Journal of Antimicrobial Chemotherapy (1997) 40, 855 862

Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer

Dyah Mutia PS

Introduction
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.

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. The incidence and severity of invasive candida infections the investigation of preventive approaches in patients undergoing intensive treatment for cancer. Although topical agents such as oral polyenes or imidazoles have been widely used for prophylaxis of mucosal candidiasis, their effectiveness in preventing invasive infections remains controversial. In contrast, randomized, doubleblind, placebo-controlled trials in adult cancer patients Fluconazole, a systemically active antifungal triazole, is effective in controlling colonization, decreasing mucosal infections and invasive disease, delaying the use of empirical amphotericin B, and reducing mortality in certain high-risk

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. Although widely used in clinical practice, published data on prophylactic fluconazole in children with cancer are scant. 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

Study design
Prospective, 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 (50,000 units/kg swirl and swallow daily in four equally divided doses). Chemoprophylaxis the start of the first or repeat cycles of chemotherapy Endpoints the incidence of superficial (mucosal) candidosis; the initiation of empirical antifungal therapy for suspected systemic fungal infections; the incidence of invasive candida infections (confirmed systemic fungal infections); and orointestinal yeast

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; - serological evidence for HIVinfection; - documented fungal infections requiring antifungal therapy; - oropharyngeal trush - history of an allergy to azoles or polyenes; - serum creatinine level of 180 mol/L ( 2.0 mg/dL); - serum bilirubin level of 51 mol/L ( 3.0 mg/dL); - AST or ALT exceeding five times the upper limit of

Clinical evaluation
Before entry to the study the patients complete

medical history Patients were evaluated for signs and symptoms of fungal infection, intercurrent illnesses and medication at baseline, daily (for inpatients) or at least once a week (for outpatients) during prophylaxis and at the end of prophylaxis. If infection was suspected during prophylaxis, appropriate samples were obtained for microbiological culture. 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.

Clinical evaluation
Prophylaxis was considered successful in the

absence of: - 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; - 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 ( 38C); - a new fever with a spike of 38.5C during antibacterial therapy; - new pulmonary or sinus infiltrates on X-ray consistent with mould infection.histology or cultures from normally sterile sites;

Mycological evaluation
Oropharyngeal swabs and stool samples were performed at

baseline, weekly during prophylaxis, and at the end of prophylaxis. 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 surface of the tongue, the palate and the pharynx with a cotton swab before medication time. Yeasts were identified by means of germ-tube production, biochemical reactions using the Api-20C strip and microscopic morphology on cornmeal agar.

Statistical considerations
Statistical evaluation of categorial data was

performed by chi-square analysis or Fishers exact test Continuous variables were compared by the MannWhitney U-test, and changes between baseline and maximum values of liver function tests were compared by the Wilcoxon rank sum test. A two-tailed P-value of 0.05 was considered statistically significant.

Results
A total of 60 patients were randomized.

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), of which 18 were in part included in a previously reported multicentre study.

Results
Table I. Demographic characteristics and duration of prophylaxis

Results
Table II. Underlying malignancies and factors predisposing to candida infections

Results of Clinical Evaluation

Table III. Incidence of confirmed or suspected fungal infections during prophylaxis

Results of Clinical Evaluation

Table III compares the overall outcome of

antifungal chemoprophylaxis, occurrence of mild and transient oropharyngeal candidosis and invasive fungal infections. There were no statistically significant or apparent differences between the two study arms. 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

Result of orointestinal colonization

Table IV. Prevalence of yeast colonization at baseline, during and at the end of antifungal prophylaxis

Result of orointestinal colonization

Patients were subdivided according to their initial

colonization status (Table IV). Initially non-colonized patients essentially remained yeast-free throughout treatment with no significant difference between the two study arms (93 vs 88%). Initially colonized patients stayed colonized throughout treatment (80 vs 81%; not significant). At the end of treatment, almost significantly more patients on fluconazole had become negative for yeasts (30 vs 68%; P 0.05)

Result of orointestinal colonization

Table V Fungal organisms isolated from oropharynx and faeces at baseline, and during or at the end of antifungal prophylaxis

Result of orointestinal colonization

Regardless of the treatment group (Table V), only

20% (18/85) of all samples positive during prophylaxis revealed a colony count of 1000 cfu/mL. C. albicans was the leading pathogen (81/85, 95%). A change in species was observed in one patient in the fluconazole group (C. albicans to Candida lusitaniae, stool) and in one in the nystatin group (C. lusitaniae to Candida guilliermondi, oropharynx

Results of toxicity and side effects

Table VI. Number of patients with toxicity and clinical side effects during antifungal prophylaxis

Results of toxicity and side effects

Isolated elevations of liver transaminases during

prophylaxis ( > 2x the upper limit of age-adjusted normal values, or, if the baseline value exceeded the upper limit of normal, 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, The mean AST value increased by 21.8 U/L in patients receiving fluconazole (from 14.4 to 36.2 U/L, P 0.05) and by 5.5 U/L in patients receiving nystatin (from 14.1 to 19.6 U/L, P 0.05). The mean ALT value increased by 44.8 U/L in patients receiving fluconazole (from 24.4 to 69.8 U/L, P 0.005)

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 0.67; ALT: P 0.26). Three patients on fluconazole developed mildly elevated blood urea levels not exceeding 1.5 times the upper limit of normal values and not associated with a simultaneous rise in serum creatinine values. All laboratory abnormalities were transient and in all cases considered to be mainly related to the concomitant administration of cytotoxic agents.

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), which did not prompt the discontinuation of the drug by the individual patient (16% vs 0%, P 0.05) (Table VI).

Conclusion
Fluconazole prophylaxis was safe, well tolerated and

did not differ from oral nystatin in its effectiveness, as assessed by colonization, the incidence of superficial or invasive fungal infections, and the empirical use of amphotericin B. In view of the potential emergence of resistant strains and cost, 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. Based on published studies in adults, the pharmacokinetic profile of the drug in children up to 16 years of age and the wide safety margin of the

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