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• W2089901750 abstract "In 2001, Kicklighter et al and Kaufman et al reported the first two randomized double-blind, placebo-controlled trials of fluconazole prophylaxis in extremely prematurely born infants to prevent Candida infections.1Kicklighter S.D. Springer S.C. Cox T. Hulsey T.C. Turner R.B. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.Pediatrics. 2001; 107: 293-298Crossref PubMed Scopus (210) Google Scholar, 2Kaufman D. Boyle R. Hazen K.C. Patrie J.T. Robinson M. Donowitz L.G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.N Engl J Med. 2001; 345: 1660-1666Crossref PubMed Scopus (424) Google Scholar Some “early adopters” have implemented such strategies. In this edition of the Journal, the Editors sought to present four new studies addressing the risks and prevention of Candida bloodstream infection (BSI) in neonates,3Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis in preterm infants. J Pediatr 2005;147:172-79.Google Scholar, 4Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents fungal invasive infection in high-risk, population of VLBW infants. J Pediatr 2005;147:162-65.Google Scholar, 5Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on rate and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.Google Scholar, 6Feja KN, Wu F, Roberts K, Loughrey M, Nesin M, Larson E, et al. Risk factors for candidemia in critically ill infants: a matched case-control study. J Pediatr 2005;147:156-61.Google Scholar including a second randomized trial of fluconazole prophylaxis, to punctuate the conclusions with an editorial to provide definitive guidance to the clinician. That naïve notion aside, the studies invite some specific commentary and a broader discussion of hospital-associated neonatal infections, the prevention of which would be a major step toward healthy survival of these exquisitely vulnerable infants.The study protocols and major findings of the two previous and three current studies of fluconazole prophylaxis are shown in Tables I and II. Kaufman et al,3Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis in preterm infants. J Pediatr 2005;147:172-79.Google Scholar extending their previous study at the same neonatal intensive care unit (NICU) at the University of Virginia, Charlottesville, hypothesized that twice weekly rather than daily fluconazole prophylaxis would prevent Candida BSI in extremely low birth weight (ELBW; <1000 g) neonates, with less risk of promoting antifungal resistance. The study was actually an equivalency test of a simplified dosing schedule of fluconazole on reduction of rates of Candida colonization. Infants were randomly assigned to receive fluconazole intravenously at 3 mg/kg dosed “daily” (with frequency scaled up from every 3 days at birth until 2 weeks of age, to every other day from 2 to 4 weeks of age, and then daily after 4 weeks), or twice weekly from entry. The study was blinded by a complex scheme of administering additional doses of saline to infants in the first group according to the schedule for the second group and vice versa. The primary outcome, adequately powered, was fungal colonization as surveyed by screening cultures performed at three body sites weekly. Colonization at a single mucocutaneous site was documented in 12% and 10% of infants receiving daily and twice weekly fluconazole, respectively (Table II) (risk difference 0.02, 95% CI −0.18, 0.14). Colonization at more than one site (associated in these and other studies7Pappu-Katikaneni L.D. Rao K.P.P. Banister E. Gastrointestinal colonization with yeast species and Candida septicemia in very low birth weight infants.Mycoses. 1990; 33: 20-23PubMed Google Scholar with risk of invasive candidiasis) was found in 2% and 3% of infants, respectively. Candida BSI occurred in two infants (day of life 13, 19) receiving daily prophylaxis and in one infant (day of life 19) receiving twice weekly prophylaxis. The authors conclude that the rate of Candida colonization during twice weekly fluconazole prophylaxis (10%) was similar to that during daily prophylaxis (12% in the current study, and 22% in their prior study), and each was lower than the rate of colonization in placebo-treated infants in their prior study (60%). Bridging to their first study in which a decrease in colonization was associated with protection from BSI, the authors conclude that efficacy of twice weekly prophylaxis likely would be maintained while reducing NICU drug exposure by more than one half.Table ICharacteristics of study populations and fluconazole dosing in studies of fluconazole prophylaxisStudy typeStudy populationFluconazole doseFluconazole durationKicklighter et al1Kicklighter S.D. Springer S.C. Cox T. Hulsey T.C. Turner R.B. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.Pediatrics. 2001; 107: 293-298Crossref PubMed Scopus (210) Google ScholarProspective, randomized, placebo-controlled, blindedAll <1500 g (med. 919, 992 g)6mg/kg/dose q 72 h → DOL 7; then qdDOL 28 (IV or enteral)Kaufman et al 12Kaufman D. Boyle R. Hazen K.C. Patrie J.T. Robinson M. Donowitz L.G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.N Engl J Med. 2001; 345: 1660-1666Crossref PubMed Scopus (424) Google ScholarProspective, randomized, placebo-controlled, blindedAll <1000 g if IV access or intubation3mg/kg/dose q 72 h → DOL 14; then q 48 h → DOL 28; then q 24 hDOL 42 (IV) or shorter if IV access not necessaryKaufman et al 23Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis in preterm infants. J Pediatr 2005;147:172-79.Google ScholarProspective, randomized, controlled, blindedAll <1000 g if IV access or intubationKaufman et al 1 vs 3mg/kg/dose twice weeklyDOL 42 (IV) or shorter if IV access not necessaryBertini et al4Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents fungal invasive infection in high-risk, population of VLBW infants. J Pediatr 2005;147:162-65.Google ScholarLongitudinal, observational, pre/post policy changeAll <1500 g if IV access (88% <1000 g)6mg/kg/dose q 72 h→ DOL 7; then qdDOL 28 (IV or enteral)Healy et al5Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on rate and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.Google ScholarLongitudinal, observational, pre/post policy changeDiscretionary <1000 g if IV accessKaufman et al 1DOL 42 (IV) or shorter if IV access not necessaryDOL, day of life; IV, intravenous; q, every, qd, once daily. Open table in a new tab Table IIOutcomes of subjects in studies of fluconazole prophylaxis∗Total study subjects placebo-treated or pre-prophylaxis policy vs fluconazole treated: Kicklighter et al=53 vs 50, Kaufman et al 1=50 vs 50, Bertini et al=120 vs 136, Healy et al=206 vs 240. Total study subjects fluconazole daily vs fluconazole twice weekly, Kaufman et al 2=41 vs 40, respectively. See Table I for characteristics of studies and dosing of fluconazole.Placebo1Kicklighter S.D. Springer S.C. Cox T. Hulsey T.C. Turner R.B. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.Pediatrics. 2001; 107: 293-298Crossref PubMed Scopus (210) Google Scholar, 2Kaufman D. Boyle R. Hazen K.C. Patrie J.T. Robinson M. Donowitz L.G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.N Engl J Med. 2001; 345: 1660-1666Crossref PubMed Scopus (424) Google Scholar or pre-fluconazole prophylaxis4Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents fungal invasive infection in high-risk, population of VLBW infants. J Pediatr 2005;147:162-65.Google Scholar, 5Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on rate and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.Google Scholar“Daily” fluconazoleTwice weekly fluconazoleCandida colonization Kicklighter et al1Kicklighter S.D. Springer S.C. Cox T. Hulsey T.C. Turner R.B. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant.Pediatrics. 2001; 107: 293-298Crossref PubMed Scopus (210) Google Scholar23 (46%)8 (15%)– Kaufman et al12Kaufman D. Boyle R. Hazen K.C. Patrie J.T. Robinson M. Donowitz L.G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.N Engl J Med. 2001; 345: 1660-1666Crossref PubMed Scopus (424) Google Scholar30 (60%)11 (22%)– Kaufman et al 23Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis in preterm infants. J Pediatr 2005;147:172-79.Google Scholar–5 (12%)4 (10%)Candida BSI during study days Kicklighter et al01 (2%)– Kaufman et al 18 (16%)0– Kaufman et al 2–2 (5%)1 (2.5%) Bertini et al4Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents fungal invasive infection in high-risk, population of VLBW infants. J Pediatr 2005;147:162-65.Google Scholar9 (7.6%)0– Healy et al5Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on rate and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.Google Scholar15 (7%)3 (1%)–Candida mortality in infected study subjects Kicklighter et al01– Kaufman et al 14 (50%)0– Kaufman et al 2–00 Bertini et al3 (33%)0– Healy et al4 (27%)0–Candida BSI in study subjects after study days Kicklighter et al1 (DOL 99)1 (DOL 83)– Kaufman et al 13 (DOL not stated)1 (DOL not stated)– Kaufman et al 2–Not statedNot stated Bertini et al00– Healy et alNot stated2 (DOL 65 & 133)–Bacterial BSI during study days Kicklighter et alNot statedNot stated– Kaufman et al 1During and after study drug.17 (34%)19 (38%)– Kaufman et al 2–12 (29%)12 (30%) Bertini et al18 (15%)17 (13%) Healy et alNot statedNot statedAll-cause mortality in study subjects Kicklighter et al10 (20%)5 (9.4%)– Kaufman et al 110 (20%)4 (8%)– Kaufman et al 2–6 (14.6%)6 (15%) Bertini et al15 (12.6%)11 (8.1%)– Healy et al33 (16%)41 (17.1%)–BSI, bloodstream infection; DOL, day of life.∗ Total study subjects placebo-treated or pre-prophylaxis policy vs fluconazole treated: Kicklighter et al = 53 vs 50, Kaufman et al 1 = 50 vs 50, Bertini et al = 120 vs 136, Healy et al = 206 vs 240. Total study subjects fluconazole daily vs fluconazole twice weekly, Kaufman et al 2 = 41 vs 40, respectively. See Table I for characteristics of studies and dosing of fluconazole.∗∗ During and after study drug. Open table in a new tab Bertini et al4Bertini G, Perugi S, Dani C, Filippi L, Pratesi S, Rubaltelli FF. Fluconazole prophylaxis prevents fungal invasive infection in high-risk, population of VLBW infants. J Pediatr 2005;147:162-65.Google Scholar studied Candida BSI during the first 28 days of life at Careggi University Hospital in Florence, Italy, in very low birth weight (<1500 g) infants (89% who were ELBW) who required initial use of a central venous catheter. They compared rates during a 3-year baseline period from 1998 through 2000 before fluconazole prophylaxis with rates during a 3-year period from 2001 through 2003 when fluconazole prophylaxis was implemented. Fluconazole was given at dose of 6 mg/kg “daily” by schedule of Kicklighter et al 1 (Table I). The incidence of Candida BSI fell from 7.6% in the pre-prophylaxis period to no cases in 136 infants in the prophylaxis period (P = .003).Healy et al5Healy CM, Baker CJ, Zaccaria E, Campbell JR. Impact of fluconazole prophylaxis on rate and outcome of invasive candidiasis in a neonatal intensive care unit. J Pediatr 2005;147:166-71.Google Scholar, like Bertini et al, compared rates of invasive candidiasis (BSI and meningitis) in ELBW infants at Woman's Hospital of Texas in Houston during a 2-year baseline period from 2000 through 2001 with rates during a 2-year period in 2002 to 2004 when it became standard policy to use fluconazole prophylaxis. Infants requiring an intravascular catheter were given fluconazole at dosage of 3 mg/kg “daily” by schedule of Kaufman et al's first study2Kaufman D. Boyle R. Hazen K.C. Patrie J.T. Robinson M. Donowitz L.G. Fluconazole prophylaxis against fungal colonization and infection in preterm infants.N Engl J Med. 2001; 345: 1660-1666Crossref PubMed Scopus (424) Google Scholar (Table I). Infants with invasive candidiasis were identified by review of microbiology laboratory records and infants receiving fluconazole prophylaxis were identified by review of pharmacy records. The incidence of invasive candidiasis during hospitalization fell from 7% in ELBW infants in pre-prophylaxis years to 2% in ELBW infants who received fluconazole in the prophylaxis years (P = .006), and to 1% in ELBW infants while receiving fluconazole prophylaxis.The study of Feja et al,6Feja KN, Wu F, Roberts K, Loughrey M, Nesin M, Larson E, et al. Risk factors for candidemia in critically ill infants: a matched case-control study. J Pediatr 2005;147:156-61.Google Scholar also reported in this issue of the Journal, is a large case-control study of risks for developing Candida BSI in the NICU. Performed in two New York City level III/IV NICUs, investigators matched infants with Candida BSI with uninfected neonates by birth weight, study site, and date of enrollment. Multivariate analysis revealed that catheter use (OR 1.06 per day of use; 95% CI 1.02-1.10), prior bacterial BSI (OR 8.02; 95% CI 2.76-23.20), and gastrointestinal pathology (OR 4.57; 95% CI 1.62-12.92) were significantly associated with Candida BSI. Fifty-eight percent of Candida BSIs occurred in infants with birth weight of ≥1000 g, who would not qualify for prophylaxis as described by Kaufman et al or implemented by Bertini et al and Healy et al.If the first simple question is, “Does 4 to 6 weeks of fluconazole prophylaxis decrease Candida BSI in ELBW infants?” the answer is, “Yes.” The number of infants and cases of Candida BSI in all prospective randomized trials conducted to date is a sobering total of 284 infants and 12 cases of Candida BSI studied in just two NICUs. Kaufman et al's first study of 100 infants in a single NICU is the only placebo-controlled trial in which the primary study outcome was Candida BSI. Combining that study with their second study reported in this issue of the Journal, it is reasonable to conclude that in this NICU, Candida BSI was significantly reduced by application of fluconazole prophylaxis. Candida BSI occurred in 3 of 91 (2.3%) infants receiving fluconazole prophylaxis versus 8 of 50 (16%) infants receiving placebo (risk difference 0.14; 95% CI, 0.05, 0.22, P <.001). One would expect to treat seven infants (95% CI of number needed to treat [NNT], 5-20 infants) to prevent one case of Candida BSI in this Virginia NICU.The observational studies of Bertini et al and Healy et al lend only circumstantial evidence in support of the beneficial effect of prophylaxis. Considering the lower incidence of Candida BSI in these NICUs, one would expect to treat 14 or 20 infants to prevent one Candida BSI in Florence or Houston, respectively. One could easily calculate the rate of Candida BSI in ELBW infants in the home NICU, apply an expected 80% risk reduction, and estimate the NNT (1 divided by the absolute risk difference) to prevent one Candida BSI. In California, the California Perinatal Quality Collaborative collects morbidity and mortality data from its member NICUs. In 2002 to 2003, the incidence of fungal BSI was 5.4% among 2990 ELBW infants. The NNT in California would be expected to be 23. At St. Christopher's Hospital for Children Level III/IV NICU in Philadelphia, there was only a single, nonfatal case of Candida BSI during the first 42 days of life among 152 ELBW infants (incidence, 0.65%) admitted from 2000 through 2004. The NNT to prevent one case would approach 200. Incidence of Candida BSI in the four new studies of BSI as well as local statistics may underestimate the true burden of invasive candidiasis as well as potential benefit of prophylaxis. Data are almost exclusively the isolation of Candida species from blood. Low bloodstream density of organisms, low volume of blood sampled from ELBW infants, and the tissue-tropic nature of Candida species each reduces the sensitivity of blood culture. Nonculture methods may more accurately reflect the true burden of infection, such as the β glucan assay that measures a major component of the fungal cell wall, the D-arabinitol assay that measures a major metabolite of most Candida species, and polymerase chain reaction testing that amplifies a genetic region common to multiple Candida species. Risks can be understood and prevention strategies can be focused and studied most accurately only after knowing the true burden of infection, morbidity, and mortality. Dealing with the data at hand, however, the merit of preventing infection (ie, the adverse effects of Candida BSI) as well as the safety of prophylaxis must be considered carefully before attempting to balance the benefit-to-risk equation even for NICUs with the highest rates of infection.If the second simple question is, “Does fluconazole prophylaxis decrease Candida-related mortality in ELBW infants?” the answer is, “Yes.” The consequences of BSIs in prematurely born neonates are not all equal,8Makhoul I.R. Sujov P. Smolkin T. Lusky A. Reichman B. Pathogen-specific early mortality in very low birth weight infants with late-onset sepsis: a national survey.Clin Infect Dis. 2005; 40: 218-224Crossref PubMed Scopus (106) Google Scholar depending on multiple factors but probably most importantly the pathogen, and the gestational and postnatal age of the infant. Candida BSI has extraordinary mortality and morbidity in young ELBW infants, mortality ranging from 11.4% to 44% in the literature (reviewed in references 1-6 and 8), 50% in ELBW placebo recipients in the first Kaufman et al study, 33% in Feja et al's ELBW cases, 33% and 27% in Bertini et al and Healy et al's subjects during the pre-prophylaxis period, and 30% in the California Collaborative's ELBW infants. Although only 22 infants had fatal invasive candidiasis in the five studies reviewed in Table II and Feja et al's case-control study (12 deaths in the randomized and observational studies and 10 deaths in the current case-control study), 21 (95%) fatal cases occurred in the first month of life. In 4 of 5 studies, death from invasive Candida infections was eliminated in ELBW infants receiving fluconazole prophylaxis. Eight cases of Candida BSI occurred in ELBW study infants after the 28- to 42-day study periods, in both those who had and had not received fluconazole; none was fatal. Before implementation of prophylaxis, Healy et al noted in their Houston NICU that fatal invasive candidiasis occurred exclusively in young ELBW infants, who accounted for 72% of cases of invasive candidiasis. Following implementation, the burden of remaining cases of invasive candidiasis shifted to an older ELBW group and infants with higher birth weight, who developed focal but not fatal Candida infection. Feja et al's case-control study extends that perspective. Their data suggest that there are two populations at risk for Candida BSI—young ELBW infants, and older and larger infants predominantly with gastrointestinal pathology and other risk factors. The latter group's infections infrequently are immediately fatal. The clustering of Candida-related deaths, but not necessarily cases, in ELBW infants in the first month of life is a striking new finding emerging from these studies that bears significantly on the potential impact of fluconazole prophylaxis. Assuming a 30% mortality of Candida BSI in ELBW infants and at least 90% relative risk reduction through implementation of fluconazole prophylaxis, the estimate of number of ELBW infants needed to treat to prevent one death might be approximately 20 in Charlottesville; 50 in Florence, Houston, and New York; 60 in California; and 560 in Philadelphia.If the third simple question is, “Does fluconazole prophylaxis of ELBW infants decrease morbidity?” the answer is that “The current studies do not address whether Candida BSIs that occur during prophylaxis or after prophylaxis have decreased morbid complications.” The immediate complications of nonfatal Candida BSI are worth preventing. They are extraordinary and include: (1) prolonged, life-threatening depressed cardiovascular function and pulmonary edema related to endotoxemia; (2) metastatic foci of infection in vital organs such as the heart, the eye, the central nervous system, the visceral organs and kidney; (3) major emboli events that threaten limbs; (4) bone and joint infections that alter function and growth; and (5) difficult-to-manage suppurative phlebitis.9Benjamin D.K. Poole C. Steinbach W.J. Rowen J.L. Walsh T.J. Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques.Pediatrics. 2003; 112: 634-640Crossref PubMed Scopus (190) Google Scholar, 10Friedman S. Richardson S.E. Jacobs S.E. O'Brien K. Systemic Candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome.Pediatr Infect Dis J. 2000; 19: 499-504Crossref PubMed Scopus (139) Google Scholar, 11Lee B.E. Cheung P.Y. Robinson J.L. Evanochko C. Robertson M.T. Comparative study of mortality and morbidity in premature infants (birth weight, <1,250 g) with candidemia or candidal meningitis.Clin Infect Dis. 1998; 27: 559-565Crossref PubMed Scopus (90) Google Scholar Additionally, management almost always entails removal and replacement of a central venous catheter (with attendant surgical risk) and lengthy antifungal therapy that can lead to further infectious and noninfectious complications. Importantly, even short-term Candida-associated mortality and morbidity are inadequately captured when outcome measure is limited to death within 3 to 7 days after a positive blood culture. Additionally, long-term central nervous system sequelae have been documented in infants with invasive candidiasis with and without documented meningitis.10Friedman S. Richardson S.E. Jacobs S.E. O'Brien K. Systemic Candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome.Pediatr Infect Dis J. 2000; 19: 499-504Crossref PubMed Scopus (139) Google Scholar, 11Lee B.E. Cheung P.Y. Robinson J.L. Evanochko C. Robertson M.T. Comparative study of mortality and morbidity in premature infants (birth weight, <1,250 g) with candidemia or candidal meningitis.Clin Infect Dis. 1998; 27: 559-565Crossref PubMed Scopus (90) Google ScholarIf the fourth simple question is, “Is fluconazole prophylaxis in ELBW infants safe?” the answer is, “It has not been proven to be.” A high bar of safety is required for prophylactic use of a drug because the vast majority of recipients do not derive benefit. Three spheres of safety are considered: (1) direct drug toxicity and drug-drug interactions; (2) emergence of resistant pathogens; and (3) unintended, unexpected consequences. Fluconazole generally is considered to have minimal toxicity. It is partially metabolized by the cytochrome P450 3A4 hepatic enzyme, which is less active in prematurely born and young infants, thus prolonging the drug's serum half-life (55 to 90 hours in healthy, term infants).12Grant S.M. Clissold S.P. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.Drugs. 1999; 39: 877-916Crossref Scopus (406) Google Scholar With doses at 6 mg/kg daily for a maximum of 28 days, Kicklighter et al reported a statistically significant but clinically unimportant elevation of serum alanine aminotransferase (ALT), and Bertini et al observed no infant with a value 3 times greater than the upper limit of normal. With dosages escalating to 3 mg/kg daily for a maximum of 42 days, Kaufman et al reported aminotransferase (ALT and aspartate aminotransferase [AST]) levels >2 SD above the mean in 5 of 90 treated infants (as well as 3 of 50 placebo recipients), and Healy et al observed transient elevation of ALT or AST in 3 of 215 infants, which returned to normal after discontinuing drug. With dosage of 3 mg/kg twice weekly, Kaufman et al reported 4 of 40 patients with ALT levels >2 SD above the mean; infants were not withdrawn from study and levels returned to normal in all patients who survived to discharge. The majority of these safety data are in infants who received intermittent dosing because one half of infants in both Kaufman set al studies and the Healy et al study discontinued prophylaxis at the approximate age of 30 days (and by protocol, “daily” dosing actually becomes daily only after 28 days). A much larger, placebo-controlled trial with short- as well as long-term outcomes for hepatic function is required to address safety. Additionally, although fluconazole is not as strong an inhibitor of cytochrome P450 3A4 as earlier azole agents, the pharmacokinetic profile of fluconazole in ELBW infants raises the caution of significant drug-drug interactions with the many other drugs metabolized by this enzyme.Although authors are sanguine about potential microbiologic risks of fluconazole prophylaxis, there are suggestions in Kaufman et al and Healy et al's data as well as experience from animals and almost every other setting in which fluconazole has been used that resistant organisms are emerging and will emerge. Candida albicans inherently is the most common colonizing species as well as the most virulent (ie, invasive) species, but is most susceptible to fluconazole (minimum inhibitory concentration [MIC] of 90% of isolates [MIC90] ≤1.0 μg/mL), and is least likely to display rising MICs during drug exposure.13Safdar A. Chaturvedi V. Cross E.W. Park S. Bernard E.M. Armstrong D. et al.Prospective study of Candida species in patients at a comprehensive cancer center.Antimicrobial Agents Chemo. 2001; 45: 2129-2133Crossref PubMed Scopus (106) Google Scholar C glabrata and C parapsilosis inherently act more as opportunists but are more resistant to fluconazole (MIC90 = 64 μg/mL) and are more capable of developing resistance under pressure of drug exposure.13Safdar A. Chaturvedi V. Cross E.W. Park S. Bernard E.M. Armstrong D. et al.Prospective study of Candida species in patients at a comprehensive cancer center.Antimicrobial Agents Chemo. 2001; 45: 2129-2133Crossref PubMed Scopus (106) Google Scholar, 14Pfaller M.A. Diekema D.J. Role of sentinel surveillance of candidemia: trends in species distribution and antifungal susceptibility.J Clin Microbiol. 2002; 40: 3551-3557Crossref PubMed Scopus (211) Google Scholar, 15Castagnola E. Machetti M. Bucci B. Viscoli C. Antifungal prophylaxis with azole derivatives.Clin Microbiol Infect. 2004; 10: 86-95Crossref PubMed Scopus (39) Google Scholar, 16Benjamin D.K. Ross K. McKinney R.E. Benjamin D.K. Auten R. Fisher R.G. When to suspect fungal infection in neonates: a clinical comparison of Candida albicans and Candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia.Pediatrics. 2000; 106: 712-718Crossref PubMed Scopus (172) Google Scholar, 17Fairchild K.D. Tomkoria S. Sharp E.C. Mena F.V. 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Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases.Pediatr Infect Dis J. 1998; 17: 504-508Crossref PubMed Scopus (261) Google Scholar, 19Girmenia C. Martino P. De Bernardis F. Gentile G. Boccanera M. Monaco M. et al.Rising incidence of Candida parapsilosis fungemia in patients with hematologic malignancies: clinical aspects, predisposing factors, and differential pathogenicity of the causative strains.Clin Infect Dis. 1996; 23: 506-514Crossref PubMed Scopus (158) Google Scholar, 20Makhoul I.R. Kassis I. Smolkin T. Tamir A. Sujov P. Review of 49 neonates with acquired fungal sepsis: further characterization.Pediatrics. 2001; 107: 61-66Crossref PubMed Scopus (126) Google Scholar, 21Rangel-Frausto M.S. Wiblin T. Blumberg H.M. Saiman L. Patterson J. Rinaldi M. et al.National epidemiology of mycoses survey (NEMIS): variations in rates of bloodstream infections due to Candida species in seven surgical intensive care units and six neonatal intensive care units.Clin Infect Dis. 1999; 29: 253-258Crossref PubMed Scopus (383) Google Scholar to predominance of C glabrata and C parapsilosis. Although C albicans did not show increasing MICs during fluc" @default.
• W2089901750 created "2016-06-24" @default.
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• W2089901750 date "2005-08-01" @default.
• W2089901750 modified "2023-10-18" @default.
• W2089901750 title "Reducing Candida Infections During Neonatal Intensive Care: Management Choices, Infection Control, and Fluconazole Prophylaxis" @default.
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