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August 2008: VOLUME 5, NUMBER 12 Neonatal Fungal Chemoprophylaxis Editor's Note: Please help us bring Johns Hopkins eNeonatal Review to our 9000+ subscribers for another year. The success of eNeonatal Review depends on your valuable input. Take our quick 4-question survey (and be entered into a drawing for an iPod Shuffle). To access the survey, please visit here. Thank you, The Editors of eNeonatal Review In this Issue... Our treatment successes in newborn care have lead to a growing population of surviving very low birth weight (VLBW) babies who are at high risk of nosocomial infection. Invasive fungal infection, particularly with Candida species, is being diagnosed more frequently. Increased mortality and worse long-term neurological outcomes are found in babies with invasive fungal infections compared with bacteraemia alone. While antifungal prophylaxis reduces the incidence of invasive fungal infection, there are concerns that widespread use of antifungals may increase the emergence of resistant strains. In this issue we review the research that argues both for and against routine antifungal prophylaxis with fluconazole for VLBW babies in NICU. THIS ISSUE IN THIS ISSUE COMMENTARY from our Guest Authors FLUCONAZOLE PROPHYLAXIS REDUCES CANDIDA COLONIZATION FLUCONAZOLE PROPHYLAXIS REDUCES INVASIVE CANDIDAL INFECTION IN PRETERM INFANTS FLUCONAZOLE PROPHYLAXIS AND SURVIVAL INCIDENCE OF INVASIVE FUNGAL INFECTION IN VLBW BABIES RISK FACTORS FOR INVASIVE FUNGAL INFECTION IN VLBW BABIES SELECTIVE FLUCONAZOLE PROPHYLAXIS FOR BABIES WITH ADDITIONAL RISK FACTORS FOR INVASIVE FUNGAL INFECTION Course Directors Edward E. Lawson, MD Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Christoph U. Lehmann, MD Associate Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Lawrence M. Nogee, MD Professor Department of Pediatrics Division of Neonatology The Johns Hopkins University School of Medicine Mary Terhaar, DNSc, RN Assistant Professor Undergraduate Instruction The Johns Hopkins University School of Nursing GUEST AUTHORS OF THE MONTH Commentary: David Sweet, MD, FRCPCH Honorary Clinical Lecturer Consultant Neonatologist Regional Neonatal Unit Royal Maternity Hospital Belfast BT12 6BB Northern Ireland, UK       Reviews: Brian McCrossan, MB, MRCPCH Specialist Registrar in Paediatrics Regional Neonatal Unit Royal Maternity Hospital Belfast BT12 6BB Northern Ireland, UK Guest Faculty Disclosure Dr. Sweet has no relevant financial relationships to disclose. Dr. McCrossan has no relevant financial relationships to disclose. Unlabeled/Unapproved Uses The author has indicated that there will be no reference to unlabeled or unapproved uses of drugs or products in the presentation. Program Directors' Disclosures LEARNING OBJECTIVES At the conclusion of this activity, participants should be able to: Discuss the epidemiology of neonatal fungal infection Describe the benefits and risks of routine antifungal prophylaxis for very low birth weight babies (VLBW) List the additional risk factors for fungal sepsis in VLBW infants

Program Information CE Info Accreditation Credit Designations Intended Audience Learning Objectives Internet CME/CNE Policy Faculty Disclosure Disclaimer Statement Length of Activity 1.0 hours Physicians 1 contact hour Nurses Release Date August 18, 2008 Expiration Date August 17, 2010 Next Issue September 13, 2008 COMPLETE THE POST-TEST Step 1. Click on the appropriate link below. This will take you to the post-test. Step 2. If you have participated in a Johns Hopkins on-line course, login. Otherwise, please register. Step 3. Complete the post-test and course evaluation. Step 4. Print out your certificate. Respiratory Therapists Visit this page to confirm that your state will accept the CE Credits gained through this program or click on the link below to go directly to the post-test.

AUGUST PODCAST eNeonatal Review is proud to continue our accredited PODCASTS for 2008. Listen here. In this audio interview Dr. David Sweet discusses fungal infections in the NICU, the scope of the problem and using fluconazole prophylaxis in the NICU. Participants can now receive 0.5 credits per podcast after completing an online post-test. In addition to our monthly newsletters, there will be 6 podcasts throughout the year. To learn more about podcasting and how to access this exciting new feature of eNeonatal Review, please visit this page. Podcasts Please remember that you don't need this to listen to our podcasts. You can listen directly from your computer. back to top

COMMENTARY Invasive fungal infection affects about 3 - 6% of very low birth weight (VLBW) babies; however, some estimates place the risk even higher in those with a birthweight less than 1 kg.1 Invasive fungal infection has a much higher mortality than bacteraemia and a higher rate of adverse neurodevelopmental outcome.2 In addition to generalized measures for reducing nosocomial sepsis, clinicians have attempted to further reduce the risk of fungal infection by using prophylactic antifungals including nystatin, miconazole, and fluconazole. In the first small randomized trial in 1988, oral nystatin was shown to reduce invasive fungal infection. However the study was not sufficiently powered to show any effect on mortality or long- term outcome.3 In 1992, a larger study of oral miconazole gel versus placebo found no difference in the rates of invasive fungal infection.4 In more recent years, fluconazole prophylaxis has been shown to reduce the incidence of, and in some studies mortality from, invasive fungal infection. The earliest publications (Kicklighter et al. reviewed in this issue) showed that prophylactic fluconazole could reduce rectal colonization with Candidal species by a third without any significant short term side effects.5 Subsequently (and reviewed herein), it was shown that prophylactic administration of 3mg/kg of fluconazole for the first 6 weeks of life to babies <1000g resulted in a reduction in invasive fungal infection from 20% to zero.1 Four randomized trials have now been completed and subjected to meta-analysis showing that fluconazole prophylaxis reduces invasive fungal infection (Relative Risk 0.23 95% CI 0.11 – 0.46). There was also a trend towards reduction in all causes of mortality, which failed to reach statistical significance (RR 0.61 95% CI 0.37 – 1.03).6 Despite these encouraging findings, neonatologists in the UK, USA, and Ireland have remained reserved about initiating widespread fluconazole prophylaxis.7-9 Although side effects are relatively uncommon, transient rises in liver transaminases have been observed and there are concerns about treating many to protect a few. The largest of the multicenter randomized trials (Manzoni et al. reviewed herein), reported a high incidence of fungal colonization (29%) and invasive fungal infection (13%) in the control arm; however, there was no observed difference in survival with prophylaxis using either 3 mg/kg or 6 mg/kg of fluconazole.10 The high infection rates seen in most of the randomized trials may reflect the particular case mix in the units involved in the studies. In contrast, the recent prospective survey from the UK by Clerihew et al. (reviewed herein) perhaps gives a better reflection of the true incidence of invasive fungal infection in VLBW babies which is closer to 1%.11 This lower incidence rate means that if all VLBW babies were to receive fluconazole prophylaxis there would be one less case of invasive fungal infection for every 125 babies treated. Such widespread use raises concerns about the emergence of fluconazole resistance, although this has not been observed and reported in the studies thus far. An alternative to routine fluconazole prophylaxis is to limit this treatment to babies perceived to be at very high risk of fungal infection. There are additional recognized risk factors for acquiring fungal sepsis, including: 3rd generation cephalosporin use, fungal colonization, prolonged broad-spectrum antibiotic use, total parenteral nutrition with lipids, endotracheal intubation, central venous catheter use, previous blood stream infection, and postnatal steroids.12-14 So far, the evidence to support a selective approach is limited to case control studies.15,16 These have shown that targeting babies at highest risk results in fewer babies receiving prophylaxis yet achieving a similar reduction in invasive fungal infection. It is time to establish recommendations and guidelines, so that clinicians may be able to decide which neonates to offer prophylaxis to according to patient risk factors, the local risk of invasive fungal infection, and antifungal resistance profile. References 1. 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(23):1660-1666. 2. Benjamin DK Jr, Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins RD, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117(1):84-92. 3. Sims ME, Yoo Y, You H, Salminen C, Walther FJ. Prophylactic oral nystatin and fungal infections in very-low-birthweight infants. Am J Perinatol. 1988;5: 33-36. 4. Wainer S, Cooper PA, Funk E, Bental RY, Sandler DA, Patel J. Prophylactic miconazole oral gel for the prevention of neonatal fungal rectal colonization and systemic infection. Pediatr Infect Dis J. 1992;11:713-716. 5. Kicklighter SD, Springer SC, Cox T, Hulsey TC, Turner RB. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics. 2001;107:293-298. 6. Clerihew L, Austin N, McGuire W. Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003850. 7. Clerihew L, McGuire W. Antifungal prophylaxis for very-low-birth-weight infants: UK national survey. Arch Dis Child Fetal Neonatal Ed. 2007 Sep 3 [Epub ahead of print]. 8. Burwell LA, Kaufman D, Blakely J, Stoll BJ, Fridkin SK. Antifungal prophylaxis to prevent neonatal candidiasis: a survey of perinatal physician practices. Pediatrics. 2006 Oct;118(4):e1019-1026. Epub 2006 Sep 18.. 9. O'Grady MJ, Dempsey EM. Antifungal prophylaxis for the prevention of neonatal candidiasis? Acta Paediatr. 2008;97:430-433. 10. Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al. Italian Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356:2483-2495. 11. Clerihew L, Lamagni TL, Brocklehurst P, McGuire W. Invasive fungal infection in very low birthweight infants: national prospective surveillance study. Arch Dis Child Fetal Neonatal Ed. 2006;91:F188-192. 12. Saiman L, Ludington E, Dawson JD, Patterson JE, Rangel-Frausto S, Wiblin RT, Dawson J, et al. National Epidemiology of Mycoses Study Group. Risk factors for Candida species colonization of neonatal intensive care unit patients. Pediatr Infect Dis J. 2001;20:1119-1124. 13. Feja KN, Wu F, Roberts K, Loughrey M, Nesin M, Larson, W, et al. Risk factors for candidemia in critically ill infants: a matched case-control study. J Pediatr. 2005;147(2):156-161. 14. Manzoni P, Farina D, Leonessa M, d'Oulx EA, Galletto P, Mostert M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics. 2006;118(6):2359-2364. 15. Uko S, Soghier LM, Vega M, Marsh J, Reinersman GT, Herring L, et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics. 2006;117:1243-1252. 16. McCrossan BA, McHenry E, O'Neill F, Ong G, Sweet DG. Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection. Arch Dis Child Fetal Neonatal Ed. 2007;92:F454-458. back to top

FLUCONAZOLE PROPHYLAXIS REDUCES CANDIDA COLONIZATION Kicklighter SD, Springer SC, Cox T, Hulsey TC, Turner RB. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics. 2001;107(2):293-298. (For non-journal subscribers, an additional fee may apply for full text articles.) View Journal Abstract View Full Article Kicklighter et al. reported the first study of fluconazole prophylaxis in neonates. One-hundred-three very low birth weight (VLBW) babies were enrolled within 72 hours postnatally to receive low dose fluconazole or saline placebo. The fluconazole (6mg/kg) was administered intravenously or enterally once intravenous access was discontinued. The dose was administered every 72 hours during the first week of life, then daily thereafter until 28 days of age. Liver function testing and rectal swabs for fungal culture were done at recruitment and on days 7, 14, and 28. The primary outcome was the effect of fluconazole prophylaxis on the presence of rectal Candidal colonization. Fifty-three babies were randomized to the fluconazole prophylaxis group and 50 to the placebo group, with baseline characteristics and risk factors for invasive fungal infection similar for both groups. The investigators found a significant reduction in Candida colonization in the fluconazole prophylaxis group: 15% vs 46%, p = 0.0005. The age at which fungal colonization was most prevalent also differed: in the fluconazole group fungal colonization was most common at day 7, whereas in the placebo group colonization continued to increase, peaking at day 28. Two babies in each group developed invasive fungal infection. No clinically important adverse effects were observed with fluconazole prophylaxis and no babies were withdrawn from the study. Alanine aminotransferase levels were slightly higher in the fluconazole group at day 14 (mean ALT 18 vs 15 IU/mL), but this normalized by day 28 and was not considered clinically significant. The mean inhibitory concentration (MIC) of fluconazole for Candida species remained unchanged throughout the study, and there was no difference between the two groups. There was also no increase found in inherently resistant Candida species. The authors concluded that fluconazole prophylaxis was safe and effective at reducing the incidence of rectal Candidal colonization in VLBW infants, and recommend further studies to assess the effectiveness at reducing invasive fungal infection. back to top

FLUCONAZOLE PROPHYLAXIS REDUCES INVASIVE CANDIDAL INFECTION IN PRETERM INFANTS 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(23):1660-1666. (For non-journal subscribers, an additional fee may apply for full text articles.) View Journal Abstract View Full Article Manzoni P, Stolfi I, Pugni L, Decembrino L, Magnani C, Vetrano G, et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356(24):2483-2495. (For non-journal subscribers, an additional fee may apply for full text articles.) View Journal Abstract View Full Article Kaufman et al. published the first study evaluating the efficacy of fluconazole prophylaxis in preventing invasive fungal infection in a single center randomized placebo-controlled trial conducted over a 30-month period. Inclusion criteria were birth weight <1000g, presence of a central venous catheter or endotracheal tube (ETT), and enrollment within the first 5 days of life. Babies were excluded if there was evidence of hepatic impairment. The treatment group received fluconazole 3mg/kg for up to 6 weeks, initially every 3rd day, then on alternate days, and then daily only until intravenous access was discontinued. Surveillance cultures were taken weekly from multiple non-invasive sites and blood cultures as clinically indicated. Liver function was monitored weekly. The primary outcomes were the rate of fungal colonization and the development of invasive fungal infection (positive culture in a normally sterile site). Of 114 extremely low birth weight (ELBW) babies born during the study period, 100 were eligible for randomization (50 to each group). The investigators found a significant reduction in Candida colonization in the fluconazole prophylaxis group (22% vs 60%; p = 0.002), as well as a significant reduction in invasive fungal infection (0% vs 20%; p = 0.008). Eight of the 10 babies who developed invasive fungal infection were born colonized with Candida. There was 40% mortality in those babies with invasive fungal infection. The authors observed no changes in sensitivity to fluconazole during the study period, and found no evidence of emergence of other Candida species. No adverse events were described. This study was the first to demonstrate a reduction in invasive fungal infection in pre-term infants using low-dose fluconazole prophylaxis. Although fewer babies died in the fluconazole prophylaxis group (8% vs 20%; p = 0.22), the study was not powered to detect a significant difference in mortality. Although the presence of a central venous catheter or ETT were used as inclusion criteria, this proved to be a superfluous detail, as only one ELBW baby was excluded on this basis. The paper by Manzoni et al. reports on the largest randomized controlled trial of fluconazole prophylaxis to date. Eight Italian centers recruited VLBW babies less than 72 hours old, excluding only babies with evidence of liver failure. The study was designed to compare two fluconazole prophylaxis dosing regimens – fluconazole 6mg/kg (FP6) and 3mg/kg (FP3) – with placebo. The dose interval in both intervention groups was the same as in Kaufman’s study (above) and fluconazole was continued for 30 days in babies with birth weight of 1.0-1.5 kg and 45 days in babies <1kg. The main outcome measures were fungal colonization, invasive fungal infection, mortality, adverse effects of fluconazole, and emergence of resistance. Multiple baseline and weekly non-invasive cultures were obtained for colonization surveillance, and liver function tests were performed weekly. Of 363 eligible infants, 322 were randomized: 106 to placebo, 112 to FP6 and 104 to FP3. The investigators report a significant reduction in fungal colonization in the intervention groups (FP6 9.8%; FP3 7.7%; placebo 29.2%; p < 0.001), but no difference between the two different dosing regimens with respect to fungal colonization. There was a significant reduction in invasive fungal infection in both intervention groups (FP6 2.7%, p = 0.005; FP3 3.8%, p = 0.02 vs placebo 13.2%), but again no difference between the two intervention groups. Despite the large reduction in invasive fungal infection, there was no reduction in all-cause mortality (FP6 8%; FP3 8.7%; Placebo 9.4%). Once colonized, fluconazole prophylaxis did not alter the conversion to invasive fungal infection. There were no reported adverse effects and no evidence of resistant Candida strains emerging or change in MIC. This study confirms that fluconazole 3mg/kg has similar efficacy to a 6mg/kg dosing regime, and that fluconazole prophylaxis reduces the incidence of invasive fungal infection in VLBW babies. However, the authors concede that the study was underpowered to detect differences in mortality (NOTE: 1100 patients would be required to detect differences in mortality). In addition, the incidence of invasive fungal infection in the placebo arm was much higher than would be expected for this population. back to top

FLUCONAZOLE PROPHYLAXIS AND SURVIVAL Clerihew L, Austin N, McGuire W. Systemic antifungal prophylaxis for very low birth weight infants: systematic review. Arch Dis Child Fetal Neonatal Ed. 2008;93(3):F198-200. Epub 2007 Sept 3. (For non-journal subscribers, an additional fee may apply for full text articles.) View Journal Abstract View Full Article The Cochrane review authors, reporting on fluconazole prophylaxis in VLBW babies, published a recent systematic review of the randomized controlled trials up to July 2007. Four randomized controlled trials (including the Kaufman and Manzoni studies described above) were analyzed involving 536 VLBW babies. All of the trials compared fluconazole prophylaxis with placebo and were of good methodological quality. The principal outcomes of the trials were the incidence of fungal colonization and invasive fungal infection. Three studies reported resistance patterns of fungi and one study documented neurodevelopmental outcomes. The meta-analysis showed that invasive fungal infection is reduced with fluconazole prophylaxis (RR 0.23 95% CI 0.11-0.46). While there was no significant difference found in mortality in individual studies or on meta-analysis (RR 0.61 95% CI (0.37 - 1.03), the trend towards reduction in mortality is encouraging. There was no significant change in the mean inhibitory concentration of fluconazole in fungal isolates in any of the studies or the meta-analysis. In the one study reporting developmental outcome, there was no significant difference in the modified Gessell test or in motor and sensory impairment at a median age of 16 months. Using the meta-analysis data, the authors calculated that for every 9 babies treated with fluconazole prophylaxis there would be one less case of invasive fungal infection. However, the authors caution that the incidence of invasive fungal infection in the placebo groups was high (13% – 16%) and the number needed to treat (NNT) would increase with decreasing incidence of fungal infection rates. The authors conclude that the available data are reassuring, but cautioned that the actual incidence of invasive fungal infection is much lower and would result in a larger number of babies needing treatment to achieve benefit. Data from further trials is needed to provide a more precise estimate of the effects on mortality. The authors suggested that further trials of systemic fluconazole prophylaxis should be restricted to babies at higher risk, such as those <1000g with additional risk factors such as prolonged broad spectrum antibiotic use. back to top

INCIDENCE OF INVASIVE FUNGAL INFECTION IN VLBW BABIES Clerihew L, Lamagni TL, Brocklehurst P, McGuire W. Invasive fungal infection in very low birthweight infants: national prospective surveillance study. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F188-192. (For non-journal subscribers, an additional fee may apply for full text articles.) View Journal Abstract View Full Article In 2006, Clerihew et al. reported a national prospective surveillance survey of all cases of invasive fungal infection in babies less than 3 months old born in the UK during a 12 month period. Invasive fungal infection was defined as the presence of one or more of the following features: culture of fungus from a sterile site including blood central venous catheter tip urine (supra-pubic aspirate or catheter) cerebrospinal fluid bone/joint aspirate peritoneal/pleural fluid ophthalmologic findings fungal balls on ultrasound scan of kidneys an autopsy diagnosis of invasive fungal infection Data were collected from 3 independent nationwide sources, including directly contacting every pediatrician in the UK monthly through the British Pediatric Surveillance Unit, as well as reports from microbiology laboratories reporting to the Communicable Disease Surveillance Center, and fungal isolates from infants referred to the UK Mycology Reference Laboratory. A 92% response rate was achieved. During the study period, 9425 VLBW and 3837 extremely low birth weight (ELBW) babies were born in the UK. There were 94 cases of invasive fungal infection reported. All affected babies were VLBW, with 86% being ELBW. The estimated incidence in VLBW babies was 1% (10 per 1000 live-born; 95% CI: 8 – 12 per 1000). The estimated incidence in ELBW babies was 2% (21.1 per 1000 live-born; 95% CI: 16.5 – 25.7 per 1000). The median (range) gestation and weight of affected babies was 25 (23 –