Fluconazole Versus Nystatin in the Prevention of Candida
-
Upload
mutia-sesunan -
Category
Documents
-
view
222 -
download
0
Transcript of Fluconazole Versus Nystatin in the Prevention of Candida
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
1/25
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
2/25
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
3/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
4/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
5/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
6/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
7/25
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
8/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
9/25
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
10/25
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
11/25
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
12/25
ResultsTable I. Demographic characteristics and duration ofprophylaxis
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
13/25
ResultsTable II. Underlying malignancies and factors predisposing to candida
infections
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
14/25
Results of Clinical EvaluationTable III. Incidence of confirmed or suspected fungal infections during
prophylaxis
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
15/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
16/25
Result of orointestinal
colonizationTable IV. Prevalence of yeast colonization at baseline, during and at the end
of antifungal prophylaxis
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
17/25
Result of orointestinal
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)
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
18/25
Result of orointestinal
colonizationTable V Fungal organisms isolated from oropharynx and faeces at baseline, and
during or at the end of antifungal prophylaxis
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
19/25
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 Candidalusitaniae, stool) and in one in the nystatin group
(C. lusitaniae to Candida guilliermondi,
oropharynx
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
20/25
Results oftoxicity and side
effectsTable VI. Number of patients with toxicity and clinical side effects during
antifungal prophylaxis
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
21/25
Results oftoxicity 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 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)
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
22/25
Results oftoxicity and side
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.
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
23/25
Results oftoxicity and side
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).
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
24/25
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
-
7/28/2019 Fluconazole Versus Nystatin in the Prevention of Candida
25/25
ThankYou