|Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants
|Uko S, Soghier L M, Vega M, Marsh J, Reinersman G T, Herring L, Dave V A, Nafday S, Brion L P
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The use of intravenous fluconazole prophylaxis (3 mg/kg) for low birth weight (LBW) babies during periods of antibiotic administration. Fluconazole was administered over 30 minutes, at intervals ranging between every third day and every day (depending on postmenstrual age).
Economic study type
The study population comprised babies with a birth weight of less than 1,500 g, or a gestational age less than 32 weeks, born at the study centre during the study periods. Babies with early onset IFI (with blood culture or spinal tap sample positive for fungus before 72 hours of age) were excluded from the analysis.
The setting was tertiary care. The economic study was carried out in New York, USA.
Dates to which data relate
The effectiveness and resource use data referred to the period from 1 July 2003 to 30 December 2004. The comparator data referred to 1 January 2001 to 31 December 2002. The price year was not stated.
Source of effectiveness data
The effectiveness data were derived from a single study.
Link between effectiveness and cost data
The costing was conducted retrospectively on the same sample of patients as that used in the effectiveness study.
Power calculations were used to determine the sample size. All infants with a gestational age of less than 32 weeks, or a birth weight of less than 1,500 g, who were born at the study centre during the control and fluconazole epochs were included in the study. There were 206 babies in the control group and 178 in the fluconazole group. Patients with early onset IFI (defined as a blood culture or spinal tap sample positive for fungus before 72 hours of age) were excluded from the analysis. It was unclear how many babies were excluded on account of early IFI. No patients who met the inclusion criteria were excluded.
This was a single-centre, retrospective, observational study that compared outcomes in very LBW babies treated at the centre during different epochs. The duration of follow-up was the period of hospitalisation. No methods of blinding were used for the assessment of outcomes.
Analysis of effectiveness
The time periods determined the groups, regardless of whether the patient received fluconazole effectively. All patients included in the study were accounted for in the analysis. The primary outcome variable was IFI, defined as blood, cerebrospinal fluid or urine culture positive for fungus. There was no significant difference in gestational age or birth weight between the groups at baseline. The Clinical Risk Index for Infants (CRIB) score was significantly lower in the fluconazole epoch, and adjustments to avoid confounding due to this factor were made during the analysis of effectiveness.
IFI was observed in 6.3% infants during the control epoch and 1.1% during the fluconazole epoch. The odds ratio (OR) was 0.166 (95% confidence interval, CI: 0.033 to 0.709; p=0.007).
After adjusting for "necrotising enterocolitis or perforation" and gestational age of 23 to 27 weeks, the adjusted OR for IFI in the fluconazole epoch was 0.133 (95% CI: 0.023 to 0.762; p=0.023).
There was no difference in late (greater than 3 days) mortality rate between the groups, which was 11 of 206 infants in the control group and 8 of 178 infants in the prophylaxis group (OR 0.795, 95% CI: 0.301 to 2.102; p=0.644) . There was also no difference in the total mortality rate, which was 9.2% in the control epoch and 9.6% in the fluconazole epoch (OR 0.988, 95% CI: 0.473 to 2.066; p=0.975).
For evidence of toxicity of fluconazole in terms of liver dysfunction, the maximal direct bilirubin and transaminase levels, and the frequencies of serum direct bilirubin levels >5 mg/dL and aspartate aminotransferase levels of >150 IU/L, were in fact significantly lower in the fluconazole epoch than in the control epoch. There was no increase in resistant strains during the prophylaxis epoch.
Short-course fluconazole prophylaxis for very LBW infants, during periods when broad-spectrum antibiotics are used, reduces late-onset IFI and is not associated with toxicity or emergence of resistant strains.
Measure of benefits used in the economic analysis
The authors did not derive a summary measure of benefit. The study was, in effect, a cost-consequences analysis.
The quantities and costs were estimated using data from the clinical study. The costs fell into two categories, the cost of fluconazole used in prophylaxis and the cost of increased length of stay (LOS) in hospital for IFI. The unit costs were reported separately. The cost of each IFI was calculated by multiplying the mean increase in LOS by the cost of one day of hospitalisation in a neonatal intensive care unit. Discounting was not carried out, but it was not relevant since the costs were incurred during less than 2 years. The price year was not reported.
Statistical analysis of costs
Ninety-five per cent CIs were reported for the cost estimates.
The indirect costs were not included.
No sensitivity analysis was carried out.
Estimated benefits used in the economic analysis
There was no summary measure of benefit. See the 'Effectiveness Results' section.
The total cost of fluconazole was $11,361.50.
The LOS for patients with IFI was approximately 25 days more than patients without IFI, resulting in an additional cost of $75,000.
The estimated net savings were $663,638 (95% CI: 72,724 to 121,388) for the whole group and $516,702 (95% CI: 17,862 to 1,072,502) for extremely LBW infants.
Synthesis of costs and benefits
The costs and benefits were not combined, owing to the cost-consequences approach adopted.
Targeted short-course fluconazole prophylaxis in very low birth weight (LBW) infants may be efficacious and cost-effective.
CRD COMMENTARY - Selection of comparators
The reason for the choice of the comparator was clear. It was chosen because it represented the routine care for patients in the authors' setting before fluconazole prophylaxis was started. Routine care was not described, other than that it omitted fluconazole prophylaxis.
Validity of estimate of measure of effectiveness
The analysis of effectiveness was based on a retrospective study using historical controls. The authors acknowledged that there were statistically significant differences in CRIB score, number of episodes of bacterial sepsis, clinical sepsis, and duration of antibiotic therapy between the first and second epochs. It is also possible that ongoing attempts to limit nosocomial infections might have reduced the rates of all infections, including IFI. This represents a serious limitation to the validity of the estimate of measure of effectiveness.
Validity of estimate of measure of benefit
No summary benefit measure was used in the analysis. In effect, a cost-consequences analysis was conducted. Please refer to the comments in the 'Validity of estimate of measure of effectiveness' field (above).
Validity of estimate of costs
The perspective adopted in the study was not explicitly reported. The unit costs were reported, but the source of these data and the price year were not. The resource quantities (of fluconazole) used in prophylaxis were reported. However, the cost of each case of IFI was calculated by simply multiplying the mean increase in LOS due to IFI by the cost of one day of hospitalisation in a neonatal intensive care unit. The actual costs in terms of additional drugs, such as amphotericin used to treat the IFI, were not included. These limitations imply that the cost results should be treated with some caution.
The authors made appropriate comparisons of their findings with those from other studies. They highlighted the fact that differences in outcomes might have arisen on account of different populations. The authors acknowledged some further limitations arising from the retrospective nature of the study and the small sample size. The authors did not present their results selectively and their conclusions reflected the scope of the analysis.
Implications of the study
The authors recommended that a multi-centre trial be carried out to assess the efficacy, cost, toxicity and potential risks of targeted fluconazole therapy.
Uko S, Soghier L M, Vega M, Marsh J, Reinersman G T, Herring L, Dave V A, Nafday S, Brion L P. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics 2006; 117(4): 1243-1252
Other publications of related interest
Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information
Subject indexing assigned by NLM
Antibiotic Prophylaxis; Antifungal Agents /administration & Candidiasis /mortality /prevention & Fluconazole /administration & Health Care Costs; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases /economics /mortality /prevention & Infant, Very Low Birth Weight; Mycoses /economics /mortality /prevention & Survival Rate; control; control; control; dosage /economics; dosage /economics
Date bibliographic record published
Date abstract record published