Fluconazole Versus Nystatin in the Prevention of Candida

7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida

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Introduction

Candida infections remain an important cause ofmorbidity

and mortality in patients treated for cancer.

No information on the natural incidence of theseinfections is available for the setting of paediatric

oncology although recent data from placebo-

controlled 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.


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Introduction Appropriate antifungal therapy crude mortality of these

infections inboth children and adults ranges from 20% to50% and almost 100% in the presence of documentedtissue involvement or persistent neutropenia.

The incidence and severity of invasive candida infections

the investigation of preventive approaches in patientsundergoing intensive treatment for cancer.

Although topical agents such as oral polyenes orimidazoles have been widely used for prophylaxis ofmucosal candidiasis, their effectiveness in preventing

invasive infections remains controversial. In contrast, randomized, doubleblind, placebo-controlled

trials in adult cancer patients Fluconazole, asystemically active antifungal triazole, is effective incontrolling colonization, decreasing mucosal infections and

invasive disease, delaying the use of empiricalamphotericin B, and reducing mortality in certain high-risk


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Introduction

Due to differences in pharmacokinetics and thecytotoxic 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


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Study design

Prospective, randomized open pilot trial evaluatethe eficacy and safety of fluconazole compared withnystatin in the prevention of candida infections inchildren and adolescents with cancer receivingchemotherapy

After Informed consent randomized by acomputer-generated fluconazole suspension (3mg/kg once daily) or nystatin suspension (50,000units/kg swirl and swallow daily in four equallydivided doses).

Chemoprophylaxis the start of the first or repeatcycles of chemotherapy

Endpoints the incidence of superficial (mucosal)candidosis; the initiation of empirical antifungaltherapy for suspected systemic fungal infections; the

incidence of invasive candida infections (confirmedsystemic fungal infections); and orointestinal yeast


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Eligibility criteria Patients of either sex with cancer were aged 6

months to 16 years and were scheduled to undergoremission induction or consolidation chemotherapy

Exclusion criteria :

- concomitant treatment with other investigationalagents;

- serological evidence for HIVinfection;

- documented fungal infections requiring antifungaltherapy;

- 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


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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 aweek (for outpatients) during prophylaxis and at the

end of prophylaxis.

If infection was suspected during prophylaxis,

appropriate samples were obtained for microbiologicalculture.

Standard antifungal therapy with amphotericin B

alone or with flucytosine was initiated if infection was

confirmed or empirically before culture confirmation atthe discretion of the primary physician of the patient.


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Clinical evaluation Prophylaxis was considered successful in the

absence of:

- documented systemic fungal infection confirmed bydocumented candida oesophagitis proven by cultureand barium-swallow or oesophagoscopy;

- clinical oropharyngeal candidosis proven bymicroscopy and culture;

- initiation of empirical systemic antifungal therapyafter a minimum of 72 h of antibiotic therapy forneutropenia and suspected

- documented bacterial infections and continuing fever( 38C);

- a new fever with a spike of 38.5C duringantibacterial therapy;

- new pulmonary or sinus infiltrates on X-ray

consistent with mould infection.histology or culturesfrom normall sterile sites


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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 superficialinfection) 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.


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Statistical considerations

Statistical evaluation of categorial data was

performed by

chi-square analysis or Fishers exact test

Continuous variables were compared by theMannWhitney U-test, and changes between

baseline andmaximum values of liver function

tests were compared by the Wilcoxon rank sum

test.A two-tailed P-value of 0.05was considered

statistically significant.


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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 fluconazolegroup) or postponement of antineoplastic

chemotherapy (two patients from the fluconazole

group and five from the nystatin group).

The final analysis consisted of 50 evaluablecycles of antifungal prophylaxis (25 in each

group), of which 18 were in part included in a

previously reported multicentre study.


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ResultsTable I. Demographic characteristics and duration ofprophylaxis


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ResultsTable II. Underlying malignancies and factors predisposing to candida

infections


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Results of Clinical EvaluationTable III. Incidence of confirmed or suspected fungal infections during

prophylaxis


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Results of Clinical Evaluation

Table III compares the overall outcome ofantifungal 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


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Result of orointestinal

colonizationTable IV. Prevalence of yeast colonization at baseline, during and at the end

of antifungal prophylaxis


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colonization

Patients were subdivided according to their initialcolonization 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%).

Initiallycolonized 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)


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colonizationTable V Fungal organisms isolated from oropharynx and faeces at baseline, and

during or at the end of antifungal prophylaxis


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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 Candidalusitaniae, stool) and in one in the nystatin group

(C. lusitaniae to Candida guilliermondi,

oropharynx


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Results oftoxicity and side

effectsTable VI. Number of patients with toxicity and clinical side effects during

antifungal prophylaxis


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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 inseven 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 inpatients receiving fluconazole (from 14.4 to 36.2 U/L,

P 0.05) and by 5.5 U/L in patients receivingnystatin

(from 14.1 to 19.6 U/L, P 0.05).

The mean ALTvalue increased by 44.8 U/L in patientsreceiving fluconazole (from 24.4 to 69.8 U/L, P 0.005)


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effects

There was no statistically significant differencewhen changes between baseline and maximum

values were compared between the two regimen

(AST: P0.67; ALT: P 0.26).

Three patients on fluconazole developed mildlyelevated 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.


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effects

Four patients on fluconazole prophylaxis reportedspontaneously 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 individualpatient (16% vs 0%, P 0.05) (Table VI).


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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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ThankYou

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Fluconazole Versus Nystatin in the Prevention of Candida