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Efficacy of antifungal drugs in the treatment of oral candidiasis: A Bayesian network meta-analysis
SYSTEMATIC REVIEW
Efficacy of antifungal drugs in the treatment of oral candidiasis: A Bayesian network meta-analysis Jiaying Fang, MD,a Bin Huang, MD,b and Zan Ding, MDc Oral candidiasis is an acute, ABSTRACT subacute, or chronic fungal Statement of problem. The comparative efficacy of antifungal drugs on oral candidiasis remains disease of the oral mucosa unclear. caused by Candida infecPurpose. The purpose of this Bayesian network meta-analysis was to investigate the efficacy of tion.1,2 Candida, as a condiantifungal drugs on oral candidiasis. tional fungus, is the most Material and methods. Databases, including PubMed, The Cochrane Library, and Web of Science, common oral lesion in pawere accessed from the dates of their establishment to October, 2018, to collect randomized tients with autoimmune controlled trials (RCTs) of different antifungal drugs for oral candidiasis. A network meta-analysis deficiency syndrome (AIDS), was then conducted by using R and Stata 12.0 software programs. with a prevalence rate of Results. A total of 31 RCTs involving 4042 participants were included. The meta-analysis showed about 1.5% among adults and that, in the treatment of oral candidiasis in reducing the mycological cure rate, itraconazole a higher prevalence rate in capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, developing countries. In both fluconazole, ketoconazole, nystatin, and amphotericin B were better than a placebo. Miconazole developing and developed oral gel, fluconazole, and ketoconazole were better than nystatin. The network meta-analysis also countries, the incidence of showed that the effects of antifungal drugs in reducing the mycological cure rate in oral oral candidiasis in children is candidiasis were better than those of a placebo: itraconazole capsule (OR=1.20, 95% CrI: 1.07about 22.5% to 83.3%.3 With 1.34), itraconazole oral solution (OR=1.50, 95% CrI: 1.14-1.86), miconazole buccal tablet (OR=2.80, 95% CrI: 1.20-4.50), miconazole oral gel (OR=2.90, 95% CrI: 1.70-4.30), clotrimazole (OR=3.80, 95% the wide application of CrI: 1.65-5.95), fluconazole (OR=2.40, 95% CrI: 1.10-3.80), ketoconazole (OR=3.40, 95% CrI: 1.76immunosuppressive agents 7.04), nystatin (OR=2.50, 95% CrI: 1.43-3.57), and amphotericin B (OR=2.60, 95% CrI: 1.91-3.29). and antibiotics in recent The SUCRA values for each antifungal drug were as follows: placebo (6.80%), itraconazole years, the overall immunity of capsule (51.2%), itraconazole oral solution (75.2%), miconazole buccal tablet (34.4%), miconazole human beings has decreased, oral gel (76.9%), clotrimazole (64.8%), fluconazole (79.3%), ketoconazole (50.7%), nystatin (15.7%), the flora has become and amphotericin B (44.4%). dysfunctional, the probability Conclusions. Antifungal drugs have efficacy in the treatment of oral candidiasis. The effect of of fungal infection in the fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than mucosa, skin, and viscera has that of other drugs. (J Prosthet Dent 2020;-:---) increased significantly, and Antifungals are the main drugs for treating oral the incidence of oral candidiasis has increased. Oral candidiasis. These include pyrrole ring antifungal drugs, candidiasis can occur in the lips, skin, and mucosa, and polyene antifungal drugs, propenyl amine drugs, and recurrence is common, which brings distress to pasecond generation triazole drugs.7,8 In recent years, tients.4-6 Therefore, interest in the treatment of oral randomized controlled trials (RCTs) have reported that candidiasis has increased.
a
Professor, Medical Department, Huadu District People’s Hospital of Guangzhou, Guangdong, PR China. Professor, Medical Department, Huadu District People’s Hospital of Guangzhou, Guangdong, PR China. c Professor, The Institute of Metabolic Diseases, Baoan Central Hospital of Shenzhen, The Fifth Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, PR China. b
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Clinical Implications The incidence of oral candidiasis has increased, and antifungal drugs have demonstrated efficacy in its treatment. Fluconazole was effective in reducing the risk of the mycological cure rate in oral candidiasis and was better than other drugs.
antifungal agents can reduce the mycological cure rate of oral candidiasis,9-39 but there is a lack of direct comparison among antifungal agents. Therefore, it is not clear which antifungal drug is the most effective. As compared with a traditional meta-analysis, a network meta-analysis can compare multiple interventions and sort according to the advantages and disadvantages of the outcome index to get the best scheme. Therefore, the purpose of this Bayesian network meta-analysis was to identify whether itraconazole capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, or amphotericin B influence the mycological cure rate in oral candidiasis and to provide clinical recommendations for appropriate antifungal drugs for oral candidiasis. MATERIAL AND METHODS Medline, Embase, The Cochrane Library, and Web of Science databases were electronically searched to collect RCTs of antifungal drugs and oral candidiasis from inception to October 2018. In addition, the reference to the published research was traced back to supplement the relevant literature. Two authors (J.Y.F., Z.D.) independently screened the literature, extracted data, and assessed the risk bias of the included studies. The search was made by means of a combination of subject words and free words, and appropriate adjustments were made according to different databases. The search terms included oral cavity, cavitas oris, vestibule of the mouth, oral cavity proper, mouth cavity proper, candidiases, moniliasis, moniliases, antifungal agents, itraconazole, miconazole, clotrimazole, fluconazole, ketoconazole, nystatin, amphotericin B, and randomized controlled trials. Only RCTs were included, regardless of whether or not they specified the allocation of hidden or blinded methods. The date of publication and the study area were not limited. Individuals with oral candidiasis treated with a stable, recommended dose of an antifungal drug were required. The control group was given an antifungal drug or placebo, and the experimental group was given an antifungal drug.
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Two authors (J.-Y.F., B.H.) independently screened the literature, extracted the data, and cross-checked. If there was any disagreement, a third author (Z.D.) was consulted to assist in the judgment. The data extraction content included basic information for inclusion in the study, including first author and publication time; the basic characteristics of the participants, including the number of in each group and the average age of the participants; intervention-specific details; key elements of bias risk assessment; and outcome indicators and outcome measurement data of interest. A Bayesian grade model was used to perform a mesh meta-analysis of outcome measures by using R software. The count data used the odds ratio (OR), and the interval estimate used 95% CI as the effect size indicator. The heterogeneity between the included studies was analyzed by the c2 test (test level was a=.10), and the size of heterogeneity was quantified by combining I2. If the heterogeneity was small, the reticular meta analysis was carried out directly; if the heterogeneity was large, the source of heterogeneity was analyzed first, the obvious clinical heterogeneity was excluded, and the reticular meta-analysis was then carried out. When heterogeneity could not be explained, only a descriptive analysis was carried out. A Bayesian network model based on the Markov chain Monte Carlo operation was used for analyzing the therapeutic effects of drugs in 2 groups and multiple groups. Indirect comparison used R software to place a mesh chart. The effect of 2 classification variables was the same as that of direct comparison: enter the data into gemtc package and set the initial value, the number of chains, annealing, repetition, step size parameters, and processing. The result was presented by using the R package igraph. All the included drugs were sorted by using the surface under the cumulative ranking (SUCRA) to determine the advantages and disadvantages of the antifungal drug treatment for oral candidiasis. The larger the SUCRA, the better the effect. RESULTS The retrieval process is shown in Figure 1. A total of 1147 clinical research articles were retrieved according to the corresponding retrieval method. By reading the summary of the title and the full text and according to the established inclusion, the exclusion criteria determined the studies that met the criteria; finally, 31 articles were included (Table 1).9-39 Figure 2 showed the risk of bias of 31 studies included in this meta-analysis. The reticular relationship between 9 antifungal drugs compared with placebo is shown in Figure 3. Each circle represents an intervention, and the larger the circle, the greater the sample size for which the intervention is accepted; the
Fang et al
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Screening
Identification
-
Articles identified through literature search: • Medline (n=1071) • Embase (n=1147) • Cochrane library (n=2) • Clinical trials (n=25) Excluded (n=38) • Duplicate studies Studies after duplicates removed (n=1109)
Included
Eligibility
Articles excluded based on abstracts (n=1051) Full-text articles reviewed (n=58)
Articles excluded based on (n=27): • No relevant outcome measure (n=2) • Insufficient network connections (n=16) • Lack of detailed information (n=9)
Articles included in this meta-analysis (n=31)
Figure 1. Flow diagram of study selection process.
line between the circle and the circle represents a comparison of the 2 interventions, and the thicker the line is, the more studies were compared. Table 2 displays the results produced by pairwise meta-analysis. The effects of antifungal drugs in reducing the risk of the mycological cure rate in oral candidiasis were better than those of placebo: itraconazole oral solution (OR=1.11, 95% CrI: 1.03-1.19), miconazole buccal tablet (OR=1.38, 95% CrI: 1.11-1.66), miconazole oral gel (OR=1.77, 95% CrI: 1.32-2.22), fluconazole (OR=1.64, 95% CrI: 1.35-1.99), nystatin (OR=1.30, 95% CrI: 1.041.57), and amphotericin B (OR=1.08, 95% CrI: 1.01-1.15). Moreover, miconazole oral gel (OR=0.35, 95% CrI: 0.170.74), fluconazole (OR=0.53, 95% CrI: 0.31-0.88), and ketoconazole (OR=0.20, 95% CrI: 0.11-0.30) were better than nystatin (P<.05). Table 3 and Figure 4 display the results produced by network meta-analysis. The effects of antifungal drugs in reducing the risk of the mycological cure rate in oral candidiasis were better than thoe of a placebo: itraconazole capsule (OR=1.20, 95% CrI: 1.07-1.34), itraconazole oral solution (OR=1.50, 95% CrI: 1.14-1.86), miconazole buccal tablet (OR=2.80, 95% CrI: 1.20-4.50), miconazole oral gel (OR=2.90, 95% CrI: 1.70-4.30), clotrimazole (OR=3.80, 95% CrI: 1.65-5.95), fluconazole (OR=2.40, 95% CrI: 1.10-3.80), ketoconazole (OR=3.40, 95% CrI: 1.76-7.04), nystatin (OR=2.50, 95% CrI: 1.433.57), and amphotericin B (OR=2.60, 95% CrI: 1.91-3.29).
Fang et al
The corresponding results of SUCRA values are presented in Figure 5. The SUCRA values for each antifungal drugs were as follows: placebo (6.80%), itraconazole capsule (51.2%), itraconazole oral solution (75.2%), miconazole buccal tablet (34.4%), miconazole oral gel (76.9%), clotrimazole (64.8%), fluconazole (79.3%), ketoconazole (50.7%), nystatin (15.7%), and amphotericin B (44.4%). The effect of fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than that by other drugs. All data points were evenly distributed on both sides of the inverted funnel plot, suggesting less likelihood of publication bias (Fig. 6). DISCUSSION The search for the influence of antifungal drugs on oral candidiasis has been assessed without clear evidence. In the present study, only RCTs were included. Metaanalysis, analysis of bias, detailed checklist, and subsequent judgment were performed. A critical evaluation was performed by using the guidelines. The metaanalysis showed that itraconazole capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, or amphotericin B could reduce the mycological cure rate in oral candidiasis, and fluconazole was effective in reducing the risk of the mycological cure rate in oral candidiasis and was better than other drugs.
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Table 1. Characteristics of included studies Treatments Study Location
Author
Year
Oude et al
2004 Netherlands
Itraconazole capsule
16.089.0
Linpiyawan et al
2000 United States
Itraconazole oral solution
De Wit et al
1998 Belgium
Philips et al
Cases/ Treatments n 3
Age (Y)
Cases/ n
Treatments 2
Age (Y)
78/126
Fluconazole
17.079.0
93/126
Mycological cure rate
15.062.0
8/14
Clotrimazole
15.062.0
11/15
Mycological cure rate
Itraconazole capsule
16.065.0
4/17
Fluconazole
16.065.0
15/20
Mycological cure rate
1998 Canada
Itraconazole oral solution
24.058.0
54/60
Fluconazole
21.065.0
65/72
Mycological cure rate
Murray et al
1997 United States
Itraconazole oral solution
40.074.0
58/75
Clotrimazole
40.074.0
52/74
Mycological cure rate
Repentigny et al
1996 France
Itraconazole capsule
38.9
33/46
Ketoconazole
36.7
39/52
Mycological cure rate
Bastian et al
2004 Denmark
Miconazole buccal tablet
>18
28/49
Miconazole oral gel
>18
13/27 Placebo
Bensadoun et al
2008 France
Miconazole buccal tablet
17-83
79/147
Miconazole oral gel
17-83
68/147
Mycological cure rate
Hoppe et al
1996 Germany
Miconazole oral gel
8.9
23/27
Nystatin
8.9
15/35
Mycological cure rate
Hoppe et al
1997 Germany
Miconazole oral gel
NA
83/98
Nystatin
NA
18/85
Mycological cure rate
Vazquez et al
2010 United States
Miconazole buccal tablet
18-73
164/ 290
Clotrimazole
18-72
175/ 287
Mycological cure rate
Van Roey et al 2004 Belgium
Miconazole buccal tablet
>18
135/ 156
Ketoconazole
>18
137/ 153
Mycological cure rate
De Wit et al
1989 Belgium
Fluconazole
7.6
17/17
Ketoconazole
7.3
12/16
Mycological cure rate
Graybill et al
1998 United States
Itraconazole oral solution
38 ±8.8
52/59
Fluconazole
39 ±9.0
46/60
Mycological cure rate
Pons et al
1997 United States
Fluconazole
>18
60/69
Nystatin
>18
36/69
Mycological cure rate
Pons et al
1993 United States
Fluconazole
>18
91/100
Clotrimazole
>18
85/100
Mycological cure rate
Flynn et al
1995 United States
Fluconazole
0-14
73/91
Nystatin
0-14
26/91
Mycological cure rate
Koletar et al
1990 Colombia
Fluconazole
NA
16/16
Clotrimazole
NA
11/17
Mycological cure rate
Hernandez et al 1994 Spain
Fluconazole
0-12
21/24
Ketoconazole
0-12
18/22
Mycological cure rate
Nyst et al
1992 Zaire
Ketoconazole
>18
10/23
Nystatin
>18
2/23
Mycological cure rate
Johnson et al
1989 United States
Nystatin
NA
4/12
Placebo
NA
0/12
Mycological cure rate
Nairn et al
1975 England
Nystatin
NA
10/13
Amphotericin B
NA
16/18 Placebo
Goins et al
2002 United States
Nystatin
NA
6/19
Fluconazole
NA
15/15
Mycological cure rate
Blomgren et al 1998 Sweden
Nystatin
60.7
24/30
Fluconazole
60.7
26/30
Mycological cure rate
Leen et al
1990 United Kingdom
Fluconazole
NA
5/12
Placebo
NA
4/12
Mycological cure rate
Marriott et al
1993 Wales
Fluconazole
18-73
25/40
Placebo
18-73
13/44
Mycological cure rate
Pagani et al
2002 Switzerland
Fluconazole
NA
64/72
Placebo
NA
41/71
Mycological cure rate
Schuman et al 1997 United States
Fluconazole
NA
68/161
Placebo
NA
42/162
Mycological cure rate
Stevens et al
Fluconazole
>18
8/13
Placebo
>18
0/12
Mycological cure rate
McKinsey et al 1999 United States
Itraconazole oral solution
>18
17/149
Placebo
>18
15/146
Mycological cure rate
MacPhail et al
Nystatin
27-60
13/20
Placebo
27-60
5/10
Mycological cure rate
1991 United States
1996 United States
Treatments 1
Cases/ Age (Y) n
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>18
NA
1/9
2/15
Outcome
Mycological cure rate
Mycological cure rate
Fang et al
2020
5
D
C
B
E
A
F
Ra
nd Al om lo s c e Bl atio qu in n en di c c Bl ng on e g in d o ce en In ing f pa alm era co o rt e ti i n o Se mp f ou cipa t (s n ( le let tc nt el se ct e om s ec le Ot iv ou e an ti ct he e r tc a d on ion r b ep om sse pe bi b ia ort e ss rso as) ias s ) in da me n g ta n ne (re ( t ( l ( a po tt de pe rti riti tec rfo ng on ti rm bi bia on an as s bi ce as ) ) ) bia s)
-
Bastian 2004 +
?
?
?
?
+
-
Bensadoun 2008 +
?
?
?
?
?
-
Blomgren 1998
?
?
?
?
?
-
-
De Wi 1998
?
?
?
?
?
+
+
De Wit 1989
?
?
?
?
?
+
-
Flynn 1995
?
?
?
+
+
-
-
Goins 2002
?
+
?
+
?
-
?
Graybill 1998 + Hernandez 1994 ? Hoppe 1996 +
?
?
-
?
?
-
?
?
?
?
-
+
-
-
?
?
?
?
Hoppe 1997 +
?
+
?
?
?
?
Johnson 1989
?
?
?
?
?
+
+
Koletar 1990
?
?
?
?
-
+
?
Leen 1990 +
?
?
?
?
?
-
?
+
?
?
?
?
Linpiyawan 2000
?
G
H
Table 2. Summary odds ratios of antifungal drugs and heterogeneity for each direct comparison Comparison
?
?
?
?
?
-
-
Marriott 1993
?
?
?
?
+
+
-
Mckinsey 1999 + Murray 1997 ?
?
?
?
?
+
+
-
?
?
?
?
+
Nairn 1975 +
-
?
?
?
?
?
?
?
?
?
?
?
?
Oude 2004 +
+
?
?
+
-
-
Pagani 2002 +
?
?
?
?
+
-
?
?
?
?
?
?
+
Pons 1993 + Pons 1997 ?
+
+
+
?
?
?
Ketoconazole vs itraconazole capsule
?
+
?
?
?
?
Repentigny 1996 +
?
+
?
?
?
-
Schuman 1997 +
?
+
?
?
?
?
Stevens 1991
?
?
+
+
?
?
?
Van Roey 2004
?
?
?
?
?
-
?
Vazquez 2010
?
?
?
?
?
-
-
Philips 1998
Figure 2. Risk of bias of included RCTs (Review authors’ judgments about each risk of bias item for each included study. +, low risk; −, high risk; ?, unclear risk.). RCT, randomized controlled trial.
Candidiasis can involve the skin, mucosa, and various internal organs, and invasive candidiasis is more lifethreatening.40 Oral mucosa is the most common site of Fang et al
I
Figure 3. Network of randomized controlled trials comparing different antifungal drugs for oral candidiasis treatment. Thickness of connecting lines represents number of trials between each comparator, and size of each node corresponds to number of participants who received same pharmacological agent (sample size). (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
MacPhail 1996
Nyst 1992
J
P ITauOR (95% CI) Heterogeneity squared squared
Itraconazole oral solution vs placebo
1.11 (1.03, 1.19)
-
-
<.001
Miconazole buccal tablet vs placebo
1.38 (1.11, 1.66)
-
-
<.001
Miconazole oral gel vs placebo
1.77 (1.32, 2.22)
-
-
<.001
Fluconazole vs placebo
1.64 (1.35, 1.99)
.340
11.5
Nystatin vs placebo
1.30 (1.04, 1.57)
.251
45.7%
<.001
Amphotericin B vs placebo 1.08 (1.01, 1.15)
-
-
<.001
Fluconazole vs itraconazole 3.53 (0.66, 9.87) capsule
.035
77.6%
.137
-
-
.431
Clotrimazole vs itraconazole 0.85 (0.44, 1.64) oral solution
.215
35.0%
.626
Fluconazole vs itraconazole 0.63 (0.30, 1.32) oral solution
.274
16.6%
.222
Miconazole oral gel 0.86 (0.70, 1.05) vs miconazole buccal tablet
.932
0.0%
.142
Clotrimazole vs miconazole 1.08 (0.89, 1.34) buccal tablet
-
-
.547
Ketoconazole vs miconazole 1.03 (0.67, 1.41) buccal tablet
-
-
.659
Nystatin vs miconazole oral 0.35 (0.17, 0.74) gel
.013
83.7%
.005
1.05 (0.78, 2.09)
<.001
Fluconazole vs clotrimazole 1.22 (0.87, 1.72)
.059
72.0%
.247
Ketoconazole vs fluconazole 0.87 (0.71, 1.03)
.281
13.9%
.101
Nystatin vs fluconazole
0.53 (0.31, 0.88)
<.001
90.7%
.015
Nystatin vs ketoconazole
0.20 (0.11, 0.30)
-
-
<.001
Amphotericin B vs nystatin 1.15 (0.87, 1.44)
-
-
.591
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Table 3. Network meta-analysis comparisons Placebo
I-ca
I-os
M-bt
1
0.83 (0.75, 0.93)
0.67 (0.54, 0.88)
0.36 (0.22, 0.85)
Placebo I-ca
1.20 (1.07, 1.34)
1
0.59 (0.06, 5.80)
0.39 (0.04, 3.90)
I-os
1.50 (1.14, 1.86)
1.70 (0.18, 16.0)
1
0.66 (0.08, 5.30)
M-bt
2.80 (1.20, 4.50)
2.50 (0.24, 13.0)
1.50 (0.20, 9.00)
1
M-og
2.90 (1.70, 4.30)
3.70 (0.34, 14.0)
2.20 (0.27, 11.0)
1.50 (0.28, 8.10)
Clotrimazole
3.80 (1.65, 5.95)
1.40 (0.13, 11.0)
0.84 (0.16, 4.10)
0.56 (0.08, 3.50)
Fluconazole
2.40 (1.10, 3.80)
3.20 (0.59, 12.0)
1.90 (0.47, 8.70)
1.20 (0.23, 7.40)
Ketoconazole
3.40 (1.76, 7.04)
1.70 (0.23, 11.0)
0.98 (0.13, 7.60)
0.65 (0.09, 4.20)
Nystatin
2.50 (1.43, 3.57)
0.54 (0.07, 4.20)
0.32 (0.06, 1.90)
0.21 (0.04, 1.30)
Amphotericin B
2.60 (1.91, 3.29)
3.00 (0.13, 11.0)
0.36 (0.13, 1.20)
2.30 (0.08, 7.70)
I-ca, itraconazole capsule; I-os, itraconazole oral solution; M-bt, miconazole buccal tablet; M-og, miconazole oral gel.
OR(95%Crl)
Compared with Placebo
OR(95%Crl)
Compared with I-ca
Compared with I-os
OR(95%Crl)
I-ca
1.02 (1.07, 1.34)
Placebo
0.83 (0.75, 0.93)
Placebo
0.67 (0.54, 0.88)
I-os
1.50 (1.14, 1.86)
I-os
1.70 (0.18, 16.00)
I-ca
0.59 (0.06, 5.80)
M-bt
2.80 (1.20, 4.50)
M-bt
2.50 (0.24, 13.00)
M-bt
1.50 (0.20, 9.00)
M-og
2.90 (1.70, 4.30)
M-og
3.70 (0.34, 14.00)
M-og
2.20 (0.27, 11.00)
Clotrimazole
3.80 (1.65, 5.95)
Clotrimazole
1.40 (0.13, 11.00)
Clotrimazole
0.84 (0.16, 4.10)
Fluconazole
2.40 (1.10, 3.80)
Fluconazole
3.20 (0.59, 12.00)
Fluconazole
1.90 (0.47, 8.70)
Ketoconazole
3.40 (1.76, 7.04)
Ketoconazole
1.70 (0.23, 11.00)
Ketoconazole
0.98 (0.13, 7.60)
Nystatin
2.50 (1.43, 3.57)
Nystatin
0.54 (0.07, 4.20)
Nystatin
0.32 (0.06, 1.90)
Amphotericin B
2.60 (1.91, 3.29)
Amphotericin B
3.00 (0.13, 11.00)
Amphotericin B
0.36 (0.13, 1.20)
01
5
0
10
Compared with M-bt
OR(95%Crl)
5
20
Compared with M-og
01 OR(95%Crl)
5
15
Compared with Clotrimazole
OR(95%Crl)
Placebo
0.36 (0.22, 0.85)
Placebo
0.35 (0.23, 0.56)
Placebo
0.26 (0.17, 0.60)
I-cs
0.39 (0.04, 3.90)
I-ca
0.26 (0.09, 2.80)
I-ca
0.69 (0.07, 7.20)
I-os
0.66 (0.08, 5.30)
I-os
0.45 (0.15, 3.80)
I-os
1.20 (0.25, 6.10)
M-og
1.50 (0.28, 8.10)
M-bt
0.68 (0.12, 3.60)
M-bt
1.80 (0.28, 13.00)
Clotrimazole
0.56 (0.08, 3.50)
Clotrimazole
0.38 (0.14, 3.00)
M-og
2.60 (0.34, 11.00)
Fluconazole
1.20 (0.23, 7.40)
Fluconazole
0.84 (0.15, 5.10)
Fluconazole
2.20 (0.51, 12.00)
Ketoconazole
0.65 (0.09, 4.20)
Ketoconazole
0.44 (0.13, 3.40)
Ketoconazole
1.20 (0.15, 9.40)
Nystatin
0.21 (0.04, 1.30)
Nystatin
0.15 (0.03, 0.72)
Nystatin
0.38 (0.07, 2.50)
Amphotericin B
2.30 (0.08, 7.70)
Amphotericin B
1.60 (0.60, 4.90)
Amphotericin B
4.00 (0.15, 14.00)
01
5
10
Compared with Ketoconazole
01 OR(95%Crl)
4
0
8
Compared with Nystatin
OR(95%Crl)
8
18
Compared with Amphotericin B
OR(95%Crl)
Placebo
0.29 (0.14, 0.57)
Placebo
0.40 (0.28, 0.70)
Placebo
0.38 (0.23, 0.52)
I-ca
0.60 (0.09, 4.30)
I-ca
1.80 (0.23, 13.00)
I-ca
0.17 (0.09, 5.40)
I-os
1.00 (0.13, 8.30)
I-os
3.10 (0.52, 17.00)
I-os
0.28 (0.06, 7.60)
M-bt
1.50 (0.24, 11.00)
M-bt
3.70 (0.76, 11.00)
M-bt
0.43 (0.08, 13.00)
M-og
2.30 (0.30, 11.00)
M-og
3.90 (1.40, 8.00)
M-og
0.63 (0.12, 11.00)
Clotrimazole
0.85 (0.11, 6.50)
Clotrimazole
2.60 (0.39, 11.00)
Clotrimazole
0.24 (0.11, 6.60)
Fluconazole
1.90 (0.42, 9.90)
Fluconazole
5.80 (1.90, 9.00)
Fluconazole
0.54 (0.14, 12.00)
Nystatin
0.33 (0.06, 1.90)
Ketoconazole
3.10 (0.53, 12.00)
Ketoconazole
0.28 (0.12, 7.40)
Amphotericin B
3.60 (0.13, 12.00)
Amphotericin B
1.20 (0.55, 2.50)
Nystatin
0.21 (0.09, 11.80)
01
5
15
0
10
20
01
5
15
Figure 4. Forest plots of odds ratios (95% creditable intervals) produced by network meta-analysis. I-ca, itraconazole capsule; I-os, itraconazole oral solution; M-bt, miconazole buccal tablet; M-og, miconazole oral gel.
candida infection and also the most common initial site of systemic fungal infection.41,42 In the case of local factors, such as oral disease or a denture, or systemic factors, such as malnutrition, malignant disease, immunosuppressant, THE JOURNAL OF PROSTHETIC DENTISTRY
steroid hormone, or broad-spectrum antibiotics, oral candidiasis can cause opportunistic infections, causing pain, erythema, irritation, or even ulcers. If oral candidiasis is not controlled in time, it will spread to the respiratory Fang et al
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Table 3. (Continued) Network meta-analysis comparisons M-og
Clotrimazole
Fluconazole
Ketoconazole
Nystatin
Amphotericin B
0.35 (0.23, 0.56)
0.26 (0.17, 0.60)
0.42 (0.26, 0.91)
0.29 (0.14, 0.57)
0.40 (0.28, 0.70)
0.38 (0.23, 0.52)
0.26 (0.09, 2.80)
0.69 (0.07, 7.20)
0.31 (0.05, 1.70)
0.60 (0.09, 4.30)
1.80 (0.23, 13.0)
0.17 (0.09, 5.40)
0.45 (0.15, 3.80)
1.20 (0.25, 6.10)
0.54 (0.12, 2.20)
1.00 (0.13, 8.30)
3.10 (0.52, 17.0)
0.28 (0.06, 7.60)
0.68 (0.12, 3.60)
1.80 (0.28, 13.0)
0.81 (0.13, 4.40)
1.50 (0.24, 11.0)
3.70 (0.76, 11.0)
0.43 (0.08, 13.0)
1
2.60 (0.34, 11.0)
1.20 (0.20, 6.80)
2.30 (0.30, 11.0)
3.90 (1.40, 8.00)
0.63 (0.12, 11.0)
0.38 (0.14, 3.00)
1
0.45 (0.09, 2.20)
0.85 (0.11, 6.50)
2.60 (0.39, 11.0)
0.24 (0.11, 6.60)
0.84 (0.15, 5.10)
2.20 (0.51, 12.0)
1
1.90 (0.42, 9.90)
5.80 (1.90, 9.00)
0.54 (0.14, 12.0)
0.44 (0.13, 3.40)
1.20 (0.15, 9.40)
0.53 (0.10, 2.40)
1
3.10 (0.53, 12.0)
0.28 (0.12, 7.40)
0.15 (0.03, 0.72)
0.38 (0.07, 2.50)
0.17 (0.05, 0.53)
0.33 (0.06, 1.90)
1
0.21 (0.09, 1.80)
1.60 (0.60, 4.90)
4.00 (0.15, 14.0)
1.90 (0.09, 4.90)
3.60 (0.13, 12.0)
1.20 (0.55, 2.50)
1
Fang et al
120%
Cumulative Probability
system, digestive system, blood system, and central nervous system and cause systemic infection that endangers life.43 In addition, hypersensitivity caused by candida metabolites can induce eczema, asthma, and gastritis.44 Therefore, the drug with the greatest efficacy is urgently needed for oral candidiasis. Pyrrole ring drugs include imidazoles and triazoles which inhibit ergosterol synthesis in fungi and thus destroy the integrity of the fungal cell membrane and achieve the antifungal effect.8 The most common drugs represented by imidazoles are clotrimazole, ketoconazole, and miconazole. The imidazole drugs have a stronger antifungal effect and are effective in the treatment of candidiasis. The most common drugs represented by triazoles are fluconazole and itraconazole. Triazole antifungal drugs have high bioavailability, strong effect, and low toxicity.45 Polyene antifungal drugs include nystatin and amphotericin B. The mechanism is that it binds to ergosterol, resulting in cell membrane changes, cell lysis, and necrosis.46 Nystatin is currently used as a local drug, and amphotericin B has been widely used because of its strong effect; however, because of its greater toxicity, it is prescribed with a lipid body agent to reduce toxic side effects.47 Fluconazole is a broad-spectrum antifungal agent and has a good effect on superficial and deep fungal infection. The fourth nitrogen atom in the triazole ring of fluconazole molecular structure binds to the iron atom on the cytochrome P450 hemagglutinin ring of fungi, which makes the fungi lose dehydrogenase activity, and then inhibits the demethylation of wool sterol C14. Ergosterol is an important component of the fungal cell membrane, and lack of ergosterol will cause damage to fungal cell membrane. The activities of enzyme and peroxidase increase peroxide accumulation in fungi and the permeability of the fungal cell membrane, so as to inhibit the growth of fungi.48-51 The oral absorption effect of fluconazole is good, and the curative effect of fluconazole is not affected by receptor blocker drug, antiacid, or food factors. The average blood concentration of fluconazole was as high as 4.5 to 8.0mg/L, and the plasma protein binding rate was low. Drugs were widely distributed in vesicular fluid and skin and excreted from the kidney and liver.52,53
100% 80% 60% 40% 20% 0%
1
2
3
4
5
6
log(OR)
7
8
9
10
B C D E (51.2%) (75.2%) (34.4%) (76.9%) F G H I J (15.7%) (44.4%) (64.8%) (79.3%) (50.7%) (6.8%)
A
Figure 5. Surface under cumulative ranking curve (SUCRA), expressed as percentages, ranking therapeutic effects and safety of treatments for oral candidiasis. For efficacy and safety assessment, pharmacological agent with highest SUCRA value would be most efficacious and safe treatment. (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
The effectiveness, safety, and cost of drugs are important indicators of clinical drug treatment. Fluconazole, a commonly used antioral candida infection drug, has no cost advantage over other drugs, but the difference in therapeutic effect is statistically significant. Therefore, this factor should be taken into account in the treatment of oral candidiasis. This meta-analysis has limitations. Different doses, administration schemes, and patients of different age were included in the studies resulting in clinical heterogeneity. The authors only evaluated the mycological cure rate, while the incidence of recurrence rate and adverse reaction rate could not be analyzed because of lack of relevant data. The quality and quantity of the literature included were low, which decrease the test efficiency. Finally, the small sample size of the interventions included in the study and the possible shortage of statistical efficiency may be insufficient. THE JOURNAL OF PROSTHETIC DENTISTRY
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Volume
-
Issue
-
Standard Error of Effect Size
0
.5
1
1.5
–4
–2
0
2
4
Effect Size Centered at Comparison-Specific Pooled Effect (yiXY - µ A vs J B vs G D vs H I vs J
A vs C B vs H E vs I
A vs D C vs F F vs G
A vs E C vs G G vs H
A vs G D vs E G vs I
XY)
A vs I D vs F H vs I
Figure 6. Comparison-adjusted funnel plot for network meta-analysis. Red line suggests null hypothesis that study-specific effect sizes do not differ from respective comparison-specific pooled effect estimates. Different colors represent different comparisons. (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
CONCLUSIONS Based on the findings of this network meta-analysis, the following conclusions were drawn: 1. Itraconazole capsule, itraconazole oral solution, miconazole buccal tablet, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, and amphotericin B can effectively reduce the mycological cure rate in oral candidiasis treatment compared with a placebo. 2. The effects of fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than those of other drugs.
10.
11. 12. 13.
14.
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Efficacy of antifungal drugs in the treatment of oral candidiasis: A Bayesian network meta-analysis Jiaying Fang, MD,a Bin Huang, MD,b and Zan Ding, MDc Oral candidiasis is an acute, ABSTRACT subacute, or chronic fungal Statement of problem. The comparative efficacy of antifungal drugs on oral candidiasis remains disease of the oral mucosa unclear. caused by Candida infecPurpose. The purpose of this Bayesian network meta-analysis was to investigate the efficacy of tion.1,2 Candida, as a condiantifungal drugs on oral candidiasis. tional fungus, is the most Material and methods. Databases, including PubMed, The Cochrane Library, and Web of Science, common oral lesion in pawere accessed from the dates of their establishment to October, 2018, to collect randomized tients with autoimmune controlled trials (RCTs) of different antifungal drugs for oral candidiasis. A network meta-analysis deficiency syndrome (AIDS), was then conducted by using R and Stata 12.0 software programs. with a prevalence rate of Results. A total of 31 RCTs involving 4042 participants were included. The meta-analysis showed about 1.5% among adults and that, in the treatment of oral candidiasis in reducing the mycological cure rate, itraconazole a higher prevalence rate in capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, developing countries. In both fluconazole, ketoconazole, nystatin, and amphotericin B were better than a placebo. Miconazole developing and developed oral gel, fluconazole, and ketoconazole were better than nystatin. The network meta-analysis also countries, the incidence of showed that the effects of antifungal drugs in reducing the mycological cure rate in oral oral candidiasis in children is candidiasis were better than those of a placebo: itraconazole capsule (OR=1.20, 95% CrI: 1.07about 22.5% to 83.3%.3 With 1.34), itraconazole oral solution (OR=1.50, 95% CrI: 1.14-1.86), miconazole buccal tablet (OR=2.80, 95% CrI: 1.20-4.50), miconazole oral gel (OR=2.90, 95% CrI: 1.70-4.30), clotrimazole (OR=3.80, 95% the wide application of CrI: 1.65-5.95), fluconazole (OR=2.40, 95% CrI: 1.10-3.80), ketoconazole (OR=3.40, 95% CrI: 1.76immunosuppressive agents 7.04), nystatin (OR=2.50, 95% CrI: 1.43-3.57), and amphotericin B (OR=2.60, 95% CrI: 1.91-3.29). and antibiotics in recent The SUCRA values for each antifungal drug were as follows: placebo (6.80%), itraconazole years, the overall immunity of capsule (51.2%), itraconazole oral solution (75.2%), miconazole buccal tablet (34.4%), miconazole human beings has decreased, oral gel (76.9%), clotrimazole (64.8%), fluconazole (79.3%), ketoconazole (50.7%), nystatin (15.7%), the flora has become and amphotericin B (44.4%). dysfunctional, the probability Conclusions. Antifungal drugs have efficacy in the treatment of oral candidiasis. The effect of of fungal infection in the fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than mucosa, skin, and viscera has that of other drugs. (J Prosthet Dent 2020;-:---) increased significantly, and Antifungals are the main drugs for treating oral the incidence of oral candidiasis has increased. Oral candidiasis. These include pyrrole ring antifungal drugs, candidiasis can occur in the lips, skin, and mucosa, and polyene antifungal drugs, propenyl amine drugs, and recurrence is common, which brings distress to pasecond generation triazole drugs.7,8 In recent years, tients.4-6 Therefore, interest in the treatment of oral randomized controlled trials (RCTs) have reported that candidiasis has increased.
a
Professor, Medical Department, Huadu District People’s Hospital of Guangzhou, Guangdong, PR China. Professor, Medical Department, Huadu District People’s Hospital of Guangzhou, Guangdong, PR China. c Professor, The Institute of Metabolic Diseases, Baoan Central Hospital of Shenzhen, The Fifth Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, PR China. b
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Clinical Implications The incidence of oral candidiasis has increased, and antifungal drugs have demonstrated efficacy in its treatment. Fluconazole was effective in reducing the risk of the mycological cure rate in oral candidiasis and was better than other drugs.
antifungal agents can reduce the mycological cure rate of oral candidiasis,9-39 but there is a lack of direct comparison among antifungal agents. Therefore, it is not clear which antifungal drug is the most effective. As compared with a traditional meta-analysis, a network meta-analysis can compare multiple interventions and sort according to the advantages and disadvantages of the outcome index to get the best scheme. Therefore, the purpose of this Bayesian network meta-analysis was to identify whether itraconazole capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, or amphotericin B influence the mycological cure rate in oral candidiasis and to provide clinical recommendations for appropriate antifungal drugs for oral candidiasis. MATERIAL AND METHODS Medline, Embase, The Cochrane Library, and Web of Science databases were electronically searched to collect RCTs of antifungal drugs and oral candidiasis from inception to October 2018. In addition, the reference to the published research was traced back to supplement the relevant literature. Two authors (J.Y.F., Z.D.) independently screened the literature, extracted data, and assessed the risk bias of the included studies. The search was made by means of a combination of subject words and free words, and appropriate adjustments were made according to different databases. The search terms included oral cavity, cavitas oris, vestibule of the mouth, oral cavity proper, mouth cavity proper, candidiases, moniliasis, moniliases, antifungal agents, itraconazole, miconazole, clotrimazole, fluconazole, ketoconazole, nystatin, amphotericin B, and randomized controlled trials. Only RCTs were included, regardless of whether or not they specified the allocation of hidden or blinded methods. The date of publication and the study area were not limited. Individuals with oral candidiasis treated with a stable, recommended dose of an antifungal drug were required. The control group was given an antifungal drug or placebo, and the experimental group was given an antifungal drug.
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Two authors (J.-Y.F., B.H.) independently screened the literature, extracted the data, and cross-checked. If there was any disagreement, a third author (Z.D.) was consulted to assist in the judgment. The data extraction content included basic information for inclusion in the study, including first author and publication time; the basic characteristics of the participants, including the number of in each group and the average age of the participants; intervention-specific details; key elements of bias risk assessment; and outcome indicators and outcome measurement data of interest. A Bayesian grade model was used to perform a mesh meta-analysis of outcome measures by using R software. The count data used the odds ratio (OR), and the interval estimate used 95% CI as the effect size indicator. The heterogeneity between the included studies was analyzed by the c2 test (test level was a=.10), and the size of heterogeneity was quantified by combining I2. If the heterogeneity was small, the reticular meta analysis was carried out directly; if the heterogeneity was large, the source of heterogeneity was analyzed first, the obvious clinical heterogeneity was excluded, and the reticular meta-analysis was then carried out. When heterogeneity could not be explained, only a descriptive analysis was carried out. A Bayesian network model based on the Markov chain Monte Carlo operation was used for analyzing the therapeutic effects of drugs in 2 groups and multiple groups. Indirect comparison used R software to place a mesh chart. The effect of 2 classification variables was the same as that of direct comparison: enter the data into gemtc package and set the initial value, the number of chains, annealing, repetition, step size parameters, and processing. The result was presented by using the R package igraph. All the included drugs were sorted by using the surface under the cumulative ranking (SUCRA) to determine the advantages and disadvantages of the antifungal drug treatment for oral candidiasis. The larger the SUCRA, the better the effect. RESULTS The retrieval process is shown in Figure 1. A total of 1147 clinical research articles were retrieved according to the corresponding retrieval method. By reading the summary of the title and the full text and according to the established inclusion, the exclusion criteria determined the studies that met the criteria; finally, 31 articles were included (Table 1).9-39 Figure 2 showed the risk of bias of 31 studies included in this meta-analysis. The reticular relationship between 9 antifungal drugs compared with placebo is shown in Figure 3. Each circle represents an intervention, and the larger the circle, the greater the sample size for which the intervention is accepted; the
Fang et al
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Screening
Identification
-
Articles identified through literature search: • Medline (n=1071) • Embase (n=1147) • Cochrane library (n=2) • Clinical trials (n=25) Excluded (n=38) • Duplicate studies Studies after duplicates removed (n=1109)
Included
Eligibility
Articles excluded based on abstracts (n=1051) Full-text articles reviewed (n=58)
Articles excluded based on (n=27): • No relevant outcome measure (n=2) • Insufficient network connections (n=16) • Lack of detailed information (n=9)
Articles included in this meta-analysis (n=31)
Figure 1. Flow diagram of study selection process.
line between the circle and the circle represents a comparison of the 2 interventions, and the thicker the line is, the more studies were compared. Table 2 displays the results produced by pairwise meta-analysis. The effects of antifungal drugs in reducing the risk of the mycological cure rate in oral candidiasis were better than those of placebo: itraconazole oral solution (OR=1.11, 95% CrI: 1.03-1.19), miconazole buccal tablet (OR=1.38, 95% CrI: 1.11-1.66), miconazole oral gel (OR=1.77, 95% CrI: 1.32-2.22), fluconazole (OR=1.64, 95% CrI: 1.35-1.99), nystatin (OR=1.30, 95% CrI: 1.041.57), and amphotericin B (OR=1.08, 95% CrI: 1.01-1.15). Moreover, miconazole oral gel (OR=0.35, 95% CrI: 0.170.74), fluconazole (OR=0.53, 95% CrI: 0.31-0.88), and ketoconazole (OR=0.20, 95% CrI: 0.11-0.30) were better than nystatin (P<.05). Table 3 and Figure 4 display the results produced by network meta-analysis. The effects of antifungal drugs in reducing the risk of the mycological cure rate in oral candidiasis were better than thoe of a placebo: itraconazole capsule (OR=1.20, 95% CrI: 1.07-1.34), itraconazole oral solution (OR=1.50, 95% CrI: 1.14-1.86), miconazole buccal tablet (OR=2.80, 95% CrI: 1.20-4.50), miconazole oral gel (OR=2.90, 95% CrI: 1.70-4.30), clotrimazole (OR=3.80, 95% CrI: 1.65-5.95), fluconazole (OR=2.40, 95% CrI: 1.10-3.80), ketoconazole (OR=3.40, 95% CrI: 1.76-7.04), nystatin (OR=2.50, 95% CrI: 1.433.57), and amphotericin B (OR=2.60, 95% CrI: 1.91-3.29).
Fang et al
The corresponding results of SUCRA values are presented in Figure 5. The SUCRA values for each antifungal drugs were as follows: placebo (6.80%), itraconazole capsule (51.2%), itraconazole oral solution (75.2%), miconazole buccal tablet (34.4%), miconazole oral gel (76.9%), clotrimazole (64.8%), fluconazole (79.3%), ketoconazole (50.7%), nystatin (15.7%), and amphotericin B (44.4%). The effect of fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than that by other drugs. All data points were evenly distributed on both sides of the inverted funnel plot, suggesting less likelihood of publication bias (Fig. 6). DISCUSSION The search for the influence of antifungal drugs on oral candidiasis has been assessed without clear evidence. In the present study, only RCTs were included. Metaanalysis, analysis of bias, detailed checklist, and subsequent judgment were performed. A critical evaluation was performed by using the guidelines. The metaanalysis showed that itraconazole capsules, itraconazole oral solution, miconazole buccal tablets, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, or amphotericin B could reduce the mycological cure rate in oral candidiasis, and fluconazole was effective in reducing the risk of the mycological cure rate in oral candidiasis and was better than other drugs.
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Table 1. Characteristics of included studies Treatments Study Location
Author
Year
Oude et al
2004 Netherlands
Itraconazole capsule
16.089.0
Linpiyawan et al
2000 United States
Itraconazole oral solution
De Wit et al
1998 Belgium
Philips et al
Cases/ Treatments n 3
Age (Y)
Cases/ n
Treatments 2
Age (Y)
78/126
Fluconazole
17.079.0
93/126
Mycological cure rate
15.062.0
8/14
Clotrimazole
15.062.0
11/15
Mycological cure rate
Itraconazole capsule
16.065.0
4/17
Fluconazole
16.065.0
15/20
Mycological cure rate
1998 Canada
Itraconazole oral solution
24.058.0
54/60
Fluconazole
21.065.0
65/72
Mycological cure rate
Murray et al
1997 United States
Itraconazole oral solution
40.074.0
58/75
Clotrimazole
40.074.0
52/74
Mycological cure rate
Repentigny et al
1996 France
Itraconazole capsule
38.9
33/46
Ketoconazole
36.7
39/52
Mycological cure rate
Bastian et al
2004 Denmark
Miconazole buccal tablet
>18
28/49
Miconazole oral gel
>18
13/27 Placebo
Bensadoun et al
2008 France
Miconazole buccal tablet
17-83
79/147
Miconazole oral gel
17-83
68/147
Mycological cure rate
Hoppe et al
1996 Germany
Miconazole oral gel
8.9
23/27
Nystatin
8.9
15/35
Mycological cure rate
Hoppe et al
1997 Germany
Miconazole oral gel
NA
83/98
Nystatin
NA
18/85
Mycological cure rate
Vazquez et al
2010 United States
Miconazole buccal tablet
18-73
164/ 290
Clotrimazole
18-72
175/ 287
Mycological cure rate
Van Roey et al 2004 Belgium
Miconazole buccal tablet
>18
135/ 156
Ketoconazole
>18
137/ 153
Mycological cure rate
De Wit et al
1989 Belgium
Fluconazole
7.6
17/17
Ketoconazole
7.3
12/16
Mycological cure rate
Graybill et al
1998 United States
Itraconazole oral solution
38 ±8.8
52/59
Fluconazole
39 ±9.0
46/60
Mycological cure rate
Pons et al
1997 United States
Fluconazole
>18
60/69
Nystatin
>18
36/69
Mycological cure rate
Pons et al
1993 United States
Fluconazole
>18
91/100
Clotrimazole
>18
85/100
Mycological cure rate
Flynn et al
1995 United States
Fluconazole
0-14
73/91
Nystatin
0-14
26/91
Mycological cure rate
Koletar et al
1990 Colombia
Fluconazole
NA
16/16
Clotrimazole
NA
11/17
Mycological cure rate
Hernandez et al 1994 Spain
Fluconazole
0-12
21/24
Ketoconazole
0-12
18/22
Mycological cure rate
Nyst et al
1992 Zaire
Ketoconazole
>18
10/23
Nystatin
>18
2/23
Mycological cure rate
Johnson et al
1989 United States
Nystatin
NA
4/12
Placebo
NA
0/12
Mycological cure rate
Nairn et al
1975 England
Nystatin
NA
10/13
Amphotericin B
NA
16/18 Placebo
Goins et al
2002 United States
Nystatin
NA
6/19
Fluconazole
NA
15/15
Mycological cure rate
Blomgren et al 1998 Sweden
Nystatin
60.7
24/30
Fluconazole
60.7
26/30
Mycological cure rate
Leen et al
1990 United Kingdom
Fluconazole
NA
5/12
Placebo
NA
4/12
Mycological cure rate
Marriott et al
1993 Wales
Fluconazole
18-73
25/40
Placebo
18-73
13/44
Mycological cure rate
Pagani et al
2002 Switzerland
Fluconazole
NA
64/72
Placebo
NA
41/71
Mycological cure rate
Schuman et al 1997 United States
Fluconazole
NA
68/161
Placebo
NA
42/162
Mycological cure rate
Stevens et al
Fluconazole
>18
8/13
Placebo
>18
0/12
Mycological cure rate
McKinsey et al 1999 United States
Itraconazole oral solution
>18
17/149
Placebo
>18
15/146
Mycological cure rate
MacPhail et al
Nystatin
27-60
13/20
Placebo
27-60
5/10
Mycological cure rate
1991 United States
1996 United States
Treatments 1
Cases/ Age (Y) n
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>18
NA
1/9
2/15
Outcome
Mycological cure rate
Mycological cure rate
Fang et al
2020
5
D
C
B
E
A
F
Ra
nd Al om lo s c e Bl atio qu in n en di c c Bl ng on e g in d o ce en In ing f pa alm era co o rt e ti i n o Se mp f ou cipa t (s n ( le let tc nt el se ct e om s ec le Ot iv ou e an ti ct he e r tc a d on ion r b ep om sse pe bi b ia ort e ss rso as) ias s ) in da me n g ta n ne (re ( t ( l ( a po tt de pe rti riti tec rfo ng on ti rm bi bia on an as s bi ce as ) ) ) bia s)
-
Bastian 2004 +
?
?
?
?
+
-
Bensadoun 2008 +
?
?
?
?
?
-
Blomgren 1998
?
?
?
?
?
-
-
De Wi 1998
?
?
?
?
?
+
+
De Wit 1989
?
?
?
?
?
+
-
Flynn 1995
?
?
?
+
+
-
-
Goins 2002
?
+
?
+
?
-
?
Graybill 1998 + Hernandez 1994 ? Hoppe 1996 +
?
?
-
?
?
-
?
?
?
?
-
+
-
-
?
?
?
?
Hoppe 1997 +
?
+
?
?
?
?
Johnson 1989
?
?
?
?
?
+
+
Koletar 1990
?
?
?
?
-
+
?
Leen 1990 +
?
?
?
?
?
-
?
+
?
?
?
?
Linpiyawan 2000
?
G
H
Table 2. Summary odds ratios of antifungal drugs and heterogeneity for each direct comparison Comparison
?
?
?
?
?
-
-
Marriott 1993
?
?
?
?
+
+
-
Mckinsey 1999 + Murray 1997 ?
?
?
?
?
+
+
-
?
?
?
?
+
Nairn 1975 +
-
?
?
?
?
?
?
?
?
?
?
?
?
Oude 2004 +
+
?
?
+
-
-
Pagani 2002 +
?
?
?
?
+
-
?
?
?
?
?
?
+
Pons 1993 + Pons 1997 ?
+
+
+
?
?
?
Ketoconazole vs itraconazole capsule
?
+
?
?
?
?
Repentigny 1996 +
?
+
?
?
?
-
Schuman 1997 +
?
+
?
?
?
?
Stevens 1991
?
?
+
+
?
?
?
Van Roey 2004
?
?
?
?
?
-
?
Vazquez 2010
?
?
?
?
?
-
-
Philips 1998
Figure 2. Risk of bias of included RCTs (Review authors’ judgments about each risk of bias item for each included study. +, low risk; −, high risk; ?, unclear risk.). RCT, randomized controlled trial.
Candidiasis can involve the skin, mucosa, and various internal organs, and invasive candidiasis is more lifethreatening.40 Oral mucosa is the most common site of Fang et al
I
Figure 3. Network of randomized controlled trials comparing different antifungal drugs for oral candidiasis treatment. Thickness of connecting lines represents number of trials between each comparator, and size of each node corresponds to number of participants who received same pharmacological agent (sample size). (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
MacPhail 1996
Nyst 1992
J
P ITauOR (95% CI) Heterogeneity squared squared
Itraconazole oral solution vs placebo
1.11 (1.03, 1.19)
-
-
<.001
Miconazole buccal tablet vs placebo
1.38 (1.11, 1.66)
-
-
<.001
Miconazole oral gel vs placebo
1.77 (1.32, 2.22)
-
-
<.001
Fluconazole vs placebo
1.64 (1.35, 1.99)
.340
11.5
Nystatin vs placebo
1.30 (1.04, 1.57)
.251
45.7%
<.001
Amphotericin B vs placebo 1.08 (1.01, 1.15)
-
-
<.001
Fluconazole vs itraconazole 3.53 (0.66, 9.87) capsule
.035
77.6%
.137
-
-
.431
Clotrimazole vs itraconazole 0.85 (0.44, 1.64) oral solution
.215
35.0%
.626
Fluconazole vs itraconazole 0.63 (0.30, 1.32) oral solution
.274
16.6%
.222
Miconazole oral gel 0.86 (0.70, 1.05) vs miconazole buccal tablet
.932
0.0%
.142
Clotrimazole vs miconazole 1.08 (0.89, 1.34) buccal tablet
-
-
.547
Ketoconazole vs miconazole 1.03 (0.67, 1.41) buccal tablet
-
-
.659
Nystatin vs miconazole oral 0.35 (0.17, 0.74) gel
.013
83.7%
.005
1.05 (0.78, 2.09)
<.001
Fluconazole vs clotrimazole 1.22 (0.87, 1.72)
.059
72.0%
.247
Ketoconazole vs fluconazole 0.87 (0.71, 1.03)
.281
13.9%
.101
Nystatin vs fluconazole
0.53 (0.31, 0.88)
<.001
90.7%
.015
Nystatin vs ketoconazole
0.20 (0.11, 0.30)
-
-
<.001
Amphotericin B vs nystatin 1.15 (0.87, 1.44)
-
-
.591
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Table 3. Network meta-analysis comparisons Placebo
I-ca
I-os
M-bt
1
0.83 (0.75, 0.93)
0.67 (0.54, 0.88)
0.36 (0.22, 0.85)
Placebo I-ca
1.20 (1.07, 1.34)
1
0.59 (0.06, 5.80)
0.39 (0.04, 3.90)
I-os
1.50 (1.14, 1.86)
1.70 (0.18, 16.0)
1
0.66 (0.08, 5.30)
M-bt
2.80 (1.20, 4.50)
2.50 (0.24, 13.0)
1.50 (0.20, 9.00)
1
M-og
2.90 (1.70, 4.30)
3.70 (0.34, 14.0)
2.20 (0.27, 11.0)
1.50 (0.28, 8.10)
Clotrimazole
3.80 (1.65, 5.95)
1.40 (0.13, 11.0)
0.84 (0.16, 4.10)
0.56 (0.08, 3.50)
Fluconazole
2.40 (1.10, 3.80)
3.20 (0.59, 12.0)
1.90 (0.47, 8.70)
1.20 (0.23, 7.40)
Ketoconazole
3.40 (1.76, 7.04)
1.70 (0.23, 11.0)
0.98 (0.13, 7.60)
0.65 (0.09, 4.20)
Nystatin
2.50 (1.43, 3.57)
0.54 (0.07, 4.20)
0.32 (0.06, 1.90)
0.21 (0.04, 1.30)
Amphotericin B
2.60 (1.91, 3.29)
3.00 (0.13, 11.0)
0.36 (0.13, 1.20)
2.30 (0.08, 7.70)
I-ca, itraconazole capsule; I-os, itraconazole oral solution; M-bt, miconazole buccal tablet; M-og, miconazole oral gel.
OR(95%Crl)
Compared with Placebo
OR(95%Crl)
Compared with I-ca
Compared with I-os
OR(95%Crl)
I-ca
1.02 (1.07, 1.34)
Placebo
0.83 (0.75, 0.93)
Placebo
0.67 (0.54, 0.88)
I-os
1.50 (1.14, 1.86)
I-os
1.70 (0.18, 16.00)
I-ca
0.59 (0.06, 5.80)
M-bt
2.80 (1.20, 4.50)
M-bt
2.50 (0.24, 13.00)
M-bt
1.50 (0.20, 9.00)
M-og
2.90 (1.70, 4.30)
M-og
3.70 (0.34, 14.00)
M-og
2.20 (0.27, 11.00)
Clotrimazole
3.80 (1.65, 5.95)
Clotrimazole
1.40 (0.13, 11.00)
Clotrimazole
0.84 (0.16, 4.10)
Fluconazole
2.40 (1.10, 3.80)
Fluconazole
3.20 (0.59, 12.00)
Fluconazole
1.90 (0.47, 8.70)
Ketoconazole
3.40 (1.76, 7.04)
Ketoconazole
1.70 (0.23, 11.00)
Ketoconazole
0.98 (0.13, 7.60)
Nystatin
2.50 (1.43, 3.57)
Nystatin
0.54 (0.07, 4.20)
Nystatin
0.32 (0.06, 1.90)
Amphotericin B
2.60 (1.91, 3.29)
Amphotericin B
3.00 (0.13, 11.00)
Amphotericin B
0.36 (0.13, 1.20)
01
5
0
10
Compared with M-bt
OR(95%Crl)
5
20
Compared with M-og
01 OR(95%Crl)
5
15
Compared with Clotrimazole
OR(95%Crl)
Placebo
0.36 (0.22, 0.85)
Placebo
0.35 (0.23, 0.56)
Placebo
0.26 (0.17, 0.60)
I-cs
0.39 (0.04, 3.90)
I-ca
0.26 (0.09, 2.80)
I-ca
0.69 (0.07, 7.20)
I-os
0.66 (0.08, 5.30)
I-os
0.45 (0.15, 3.80)
I-os
1.20 (0.25, 6.10)
M-og
1.50 (0.28, 8.10)
M-bt
0.68 (0.12, 3.60)
M-bt
1.80 (0.28, 13.00)
Clotrimazole
0.56 (0.08, 3.50)
Clotrimazole
0.38 (0.14, 3.00)
M-og
2.60 (0.34, 11.00)
Fluconazole
1.20 (0.23, 7.40)
Fluconazole
0.84 (0.15, 5.10)
Fluconazole
2.20 (0.51, 12.00)
Ketoconazole
0.65 (0.09, 4.20)
Ketoconazole
0.44 (0.13, 3.40)
Ketoconazole
1.20 (0.15, 9.40)
Nystatin
0.21 (0.04, 1.30)
Nystatin
0.15 (0.03, 0.72)
Nystatin
0.38 (0.07, 2.50)
Amphotericin B
2.30 (0.08, 7.70)
Amphotericin B
1.60 (0.60, 4.90)
Amphotericin B
4.00 (0.15, 14.00)
01
5
10
Compared with Ketoconazole
01 OR(95%Crl)
4
0
8
Compared with Nystatin
OR(95%Crl)
8
18
Compared with Amphotericin B
OR(95%Crl)
Placebo
0.29 (0.14, 0.57)
Placebo
0.40 (0.28, 0.70)
Placebo
0.38 (0.23, 0.52)
I-ca
0.60 (0.09, 4.30)
I-ca
1.80 (0.23, 13.00)
I-ca
0.17 (0.09, 5.40)
I-os
1.00 (0.13, 8.30)
I-os
3.10 (0.52, 17.00)
I-os
0.28 (0.06, 7.60)
M-bt
1.50 (0.24, 11.00)
M-bt
3.70 (0.76, 11.00)
M-bt
0.43 (0.08, 13.00)
M-og
2.30 (0.30, 11.00)
M-og
3.90 (1.40, 8.00)
M-og
0.63 (0.12, 11.00)
Clotrimazole
0.85 (0.11, 6.50)
Clotrimazole
2.60 (0.39, 11.00)
Clotrimazole
0.24 (0.11, 6.60)
Fluconazole
1.90 (0.42, 9.90)
Fluconazole
5.80 (1.90, 9.00)
Fluconazole
0.54 (0.14, 12.00)
Nystatin
0.33 (0.06, 1.90)
Ketoconazole
3.10 (0.53, 12.00)
Ketoconazole
0.28 (0.12, 7.40)
Amphotericin B
3.60 (0.13, 12.00)
Amphotericin B
1.20 (0.55, 2.50)
Nystatin
0.21 (0.09, 11.80)
01
5
15
0
10
20
01
5
15
Figure 4. Forest plots of odds ratios (95% creditable intervals) produced by network meta-analysis. I-ca, itraconazole capsule; I-os, itraconazole oral solution; M-bt, miconazole buccal tablet; M-og, miconazole oral gel.
candida infection and also the most common initial site of systemic fungal infection.41,42 In the case of local factors, such as oral disease or a denture, or systemic factors, such as malnutrition, malignant disease, immunosuppressant, THE JOURNAL OF PROSTHETIC DENTISTRY
steroid hormone, or broad-spectrum antibiotics, oral candidiasis can cause opportunistic infections, causing pain, erythema, irritation, or even ulcers. If oral candidiasis is not controlled in time, it will spread to the respiratory Fang et al
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7
Table 3. (Continued) Network meta-analysis comparisons M-og
Clotrimazole
Fluconazole
Ketoconazole
Nystatin
Amphotericin B
0.35 (0.23, 0.56)
0.26 (0.17, 0.60)
0.42 (0.26, 0.91)
0.29 (0.14, 0.57)
0.40 (0.28, 0.70)
0.38 (0.23, 0.52)
0.26 (0.09, 2.80)
0.69 (0.07, 7.20)
0.31 (0.05, 1.70)
0.60 (0.09, 4.30)
1.80 (0.23, 13.0)
0.17 (0.09, 5.40)
0.45 (0.15, 3.80)
1.20 (0.25, 6.10)
0.54 (0.12, 2.20)
1.00 (0.13, 8.30)
3.10 (0.52, 17.0)
0.28 (0.06, 7.60)
0.68 (0.12, 3.60)
1.80 (0.28, 13.0)
0.81 (0.13, 4.40)
1.50 (0.24, 11.0)
3.70 (0.76, 11.0)
0.43 (0.08, 13.0)
1
2.60 (0.34, 11.0)
1.20 (0.20, 6.80)
2.30 (0.30, 11.0)
3.90 (1.40, 8.00)
0.63 (0.12, 11.0)
0.38 (0.14, 3.00)
1
0.45 (0.09, 2.20)
0.85 (0.11, 6.50)
2.60 (0.39, 11.0)
0.24 (0.11, 6.60)
0.84 (0.15, 5.10)
2.20 (0.51, 12.0)
1
1.90 (0.42, 9.90)
5.80 (1.90, 9.00)
0.54 (0.14, 12.0)
0.44 (0.13, 3.40)
1.20 (0.15, 9.40)
0.53 (0.10, 2.40)
1
3.10 (0.53, 12.0)
0.28 (0.12, 7.40)
0.15 (0.03, 0.72)
0.38 (0.07, 2.50)
0.17 (0.05, 0.53)
0.33 (0.06, 1.90)
1
0.21 (0.09, 1.80)
1.60 (0.60, 4.90)
4.00 (0.15, 14.0)
1.90 (0.09, 4.90)
3.60 (0.13, 12.0)
1.20 (0.55, 2.50)
1
Fang et al
120%
Cumulative Probability
system, digestive system, blood system, and central nervous system and cause systemic infection that endangers life.43 In addition, hypersensitivity caused by candida metabolites can induce eczema, asthma, and gastritis.44 Therefore, the drug with the greatest efficacy is urgently needed for oral candidiasis. Pyrrole ring drugs include imidazoles and triazoles which inhibit ergosterol synthesis in fungi and thus destroy the integrity of the fungal cell membrane and achieve the antifungal effect.8 The most common drugs represented by imidazoles are clotrimazole, ketoconazole, and miconazole. The imidazole drugs have a stronger antifungal effect and are effective in the treatment of candidiasis. The most common drugs represented by triazoles are fluconazole and itraconazole. Triazole antifungal drugs have high bioavailability, strong effect, and low toxicity.45 Polyene antifungal drugs include nystatin and amphotericin B. The mechanism is that it binds to ergosterol, resulting in cell membrane changes, cell lysis, and necrosis.46 Nystatin is currently used as a local drug, and amphotericin B has been widely used because of its strong effect; however, because of its greater toxicity, it is prescribed with a lipid body agent to reduce toxic side effects.47 Fluconazole is a broad-spectrum antifungal agent and has a good effect on superficial and deep fungal infection. The fourth nitrogen atom in the triazole ring of fluconazole molecular structure binds to the iron atom on the cytochrome P450 hemagglutinin ring of fungi, which makes the fungi lose dehydrogenase activity, and then inhibits the demethylation of wool sterol C14. Ergosterol is an important component of the fungal cell membrane, and lack of ergosterol will cause damage to fungal cell membrane. The activities of enzyme and peroxidase increase peroxide accumulation in fungi and the permeability of the fungal cell membrane, so as to inhibit the growth of fungi.48-51 The oral absorption effect of fluconazole is good, and the curative effect of fluconazole is not affected by receptor blocker drug, antiacid, or food factors. The average blood concentration of fluconazole was as high as 4.5 to 8.0mg/L, and the plasma protein binding rate was low. Drugs were widely distributed in vesicular fluid and skin and excreted from the kidney and liver.52,53
100% 80% 60% 40% 20% 0%
1
2
3
4
5
6
log(OR)
7
8
9
10
B C D E (51.2%) (75.2%) (34.4%) (76.9%) F G H I J (15.7%) (44.4%) (64.8%) (79.3%) (50.7%) (6.8%)
A
Figure 5. Surface under cumulative ranking curve (SUCRA), expressed as percentages, ranking therapeutic effects and safety of treatments for oral candidiasis. For efficacy and safety assessment, pharmacological agent with highest SUCRA value would be most efficacious and safe treatment. (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
The effectiveness, safety, and cost of drugs are important indicators of clinical drug treatment. Fluconazole, a commonly used antioral candida infection drug, has no cost advantage over other drugs, but the difference in therapeutic effect is statistically significant. Therefore, this factor should be taken into account in the treatment of oral candidiasis. This meta-analysis has limitations. Different doses, administration schemes, and patients of different age were included in the studies resulting in clinical heterogeneity. The authors only evaluated the mycological cure rate, while the incidence of recurrence rate and adverse reaction rate could not be analyzed because of lack of relevant data. The quality and quantity of the literature included were low, which decrease the test efficiency. Finally, the small sample size of the interventions included in the study and the possible shortage of statistical efficiency may be insufficient. THE JOURNAL OF PROSTHETIC DENTISTRY
8
Volume
-
Issue
-
Standard Error of Effect Size
0
.5
1
1.5
–4
–2
0
2
4
Effect Size Centered at Comparison-Specific Pooled Effect (yiXY - µ A vs J B vs G D vs H I vs J
A vs C B vs H E vs I
A vs D C vs F F vs G
A vs E C vs G G vs H
A vs G D vs E G vs I
XY)
A vs I D vs F H vs I
Figure 6. Comparison-adjusted funnel plot for network meta-analysis. Red line suggests null hypothesis that study-specific effect sizes do not differ from respective comparison-specific pooled effect estimates. Different colors represent different comparisons. (A: placebo; B: itraconazole capsule; C: itraconazole oral solution; D: miconazole buccal tablet; E: miconazole oral gel; F: clotrimazole; G: fluconazole；H: ketoconazole; I: nystatin; J: amphotericin B).
CONCLUSIONS Based on the findings of this network meta-analysis, the following conclusions were drawn: 1. Itraconazole capsule, itraconazole oral solution, miconazole buccal tablet, miconazole oral gel, clotrimazole, fluconazole, ketoconazole, nystatin, and amphotericin B can effectively reduce the mycological cure rate in oral candidiasis treatment compared with a placebo. 2. The effects of fluconazole in reducing the risk of the mycological cure rate in oral candidiasis was better than those of other drugs.
10.
11. 12. 13.
14.
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