a Department of Paediatrics and Department of Pharmacology, University of Trnava, School of Public Health, Bratislava 812 50, Slovak Republic; b Department of Health Management, School of Health, University of Scranton, Scranton, PA, USA; c Department of Neonatology, St Cyrillus Hospital, Bratislava 833 03; d Department of Pediatrics, FD Roosvelt Hospital, 971 01 Banska Bystrica; e Department of Microbiology, HPL Laboratory of the Children's Faculty Hospital, Bratislava; f Departments of Neonatology and Microbiology, University Hospital, Nitra 997 02; g Departments of Neonatology and Microbiology,Faculty Hospital, Kosice, Slovak Republic
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Abstract |
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Introduction |
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Here we report 40 breakthrough fungaemias appearing during therapy and prophylaxis with fluconazole in infants and neonates within the last 12 years.
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Materials and methods |
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Fungi isolated from a routine blood culturing process with the BACTEC Signal System (BBL, Becton Dickinson, Cockeysville, MD, USA) were identified by the Vitek Jr. identification system (VITEK; bioMérieux, Hazelwood, MO, USA). Breakthrough cases (40 neonates and infants) were compared with a group of 161 children with non-breakthrough fungaemias, e.g. fungaemias that occurred when a patient was not receiving an antifungal prophylaxis or treatment.
Fluconazole susceptibility was tested with an agar disc diffusion test (DDT) carried out with 25 mg fluconazole discs according to Bille & Glauser,13 which showed close correlation13,14 (95%) with the NCCLS recommended method.15 Notwithstanding this correlation, we understand that fluconazole disc diffusion testing is not a standardized method in Europe. Inhibition zones <19 mm were interpreted as indicating susceptibility of fluconazole, 1318 mm as susceptible dose-dependent and 2 mm as resistant.
Quality control strains of C. albicans (ATCC 90028) and C. parapsilosis (ATCC 22019) were included with each batch of yeasts tested. The agar DDT was carried out exactly as described by Bille & Glauser13 on 4 mm deep high resolution agar medium in 90 mm Petri plates. After incubation for 48 h at 35°C, the diameter of the zone of inhibition of yeast growth around the disc was measured.
Univariate analysis was carried out with the 2 test in MantelHaenzsel modification with Yates' correction (Fisher's exact test was used in members <5). P < 0.05 was considered statistically significant (EPI INFO computerized package manufactured by CDC, Atlanta, GA, USA). Student's t-test was used for the comparison of the mean APACHE II score, mean MICs and mean doses of fluconazole. In addition, a logistic regression model was used for multivariate analysis. Cases were enrolled to the model and only those variables that showed statistical significance in the univariate analysis with P < 0.05 were compared. They were included into the logistic regression model looking for independence while predicting breakthrough versus non-breakthrough fungaemia (STAT-ADV 23 B computerized package of the Postgraduate Medical School, Bratislava).
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Results |
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The MIC of fluconazole for all Candida spp. isolated was 0.254 mg/mL, indicating that all isolates were susceptible in vitro. In eight patients (20%) the same organism was isolated from blood cultures and catheter tips (catheter-related fungaemia). Thirty patients were cured (75%), six (15%) died due to fungal infections (fungaemia) and four (10%) died due to underlying diseases, which were relatively severe in most patients with breakthrough fungaemia (mean APACHE score was 15.9). Concerning the underlying disease, 28 of 40 cases (70%) appeared in neonates with a very low birth weight, all had central vascular catheters (in eight the catheter was also infected with the same species), 34 (85%) had ventilatory support and 24 (60%) received total parenteral nutrition. All but two received broad-spectrum antibiotic therapy for 322 days. All children received fluconazole for 417 days at doses of 610 mg/kg/day before the first positive blood culture for a Candida sp. appeared. In 14 children, the dose was 10 mg/kg/day, and in 26 it was 69 mg/kg/day in an od infusion.
The Table presents results of a univariate and multivariate analysis of risk factors and outcome between breakthrough and non-breakthrough fungaemias: neonatal age (P < 0.0001), very low birth weight (P < 0.0001), before surgery (P < 0.04), central or umbilical catheter insertion (P < 0.008), artificial ventilation (P < 0.0001), total parenteral nutrition (P < 0.0001), C. albicans (P < 0.002) and C. parapsilosis (P < 0.005) were significantly related to breakthrough fungaemia. Only central or umbilical catheter insertion was a significant independent risk factor, a predictor for breakthrough fungaemia in a multivariate analysis (P < 0.02, OR 3.06). Surprisingly, the outcome of breakthrough fungaemia was better than that of non-breakthrough fungaemiaoverall and attributable mortality in the latter group were significantly higher (P < 0.04 and P < 0.03) in comparison with the former.
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Discussion |
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An interesting fact concerning mortality was observed in our study: children with breakthrough fungaemia had significantly lower overall and attributable mortality than those with fungaemia that arose before antifungal therapy. The only explanation we have for this observation may be that when fungaemia broke through during treatment the patients were already receiving at least partially effective antifungal therapy.
Previous studies in cancer patients410 found at least three risk factors for the development of breakthrough fungaemia. The first risk factor is decreased in vitro susceptibility or resistance in the infecting organism. Our previous study in cancer patients12 found that c. 80% of breakthrough fungaemias were caused by fungi that were less susceptible to antifungals in vitro (non-Candida spp. and Candida spp. other than C. albicans). Breakthrough fungaemias caused by C. krusei and C. glabrata during prophylaxis with fluconazole were also described.8,9
The second risk factor is insufficient antifungal dosing. Low doses of amphotericin B resulted in 12 cases of breakthrough fungaemia due to C. albicans in at least two studies.5,10 Because several fungaemias have been seen in adults receiving fluconazole in the dose range 50200 mg/day, higher doses for therapy of fungaemia (400800 mg) are recommended.16
The third risk factor may be an infected foreign body resulting in persistent/breakthrough fungaemia. Three other studies6,17,18 observed breakthrough fungaemia due to organisms resistant in vitro and in patients with infected vascular catheters. Lecciones et al.17 underlined the necessity of catheter removal in fungaemia, as was recommended by the advisory panel of the Infectious Diseases Society of America in 1997.16
Analysis of the reasons for breakthrough of fungaemia in our 40 cases found that none were caused by species such as C. glabrata, C. krusei or Candida dubliniensis with reduced susceptibility to fluconazole, and none of the C. albicans isolates was resistant in vitro, but eight cases were catheter related. In the remaining 32 cases, we have no explanation for fungaemia breakthrough apart from the fluconazole dose that was administered. Twenty-six children received 69 mg/kg/day and 14 received 10 mg/kg/day despite a current recommended dose in neonates of 1019 mg/kg/day of fluconazole.16,19 In addition, bd dosing in neonates has been recommended.19 The reason for underdosing of the paediatric patients in our study was possibly the absence of knowledge of published guidelines,16 and the absence of guidelines for antifungal therapy in the Slovak Republic (National Clinical and Laboratory Standards are currently in press and may appear in late 2001). The cost of fluconazole in neonates is minimal and the drug has been available for 10 years in all hospitals over the country, so we do not expect that insufficient dosing occurs for economic reasons. Therefore, in neonates and infants, at least 10 mg/kg/day of fluconazole divided into two daily doses should be administered when fungaemia appears. All foreign bodies, if present (vascular catheters, shunts), should be removed. Antifungal susceptibility testing for all isolates should be carried out (i) if organisms other than C. albicans are present, (ii) in breakthrough fungaemias and (iii) in neonates/infants not responding to appropriate doses of antifungal therapy after 35 days.
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Acknowledgements |
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Notes |
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References |
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Received 20 December 2000; returned 6 March 2001; revised 23 April 2001; accepted 5 July 2000