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Prevention and treatment of invasive fungal infection in very low birthweight infants
M Brecht,1 L Clerihew,2 W McGuire1
Australian National University Medical School, Canberra, Australia; 2 Ninewells Hospital and Medical School, Dundee, UK Correspondence to: Dr W McGuire, Centre for Newborn Care, The Canberra Hospital, ACT 2606, Australia; william.mcguire@act.gov.au Accepted 9 September 2008 Published Online First 6 October 2008
1

ABSTRACT Invasive fungal infection is an important cause of mortality and morbidity in very low birthweight (VLBW) infants. Extremely preterm and extremely low birthweight infants are at highest risk because of the intensive and invasive nature of the care that these infants receive. Additional specific risk factors include prolonged use of parenteral nutrition and exposure to broad-spectrum antibiotics and histamine type 2 receptor blockers. Diagnosis is difficult and often delayed, and this may contribute to the high levels of deep-organ dissemination and associated mortality and morbidity. The most commonly used antifungal agents are amphotericin B and fluconazole. Recent research has assessed the value of early empirical and prophylactic treatment. However, although systemic antifungal prophylaxis reduces the incidence of invasive fungal infection, there is no evidence of effect on mortality. Concern exists about the impact that widespread use of prophylaxis may have on the emergence of antifungal resistance.

Other Candida species, such as C glabrata and C krusei, that harbour innate resistance to the azole class of antifungal agents are also increasingly prevalent causes of colonisation and invasive infection. Evidence exists that C parapsilosis infection is associated with fewer deep-seated infections than C albicans, perhaps because of its poorer ability to adhere to and penetrate endothelium.14 15 However, death rates associated with C albicans and C parapsilosis are similar, and investigation and management of invasive fungal infection should not be altered depending on the infecting Candida species.

CLINICAL FEATURES OF INFECTION Congenital candidiasis

Congenital fungal infection is rare. In utero infection may be associated with chorioamnionitis, funisitis and preterm birth. The most commonly reported neonatal presentation is severe mucocutaneous candidiasis. This may be associated with bloodstream and deep-organ infection, especially in ELBW infants, for whom the associated mortality is high.16 Disseminated congenital invasive fungal infection without cutaneous involvement has also been described.17

EPIDEMIOLOGY
Invasive fungal infection accounts for ,10% of all cases of nosocomial sepsis in very low birthweight (VLBW: ,1500 g) infants.1 The overall incidence in VLBW infants is 14%, but the risk of infection is inversely related to gestational age and birth weight. In extremely preterm or extremely low birthweight (ELBW: ,1000 g) infants, reported incidences are 28%. Much higher incidences, up to 20%, have been reported for infants of birth weight ,750 g or gestational age at birth ,26 weeks.17 Variation in the incidence of invasive fungal infection between neonatal units is not explained fully by case mix or population heterogeneity. Interunit differences in care practices, particularly infection control, enteral feeding and antibioticprescribing policies, are potentially modifiable risk factors (box 1). Postnatal corticosteroid exposure has been found to be associated with invasive fungal infection inconsistentlylarge multivariate analyses have not identified steroid use as an independent risk factor.8 9

Nosocomial infection
The peak incidence of nosocomial invasive fungal infection in VLBW infants is between the second and sixth weeks after birth. The clinical presentation is similar to that of bacterial sepsis, and this may cause delays in diagnosis and treatment. These delays may contribute to the prevalence of deep-seated fungal infection (table 1).18 The mortality attributable to invasive fungal infection is .25%, similar to that associated with late-onset Gram-negative bacterial infection.1 3 7 Invasive fungal infection is also associated with substantial short-term and long-term morbidity in VLBW infants. In particular, fungal infection of the central nervous system is associated with adverse long-term neurodevelopmental outcomes.7 19

MYCOLOGY
Most invasive fungal infection in VLBW infants is due to Candida species. Infection with other fungi, for example Aspergillus species and Malassezia species, is extremely rare.3 5 7 Historically, Candida albicans has been the most commonly isolated organism. Over the past decade, Candida parapsilosis has emerged as an important nosocomial pathogen and now accounts for ,25% of all cases of invasive fungal infection in VLBW infants.13 14
Arch Dis Child Fetal Neonatal Ed 2009;94:F65F69. doi:10.1136/adc.2007.133769

DIAGNOSIS
Microbiological culture of fungi from blood, urine, cerebrospinal fluid (CSF) and other normally sterile body fluids sampled using techniques to minimise contamination with surface colonising organisms remains the diagnostic gold standard. However, these conventional microbiological diagnostic techniques have the following limitations.
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Box 1 Risk factors for invasive fungal infection712
c c c c

Table 1 Deep-seated fungal infection in very low birthweight infants (adapted from Benjamin et al18)
Site of infection Meningoencephalitis Endocarditis Renal parenchymal infection Cerebral abscess Endophthalmitis Hepatic abscess % of cases 15 5 5 4 3 3

c c

Fungal colonisation of multiple sites Prolonged endotracheal intubation Gastrointestinal disease or surgery Broad-spectrum antibiotic use (especially third-generation cephalosporins) Histamine type 2 receptor blockers and proton-pump inhibitors Prolonged use of parenteral nutrition/delayed enteral feeding

Culture of Candida species from neonatal blood samples may take more than 36 h and may be negative even in cases of deep-organ involvement.20 c Fungi are not isolated from blood culture in about half of all infants with confirmed Candida meningoencephalitis.7 c Microscopic and biochemical findings in CSF can be within normal limits in infants with confirmed fungal meningoencephalitis.21 A high index of suspicion and the use of additional laboratory and clinical tests, including retinal examination, echocardiography and renal ultrasonography, may be needed to confirm the suspected diagnosis. Novel diagnostic methods based on detection of fungal DNA, antifungal antibodies or fungal cell wall components or metabolites have shown promise in other populations, but are yet to be prospectively assessed in VLBW infants.
c

if used as a monotherapy.27 Because flucytosine achieves good CSF penetration, its main use has been in combination with amphotericin B for treating fungal meningitis. Amphotericin B and flucytosine are not antagonistic, but the evidence for synergism is inconsistent.28 However, as amphotericin B can achieve fungicidal CSF concentrations in VLBW infants, and given the potential for drug interactions and toxicity, it may be appropriate to reserve adjunctive flucytosine for infants in whom amphotericin B monotherapy has not achieved fungal CSF clearance.29

Triazoles
Fluconazole is by far the most widely used azole and has been reported to be well tolerated by VLBW infants. The only relatively commonly reported side effect, described in ,5% of VLBW infants, is a mild and transient increase in plasma concentrations of hepatic enzymes.30 Fluconazole penetrates into CSF and is an appropriate treatment for infants with bloodstream or urinary tract fungal infection (with susceptible species) in whom meningitis has not yet been excluded. It is well absorbed enterally and can be continued as a prolonged treatment course without the presence of an intravenous catheter. Although fluconazole has these potential advantages compared with amphotericin B, it has not become an established first-line treatment choice because of the emergence of fluconazole-resistant Candida species, such as C glabrata and C krusei, as potential nosocomial pathogens. Clinical experience of treating VLBW infants with the newer triazoles is much more limited. Voriconazole has a potential role in treating infections due to fluconazole-resistant Candida species, but triazole cross-resistance has already been reported.31

ANTIFUNGAL TREATMENT
Four major groups of antifungal agents are available for treating VLBW infants with invasive fungal infection (table 2). As there are insufficient trial data to favour one antifungal agent or combination, prescribing practices vary and are largely determined by considerations of toxicity (extrapolated from studies in older populations of patients), cost and convenience of use.22 23

Amphotericin B
Amphotericin B remains a good initial treatment option for VLBW infants with suspected invasive fungal infection because antifungal resistance is extremely rare and there is no evidence that newer drugs are superior.23 Although drug toxicity, particularly nephrotoxicity, limits the total dose that may be given, renal complications can be minimised with careful management of fluid and electrolyte balance.24 Amphotericin B is highly protein bound, and studies in adult populations have suggested that penetration into extracellular fluid spaces, including CSF, is poor. However, evidence exists that CSF concentrations of 4090% of plasma concentrations are achieved with standard dose regimens in VLBW infants.25 Lipid complex formulations of amphotericin B are less cytotoxic and can be given at higher total doses because the active drug is delivered directly to the site of action on the fungal cell membrane. Because these formulations are very much more expensive, their use is usually restricted to infants who are intolerant of, or do not respond to, conventional amphotericin B, or to infants with pre-existing renal dysfunction.26

Echinocandins
In other patient populations, a new class of fungicidal agents, the echinocandins, has been reported to be as effective as amphotericin B but with fewer adverse effects and drug interactions.32 There is a lack of pharmacokinetic and safety data relevant to VLBW infants; the published experience for using echinocandins (principally caspofungin) to treat VLBW infants is limited to case reports of infections unresponsive or resistant to amphotericin B and fluconazole.31 33

Empirical treatment
Treatment algorithms for adult and paediatric immunocompromised patients suggest giving empirical antifungal therapy as soon as invasive fungal infection is suspected in order to minimise sepsis progression and deep-organ involvement. The adoption of a similar empirical antifungal treatment approach for VLBW infants has been proposed. In a large retrospective multivariate analysis, Benjamin and colleagues34 examined risk factors and presenting features to develop a predictive model for invasive fungal infection
Arch Dis Child Fetal Neonatal Ed 2009;94:F65F69. doi:10.1136/adc.2007.133769

Flucytosine
Flucytosine (5-fluorocytosine) is rarely used for treating VLBW infants because of potential toxicity, lack of a parenteral formulation, and concerns that resistance may develop rapidly
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Table 2 Antifungal drugs
Class Polyenes Examples Mode of action Major side effects Renal distal tubule toxicity causing renal impairment (usually transient) Infusion-related fever Amphotericin B React with ergosterol in fungal cell deoxycholate membranes to cause cell lysis Amphotericin B lipid formulations c lipid complex (ABLC) c colloidal dispersion (ABCD) c liposomal (L-AmB) Fluorine analogue of cytosine; antimetabolite; disrupts DNA and protein synthesis Inhibit sterol 14a-demethylase by binding preferentially to fungal cytochrome P450 and interfering with ergosterol synthesis in the cell membrane

Fluorinated pyrimidines Flucytosine (5fluorocytosine)

Dose-dependent myelosuppression, gastrointestinal and hepatic toxicity

Triazoles

Fluconazole Voriconazole

Skin rashes, transient increase in plasma levels of bilirubin and hepatic transaminases

Echinocandins

Caspofungin Micafungin Anidulafungin

Interfere with cell wall integrity by Limited data in newborn infants: selective inhibition of 1,3-b-D-glucan safe and well tolerated in older synthase (target enzyme not present in children mammalian cells)

in infants of birth weight ,1250 g. The authors recommended that empirical antifungal therapy should be strongly considered for infants with suspected nosocomial infection who have the following additional features: c gestational age ,25 weeks c thrombocytopenia (,150 000/ml) at the time of blood culture c 2527 weeks gestational age and a history of third-generation cephalosporin or carbapenem exposure in the 7 days before the blood culture However, even this combination of variables generates only a modest likelihood ratio. The model has yet to be validated prospectively in an independent population and assessed in a randomised controlled trial.

Preventing invasive fungal infection

Three broad strategies may reduce the incidence of invasive fungal infection in VLBW infants: c generic infection control practices such as hand washing and aseptic vascular catheter handling c avoidance of modifiable risk factors, in particular rational antibiotic prescribing, minimising the duration of use of parenteral nutrition and endotracheal intubation, and avoiding gastric acid suppressants c specific prophylaxis with topical/non-absorbed or systemic antifungal drugs

Antifungal prophylaxis Topical/oral non-absorbed prophylaxis

Evidence exists that prophylactic topical or oral non-absorbed antifungal agents (eg, nystatin and miconazole) decrease fungal colonisation on the skin and mucosal surfaces, including the gastrointestinal tract, in VLBW infants. The available trial data also indicate that topical/oral non-absorbed prophylaxis lowers the incidence of invasive fungal infection. These data should be interpreted cautiously because of the very high rates of infection in the control groups of the trial cohorts. Furthermore, there is as yet no evidence of an effect on mortality in VLBW infants cared for in the modern neonatal intensive care setting.37 38 However, given that topical/oral non-absorbed prophylaxis is inexpensive, simple and safe, current practice favours routine use in at-risk VLBW infants.39 40

Duration of treatment
In the absence of data from VLBW infants, consensus recommendations for the duration of therapy have been extrapolated from studies in older children and adults.35 It is recommended that infants with proven bloodstream infection continue antifungal treatment for 2 weeks after the first negative blood culture, and that treatment is extended beyond 4 weeks for infants with fungal meningitis.

Central line removal

Consensus recommendations favour removal of central vascular catheters that may represent a focus for persistent infection for example, from an infected thrombus. Observational studies suggest that delaying the removal of central venous catheters is associated with a longer duration of candidaemia and higher mortality in VLBW infants with invasive fungal infection.7 36 However, these findings may be due to confounding factors. Clinicians may have elected to delay catheter removal in smaller, or less mature, or sicker infants. Given the critical role of secure vascular access in providing nutrition and antiinfective treatment for these infants, a randomised controlled trial of early versus delayed removal of central venous catheters is needed to resolve this uncertainty.
Arch Dis Child Fetal Neonatal Ed 2009;94:F65F69. doi:10.1136/adc.2007.133769

Systemic prophylaxis
Several good-quality randomised controlled trials, including a large multicentre trial,41 have assessed the effect of fluconazole prophylaxis in VLBW infants. Meta-analysis of their data suggests that fluconazole reduces the incidence of invasive fungal infection.42 However, this effect may be partly due to ascertainment bias, as systemic antifungal prophylaxis lowers the sensitivity of microbiological culture for detecting fungi in blood, urine or CSF. The meta-analysis does not demonstrate a statistically significant effect on mortality (which is not affected by ascertainment bias). Currently, only very limited data exist
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on the long-term neurodevelopmental consequences for infants exposed to this intervention. The generalisabilty of these data is limited because of the very high incidence of invasive fungal infection in the placebo groups of some of the trials. For example, in a recent large Italian multicentre trial,41 invasive fungal infection occurred in 13% of all VLBW infants. The investigators calculated that the number of VLBW infants needed to treat to prevent one extra case of invasive fungal infection to be eight. In contrast, only 1% of VLBW infants who participated in the UK prospective national surveillance study developed invasive fungal infection.3 In neonatal units where the incidence of invasive fungal infection matches the UK national estimate, 130 VLBW (or 62 ELBW) infants would need to be exposed to fluconazole prophylaxis in order to prevent a single extra case of invasive fungal infection. Despite these issues, systemic antifungal prophylaxis has been adopted as standard practice in a substantial minority of neonatal intensive care units in the UK and USA.39 40 Prophylaxis is usually limited to the smallest and least mature ELBW infants with additional risk factors such as prolonged use of multiple broadspectrum antibiotics or central venous catheters and total parenteral nutrition.43 However, concern exists that even this targeted policy will still drive the emergence of azole resistance.44 Although the data from the trials undertaken to date are reassuring in this regard, the follow-up periods (up to 30 months) are probably insufficient to detect clinically significant changes in the resistance profile of fungal isolates. Antifungal resistance may take many years after the introduction of fluconazole prophylaxis to become established in neonatal intensive care units.45 Continued mycological surveillance in those units where systemic antifungal prophylaxis is used is essential.
7. 8. 9. 10. Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117:8492. Rowen JL, Rench MA, Kozinetz CA, et al. Endotracheal colonization with Candida enhances risk of systemic candidiasis in very low birth weight neonates. J Pediatr 1994;124:78994. Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics 2006;118:235964. Saiman L, Ludington E, Pfaller M, et al. Risk factors for candidemia in neonatal intensive care unit patients. The National Epidemiology of Mycosis Survey Study Group. Pediatr Infect Dis J 2000;19:31924. Manzoni P, Farina D, Galletto P, et al. Type and number of sites colonized by fungi and risk of progression to invasive fungal infection in preterm neonates in neonatal intensive care unit. J Perinat Med 2007;35:2206. Cotten CM, McDonald S, Stoll B, et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118:71722. Benjamin DK Jr, Ross K, McKinney RE Jr, et al. When to suspect fungal infection in neonates: a clinical comparison of Candida albicans and Candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia. Pediatrics 2000;106:71218. Clerihew L, Lamagni TL, Brocklehurst P, et al. Candida parapsilosis infection in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2007;92:F1279. Weems JJ. Candida parapsilosis: epidemiology, pathogenicity, clinical manifestations, and antimicrobial susceptibility. Clin Infect Dis 1992;14:75666. Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidiasis: clinical presentation, pathogenesis, and management guidelines. Pediatrics 2000;105:43844. Carmo KB, Evans N, Isaacs D. Congenital candidiasis presenting as septic shock without rash. Arch Dis Child 2007;92:6278. Benjamin DK Jr, Poole C, Steibach WJ, et al. Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques. Pediatrics 2003;112:63440. Friedman S, Richardson SE, Jacobs SE, et al. Systemic candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome. Pediatr Infect Dis J 2000;19:499504. Schelonka RL, Moser SA. Time to positive culture results in neonatal Candida septicemia. J Pediatr 2003;142:5645. Cohen-Wolkowiez M, Smith PB, Mangum B, et al. Neonatal Candida meningitis: significance of cerebrospinal fluid parameters and blood cultures. J Perinatol 2007;27:97100. Rowen JL, Tate JM. Management of neonatal candidiasis. Neonatal Candidiasis Study Group. Pediatr Infect Dis J 1998;17:100711. Clerihew L, McGuire W. Systemic antifungal drugs for invasive fungal infection in preterm infants. Cochrane Database Syst Rev 2004;(1):CD003953. Holler B, Omar SA, Farid MD, et al. Effects of fluid and electrolyte management on amphotericin B-induced nephrotoxicity among extremely low birth weight infants. Pediatrics 2004;113:e60816. Baley JE, Meyers C, Kliegman RM, et al. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr 1990;116:7917. Adler-Shohet F, Waskin H, Lieberman JM. Amphotericin B lipid complex for neonatal invasive candidiasis. Arch Dis Child Fetal Neonatal Ed 2001;84:F1313. Bliss JM, Wellington M, Gigliotti F. Antifungal pharmacotherapy for neonatal candidiasis. Semin Perinatol 2003;27:36574. Te Dorsthorst DT, Verweij PE, Meletiadis J, et al. In vitro interaction of flucytosine combined with amphotericin B or fluconazole against thirty-five yeast isolates determined by both the fractional inhibitory concentration index and the response surface approach. Antimicrob Agents Chemother 2002;46:29829. Faix RG, Chapman RL. Central nervous system candidiasis in the high-risk neonate. Semin Perinatol 2003;27:38492. Huttova M, Hartmanova I, Kralinsky K, et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J 1998;17:101215. Smith PB, Steinbach WJ, Cotten CM, et al. Caspofungin for the treatment of azole resistant candidemia in a premature infant. J Perinatol 2007;27:1279. Falagas ME, Ntziora F, Betsi GI, et al. Caspofungin for the treatment of fungal infections: a systematic review of randomized controlled trials. Int J Antimicrob Agents 2007;29:13643. Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J 2004;23:10937. Benjamin DK Jr, DeLong ER, Steinbach WJ, et al. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics 2003;112:5437. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004;38:16189. Karlowicz MG, Hashimoto LN, Kelly RE Jr, et al. Should central venous catheters be removed as soon as candidemia is detected in neonates? Pediatrics 2000;106:E63. Austin NC, Darlow B. Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants. Cochrane Database Syst Rev 2004;(1):CD003478. Ozturk MA, Gunes T, Koklu E, et al. Oral nystatin prophylaxis to prevent invasive candidiasis in neonatal intensive care unit. Mycoses 2006;49:48492.

11. 12. 13.

14. 15. 16.

17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

CONCLUSIONS
Invasive fungal infection, predominantly due to Candida species, has become an important cause of late mortality and morbidity in VLBW infants. ELBW infants, particularly those receiving prolonged invasive and intensive care, are at greatest risk. Because diagnosis and treatment are often delayed, recent research attention has focused on empirical and prophylactic treatment strategies. However, although these approaches have been adopted in many neonatal care centres, their further prospective evaluation is merited. Most importantly, the potential clinical consequences at the population level of altering the pattern of antifungal resistance must be considered.
Competing interests: WMcG and LC have previously received an educational grant from Pfizer UK Ltd, a manufacturer of antifungal agents. This company had no role in the commissioning or writing of the review or decision to submit for publication.

29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

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Prevention and treatment of invasive fungal infection in very low birthweight infants
M Brecht, L Clerihew and W McGuire Arch Dis Child Fetal Neonatal Ed 2009 94: F65-F69 originally published online October 6, 2008

doi: 10.1136/adc.2007.133769

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