Published online April 1, 2008
PEDIATRICS Vol. 121 No. 4 April 2008, pp. 703-710 (doi:10.1542/10.1542/peds.2007-1130)
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ARTICLE

Fluconazole Prophylaxis in Extremely Low Birth Weight Neonates Reduces Invasive Candidiasis Mortality Rates Without Emergence of Fluconazole-Resistant Candida Species

C. Mary Healy, MDa,b, Judith R. Campbell, MDa,b, Elena Zaccaria, CICb and Carol J. Baker, MDa,b,c

Departments of a Pediatrics
c Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
b Woman's Hospital of Texas, Houston, Texas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. We evaluated the impact of fluconazole prophylaxis for extremely low birth weight infants on invasive candidiasis incidence, invasive candidiasis-related mortality rates, and fluconazole susceptibility of Candida isolates.

METHODS. Extremely low birth weight infants <5 days of age, except those with liver dysfunction, were eligible for fluconazole prophylaxis. NICU infants (all birth weights) with invasive candidiasis between April 2002 and March 2006 were compared with those with invasive candidiasis before fluconazole prophylaxis (2000–2001).

RESULTS. Twenty-two infants had invasive candidiasis (all candidemia) during fluconazole prophylaxis; before fluconazole prophylaxis, there were 19 cases (candidemia: 17 cases; meningitis: 2 cases). Invasive candidiasis incidence in NICU infants decreased from 0.6% (19 of 3012 infants) before fluconazole prophylaxis to 0.3% (22 of 6393 infants) in 2002–2006 and that in extremely low birth weight infants decreased 3.6-fold. No Candida-attributable deaths occurred during 2002–2006 fluconazole prophylaxis, compared with 4 (21%) before fluconazole prophylaxis. The onset of invasive candidiasis was later during 2002–2006 (23.5 vs 12 days), but risk factors were similar. The invasive candidiasis species distribution remained stable. Of 409 infants who received fluconazole prophylaxis, 119 (29%) received 42 days. Shorter fluconazole prophylaxis duration was related to intravenous access no longer being necessary in 242 cases (59%), noninvasive candidiasis-related death in 29 (7%), hospital transfer in 8 (2%), invasive candidiasis diagnosis in 8 (2%), and transient increase in serum transaminase levels in 4 (1%). One hundred twenty-seven infants (31%) who received fluconazole prophylaxis developed cholestasis during hospitalization, two thirds of whom had other predisposing conditions. On multivariate logistic regression necrotizing enterocolitis and increasing days of total parenteral nutrition, but not increasing number of doses on days of fluconazole, were significantly associated with the development of cholestasis.

CONCLUSION. During 4 years of fluconazole prophylaxis, the incidence of invasive candidiasis and invasive candidiasis-associated mortality rates in extremely low birth weight infants were reduced significantly, without the emergence of fluconazole-resistant Candida species.

Key Words: neonates • extremely low birth weight • Candida infection • fluconazole prophylaxis • resistance

Abbreviations: VLBW—very low birth weight • IC—invasive candidiasis • ELBW—extremely low birth weight • FP—fluconazole prophylaxis • CVC—central vascular catheter • BW—birth weight • TPN—total parenteral nutrition • MIC—minimal inhibitory concentration

The disease burden attributable to invasive fungal infections in preterm infants in NICUs is considerable,1–4 with reported case fatality rates as high as 44%. The most common fungi causing invasive infections in these hosts are Candida species, which account for up to 12% of late-onset sepsis cases in very low birth weight (VLBW) infants (≤1500 g).3 Even in nonfatal cases with prompt appropriate treatment, invasive candidiasis (IC) is prone to causing disseminated infection, prolonged hospitalization, and long-term sequelae.2–13 Designing a preventative strategy for IC in this setting is problematic, because so many of the manipulations necessary for the intensive care of preterm infants predispose the infants to the development of IC.

During the past decade, strategies to prevent IC have focused on good infection control policy adherence, avoidance of broad-spectrum antimicrobial agent use, and prompt removal of infected devices.14,15 More recently, there have been numerous reports detailing the success of fluconazole prophylaxis (FP) in reducing fungal colonization and invasive infection in VLBW infants.5,16–24 Fluconazole is an attractive choice for prophylaxis of invasive fungal infections because it reduces colonization at sites such as the skin, gastrointestinal tract, and respiratory tract. Colonization at these sites is required for development of IC in preterm infants. Data from animal and adult studies suggest that prevention of infection is likely attributable to higher tissue concentrations than plasma concentrations of fluconazole.25,26 To date, the only untoward effects reported with fluconazole use in VLBW and extremely low birth weight (ELBW) infants (<1000 g), including infants with birth weights (BWs) of <750 g, are elevations in liver enzyme or bilirubin levels that are reversible and without long-term sequelae.5,16,19–24 Furthermore, fluconazole is not the preferred treatment for IC in neonates; therefore, FP should not interfere with treatment options.1,14,15 We recently reported our experience after implementation of a FP protocol for ELBW infants in our NICU and demonstrated a 3.5-fold decrease in IC incidence and a shift of IC to older, more-mature infants, who seemed to have more favorable outcomes.19 Despite the success of this and similar approaches in other NICUs, there are legitimate concerns that FP may promote the emergence of fluconazole-resistant Candida species or predispose patients to inherently more-resistant Candida species (C krusei or C glabrata) or filamentous fungi in the NICU.27,28 We now report our experience with this prevention strategy in place for 4 years.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
In April 2002, a FP protocol, as described previously,19 was initiated in the NICU of the Woman's Hospital of Texas (Houston, TX), a tertiary care nursery with a 40-bed level III and 80-bed level II NICU. Briefly, ELBW infants were eligible to receive intravenous fluconazole therapy (3 mg/kg per dose) if they were ELBW, were ≤5 days of age, and did not have liver failure. The decision to initiate FP for any individual infant was at the discretion of the neonatologist. Therefore, some infants with BWs of ≥1000 g who were judged likely to have many risk factors for IC (eg, 1 of multiple gestation) received FP, whereas fluconazole might have been withheld from other ELBW infants if IC risk factors were not apparent (eg, a mature infant with intrauterine growth retardation). Fluconazole was administered at different intervals (every third day for 2 weeks, alternate days for 2 weeks, and daily for 2 weeks) for a maximum of 6 weeks or until intravenous access was no longer needed, breakthrough Candida infection developed, possible fluconazole-related adverse effects developed, or the infant was transferred to another facility, whichever occurred first.

To assess the safety and tolerability of FP, all infants who received FP between April 1, 2002, and March 31, 2006 (2002–2006), were identified through pharmacy administration records, and their electronic medical records were reviewed for demographic features, number of fluconazole doses received, laboratory monitoring test results, culture data, and outcome. The incidence of cholestasis (defined as direct bilirubin levels of ≥2 mg/dL) and factors likely to contribute to cholestasis (eg, antimicrobial agent treatment, H2 receptor blocker treatment, total parenteral nutrition [TPN] administration, and necrotizing enterocolitis) also were recorded. The impact of FP on IC in the NICU was assessed in 3 ways. First, the clinical characteristics and outcomes of all infants in the NICU who developed IC (both ELBW infants and infants with BWs of ≥1000 g) during the 2-year period of January 1, 2000, through December 31, 2001 (2000–2001), were compared with those who developed IC during FP (2002–2006). Second, the overall effects of FP on IC in the NICU were determined by calculating the IC rate and IC-related mortality rate for all infants admitted to the NICU during the 2 time periods. Third, to assess the effect of FP in the target population of ELBW infants, the aforementioned calculations were repeated for ELBW infants only. Finally, the impact of FP on the occurrence of IC involving fluconazole-resistant Candida species was assessed retrospectively by examining the Candida species distribution over a 6-year period (2000-2001, before FP, and 2002-2006, after FP) and by assessing fluconazole and amphotericin B minimal inhibitory concentration (MIC) values for invasive Candida isolates from January 2004 through March 2006.

Candida identification and susceptibility testing were performed by the fungus testing laboratory at the University of Texas Health Science Center (San Antonio, TX). Candida identification was performed by using the bioMerieux API 20C yeast assimilation system (bioMerieux, St Louis, MO). This system uses 19 sugars, and a code is derived from the resulting growth pattern. In addition to the API 20C yeast assimilation system results, yeast were tested for temperature tolerance, cycloheximide susceptibility, and microscopic appearance on cornmeal agar. Antifungal susceptibility testing was performed according to the methods outlined in Clinical and Laboratory Standards Institute document M27-A2 (formerly National Committee for Clinical Laboratory Standards document M27-A2).29 This is a microtiter method that involves testing in RPMI 1640 medium for the azoles and in antibiotic medium 3 for amphotericin B. The inoculum is 0.5 to 2.5 x 103 colony-forming units per mL, with the tests being incubated at 35°C for 48 hours. The MIC is the lowest concentration that results in an optically clear well for amphotericin B or a 50% reduction in turbidity for the azoles.

IC was defined as isolation of Candida species from blood or cerebrospinal fluid cultures. Urine or tracheal aspirate cultures that grew Candida species were not considered to indicate IC, because Candida from these sites could represent colonization rather than invasion. The medical record of each infant with IC was reviewed by a single investigator (C.M.H.). Data were gathered on demographic features, prenatal history, mode of delivery, complications of prematurity, known risk factors for IC1,3,4,7,9,30–32 (parenteral hyperalimentation, central vascular catheter [CVC] type and use, history of antiinfective agent use, indication and duration of use, and history of H2 receptor blocker use), clinical presentation of infection, laboratory test results, history of Candida colonization, diagnostic imaging test results, therapeutic interventions, and clinical outcomes. Skin, soft-tissue, lung, bone, or joint complications were defined on the basis of clinical signs with supporting culture or radiographic findings (eg, pneumonia or osteomyelitis). Peritonitis was defined on the basis of positive peritoneal culture results. Renal disease was defined on the basis of renal ultrasonographic abnormalities (eg, mycetoma or pyelonephritis) in an infant known to have IC and not on the basis of positive urine culture results alone. Endocarditis was presumptively diagnosed if vegetations and/or thrombi were detected in the heart or great vessels through 2-dimensional echocardiography. Morbidity was defined as complications likely to have long-term consequences for the infant. Death or morbidity was classified as IC-related if the infant had positive blood or cerebrospinal fluid culture results within 48 hours before death or if the likely cause of death or sequelae (eg, multiorgan failure) was a direct result of the infant developing IC.

During the 6 years of the study, there were no changes in infection control practices within the NICU. Strict cohorting of infants from admission to level III care until discharge to the level II NICU was enforced. This practice ensures that each infant remains in the same bed space for the entire level III stay unless an indication for isolation arises. No clusters of invasive infections occurred. Furthermore, all NICU patients were screened for methicillin-resistant Staphylococcus aureus colonization of throat and rectal sites either twice weekly (level III) or weekly (level II), so that all infants with methicillin-resistant S aureus colonization could be placed in an isolation room with contact isolation procedures. There were no changes in the policies or guidelines governing the use of CVCs or in antibiotic utilization, particularly regarding use of third-generation cephalosporins.

Statistical analyses were performed by using SPSS for Windows 13 (SPSS, Chicago, IL). Categorical data for infants receiving FP were calculated. Infants who received FP and subsequently developed cholestasis were compared with those who did not. IC in infants of any BW in 2000–2001 and 2002–2006 were compared for baseline maternal and neonatal characteristics, details of clinical presentation, laboratory data, therapy, and outcomes. Only the first episode of IC was included in the analysis of baseline variables unless the recurrence was with a new Candida species or occurred >14 days after the conclusion of antifungal therapy. To determine the impact of FP on the target population of ELBW infants, a separate subanalysis was performed, calculating the infection and mortality rates for this population. Statistical significance for dichotomous outcomes was determined with {chi}2 and Fisher's exact tests. Normally distributed data were assessed with means and Student's t test; when positive or negative skewing of data occurred, statistical significance was assessed with medians and the Mann-Whitney U test. Multivariate logistic regression assessed the significance of variables where appropriate. This study was approved by the institutional review boards of Baylor College of Medicine and the Woman's Hospital of Texas.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Infants Who Received FP
In 2002–2006, 362 (81%) of 448 ELBW infants and 47 (0.8%) of 5945 infants with BWs of >1000 g (ie, a total of 409 infants) received FP. The reasons for administration of FP to infants with BWs of >1000 g included multiple gestations with siblings with BWs of <1000 g, maternal factors predisposing infants to infection (eg, HIV infection), congenital anomalies (eg, colon atresia or renal agenesis), or BW near 1000 g and several clinical risk factors for IC, in the opinion of the neonatologist. The median BW of infants who received FP was 775 g (range: 310–1460 g), and the median gestation was 26 weeks (range: 23–32 weeks). Infants received a median of 13 doses of fluconazole, over a median of 29 days. Of 409 infants who received FP, 118 (29%) received it for 42 days. FP was discontinued before 42 days for 242 infants (59%) because intravenous access was no longer necessary; 29 infants (7%) died as a result of unrelated causes, 8 (2%) were transferred to another hospital, 8 (2%) developed IC while receiving FP, and 4 (1%) experienced transient increases in serum transaminase levels.

Seven of 8 infants who developed IC while receiving FP had candidemia (2 infants had C albicans, 3 C parapsilosis, and 2 C glabrata). One infant discontinued FP because of persistent candiduria (C parapsilosis) and subsequently developed candidemia despite therapy with amphotericin B. In addition to these 8 infants, C glabrata and C parapsilosis fungemia developed in 2 infants after FP had been discontinued. The latter infants had received FP for 6 and 2 weeks and developed IC on day of life 65 and 133, respectively. All infants recovered without long-term sequelae.

Cholestasis During FP
One hundred twenty-seven infants (31%) who received FP developed cholestasis at some time during hospitalization. The median duration of cholestasis was 39 days (range: 1–301 days), and 99 (78%) of 127 infants received ursodeoxycholic acid therapy, for a median of 42 days (range: 2–322 days). Of 127 infants with cholestasis, 85 (67%) had other conditions likely to contribute to this condition, 78 (61%) had a BW of <750 g, and 40 (31%) had cholestasis at hospital discharge or transfer to another facility. No infant died or needed a liver transplant as a result of cholestasis. Infants with cholestasis had more exposure to H2 receptor blockers, third-generation cephalosporins, clindamycin, nafcillin, and vancomycin, were more likely to have necrotizing enterocolitis, and had a greater duration of exposure to TPN and fluconazole (Table 1). However, in multivariate regression analyses with a cutoff value of P < .2 for all significant variables, only necrotizing enterocolitis (odds ratio: 3.14; 95% confidence interval: 1.43–6.89; P = .004) and TPN duration (odds ratio for each additional day: 1.05; 95% confidence interval: 1.03–1.07; P < .001) were significantly associated; the P values for total fluconazole duration (days) and doses were .99 and .69, respectively.


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  		TABLE 1 Risk Factors for Developing Cholestasis Among Infants Receiving FP

 
Impact of FP on the Clinical Manifestations of IC in the NICU
Nineteen infants (16 with candidemia, 2 with meningitis, and 1 with candidemia and meningitis) developed IC in 2000–2001. During the first 4 years of FP in the NICU, there were 22 cases of IC (all with candidemia; 2 also had meningitis). ELBW infants accounted for 79% of IC cases (15 of 19 cases) in 2000–2001 and 45% (10 of 22 cases) in 2002–2006 (P = .05). Overall, infants who developed IC in 2002–2006 had substantially higher BWs (P = .004) and gestational ages (P = .03) than did infants infected before the initiation of FP in the NICU (Table 2). These infants also developed IC later in life and had greater frequency and duration of acknowledged risk factors for IC, although only H2 receptor blocker exposure reached statistical significance.


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  		TABLE 2 Infant Demographic Features and Risk Factors Before Development of IC in 2000–2001 and 2002–2006

 
Although some variations in clinical manifestations occurred, the overall rates of focal candidiasis were similar before and after FP (53% and 64%, respectively; P = .5) (Fig 1). The durations of candidemia were also similar (2000–2001: median: 2 days; range: 1–14 days; 2002–2006: median: 3.5 days; range: 1–19 days; P = .32). Four (21%) of 19 infected infants in 2000–2001, all with BWs of <750 g (3 with C albicans and 1 with C parapsilosis), had IC-related deaths, compared with no deaths in 2002–2006 (P = .038). Three deceased infants had candidemia when death occurred; the fourth had multiorgan failure dating from IC diagnosed 40 days earlier.


Figure 1
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  		FIGURE 1 Clinical manifestations and complications of IC in 2000–2001 and 2002–2006 (FP period). a P = .04; b in 2000–2001, there was 1 infant with severe developmental delay; in 2002–2006, 1 infant developed severe developmental delay, 1 developed renal insufficiency, and 1 had bone/joint deformity.

 
The treatment of IC was similar before and after the initiation of FP. All infants received amphotericin B deoxycholate (dose: 1 mg/kg per day) for similar durations (2000–2001: median: 25 days; range: 4–36 days; 2002–2006: median: 27.5 days; range: 7–48 days; P = .7). In 2002–2006, 3 infants also received caspofungin, although in each case sterilization of blood cultures occurred only after removal or drainage of an infected focus (CVC, septic thrombophlebitis, or bone abscess). Nine (69%) of 13 infants in 2000–2001 and 14 (93%) of 15 infants in 2002–2006 who had a CVC in place when IC was diagnosed had the CVC removed. For 3 of 4 infants in 2000–2001 for whom the CVC was not removed, death occurred before alternative intravenous access could be obtained.

Impact of FP on IC Rates in the NICU
In 2000–2001 and 2002–2006, 3012 and 6393 live-born infants, respectively, of any BW were admitted to the NICU. The incidence of IC decreased from 0.6% (19 of 3012 infants) to 0.3% (22 of 6393 infants) during those time periods (P = .05), and the IC-related mortality rate decreased from 0.1% to 0% (P = .004). The all-cause mortality rate decreased from 1.8% (54 of 3012 infants) to 1.2% (79 of 6393 infants; P = .03).

In the target population for FP, namely, ELBW infants, 206 and 448 infants were admitted to the NICU in 2000–2001 and 2002–2006, respectively. In this cohort, the IC rate decreased 3.6-fold from 7.3% (15 of 206 infants) to 2% (9 of 448 infants; P = .003), and the IC-related mortality rate decreased from 2% (4 of 206 infants) to 0% (P = .01). The all-cause mortality rate decreased from 19% (40 of 206 infants) to 15% (65 of 448 infants; P = .13).

Impact of FP on Invasive Candida Species Distribution and Susceptibility Patterns
The proportion of IC cases attributable to non-albicans Candida species increased from 26% (5 of 19 cases) in 2000–2001 to 41% (9 of 22 cases) after the introduction of FP (P = .5). This change was attributable to a reduction in cases caused by C albicans after FP was introduced, rather than an absolute increase in the numbers of non-albicans Candida cases (Fig 2). There was no increase in incidence of IC caused by species likely to be inherently resistant to fluconazole (C krusei or C glabrata), with 1 case of C glabrata occurring in 2000 and in years 2 and 4 of FP. Routine susceptibility testing of IC Candida species isolates since January 2004 indicated that all isolates were susceptible to fluconazole and amphotericin B (Table 3). MIC values were available for 2 infants for whom FP was discontinued early because of IC onset; no isolate was resistant to fluconazole (MIC values of 2.0 µg/mL and ≤0.125 µg/mL for C parapsilosis and C albicans, respectively). There was 1 infant with filamentous fungal infection in 2002–2006 (an infant of gestational age of 23 weeks with invasive Aspergillus diagnosed through skin biopsy on day of life 12); another case occurred in the 2 years before FP was introduced.


Figure 2
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  		FIGURE 2 Distribution of invasive Candida species in infected infants of any BW before and after initiation of FP.

 

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  		TABLE 3 Ranges of Fluconazole and Amphotericin B MIC Values for IC Isolates in 2004–2006

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
During 4 years of FP in our NICU, the incidence of and rate of death attributable to IC among ELBW infants decreased significantly, which was not associated with the emergence of fluconazole-resistant Candida species or other fungi. Although limited by our retrospective study design, our findings are encouraging, given the substantial concern expressed by some when commenting on studies of shorter duration.27,28 Preventing IC in preterm neonates is desirable because up to 73% of affected ELBW infants die or have neurodevelopmental sequelae in the second year of life.12 However, the optimal strategy for prevention remains controversial, definitive guidelines are lacking, and practices vary widely among neonatologists.33 In the past 6 years, FP has been evaluated in a number of different centers, in the setting of 4 prospective controlled trials (N = 81–322)5,16,18,24 and 5 cohort studies using historical control subjects (N = 255–465).19–23 On the basis of these reports, there are considerable data supporting the use of FP to prevent IC. In all reports to date, FP decreased Candida spp colonization and invasive infection rates in the target population of ELBW or VLBW infants. Although IC-related mortality rates did not decrease significantly in each of the previous studies, the trend was consistently toward decreased mortality rates when the data were taken together.

Our current and previous studies are unique in that, to our knowledge, they are the only reports to focus on the overall impact of FP on the IC-related disease burden in infants of any BW in a NICU, providing a portrait of the potential impact of this prevention strategy if it is introduced universally. Our current report, 4 years after FP was introduced in our NICU, demonstrates an overall decrease in IC incidence and validates our earlier observations that IC now occurs more commonly in larger, more-mature infants who are older, compared with infants in the pre-FP era. These shifts in BW and age have been associated with a significant decrease in the all-cause mortality rate in our entire NICU population. One noteworthy change is that Candida-infected infants in the FP era generally have had more exposure to recognized risk factors for IC, particularly H2 receptor blockers and antimicrobial agents. This observation is biologically plausible, given the considerable data indicating that FP prevents Candida colonization during the first 4 to 6 weeks of life.5,16,18,20,34 This prevention is beneficial, allowing many infants to overcome the most vulnerable period of life, have a more-mature immune system, and become free of the many attendant risks for infection (eg, the presence of endotracheal tubes and CVCs) by the time FP is discontinued.

One major concern that was raised after the first studies of FP in the NICU were reported was that fluconazole-resistant Candida and filamentous fungi might emerge as more-common pathogens.27,28 This concern, if valid, would be more likely to be found with longer durations of FP in a given population. Animal data suggest 4 years as the critical duration for detection of this change,35 and it is encouraging that our study did not find this shift to fluconazole-resistant Candida or new fungal pathogens. The distribution of Candida species changed during FP concomitant with the reduction of C albicans-attributable infections, a consequence that could have been anticipated, given the fact that this species is exquisitely susceptible to fluconazole. As others have reported, however, this reduction did not lead to replacement with non-albicans Candida species.5,16,18–20,24,34 Our study design did not include routine surveillance for Candida colonization or MIC testing for isolates obtained before 2004, but Candida isolates from nonsterile site cultures indicating colonization of those sites during the study period showed a similar distribution, compared with invasive isolates (data not shown). There are reasons for optimism regarding fluconazole resistance being less likely to arise in the NICU population. The treated group is less likely to be colonized with resistant isolates at the time FP is started. The dose of fluconazole used for FP is less than in adults and the duration of exposure is limited to periods of highest risk, although definitions of "high risk" vary between studies. Findings with a less-frequent dosing schedule and a decrease in the maximal number of doses by 50%18 (a protocol we have adopted for year 5 in our center) or with administration of FP only to infants receiving antimicrobial agents22 demonstrated efficacy similar to that of more-frequent dosing schedules. While data are accumulating, the optimal schedule remains undefined. The use of an alternative agent for invasive disease (most studies used amphotericin B preparations, as recommended by the American Academy of Pediatrics15) also contributes to reduced fluconazole exposure.

The safety of FP is difficult to assess other than in an adequately powered, prospective, randomized, placebo-controlled trial. The potential link between FP and cholestasis highlighted by Aghai et al23 is difficult to interpret because of the retrospective design of that study. The increasing incidence of cholestasis in ELBW infants and its multifactorial pathogenesis36 (of which many factors are implicated in the pathogenesis of IC) make this a challenging issue to study, a fact highlighted by our observations that approximately two thirds of our cohort had other risk factors for developing this condition. Although we lacked a matched control group, it is reassuring that fluconazole was not associated with the development of cholestasis in infants receiving FP, after controlling for exposure to antibiotics, use of H2 receptor blockers, use of other hepatically metabolized medications, use of TPN, and gastrointestinal pathologic conditions. This lack of association also has been noted in randomized, controlled trials and other retrospective studies; in 1 study, the incidence of direct hyperbilirubinemia actually decreased in the FP group.22 However, it is prudent to remain alert for this and other possible fluconazole-related adverse events.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our experience with FP in our NICU supports its efficacy in decreasing IC incidence and IC-attributable mortality rates, not only in our target population of ELBW infants but also in our population of NICU patients of any BW. This benefit occurred without any indication that fluconazole-resistant Candida species or other fungi are emerging. A multifaceted approach to preventing IC is necessary, and FP may not be appropriate for all units, especially those with baseline rates of Candida infection that are lower than average. Such units may prefer to focus prophylaxis on infants of lower BW or gestational age, for whom IC rates and IC-related mortality rates are especially high. We think that our study and others demonstrate that FP should be strongly considered in NICUs caring for infants with BWs of <1000 g or <750 g and infants who have significant ongoing risk factors, in a manner that limits total fluconazole exposure.


   ACKNOWLEDGMENTS
 
We thank Jayne Finkowski-Rivera, MD, and the physicians of Medical Center Neonatology Associates, Aisha Riaz, RPh, MBA, Director of Pharmacy, and NICU pharmacists, Ann Franklin, RN, BSN, MBA, NICU Outcomes Coordinator, Sally K. Chabavizadeh, MASCP, MS, Department of Microbiology, and the staff members of the Medical Records Department, Woman's Hospital of Texas (Houston, TX), for their assistance in performing this study. We thank Dora McCarthy, BS, and Annette Fothergill, MBA, Fungus Testing Laboratory, University of Texas Health Science Center (San Antonio, TX), for technical assistance. We thank Marcia A. Rench, BSN, for helpful advice on study design, data collection, and data analysis, Morven S. Edwards, MD, for manuscript review, and Robin Schroeder (Baylor College of Medicine, Houston, TX) for assistance in preparing this manuscript.


   FOOTNOTES
 
Accepted Aug 29, 2007.

Address correspondence to C. Mary Healy, MD, Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Room 302A, MS BCM 320, Houston, TX 77030. E-mail: chealy{at}bcm.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Fluconazole prophylaxis during the first 6 weeks of life prevents Candida colonization and decreases invasive candidiasis in very low birth weight infants. Fluconzaole is well tolerated, but concerns that it may predispose patients to cholestasis or fluconazole-resistant Candida species remain.

 

What This Study Adds

This article describes the impact of fluconazole prophylaxis for high-risk infants on invasive candidiasis rates in an entire NICU population. Over 4 years of fluconazole prophylaxis, fluconazole-resistant Candida species did not emerge and treatment was unrelated to cholestasis.

 


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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