefits of fluconazole prophylax- is appears to be growing, published commentaries and an updated meta-analysis demonstrate a lack of consensus among experts.24-27
One of the most significant limitations of the literature
published to date is an overall lack of consistency with re- gard to study population, prophylaxis regimen, and re- search methodology. Inclusion criteria in early studies in- cluded all neonates within certain weight or age parame- ters, while others named specific risk factors, such as the presence of central venous access15,20,21 or duration of an- tibiotic therapy.18,20 Additionally, fluconazole administra- tion was not consistent across each investigation regarding dose, dosage interval, or duration of therapy. Many studies used a dosing regimen based on early pharmacokinetic data,11,12 while others used the twice-weekly regimen pub- lished by Kaufman et al.13
The definition of invasive fungal infection also varied among studies included in this review. The majority of inves- tigators defined invasive infection as a positive culture isolat- ed from blood, urine, or cerebrospinal fluid.10,13-15,18 Others specifically excluded cultures obtained from urine or tracheal aspirates, suspecting that these isolates were instead indica- tive of colonization rather than invasive infection.16,22
Finally, overall study designs also limit conclusions, as only 4 of the investigations were conducted as prospective randomized controlled trials. The remaining data on flu- conazole prophylaxis have been published as part of retro- spective cohort studies using historical controls.
Although several studies performed surveillance for the emergence of fluconazole-resistant fungal pathogens,14,16,20 recent investigations have specifically addressed these concerns. Manzoni et al.28 have published a retrospective study evaluating all fungal isolates obtained from VLBW infants over a 10-year period (4 y prior to and 6 y after im- plementation of a fluconazole prophylaxis protocol). Their results showed no significant changes in the emergence of resistant strains such as C. krusei and C. glabrata.
Questions also remain as to the impact of fluconazole prophylaxis on long-term morbidity and mortality. Few of the included studies reported any long-term outcomes, such as changes in neurodevelopment as a result of inva- sive fungal infections. In 2004,26 a Cochrane systematic analysis identified a small difference in mortality, but a 200727 update could not draw similar conclusions, noting

that effects on mortality approached but did not reach sta- tistical significance. According to Long and Stevenson,29 the number needed-to-treat also varies significantly; be- tween 5–200 and 20 –560 ELBW infants may be neces- sary to prevent one invasive Candida infection and one in- fection-related death, respectively.

Summary
Based on the studies reviewed here, there is insufficient evidence to support a widespread recommendation for flu- conazole prophylaxis based on birth weight or gestational age alone. However, these studies indicate that it may be reasonable to recommend prophylaxis in at-risk popula- tions where this practice appears to have some benefit. Among those receiving the most benefit were neonates with additional risk factors predisposing them to invasive fungal disease, such as central venous access or exposure to broad-spectrum agents for extended periods of time. In the absence of additional risk factors, fluconazole prophy- laxis may mostly benefit institutions with a high incidence of invasive fungal infections unsuccessfully treated with other approaches. Multifactor analysis evaluating the effect of fluconazole prophylaxis in neonates with and without certain risk factors should be performed in order to deter- mine which patients would benefit most from this practice.

Brent N Reed PharmD, Pharmacy Practice Resident, University of North Carolina Hospitals & Clinics, Chapel Hill, NC
Kelly E Caudle PharmD, PhD candidate in Pharmaceutical Sci- ences, Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, TN; LeBonheur Children’s Medi- cal Center, Memphis
P David Rogers PharmD PhD FCCP, First Tennessee Chair of Ex- cellence in Pediatric Clinical Pharmacy; Associate Dean for Trans- lational Research; Professor and Vice Chair, Department of Clinical Pharmacy, Le Bonheur Children’s Medical Center
Reprints: Dr. Rogers, 304 WPT Children’s Foundation Research Center, Le Bonheur Children’s Medical Center, 50 N. Dunlap St., Memphis, TN 38106, fax 901/287-5036, [email protected]
Financial disclosure: None reported

References
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD neonatal research network. Pediatrics 2002;110:285-91.
2. Saiman L, Ludington E, Pfaller M, et al. Risk factors for candidemia in neonatal intensive care unit patients: the National Epidemiology of My- cosis Survey Study Group. Pediatr Infect Dis J 2000;19:319-24.
3. Benjamin DK, DeLong ER, Steinbach WJ, Cotton CM, Walsh TJ, Clark RH. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics 2003;112:543-7.
4. Feja KN, Wu F, Roberts K, et al. Risk factors for candidemia in critically ill infants: a matched case-control study. J Pediatr 2005;147:156-61.
5. Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics 2006;118:2359-64.
6. Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004;17:638- 80.

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7. Smith PB, Morgan J, Benjamin DK, et al. Increased costs associated with neonatal candidemia. Presented at: Pediatric Academic Societies Annual Meeting, 2006.
8. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and

Fluconazole Prophylaxis in High-Risk Neonates
29. Long SS, Stevenson DK. Reducing Candida infections during neonatal intensive care: management choices, infection control and fluconazole prophylaxis. J Pediatr 2005;147:135- 41.

growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357-65.

9. Kicklighter SD, Springer SC, Cox T, Hulsey TC, Turner RB. Flucona- zole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics 2001;107:293-8.
10. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001;345:1660-6.
11. Saxén H, Hoppu K, Pohjavuori M. Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life. Clin Pharmacol Ther 1993;54:269-77.
12. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis 1994;13:325-9.
13. Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis for prevention of invasive Candi- da infection in high-risk infants of <1000 grams birth weight. J Pediatr 2005;147:172-9.
14. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of pro- phylactic fluconazole in preterm neonates. N Engl J Med 2007;356:2483- 95.
15. Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Flucona- zole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infants. J Pediatr 2005;147:162-5.
16. Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on incidence and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.
17. Manzoni P, Arisio R, Mostert M, et al. Prophylactic fluconazole is effec- tive in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pe- diatrics 2006;117:e22-32.
18. Uko S, Soghier LM, Vega M, et al. Targeted short-term fluconazole pro- phylaxis among very low birth weight and extremely low birth weight infants. Pediatrics 2006;117:1243-52.
19. Aghai ZH, Mudduluru M, Nakhla TA, et al. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis. J Peri- natol 2006;26:550-5.
20. McCrossan BA, McHenry E, O’Neill F, Ong G, Sweet DG. Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal in- fection. Arch Dis Child Fetal Neonatal Ed 2007;92:F454-8.
21. Weitkamp JH, Ozdas A, LaFleur B, Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure. J Perinatol 2008;28:405-11.
22. Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida species. Pediatrics 2008;121:703-10.
23. American Academy of Pediatrics. Candidaisis. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red book: 2009 report of the Com- mittee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2009:245-9.
24. Neely MN, Schreiber JR. Fluconazole prophylaxis in the very low birth weight infant: not ready for prime time. Pediatrics 2001;107:404-5.
25. Fanaroff AA. Fluconazole for the prevention of fungal infections: get ready, get set, caution. Pediatrics 2006;117:214-5.
26. McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight in- fants. Cochrane Database Syst Rev 2004;1:CD003850.
27. Clerihew L, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight in- fants. Cochrane Database Syst Rev 2007;4:CD003850.
28. Manzoni P, Leonessa M, Galletto P, et al. Routine use of fluconazole prophylaxis in a neonatal intensive care unit does not select natively flu- conazole-resistant Candida subspecies. Pediatr Infect Dis J 2008;27:731-7.

Profilaxis con Fluconazol en Neonatos de Alto Riesgo
BN Reed, KE Caudle, y PD Rogers
Ann Pharmacother 2010;44:178-84.

EXTRACTO
OBJETIVO: Evaluar la literatura concerniente a la profilaxis con fluconazol en neonatos de alto riesgo.
FUENTES DE DATOS: La literatura se obtuvo a través de MEDLINE (febrero 2001–agosto 2009) utilizando los términos de búsqueda fluconazol y profilaxis con límites para grupos de edades (p ej desde nacimiento hasta los 18 años). También se analizaron las referencias de los artículos identificados.
SELECCIÓN DE DATOS Y MÉTODO DE EXTRACCIÓN DE LA INFORMACIÓN: Se
evaluaron todos los estudios prospectivos y retrospectivos identificados a través de MEDLINE y escritos en inglés.
SÍNTESIS DE LOS DATOS: Los neonatos críticamente enfermos presentan diferentes factores de riesgo que los predisponen a sufrir colonizaciones de especies de Candida. En muchos casos, la colonización puede progresar a infecciones sistémicas invasivas a pesar de los esfuerzos empleados con un diagnóstico y tratamiento tempranos. Debido al éxito de la profil- axis con fluconazol entre los pacientes inmunocomprometidos, ésta se ha sugerido como posible método para reducir las tasas de colonización y de infecciones fúngicas invasivas entre los neonatos de alto riesgo.
Hasta la fecha, 4 ensayos prospectivos aleatorizados y 8 estudios de cohortes retrospectivos han estudiado la profilaxis con fluconazol en neonatos. A pesar de que la profilaxis con fluconazol parece reducir las tasas de colonización y de infecciones fúngicas invasivas, ningún ensayo revisado en este análisis pudo demostrar una diferencia significativa en cuanto a la morbi-mortalidad a largo plazo. También hay que tener en cuenta los efectos adversos asociados a la exposición prolongada a flu- conazol. La falta de diseños estandarizados de estudios y de pautas posológicas también limitan la recomendación generalizada de profilaxis con fluconazol en la práctica clínica.
CONCLUSIONES: A pesar de que pueda ser beneficiosa para neonatos críticamente enfermos con ciertos factores de riesgos predisponentes (como accesos venosos centrales, exposición sostenida a antibióticos de amplio espectro o unidades con incidencia significativamente alta de infecciones fúngicas invasivas) las investigaciones realizadas no respaldan la profilaxis con fluconazol basada únicamente en el peso al nacer y en la edad gestacional. Es necesario realizar un análisis multifactorial que evalúe el efecto de la profilaxis con fluconazol para determinar qué neonatos podrían beneficiarse de esta práctica.
Traducido por Violeta Lopez Sanchez

La Prophylaxie au Fluconazole chez les Nouveaux-nés à Haut Risque
BN Reed, KE Caudle, et PD Rogers
Ann Pharmacother 2010;44:178-84.

RÉSUMÉ
OBJECTIF: Évaluer la littérature concernant l’utilisation du fluconazole en prophylaxie chez les nouveaux-nés à haut risque.
REVUE DE LITTÉRATURE: La littérature fut obtenue par une recherche informatisée via MEDLINE (fevrier 2001–aout 2009) et utilisant les mots clés suivants: fluconazole, prophylaxie avec une limite d’âge (de la naissance à 18 ans). Les bibliographies d’articles furent également consultées.
SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Toute étude prospective et rétrospective de langue anglaise identifiée via MEDLINE fut évaluée.

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BN Reed et al.
RÉSUMÉ: Les nouveaux-nés en soins critiques possèdent un certain nombre de facteurs de risque les prédisposant à une colonisation fongique à Candida sp. Dans plusieurs cas, la colonisation progresse pour devenir invasive malgré les efforts d’un diagnostic précoce et d’un traitement rapide. Considérant son succès auprès des patients immunosupprimés, la prophylaxie au fluconazole a été suggérée comme une approche possible pour réduire le taux de colonisation et le taux d’infections fongiques invasives parmi les nouveaux-nés à risque. A ce jour, 4 études ran- domisées contrôlées et 8 cohortes rétrospectives ont examiné le rôle de la prophylaxie au fluconazole chez ces nouveaux-nés. Bien que la prophylaxie semble réduire le taux de colonisation et d’infections fongiques invasives, aucune étude n’a démontré une différence de la morbidité à long terme ou de la survie. Il existe aussi des effets secondaires associés à une exposition prolongée au fluconazole. Une méthodologie des études comportant des failles limite les recommandations du fluconazole en prophylaxie.

CONCLUSIONS: Bien que le fluconazole puisse être bénéfique chez les nouveaux-nés avec certains facteurs de risque prédisposant tels accès veineux central, exposition soutenue aux antibiotiques à large spectre ou des unités à haute incidence d’infections fongiques, les données actuelles ne supportent pas l’utilisation de la prophylaxie au fluconazole basée sur le poids à la naissance ou l’âge gestationnel. Une analyse multifactorielle évaluant les effets de la prophylaxie semble nécessaire en vue de déterminer parmi les nouveaux-nés ceux qui bénéficieront de cette modalité thérapeutique.
Traduit par Marc M Perreault

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