PEDIATRICS Vol. 107 No. 2 February 2001, pp. 404-405

COMMENTARY:
Fluconazole Prophylaxis in the Very Low Birth Weight Infant: Not Ready for Prime Time

Candida species are now the fourth leading cause of nosocomial bloodstream infections (8%) across all age groups with the highest crude mortality (40%).¹ Among children, neonates, particularly the increasing numbers of very low birth weight (VLBW) premature infants (<1500 g), are at great risk. The National Epidemiology of Mycosis Study Group reported that over a 2-year period, in 6 neonatal intensive care units (NICUs) across the country, 1.2% of all neonates developed candidemia, and of these, 82% were VLBW. The crude mortality of the infants with candidemia was 23%, compared with 4.7% of those without fungal disease.² Furthermore, invasive candidiasis in the NICU is becoming more common. From 1981 to 1995, the number of cases of candidemia in one NICU increased from 2.5/1000 to 28.5/1000.³

In this issue of Pediatrics, Kicklighter et al⁴ provide a well-designed, prospective, double-blinded, randomized, placebo-controlled, intention-to-treat study to determine if prophylactic fluconazole given to VLBW infants during the first 28 days of life decreases the incidence of candidal colonization. This is an important question to address, not so much because colonization with Candida is unusual, but because in this age group it is a primary risk factor for the subsequent development of invasive candidiasis and meningitis.^5,6 They found an overall reduction in rectal colonization of approximately two-thirds from 46% to 15% in the placebo and treated groups, respectively.

Despite these results, one must consider several criteria before using prophylactic antimicrobial agents: 1) What is the most appropriate clinical variable to monitor, and does the medication positively affect that variable? 2) Which patients are at high risk and could benefit from prophylaxis? 3) Do adverse effects outweigh benefits? 4) How long should prophylaxis continue? 5) What is the effect on population organism resistance patterns? 6) Is it cost-effective to use the drug prophylactically?

The outcome variable of this study was the effectiveness of fluconazole to reduce Candida rectal colonization in VLBW infants. The authors state in their discussion that their study was not designed to measure the effectiveness of fluconazole in the prevention of invasive candidal disease, and this point must be strongly emphasized. The outcome variable most important to clinicians is not colonization, but morbidity and mortality from invasive candidiasis. In this study, despite the reduction in colonization, there was no difference in the rate of invasive candidiasis between the two groups (although the numbers were small). Larger studies in older, immunocompromised, or postsurgical patient populations given prophylactic fluconazole have shown a reduction in the infection rates from Candida species,^7-9 but have not always demonstrated a reduction in associated mortality.¹⁰ Therefore, for VLBW infants, although fluconazole appears to reduce Candida rectal colonization, the clinical significance of this has not been demonstrated. Furthermore, even in the treated group, 15% were still colonized with Candida after 1 month of fluconazole. Although this is certainly a lower prevalence than the untreated group, it may be unacceptably high when potential adverse effects, selection of resistant organisms, and cost are considered.

The authors have provided comprehensive background describing that nearly two-thirds of VLBW infants are colonized with Candida species within the first month of life. Although they state that colonization is the most important risk factor for the subsequent development of invasive candidal disease, they do not specifically justify the ability of rectal colonization alone to predict invasive disease. In fact, in a study referenced by the authors, 24% of the colonized infants did not have yeast isolated from the rectum, but rather from the oral cavity, skin, endotracheal aspirate, or urine.¹¹ The effect of fluconazole on colonization at these sites and subsequent rates of invasive disease in VLBW infants remain unknown.

Two studies demonstrated that 7% to 28% of premature neonates colonized with Candida developed disease.^5,6 These high rates of infection in colonized infants make prophylaxis with fluconazole potentially more useful than it would be if very few colonized infants actually developed infection. However, because a large percentage of the patients in many NICUs are VLBW (18%-20% at our institution), instituting indiscriminant prophylaxis of fluconazole in this group would result in large numbers of neonates receiving the drug. It may be possible with future studies to refine the definition of a VLBW infant at high risk for systemic candidiasis, perhaps by using burden of candidal colonization as a factor to initiate prophylaxis rather than as an outcome measurement of less discriminate fluconazole use. For example, in the study by Pappu-Katikaneni et al,⁵ nearly 30% of the infants with >8 × 10⁶ colony-forming units of Candida per g of stool developed invasive candidiasis. Other independent risk factors for neonatal candidemia, as defined by the National Epidemiology of Mycosis Study Group, include gestational age <32 weeks, use of >2 antibiotics, parenteral nutrition, presence of a central catheter, and use of H₂ blockers. In this study, colonization was not an independent risk factor after multivariate analysis, but molecular typing confirmed that a high proportion of infants with invasive candidiasis had been previously colonized with the same organism.² Based on these data, a truly high-risk VLBW infant for whom fluconazole prophylaxis is appropriate may be one who is heavily colonized, on broad-spectrum antibiotics and H₂ blockers, and receiving parenteral nutrition through a central catheter.

Because prophylactic drugs are used to prevent rather than treat disease, it is particularly advantageous to use a drug with minimal adverse effects. In this study, although there was a statistically significant increase in serum alanine aminotransferase in the fluconazole-treated patients, the authors correctly point out that this was not clinically significant, nor did any patient terminate therapy because of unacceptable adverse reactions. Although data are limited, fluconazole in therapeutic doses of up to 6 mg/kg/day appears to be safe in VLBW infants.^12,13 It should be noted, however, that fluconazole is partially metabolized by the cytochrome P450 (CYP) 3A4 hepatic enzyme,¹⁴ and that this enzyme is less active in premature infants than in older infants,¹⁵ prolonging the serum half-life of fluconazole.¹⁶ Although fluconazole is not as strong an inhibitor of CYP3A4 as are itraconazole and ketoconazole,¹⁴ the pharmacokinetic profile of fluconazole in VLBW infants raises the possibility of significant drug-drug interactions with the numerous other drugs metabolized by the CYP3A4 enzyme.

In this study, the investigators administered fluconazole for 1 month, presumably because the epidemiologic data they presented in the introduction suggested that the maximal prevalence of candidal rectal colonization occurred by 1 month postnatal age. After stopping fluconazole, >20% of those infants (<1250 g) whom they continued to swab for rectal colonization were colonized on study termination at 2 months postnatal age. Although candidal sepsis generally occurs during the first month of life in these infants,^6,11,17 prolonged colonization raises the specter of continued risk for invasive disease and the need for longer duration of prophylaxis. In practice, it is easy to imagine nurseries full of VLBW infants who have been on fluconazole for 2 or more months because of uncertainty when to stop prophylaxis. This kind of intense antifungal pressure would undoubtedly lead to increased fluconazole resistance among Candida species prevalent in the nursery.

The selection of resistant organisms while on prophylactic antimicrobials and subsequent treatment difficulties are familiar to all clinicians. Although the authors attempted to address this concern by tracking minimal inhibitory concentratons of isolates to fluconazole, they admit that small numbers and short study duration preclude any real conclusions about the effect of widespread fluconazole use in the nursery. There are already reports of an increasing prevalence of organisms with intrinsic fluconazole resistance, such as C glabrata, that have been isolated from patients' blood, urine, or sputum samples.¹⁸ Most infants who develop invasive candidiasis will be treated with amphotericin B, which may make the issue of fluconazole resistance less relevant. However, eliminating fluconazole as a therapeutic option forces the use of a more toxic drug in the nursery at a time when numerous case reports^13,19,20 and 1 small comparative trial²¹ suggest that fluconazole may be an effective and less toxic treatment option for certain neonates.

Because the true effect of fluconazole prophylaxis on invasive candidal disease is unknown, a cost analysis cannot be performed. However, fluconazole is an expensive medication, both in its oral and intravenous forms. Therefore, the most economical scenario would be to give it to a limited, clearly defined number of patients for whom it is highly effective.

In summary, Kicklighter et al⁴ have produced a thoughtful preliminary study that begins to answer the ultimate question whether invasive candidiasis can be safely prevented in VLBW infants with fluconazole prophylaxis. By applying criteria designed to assess the usefulness of a prophylactic regimen, it is clear that there are several issues left to address before this question can be answered. This preliminary study does not measure a clinically relevant endpoint; it does not refine the definition of a truly high-risk population; it does not define optimal duration of prophylaxis; it does not address the issue of organism resistance with the pressure of long-term prophylaxis in a sizable proportion of neonates in an average NICU; and it provides no information on cost-effectiveness. These data do suggest that fluconazole can be safely used in VLBW infants (with appropriate concerns for drug-drug interactions), and that it can reduce rectal colonization. The authors plainly acknowledge that this study is preliminary and more work must be done. Their final conclusion is important and should be adhered to: routine fluconazole prophylaxis is not presently justified in VLBW infants.

Michael N. Neely, MD^*,
John R. Schreiber, MD^*
Department of Pediatrics Case Western Reserve University ^* Division of Pediatric Infectious Diseases  Division of Pediatric Clinical Pharmacology and   Critical Care Rainbow Babies and Children's Hospital Cleveland, OH 44106

FOOTNOTES

Received for publication Aug 2, 2000; accepted Aug 2, 2000.

Address correspondence to John R. Schreiber, MD, Department of Pediatrics, Case Western Reserve University, *Division of Pediatric Infectious Diseases, Rainbow Babies and Children's Hospital, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: jrs3{at}po.cwru.edu

ABBREVIATIONS

VLBW, very low birth weight; NICU, neonatal intensive care unit; CYP, cytochrome P450.

REFERENCES

1. Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999; 29:239-244 [Medline]
2. Saiman L, Ludington E, Pfaller M, Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey Study Group. Pediatr Infect Dis J. 2000; 19:319-324 [CrossRef][Medline]
3. Kossoff EH, Buescher ES, Karlowicz MG Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases. Pediatr Infect Dis J. 1998; 17:504-508 [CrossRef][Medline]
4. 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 [Abstract/Free Full Text]
5. Pappu-Katikaneni LD, Rao KP, Banister E Gastrointestinal colonization with yeast species and Candida septicemia in very low birth weight infants. Mycoses. 1990; 33:20-23 [Medline]
6. Baley JE, Kliegman RM, Boxerbaum B, Fanaroff AA Fungal colonization in the very low birth weight infant. Pediatrics. 1986; 78:225-232 [Abstract/Free Full Text]
7. Winston DJ, Pakrasi A, Busuttil RW Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999; 131:729-737 [Abstract/Free Full Text]
8. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845-851. See comments
9. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high- risk surgical patients. Crit Care Med. 1999;27:1066-1072. See comments
10. Slavin MA, Osborne B, Adams R, Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantationa prospective, randomized, double-blind study. J Infect Dis. 1995; 171:1545-1552 [Medline]
11. Huang YC, Li CC, Lin TY, Association of fungal colonization and invasive disease in very low birth weight infants. Pediatr Infect Dis J. 1998; 17:819-822 [CrossRef][Medline]
12. Wenzl TG, Schefels J, Hornchen H, Skopnik H Pharmacokinetics of oral fluconazole in premature infants. Eur J Pediatr. 1998; 157:661-662 [CrossRef][Medline]
13. Schwarze R, Penk A, Pittrow L Treatment of candidal infections with fluconazole in neonates and infants. Eur J Med Res. 2000; 5:203-208 [Medline]
14. Groll AH, Piscitelli SC, Walsh TJ Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol. 1998; 44:343-500
15. Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T Expression of CYP3A in the human liverevidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997; 247:625-634 [Medline]
16. Saxen H, Hoppu K, Pohjavuori M Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life. Clin Pharmacol Ther. 1993; 54:269-277 [Medline]
17. el-Mohandes AE, Johnson-Robbins L, Keiser JF, Simmens SJ, Aure MV Incidence of Candida parapsilosis colonization in an intensive care nursery population and its association with invasive fungal disease. Pediatr Infect Dis J. 1994; 13:520-524 [Medline]
18. Price MF, LaRocco MT, Gentry LO Fluconazole susceptibilities of Candida species and distribution of species recovered from blood cultures over a 5-year period. Antimicrob Agents Chemother. 1994; 38:1422-1427 [Abstract/Free Full Text]
19. Huttova M, Hartmanova I, Kralinsky K, Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J. 1998; 17:1012-1015 [CrossRef][Medline]
20. Driessen M, Ellis JB, Muwazi F, De Villiers FP The treatment of systemic candidiasis in neonates with oral fluconazole. Ann Trop Paediatr. 1997; 17:263-271 [Medline]
21. Driessen M, Ellis JB, Cooper PA, Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective randomized trial. Pediatr Infect Dis J. 1996; 15:1107-1112 [CrossRef][Medline]