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Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer
Dyah Mutia PS
Candida infections remain an important cause of
morbidity and mortality in patients treated for cancer. No information on the natural incidence of these infections is available for the setting of paediatric oncology although recent data from placebocontrolled trials in adults receiving no antifungal prophylaxis but empirical amphotericin B oropharyngeal candidiasis may develop in up to one third and proven invasive infections in up to 15% of patients undergoing intensive chemotherapy or bone marrow transplantation.
Although topical agents such as oral polyenes or imidazoles have been widely used for prophylaxis of mucosal candidiasis. is effective in controlling colonization. The incidence and severity of invasive candida infections the investigation of preventive approaches in patients undergoing intensive treatment for cancer. decreasing mucosal infections and invasive disease. delaying the use of empirical amphotericin B. placebo-controlled trials in adult cancer patients Fluconazole. and reducing mortality in certain high-risk . randomized. In contrast. their effectiveness in preventing invasive infections remains controversial.Introduction Appropriate antifungal therapy crude mortality of these infections inboth children and adults ranges from 20% to 50% and almost 100% in the presence of documented tissue involvement or persistent neutropenia. a systemically active antifungal triazole. doubleblind.
published data on prophylactic fluconazole in children with cancer are scant.Introduction Due to differences in pharmacokinetics and the cytotoxic regimens employed in the treatment of childhood malignancies results obtained in adults cannot be simply extrapolated to paediatric patients. This research is to evaluate the safety and efficacy of prophylactic fluconazole in children and adolescents undergoing intensive chemotherapy for leukaemia and solid tumours and being at risk of developing superficial and . Although widely used in clinical practice.
Chemoprophylaxis the start of the first or repeat cycles of chemotherapy Endpoints the incidence of superficial (mucosal) candidosis. and orointestinal yeast . randomized open pilot trial evaluate the eficacy and safety of fluconazole compared with nystatin in the prevention of candida infections in children and adolescents with cancer receiving chemotherapy After Informed consent randomized by a computer-generated fluconazole suspension (3 mg/kg once daily) or nystatin suspension (50.Study design Prospective.000 units/kg ‘swirl and swallow’ daily in four equally divided doses). the initiation of empirical antifungal therapy for suspected systemic fungal infections. the incidence of invasive candida infections (confirmed systemic fungal infections).
Eligibility criteria Patients of either sex with cancer were aged 6 months to 16 years and were scheduled to undergo remission induction or consolidation chemotherapy Exclusion criteria : .concomitant treatment with other investigational agents.serum bilirubin level of 51 mol/L ( 3.serum creatinine level of 180 mol/L ( 2. .0 mg/dL).0 mg/dL). .oropharyngeal trush .documented fungal infections requiring antifungal therapy. . . .AST or ALT exceeding five times the upper limit of .serological evidence for HIVinfection. .history of an allergy to azoles or polyenes.
. intercurrent illnesses and medication at baseline. Standard antifungal therapy with amphotericin B alone or with flucytosine was initiated if infection was confirmed or empirically before culture confirmation at the discretion of the primary physician of the patient. daily (for inpatients) or at least once a week (for outpatients) during prophylaxis and at the end of prophylaxis.Clinical evaluation Before entry to the study the patient’s complete medical history Patients were evaluated for signs and symptoms of fungal infection. appropriate samples were obtained for microbiological culture. If infection was suspected during prophylaxis.
. . .a new fever with a spike of 38.initiation of empirical systemic antifungal therapy after a minimum of 72 h of antibiotic therapy for neutropenia and suspected .documented bacterial infections and continuing fever ( 38°C).documented systemic fungal infection confirmed by documented candida oesophagitis proven by culture and barium-swallow or oesophagoscopy. .clinical oropharyngeal candidosis proven by microscopy and culture.Clinical evaluation Prophylaxis was considered successful in the absence of: .5°C during antibacterial therapy.new pulmonary or sinus infiltrates on X-ray consistent with mould infection.histology or cultures from normally sterile sites. .
and at the end of prophylaxis.Mycological evaluation Oropharyngeal swabs and stool samples were performed at baseline. the surface of the tongue. Yeasts were identified by means of germ-tube production. Colonization (positive cultures without evidence of superficial infection) was assessed by comparing oropharyngeal swab and stool cultures during and at the end of prophylaxis with those taken at baseline. Specimens from the oropharynx were obtained by swabbing the buccal mucosa. the palate and the pharynx with a cotton swab before medication time. . weekly during prophylaxis. biochemical reactions using the Api-20C strip and microscopic morphology on cornmeal agar.
. A two-tailed P-value of 0. and changes between baseline and maximum values of liver function tests were compared by the Wilcoxon rank sum test.05 was considered statistically significant.Statistical considerations Statistical evaluation of categorial data was performed by chi-square analysis or Fisher’s exact test Continuous variables were compared by the Mann–Whitney U-test.
Results A total of 60 patients were randomized. of which 18 were in part included in a previously reported multicentre study. Ten patients were taken off the study prior to the start of treatment because of either withdrawal of consent (three patients from the fluconazole group) or postponement of antineoplastic chemotherapy (two patients from the fluconazole group and five from the nystatin group). . The final analysis consisted of 50 evaluable cycles of antifungal prophylaxis (25 in each group).
Demographic characteristics and duration of prophylaxis .Results Table I.
Results Table II. Underlying malignancies and factors predisposing to candida infections .
Incidence of confirmed or suspected fungal infections during prophylaxis .Results of Clinical Evaluation Table III.
The only confirmed invasive infection and the only death occurred in the fluconazole arm where the patient with recurrent acute lymphoblastic leukaemia died 2 weeks after initiation of empirical amphotericin B/flucytosine therapy during protracted pancytopenia from cerebral mass . occurrence of mild and transient oropharyngeal candidosis and invasive fungal infections.Results of Clinical Evaluation Table III compares the overall outcome of antifungal chemoprophylaxis. There were no statistically significant or apparent differences between the two study arms.
Result of orointestinal colonization Table IV. Prevalence of yeast colonization at baseline. during and at the end of antifungal prophylaxis .
almost significantly more patients on fluconazole had become negative for yeasts (30 vs 68%. Initially non-colonized patients essentially remained yeast-free throughout treatment with no significant difference between the two study arms (93 vs 88%). At the end of treatment. Initially colonized patients stayed colonized throughout treatment (80 vs 81%.05) .Result of orointestinal colonization Patients were subdivided according to their initial colonization status (Table IV). not significant). P 0.
and during or at the end of antifungal prophylaxis .Result of orointestinal colonization Table V Fungal organisms isolated from oropharynx and faeces at baseline.
oropharynx . A change in species was observed in one patient in the fluconazole group (C. albicans was the leading pathogen (81/85.Result of orointestinal colonization Regardless of the treatment group (Table V). C. 95%). lusitaniae to Candida guilliermondi. stool) and in one in the nystatin group (C. albicans to Candida lusitaniae. only 20% (18/85) of all samples positive during prophylaxis revealed a colony count of 1000 cfu/mL.
Number of patients with toxicity and clinical side effects during antifungal prophylaxis .Results of toxicity and side effects Table VI.
2 U/L. P 0.5 U/L in patients receiving nystatin (from 14. The mean AST value increased by 21.005) .8 U/L in patients receiving fluconazole (from 14. The mean ALT value increased by 44. to > 2x the baseline value) were noted in seven patients on fluconazole and in three patients on baseline values were compared with maximum values during prophylaxis. P 0.05).4 to 69.8 U/L.Results of toxicity and side effects Isolated elevations of liver transaminases during prophylaxis ( > 2x the upper limit of age-adjusted normal values. or. P 0.4 to 36.6 U/L.1 to 19.8 U/L in patients receiving fluconazole (from 24.05) and by 5. if the baseline value exceeded the upper limit of normal.
67. All laboratory abnormalities were transient and in all cases considered to be mainly related to the concomitant administration of cytotoxic agents.26). ALT: P 0.5 times the upper limit of normal values and not associated with a simultaneous rise in serum creatinine values. Three patients on fluconazole developed mildly elevated blood urea levels not exceeding 1.Results of toxicity and side effects There was no statistically significant difference when changes between baseline and maximum values were compared between the two regimen (AST: P 0. .
P 0.Results of toxicity and side effects Four patients on fluconazole prophylaxis reported spontaneously reversible grade I gastrointestinal symptoms (nausea and abdominal discomfort (n 3)) or skin pruritus (n 1).05) (Table VI). which did not prompt the discontinuation of the drug by the individual patient (16% vs 0%. .
as assessed by colonization. the pharmacokinetic profile of the drug in children up to 16 years of age and the wide safety margin of the . and the empirical use of amphotericin B. the incidence of superficial or invasive fungal infections. Based on published studies in adults. fluconazole prophylaxis should probably be limited to patients with expected courses of prolonged and profound neutropenia and mucositis and epidemiological circumstances where candida infections are frequently encountered. well tolerated and did not differ from oral nystatin in its effectiveness. In view of the potential emergence of resistant strains and cost.Conclusion Fluconazole prophylaxis was safe.
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