Cohort and case control studies have identified a number of risk factors for systemic fungal infection including vaginal birth, longer duration of antibiotic treatment, artificial ventilation, total parenteral nutrition (TPN), duration of lipids, hyperglycaemia, the presence of invasive catheterization, H2 receptor blockers, hydrocortisone treatment for hypotension and postnatal steroid use (Botas 1995, Rowen 1995, Lee 1998, Karlowicz 2000, Saiman 2000). Systemic infection has been associated with increased mortality and significant morbidity including retinopathy of prematurity, intraventricular haemorrhage, and late neurodevelopmental disabilities in affected infants (Mittal 1998, Lee 1998, Friedman 2000).
As a result of the frequency of systemic fungal infection in some units where outbreaks have occurred, selective reduction in mucocutaneous carriage by the administration of oral nystatin, either alone or in combination with polymyxin and tobramycin has been reported (Herruzo-Cabrera 1994, Damjanovic 1993). These studies have shown that high yeast concentrations in the throat and intestine preceded systemic infection and that outbreaks were linked with high carriage rates in a unit. Routine infection control measures alone are insufficient to interrupt transmission of yeasts, and topical (oral and skin) and systemic treatments have been required. Control of an outbreak is associated with both a reduction in the yeast concentration in saliva or faeces and a lower overall carriage rate.
Oral nystatin is the most commonly used non-absorbable agent to treat mucocutaneous candida infection or carriage. Following the report by Sims 1988 of nystatin prophylaxis among infants < 1500g, prophylactic nystatin for infants with risk factors e.g during postnatal steroid treatment, has been used. Oral miconazole, which is also non-absorbable, is an alternative to nystatin. Oral or intravenous fluconazole, a newer, systemic antifungal agent has been used both in the treatment of systemic infection in neonates (Driessen 1996) and more recently to reduce candidal colonisation in very low birthweight infants (Kicklighter 2001, Kaufman 2001).
Each author independently assessed eligibility of retrieved reports and extracted data. The results were compared and any differences resolved by discussion and consensus.
Data were analysed using relative risk (RR), risk difference (RD), and number needed to treat (NNT) for categorical outcomes; mean difference (MD) and weighted mean difference (WMD) for outcomes measured on a continuous scale. Precision of treatment effect estimates are described using 95% confidence intervals in brackets. A fixed effect model was assumed for meta analysis.
Five trials were excluded from analysis. In the study by Harris 1960, 1500 newborn infants were alternately allocated to either oral administration of 100,000 units of nystatin daily or no treatment to try to prevent thrush. The gestational age of these infants was not reported but we have assumed that this study population included term and preterm infants. The study by Kicklighter 2001 randomised infants to intravenous fluconazole which was changed to oral fluconazole after oral feeds were tolerated; and the study by Kaufman 2001 was excluded because fluconazole was only administered intravenously. These studies are included in the Cochrane review of intravenous prophylaxis agents (McGuire 2003). Two further studies giving nystatin either alone or with other oral antibiotics with the aim of reducing colonisation, Damjanovic 1993, Herruzo-Cabrera 19994, were not randomised or quasi-randomised controlled trials.
The two included studies comparing antifungal agents with placebo or no
treatment were undertaken in the mid to late 1980s in California, USA (Sims 1988) and South Africa (Wainer 1992). The studies recruited infants of
different birthweight and gestational age. The Sims
1988 study took place during a period of over crowding in their unit;
222 infants with a birthweight 500-1250g were born during a 12 month period,
55 died within 48 hours, 88 relatively healthy infants were transferred elsewhere
and 67 of the remaining 88 infants were recruited to the study. They were
randomised to either oral nystatin or no treatment. The Wainer 1992 study in South Africa recruited 600
infants weighing less than 1750 grams. These infants were randomised to receive
either oral miconazole or placebo. Due to insufficient resources in South
Africa, ventilation was not offered to infants less than 1000 grams. These
differences between the studies are reflected in fewer days on a ventilator,
shorter stay in hospital, and fewer days on antibiotics in the Wainer 1992 study. Mortality, however, was higher
in the Wainer 1992 study, despite the higher
birthweight and gestational age. The Wainer 1992 study was included after
careful consideration. The study infants included infants weighing between
1500 and 1750 grams. Although this weight is above our inclusion criteria
they were born during an era when these infants had similar difficulties to
infants currently in the 1250-1500 gram weight category. In addition, the
study was carried out in a setting which was unable to offer intensive care
to infants below 1000 grams. This group made up 12 % (73/600) of the infants
and had a high mortality rate (67%).
Oral antifungals were commenced after consent and continued until one week
after ventilation in the Sims study (on average 5 weeks) and until discharge
in the Wainer 1992 study. The measure of fungal
colonisation was assessed on day one of life and weekly thereafter in both
studies.
The primary outcome measure of systemic fungal infection was defined in a similar manner and growth in blood, urine, endotracheal aspirates and cerebrospinal fluid were monitored. Details of in-hospital morbidity were similar. No details of outcome after discharge were given.
In the study by Violaris 1998 comparing oral fluconazole with nystatin, 21 infants weighing 501-1500 grams were randomly assigned to receive either low dose fluconazole (N=8) or nystatin (N=13) beginning on days 5-7 of life. Systemic fungal infections and mortality were reported.
I. Antifungal agent vs no treatment or placebo
1. Systemic fungal infection
Sims 1988 reported infants treated with nystatin
had a statistically significant reduction in the incidence of systemic fungal
infection with 2 of the 33 treated infants and 11 of the 34 control infants
having systemic fungal infection [RR 0.19 (0.04,0.78); RD -0.26 (-0.44,-0.09)].
One infant in the control group had Candida albicans pneumonia supported by
postmortem evidence, while all the other affected infants had positive urine
and blood cultures. Wainer 1992 did not find
any statistically significant difference in systemic fungal infection [RR
1.32 (0.46,3.75); RD 0.01 (-0.02,0.03)].
2. Mortality
Sims 1988 reported no significant difference
in mortality in the nystatin treated group compared with the placebo group
[RR 0.59 (0.19,1.82); RD -0.08 (-0.26,0.09)]. Only one infant death was attributed
to fungal infection. Wainer 1992 also reported
no significant difference in death between study groups [RR 0.87 (0.70,1.07);
RD -0.085 (-0.13,0.02)].
3. Morbidity
a. Duration of ventilation
Neither study found a statistically significant difference in the mean number
of days infants were ventilated between those treated with antifungal agents
and those with placebo or no treatment [Sims 1988:
MD 2.00 days (-9.02,13.02)]; Wainer 1992: MD
0.20 days (-1.14,1.54)].
b. Length of stay in NICU
The number of days infants stayed in the neonatal intensive care unit was
not significantly affected by treatment with an oral antifungal agent [Sims 1988: MD 4.00 days (-12.53,20.52); Wainer 1992: MD -0.20 days (-4.96,4.56)].
c. Duration of oxygen therapy
Not reported.
d. Retinopathy of prematurity
Not reported.
e. Intraventricular haemorrhage
Not reported.
f. Neurodevelopmental outcome
Not reported.
4. Adverse drug reactions
No adverse drug reactions were mentioned in the discussion in Wainer 1992
and they were not reported in the other studies.
II. Comparison of antifungal agents
1. Systemic fungal infection
Violaris 1998 reported no significant difference
in the incidence of systemic fungal infection in infants treated with fluconazole
compared with nystatin [RR 0.17 (0.01,2.84].
2. Mortality
There was a no significant difference in mortality [RR 0.17 (0.01,2.84)]
for fluconazole compared with nystatin (Violaris
1998).
No other outcomes were reported in the Violaris 1998 abstract.
The incidence of systemic fungal infection was significantly reduced in the small study of very low birthweight infants treated with nystatin (Sims 1988), but not in the study using miconazole (Wainer 1992). Although there was a trend to reduced mortality in both the studies where infants were treated with nystatin or miconazole compared with no treatment or placebo, these differences were not significant. Deaths directly attributable to fungal systemic infection were low (one in Sims 1988, unspecified in Wainer 1992). There was a lower incidence of mortality in the infants who did not become colonised in the Sims 1988 study.
While the two studies comparing oral antifungal agents with no treatment or placebo had major differences, the rate of fungal colonisation in the control groups of both studies was similar (Sims 1988: 44.1%, Wainer 1992: 41.3%). These rates are comparable to one of the studies assessing the use of oral agents in selective decontamination (Damjanovic 1993: 50%) as well as those using intravenous fluconazole prophylaxis (Kicklighter 2001: 46%, Kaufman 2001: 60%).
Both Sims 1988 and Wainer 1992 reported a statistically significant reduction in fungal colonisation in the treatment groups during this surveillance period, to 12% and 27.2% respectively. This change confirms the effectiveness of the agents to reduce colonisation as seen in the earlier study by Harris 1960 and the more recent studies of intravenous fluconazole by Kicklighter 2001 and Kaufman 2001. Despite this reduction in colonisation the outcomes of systemic fungal infection and mortality were not consistently improved. This is similar to the multivariate analysis of risk factors for candidaemia by Saiman 2000, where after adjusting for birthweight < 1000g and abdominal surgery, colonisation was not a significant risk factor (adjusted OR 1.71 (0.765, 3.748) p=0.208).
Only one small study of 21 infants, published only as an abstract, compared different antifungal agents. In this study, oral fluconazole was compared with oral nystatin. No significant differences in mortality or systemic fungal infections were reported (Violaris 1998).
Side effects of treatment were not reported in any study.
The effectiveness of oral antifungals in reducing systemic fungal infection in the current neonatal intensive care setting is unknown. The two placebo controlled studies included in this review recruited infants between June 1985 and July 1990. Even at the time of writing the authors of the Wainer 1992 study commented on the lack of applicability of the results to other units particularly due to ventilation not being offered to infants < 1000g. The incidence of fungal colonisation was moderately high in the control group in both of the included placebo controlled studies. Since the time of these studies many changes have occured in neonatal intensive care and some, at least, may be expected to reduce the risk of systemic fungal infection. In particular the duration of total parenteral nutrition and time to full oral feeds in days have decreased, in association with a shorter time of need for central lines. Also, treatment with postnatal steroids has become much less common (Shinwell 2003). A study in the current era is required to address these differences and ensure the agents used are appropriate for Candida subspecies types, current senstivity patterns and background colonisation rates.
Although clinical use in some neonatal units has targetted specific groups at higher risk of systemic fungal infection (for example infants who are colonised in the first three days; infants who receive systemic steroids or total parenteral nutrition; or low birth weight or very preterm infants) no data from randomised trials exist to support this usage. We were unable to perform subgroup analyses for infants of differing birthweight or gestation age. Other measures such as hand washing, vascular access systems, and central line insertion technique may be important in reducing the incidence of systemic infections and these have been highlighted in the reports by Kilbride 2003.
There is not enough evidence from this review to recommend oral antifungal agents to prevent systemic fungal infection, or to recommend one agent over another. The Cochrane review by McGuire 2003 assessed intravenous antifungal prophylactic use. Fluconazole can be used orally even with minimal enteral feeding and a large randomised controlled trial comparing fluconazole with nystatin as suggested by McGuire 2003 may be useful. Fluconazole is used by some in the treatment of systemic fungal infection. Any increase in the use of fluconazole for prophylaxis may affect the sensitivity spectrum of fungal organisms to this group of agents.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Sims 1988 | Blinding of allocation: No (quasi- randomised) Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measures: No |
67 infants above 500 g and less than 1250 g. Los-Angeles County-University of Southern California Medical Centre, June 1 1985 to May 31 1986 |
Nystatin 1ml orally, 8 hourly N=33 or none N=34 Treatment from inclusion until one week after extubation |
Fungal colonisation Systemic fungal infection |
C | |
| Violaris 1998 | 'Randomly assigned', but randomisation not described. No information on blinding of intervention or outcome assessment. Follow-up: complete for mortality and systemic infection. | 21 infants weighing 501-1500 gms. Place and time not stated. | Fluconazole (4mg/kg OD) orally (N=8) or Nystatin (100,000 units/kg/day QID) in each side of the mouth (N=13), beginning on days 5-7 of life. Medications were continued until full oral feedings were attained or systemic fungal infection was diagnosed. | Systemic fungal infection (presence of fungus in blood, cerebrospinal fluid or urine collected by suprapubic aspiration), Mortality | B | |
| Wainer 1992 | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measures: No |
600 infants < 1750 grams enrolled. Baragwanath Hospital, South Africa from October 1989 to July 1990 |
Miconazole 0.75ml orally 3 times daily N=302 or placebo N=298 | Fungal colonisation, System fungal infection |
Infants < 1000g were not ventilated and mortality in this group was high (72.2% in the control group and 62.2% in the miconazole group: NS) | A |
| Study | Reason for exclusion |
| Damjanovic 1993 | Not a randomised controlled trial, only one third of infants less than 1500g. |
| Harris 1960 | The gestational age or birthweight of participants was not reported - assumed to include term and preterm infants. |
| Herruzo-Cabrera 1994 | A prospective cohort study. |
| Kaufman 2001 | Infants were randomised to receive fluconazole or placebo intravenously. |
| Kicklighter 2001 | Infants were randomised to receive fluconazole or placebo intravenously, later given orally. |
Sims ME, Yoo Y, You H, Salminen C, Walther FJ. Prophylactic oral nystatin and fungal infections in very-low-birthweight infants. American Journal of Perinatology 1988;5:33-36.
Violaris 1998 {published data only}
Violaris K, Doraiswamy B, Olawepo O, Gulrajani-LaCorte M. Fluconazole vs. nystatin prophylaxis for fungal infection in very low birth weight (VLBW) infants. Pediatric Research 1998;43:254A.
Wainer 1992 {published data only}
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. Pediatric Infectious Disease Journal 1992;11:713-16.
Damjanovic V, Connolly CM, van Saene HK, Cooke RW, Corkill JE, van Belkum A, van Velzen D. Selective decontamination with nystatin for control of a candida outbreak in a neonatal intensive care unit. Journal of Hospital Infection 1993;24:245-59.
Harris 1960 {published data only}
Harris LJ. Further observations on a simple procedure to eliminate thrush from hospital nurseries. American Journal of Obstetrics and Gynecology 1960;80:30-31.
Herruzo-Cabrera 1994 {published data only}
Herruzo-Cabrera R, Garcia Gonzalez JI, Garcia Magan P, del Rey-Calero J. Nosocomial infection in a neonatal intensive care unit and its prevention with selective intestinal decolonization. A multivariant evaluation of infection reduction. European Journal of Epidemiology 1994;10:573-80.
Kaufman 2001 {published data only}
Kaufman D, Boyle R, Hazen K, Patrie J, Robinson M, Donowitz L. Fluconazole prophylaxis against fungal colonisation and infection in preterm infants. New England Journal of Medicine 2001;345:1660-66.
Kicklighter 2001 {published data only}
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;107:293-98.
* indicates the primary reference for the study
Botas CM, Kurlat I, Young SM, Sola A. Disseminated candidal infections and intravenous hydrocortisone in preterm infants. Pediatrics 1995;95:883-87.
Driessen M, Ellis JB, Cooper PA, Wainer S, Muwazi F, Hahn D, Gous H, De Villiers FP. Fluconazole vs amphotericin for the treatment of neonatal fungal septicaemia: a prospective randomized trial. Pediatric Infectious Disease Journal 1996;15:1107-12.
Faix RG, Kovarik SM, Shaw TR, Johnson RV. Mucocutaneous and invasive candidiasis among very low birth weight (<1,500 grams) infants in intensive care nurseries: a prospective study. Pediatrics 1989;83:101-7.
Friedman S, Richardson SE, Jacobs SE, O'Brien K. Systemic candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome. Pediatric Infectious Disease Journal 2000;19:499-504.
Gupta P, Faridi MM, Rawat S, Sharma P. Clinical profile and risk factors for oral candidosis in sick newborns. Indian Pediatrics 1996;33:299-303.
Karlowicz MG, Hashimoto LN, Kelly RE, Buescher ES. Should central venous catheters be removed as soon as candidemia is detected in neonates? Pediatrics 2000;106:e63.
Kilbride HW, Wirtschafter DD, Powers RJ, Sheehan MB. Implementation of evidenced-based potentially better practices to decrease nosocomial infections. Pediatrics 2003;111:e519-33.
Kossoff EH, Buescher ES, Karlowicz MG. Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases. Pediatric Infectious Disease Journal 1998;17:504-8.
Lee BE, Cheung PY, Robinson JL, Evanochko C, Robertson CM. Comparative study of mortality and morbidity in premature infants (birth weight < 1,250g) with candidemia or candidal meningitis. Clinical Infectious Diseases 1998;27:559-65.
McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software.
Mittal M, Dhanireddy R, Higgins RD. Candida sepsis and association with retinopathy of prematurity. Pediatrics 1998;101:654-7.
Pfaller MA. Epidemiology and control of fungal infections. Clinical Infectious Diseases 1994;19:S8-13.
Rowen JL, Rench MA, Kozinetz CA, Adams JM, Baker CJ. Endotracheal colonization with candida enhances risk of systemic candidiasis in very low birth weight neonates. Journal of Pediatrics 1994;124:789-94.
Rowen JL, Atkins JT, Levy ML, Baer SC, Baker CJ. Invasive fungal dermatitis in the < or = 1000-gram neonate. Pediatrics 1995;95:682-7.
Saiman L, Ludington BA, Pfaller M, Rangel-Frausto S, Wiblin RT, Dawson J, et al. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The national epidemiology of mycosis survey study group. Pediatric Infectious Disease Journal 2000;19:319-24.
Saiman L, Ludington E, Dawson JD, Patterson JE, Rangel-Frausto S, Wiblin RT, Blumberg HM, Pfaller M, Rinaldi M, Edwards JE, Wenzel RP, Jarvis W. Risk factors for Candida species colonization of neonatal intensive care unit patients. Pediatric Infectious Disease Journal 2001;20:1119-24.
Shinwell ES, Karplus M, Bader D, Dollberg S. Gur I, Weintraub Z et al. Neonatologists are using much less dexamethasone. Archives of Diseases of Childhood Fetal Neonatal Ed 2003;88:F432-3.
Waggoner-Fountain LA, Walker MW, Hollis RJ, Pfaller MA. Vertical and horizontal transmission of unique candida species to premature newborns. Clin Infect Dis 1996;22:803-8.
01.01 Systemic fungal infection
01.02 Mortality
01.03 Duration of ventilation
01.04 Length of stay in NICU (days)
02 Fluconazole vs nystatin
02.01 Systemic fungal infection
02.02 Mortality
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Oral antifungal prophylaxis vs placebo or nothing | ||||
| 01 Systemic fungal infection | RR (fixed), 95% CI | No total | ||
| 02 Mortality | RR (fixed), 95% CI | No total | ||
| 03 Duration of ventilation | WMD (fixed), 95% CI | No total | ||
| 04 Length of stay in NICU (days) | WMD (fixed), 95% CI | No total | ||
| 02 Fluconazole vs nystatin | ||||
| 01 Systemic fungal infection | RR (fixed), 95% CI | No total | ||
| 02 Mortality | RR (fixed), 95% CI | No total | ||
| This review is published as a Cochrane review in
The Cochrane Library 2004, Issue 1, 2004 (see www.CochraneLibrary.net for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Librayr should
be consulted for the most recent version of the Review. |
