Efficacy of antifungal drugs in the treatment of vulvovaginal candidiasis: a Bayesian network meta-analysis.

PURPOSE: Antifungal drugs are used frequently in the treatment of vulvovaginal candidiasis (VVC), but have shown controversial results. In this study, we aimed to evaluate the effectiveness of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use.
METHODS: The published studies on the effectiveness of antifungal drugs in the treatment of VVC (up to April 2018) were retrieved from PubMed, Embase, the Cochrane Library, and Clini-calTrials.gov. We sifted through the literature according to Patients, Interventions, Comparisons and Outcomes principle, extracted data on the basic characteristics of the study, and evaluated the quality of included studies. We used R software for statistical analysis.
RESULTS: In total, 41 randomized controlled trials were included in this meta-analysis. The relative risk of VVC associated with ten drugs, including placebo, fluconazole, clotrimazole, miconazole, itraconazole, ketoconazole, econazole, butoconazole, terbinafine, and terconazole, was analyzed. The following drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =6.45, 95% CrI 4.42-9.41), clotrimazole (OR =2.99, 95% CrI 1.61-5.55), miconazole (OR =5.96, 95% CrI 3.17-11.2), itraconazole (OR =2.29, 95% CrI 1.21-4.33), ketoconazole (OR =2.40, 95% CrI 1.55-3.71), butoconazole (OR =1.18, 95% CrI 1.06-1.31), and terconazole (OR =5.60, 95% CrI 2.78-11.3). The value of surface under the cumulative ranking curve of each drug was as follows: placebo (0.5%), fluconazole (91.5%), clotrimazole (61.8%), miconazole (33.8%), itraconazole (50.5%), ketoconazole (42.8%), econazole (46.8%), butoconazole (82.2%), terbinafine (20.9%), and terconazole (65.0%).
CONCLUSION: Antifungal drugs are effective in the treatment of VVC. Fluconazole appeared to be the best drug for the treatment of VVC according to our analysis.

Introduction

Vulvovaginal candidiasis (VVC) is an infectious disease affecting the female genital tract and is caused by Candida spp. Of all the VCC cases, 80%–90% are caused by Candida albicans, and a minority are caused by Candida glabrata, Candida parapsilosis, and Candida tropicalis.1 As one of the most common infectious diseases of the female genital tract, VVC is found worldwide affecting the health of women at all levels of the society.2 With the widespread use of corticosteroids, broad-spectrum antibiotics, and immunosuppressants, as well as the emergence of AIDS, VVC is more commonly encountered in clinical practice,3,4 and the treatment of VVC has become a hot issue.

Antifungal drugs exert their effect by changing the permeability of fungal cell membrane. At present, two groups of antifungal drugs are mainly used to treat VVC: polyene anti-fungal drugs and pyrrole ring antifungal drugs. The former group is represented by amphotericin B. Amphotericin B has a strong antifungal activity and a wide antibacterial spectrum, but it is quite toxic. The latter group includes azoles, such as ketoconazole, fluconazole, and itraconazole. These are also most widely used and have a wide antibacterial spectrum.5,6

To evaluate the clinical efficacy of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use, we conducted a network meta-analysis based on randomized controlled trials on the efficacy of antifungal drugs in the treatment of VVC.

Methods

Search strategy

The published studies on the effectiveness of antifungal drugs in the treatment of oral candidiasis (up to April 2018) were retrieved from PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov, with keywords including “Vulvovaginal Candidiases” [MeSH] OR “Vulvovaginal Candidiasis” [MeSH] OR “Vulvovaginal Moniliases” [MeSH] OR “Vul-vovaginal Moniliasis” [MeSH] OR “Vaginal Yeast Infections” [MeSH] OR “Genital Vulvovaginal Candidiasis” [MeSH] OR “Genital Vulvovaginal Candidiases” [MeSH] OR “Genital Candidiases” [MeSH] OR “Genital Candidiasis” [MeSH] OR “Monilial Vaginitides” [MeSH] OR “Monilial Vaginitis” [MeSH] AND “Antifungal Agents” [MeSH] OR “Itraconazole” [MeSH] OR “Miconazole” [MeSH] OR “Clotrimazole” [MeSH] OR “Fluconazole” [MeSH] OR “Ketoconazole” [MeSH] OR “Econazole” [MeSH] OR “Butoconazole” [MeSH] OR “Terbinafine” [MeSH] OR “Terconazole” [MeSH] AND “Randomized Controlled Trials” [MeSH] OR “RCT” [MeSH].

Inclusion and exclusion criteria

We included randomized controlled trials written in English, regardless of whether or not specific random allocation methods and blind data hiding scheme are mentioned and the timing of publication. Study subjects were females with typical clinical symptoms and signs of VVC confirmed by mycological examination.

We imported the literature retrieved from the database into EndNote and eliminated duplicates. We screened the titles and abstracts according to the Patients, Interventions, Comparisons and Outcomes principle, and then read the full text of the eligible articles. The data were extracted and evaluated by two reviewers. Any differences in opinion were discussed and resolved by the reviewers. The following data were extracted: first author of the study, publication time, sample size, age, and intervention measures. Quality evaluation was performed using Cochrane risk-of-bias assessment tool.

Statistical analysis

We conducted a network meta-analysis (Bayesian approach) which included both direct and indirect evidence in the network. Direct comparison was performed using Stata14.0 software for statistical analysis. The risk of vulvovaginal candidiasis in each group was compared using the OR. Before the combined data were analyzed by meta-analysis, the heterogeneity of each group was tested. If there was no heterogeneity (P≥0.05 or I2≤50%), the combined statistics were calculated by fixed-effect model analysis. If there was significant heterogeneity among the groups (P<0.05 or I2>50%), the source of heterogeneity was analyzed, and a subgroup analysis of the factors leading to heterogeneity was carried out. Indirect comparison was made using R software to draw a mesh diagram. Drugs were ranked based on the surface under the cumulative ranking curve (SUCRA) values. A drug was considered more preferable than another if it had a larger SUCRA value.

Results

Literature search results

A total of 566 studies from Medline, 596 studies from Embase, one study from Cochrane Library, and eight studies from Clin-icalTrials.gov were selected. After removing duplicates, 581 studies remained. After reviewing their titles and abstracts, 521 citations were excluded. The remaining 60 citations were assessed in more detail for eligibility by reading the full text. Among them, two were excluded due to lack of relevant outcome measure, 14 were excluded due to insufficient network connections, and three were excluded due to lack of detailed information. Finally, 41 studies were used for the final data synthesis.5,7–46 The flowchart of literature search is presented in Figure 1. The risk of bias of the 41 studies included in this meta-analysis is summarized in Figure 2. The characteristics of the included studies are shown in Table 1. The pattern of evidence within the network is displayed in Figure 3.

Figure 1

Flow diagram of the study selection process.

Figure 2

Risk of bias of the included randomized controlled trials (review authors’ judgments about each risk-of-bias item for each included study).

Note: +, low risk; −, high risk; ?, unclear risk.

Table 1

Characteristics of the included studies

Study	Year	Study location	Treatments
			Treatment 1	Age (years)	Cases/n	Treatment 2	Age (years)	Cases/n	Treatment 3	Age (years)	Cases/n
Andersen et al7	1989	France	Fluconazole	32.1	143/169	Clotrimazole	30.6	131/161
Corić et al8	2006	Croatia	Fluconazole	NA	41/56	Clotrimazole	NA	9/13
Costa et al9	2004	Brazil	Fluconazole	NA	30/38	Itraconazole	NA	27/42
de Punzio et al10	2003	Italy	Fluconazole	>18.0	29/38	Itraconazole	>18.0	21/32
Fan et al11	2015	China	Fluconazole	19.0–45.0	241/287	Miconazole	19.0–45.0	220/290
Ferahbas et al12	2006	Turkey	Fluconazole	17.0–54.0	10/15	Itraconazole	17.0–54.0	6/10	Terbinafine	17.0–54.0	4/12
Li et al13	2015	China	Fluconazole	29.6	46/58	Terconazole	31.0	47/66
McClelland et al14	2015	USA	Miconazole	24.0–34.0	75/118	Placebo	23.0–35.0	30/116
Mendling et al15	2004	Germany	Fluconazole	NA	129/161	Clotrimazole	NA	117/154
Mikamo et al16	1995	Japan	Fluconazole	18.0–54.0	38/50	Clotrimazole	18.0–54.0	30/50
Mikamo et al5	1998	Japan	Fluconazole	18.0–55.0	40/50	Itraconazole	17.0–55.0	42/50	Clotrimazole	21.0–54.0	36/50
O-Prasertsawat and Bourlert17	1995	China	Fluconazole	33.9±8.1	42/53	Clotrimazole	35.3±8.4	40/50
Osser et al18	1991	Sweden	Fluconazole	16.0–52.0	100/121	Econazole	18.0–60.0	84/114
Seidman and Skokos19	2005	USA	Fluconazole	37.0±12.2	76/93	Butoconazole	38.8±13.8	56/88
Sekhavat et al20	2011	Iran	Fluconazole	39.4±13.1	60/72	Clotrimazole	42.2±15.9	49/70
Sobel et al21	1995	USA	Fluconazole	18.0–63.0	133/182	Clotrimazole	17.0–64.0	118/176
Sobel et al22	2004	USA	Fluconazole	NA	160/166	Placebo	NA	23/154
Stein et al23	1991	USA	Fluconazole	18.0–51.0	80/90	Clotrimazole	18.0–60.0	88/95
Stein and Mummaw24	1993	USA	Itraconazole	18.0–43.0	35/48	Clotrimazole	18.0–33.0	19/20	Placebo	18.0–39.0	7/22
Timonen25	1992	Finland	Fluconazole	>18.0	50/54	Miconazole	>18.0	33/47
Tobin et al26	1992	UK	Itraconazole	>18.0	60/92	Clotrimazole	>18.0	49/88
van Heusden et al27	1990	Netherlands	Fluconazole	NA	47/49	Miconazole	NA	48/50
Zhou et al28	2016	China	Fluconazole	29.9±6.5	61/110	Clotrimazole	29.4±6.2	62/115
Sobel et al42	1994	USA	Ketoconazole	>18.0	86/101	Clotrimazole	>18.0	41/51
Fong29	1992	Canada	Itraconazole	18.0–65.0	17/22	Clotrimazole	18.0–65.0	21/22
Gerhard et al43	1989	USA	Ketoconazole	>18.0	27/45	Placebo	>18.0	21/47
Kutzer et al46	1988	UK	Fluconazole	17.0–65.0	63/80	Ketoconazole	17.0–72.0	55/72
Sobel44	1986	USA	Ketoconazole	31.9	15/21	Placebo	31.9	6/21
van der Meijden et al45	1986	Netherlands	Ketoconazole	29.0±6.9	20/23	Miconazole	28.0±7.4	18/19
Kjaeldgaard58	1986	USA	Terconazole	>18.0	18/20	Clotrimazole	>18.0	17/20
Puolakka and Tuimala30	1983	Finland	Ketoconazole	16.0–46.0	40/49	Miconazole	18.0–47.0	34/49
Corson et al31	1991	USA	Terconazole	18.0–54.0	250/299	Miconazole	18.0–54.0	239/294
Thomason et al32	1990	USA	Terconazole	NA	40/50	Miconazole	NA	34/50	Placebo	NA	7/49
Brown et al39	1999	USA	Butoconazole	18.0–65.0	93/101	Miconazole	18.0–65.0	90/104
Ruf and Vitse40	1990	France	Butoconazole	18.0–56.0	26/29	Econazole	16.0–49.0	24/32
Kaufman et al37	1989	USA	Butoconazole	>18.0	101/115	Miconazole	>18.0	93/114
Hajman38	1988	Sweden	Butoconazole	20.0–63.0	28/32	Clotrimazole	19.0–32.0	24/31
Brown et al33	1986	USA	Butoconazole	>18.0	26/32	Miconazole	>18.0	21/30	Placebo	>18.0	2/29
Adamson et al34	1986	USA	Butoconazole	NA	92/97	Clotrimazole	NA	74/88
Stettendorf et al35	1982	USA	Clotrimazole	16.0–62.0	45/54	Econazole	16.0–66.0	41/57
Perera and Seneviratne36	1994	Sri Lanka	Econazole	NA	49/51	Clotrimazole	NA	45/50

Figure 3

Network of randomized controlled trials comparing different antifungal drugs for vulvovaginal candidiasis treatment.

Note: The thickness of the connecting lines represents the number of trials between each comparator, and the size of each node corresponds to the number of subjects who received the same pharmacological agent (sample size) (A: placebo; B: fluconazole; C: clotrimazole; D: miconazole; E: itraconazole; F: ketoconazole; G: econazole; H: butoconazole; I: terbinafine; J: terconazole).

Results of pairwise meta-analysis

Table 2 displays the results produced by pairwise meta-analysis. The following drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =6.45, 95% CrI 4.42–9.41), clotrimazole (OR =2.99, 95% CrI 1.61–5.55), miconazole (OR =5.96, 95% CrI 3.17–11.2), itraconazole (OR =2.29, 95% CrI 1.21–4.33), ketoconazole (OR =2.40, 95% CrI 1.55–3.71), butoconazole (OR =1.18, 95% CrI 1.06–1.31), and terconazole (OR =5.60, 95% CrI 2.78–11.3). Moreover, there was no significant heterogeneity among the studies for the above results (P-heterogeneity >0.05 and I2<50%).

Table 2

Summary ORs of antifungal drugs and heterogeneity of each direct comparison

Comparison	OR (95% CI)	P-heterogeneity	I2	Tau2
Fluconazole vs placebo	6.45 (4.42, 9.41)	–	–	<0.001
Clotrimazole vs placebo	2.99 (1.61, 5.55)	–	–	0.001
Miconazole vs placebo	5.96 (3.17, 11.2)	0.323	0.0%	<0.001
Itraconazole vs placebo	2.29 (1.21, 4.33)	–	–	0.011
Ketoconazole vs placebo	2.40 (1.55, 3.71)	0.894	0.0%	<0.001
Butoconazole vs placebo	1.18 (1.06, 1.31)	–	–	<0.001
Terconazole vs placebo	5.60 (2.78, 11.3)	–	–	<0.001
Clotrimazole vs fluconazole	0.94 (0.89, 0.99)	0.387	5.7%	0.016
Miconazole vs fluconazole	0.90 (0.84, 0.96)	0.108	46.7%	0.001
Itraconazole vs fluconazole	0.92 (0.80, 1.06)	0.408	0.0%	0.245
Ketoconazole vs fluconazole	0.97 (0.82, 1.15)	–	–	0.728
Econazole vs fluconazole	0.89 (0.77, 1.02)	–	–	0.100
Butoconazole vs fluconazole	0.78 (0.65, 0.94)	–	–	0.008
Terbinafine vs fluconazole	0.50 (0.21, 1.20)	–	–	0.121
Terconazole vs fluconazole	0.89 (0.73, 1.10)	–	–	0.296
Itraconazole vs clotrimazole	0.96 (0.75, 1.23)	0.002	47.1%	0.738
Ketoconazole vs clotrimazole	1.05 (0.90, 1.24)	–	–	0.476
Econazole vs clotrimazole	0.97 (0.76, 1.24)	0.032	38.4%	0.821
Butoconazole vs clotrimazole	1.13 (1.03, 1.24)	0.987	0.0%	0.013
Terconazole vs clotrimazole	1.06 (0.83, 1.34)	–	–	0.634
Ketoconazole vs miconazole	1.08 (0.92, 1.27)	0.066	44.7%	0.349
Butoconazole vs miconazole	1.08 (1.01, 1.16)	0.844	0.0%	0.037
Terconazole vs miconazole	1.04 (0.98, 1.12)	0.281	13.9%	0.210
Terbinafine vs itraconazole	0.56 (0.22, 1.43)	–	–	0.224
Butoconazole vs econazole	1.19 (0.95, 1.51)	–	–	0.137

Network meta-analysis

Table 3 displays the results produced by network meta-analysis. The following nine drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =26.0, 95% CrI 14.0–50.0), clotrimazole (OR =17.0, 95% CrI 8.70–34.0), miconazole (OR =12.0, 95% CrI 6.30–22.0), itra-conazole (OR =14.0, 95% CrI 6.40–32.0), ketoconazole (OR =13.0, 95% CrI 6.10–27.0), econazole (OR =14.0, 95% CrI 5.10–38.0), butoconazole (OR =25.0, 95% CrI 12.0–56.0), terbinafine (OR =5.20, 95% CrI 1.70–35.0), and terconazole (OR =18.0, 95% CrI 7.80–43.0).

Table 3

Network meta-analysis comparisons

	Placebo	Fluconazole	Clotrimazole	Miconazole	Itraconazole	Ketoconazole	Econazole	Butoconazole	Terbinafine	Terconazole
Placebo	1	0.04 (0.02, 0.07)	0.06 (0.03, 0.12)	0.09 (0.05, 0.16)	0.07 (0.03, 0.15)	0.08 (0.04, 0.16)	0.07 (0.03, 0.19)	0.04 (0.02, 0.09)	0.19 (0.03, 0.58)	0.06 (0.02, 0.13)
Fluconazole	26.0 (14.0, 50.0)	1	1.50 (1.1, 2.20)	2.20 (1.30, 3.90)	1.80 (0.99, 3.30)	2.00 (1.00, 4.10)	1.90 (0.84, 4.20)	1.00 (0.54, 1.90)	4.90 (0.85, 32.0)	1.40 (0.65, 3.10)
Clotrimazole	17.0 (8.70, 34.0)	0.66 (0.45, 0.95)	1	1.50 (0.80, 2.70)	1.20 (0.65, 2.20)	1.30 (0.64, 2.80)	1.20 (0.56, 2.70)	0.68 (0.35, 1.30)	3.30 (0.55, 22.0)	0.95 (0.41, 2.10)
Miconazole	12.0 (6.30, 22.0)	0.45 (0.26, 0.78)	0.68 (0.37, 1.20)	1	0.79 (0.38, 1.80)	0.90 (0.44, 1.90)	0.84 (0.33, 2.10)	0.47 (0.24, 0.87)	2.20 (0.36, 15.0)	0.65 (0.31, 1.30)
Itraconazole	14.0 (6.40, 32.0)	0.56 (0.30, 1.00)	0.85 (0.46, 1.50)	1.30 (0.57, 2.70)	1	1.10 (0.47, 2.70)	1.10 (0.39, 2.70)	0.58 (0.24, 1.30)	2.80 (0.48, 18.0)	0.81 (0.30, 2.10)
Ketoconazole	13.0 (6.10, 27.0)	0.50 (0.24, 1.00)	0.76 (0.36, 1.60)	1.10 (0.53, 2.30)	0.88 (0.37, 2.20)	1	0.94 (0.33, 2.60)	0.52 (0.21, 1.20)	2.50 (0.38, 18.0)	0.72 (0.27, 1.80)
Econazole	14.0 (5.10, 38.0)	0.53 (0.24, 1.20)	0.80 (0.36, 1.80)	1.20 (0.47, 3.00)	0.94 (0.37, 2.50)	1.10 (0.38, 3.00)	1	0.55 (0.22, 1.40)	2.60 (0.38, 20.0)	0.77 (0.26, 2.20)
Butoconazole	25.0 (12.0, 56.0)	0.96 (0.51, 1.80)	1.50 (0.77, 2.80)	2.10 (1.10, 4.10)	1.70 (0.76, 4.40)	1.90 (0.83, 4.70)	1.80 (0.73, 4.60)	1	4.70 (0.74, 34.0)	1.40 (0.57, 3.40)
Terbinafine	5.20 (1.70, 35.0)	0.20 (0.03, 1.20)	0.31 (0.05, 1.80)	0.45 (0.06, 2.80)	0.35 (0.05, 2.10)	0.40 (0.06, 2.70)	0.38 (0.05, 2.60)	0.21 (0.03, 1.30)	1	0.29 (0.04, 2.00)
Terconazole	18.0 (7.80, 43.0)	0.69 (0.32, 1.50)	1.10 (0.47, 2.40)	1.50 (0.75, 3.20)	1.20 (0.49, 3.30)	1.40 (0.55, 3.70)	1.30 (0.45, 3.90)	0.72 (0.29, 1.80)	3.40 (0.51, 26.0)	1

The corresponding SUCRA values of the drugs were as follows: placebo (0.5%), fluconazole (91.5%), clotrimazole (61.8%), miconazole (33.8%), itraconazole (50.5%), ketoconazole (42.8%), econazole (46.8%), butoconazole (82.2%), terbinafine (20.9%), and terconazole (65.0%) (Figure 4). Incorporating adjuvants particularly fluconazole appeared to be the best strategy for the treatment of oral candidiasis.

Figure 4

Surface under the cumulative ranking curve (SUCRA), expressed as percentages, ranking the therapeutic effects and safety of treatments for vulvovaginal candidiasis.

Note: For efficacy and safety assessment, the pharmacological agent with the highest SUCRA value would be the most efficacious and safe treatment (A: placebo; B: fluconazole; C: clotrimazole; D: miconazole; E: itraconazole; F: ketoconazole; G: econazole; H: butoconazole; I: terbinafine; J: terconazole).

Publication bias

The results of the comparison-adjusted funnel plots did not reveal any evidence of apparent asymmetry (Figure 5). No significant publication bias was observed.

Figure 5

Comparison-adjusted funnel plot for the network meta-analysis.

Notes: The red line suggests the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors represent different comparisons (A: placebo; B: fluconazole; C: clotrimazole; D: miconazole; E: itraconazole; F: ketoconazole; G: econazole; H: butoconazole; I: terbinafine; J: terconazole).

Discussion

VVC has a high incidence and recurrence rate, but its pathogenesis is not yet clear.47 At present, it is believed that the pathogenesis and recurrence of VVC are related to many factors, such as the increasing resistance of Candida, the local immune response of host against Candida, and the change of virulence factor of Candida.48,49 Available data show that 75% of women have VVC at least once in their lifetime, and 50% of women with VVC have recurrent infections, with the highest incidence found among women of reproductive age.50 VVC is the most common cause of vaginal infections, second only to bacterial vaginitis. Candida has a high rate of intravaginal colonization; it can be isolated from the vagina of about 20% of healthy asymptomatic women and 30% of pregnant women.51

Candida, as a part of normal flora, can be found on the surface of the skin, digestive tract, and genitourinary tract; however, the mechanism of colonization and pathogenicity of Candida are unclear. The pathogens of VVC include C. albicans, C. tropicalis, C. parapsilosis, Candida krusei, and C. glabrata.52 C. albicans is the main pathogen of VVC, and accounts for 73.8%–95.0% of all Candida spp. isolated from the vagina. The most common non-albicans species is C. glabrata, which accounts for 10%–20% of all VVC pathogens.53 VVC causes increased leucorrhea, vulva itching, burning pain, urinal pain, and intercourse pain, and seriously affects the physical and mental health of the majority of women. Therefore, there is an urgent need for most suitable drugs for the treatment of VVC.

At present, pyrrole ring drugs are mainly used to treat VVC in clinical practice. Pyrrole ring drugs such as imidazoles and triazoles are related to the inhibition of ergosterol synthesis in fungi and thus destroy the integrity of fungal cell membrane and achieve the antifungal effect.54 The most common drugs represented by imidazoles are clotrimazole, ketoconazole, and miconazole. Triazoles are represented by fluconazole and itraconazole. Triazole antifungal drugs have a high bioavailability and strong antifungal effect, and the associated liver toxicity is relatively small.55

This network meta-analysis attempted to analyze the effectiveness of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use. Our analysis suggested that antifungal drugs are effective in the treatment of VVC, and fluconazole appeared to be best drug for the treatment of VVC. The American and European guidelines for the treatment of VVC, based on a large number of evidence-based clinical practice, recommended the use of fluconazole (150 mg) for the treatment of moderate-to-severe VVC, which is consistent with our results.

Fluconazole is a triazole antifungal drug that can inhibit or kill fungi by competitively inhibiting the synthesis of ergosterol. It has shown a significant effect in the treatment of deep fungal infections, especially those caused by C. albicans and Cryptococcus neoformans.56 Since it was launched in 1988, fluconazole has been widely used in clinical practice because of its excellent pharmacokinetic properties, such as broad antifungal spectrum, low hepatotoxicity, good oral absorption, high bioavailability, and wide tissue distribution.57 Designated by the WHO as the first choice for the treatment of systemic fungal infections, fluconazole is effective for various human and animal fungal infections, such as Candida infection (including systemic candidiasis in normal or immune-impaired people and animals), new cryptococcus infection (including intracranial infection), Malassezia, Microsporum, and Trichophyton infections, psoriasis, dermatitis, and rougherosporum (including intracranial infection). The antibacterial activity of fluconazole in vitro was found to be significantly lower than that of ketoconazole, but the antifungal activity of this drug was significantly higher than ketoconazole in vitro.57

This meta-analysis also has some limitations. The results of statistical heterogeneity analysis of the antifungal drugs are limited in randomized controlled trials. In addition, the limited evidence of a dose-dependent association between antifungal drugs and VVC treatment provides limited confi-dence in the study findings. Second, there is no record for a standardized treatment of VVC, which leads to difference in results between the trials; therefore, these results should be carefully interpreted with caution. Third, the study durations were short in these randomized controlled trials and patients included in these trials might be different from patients in the real life. Fourth, these findings may not be generalizable to a specific group of patients because randomized controlled trials tended to exclude participants. Fifth, most of the including studies have not enough detail in their reports, such as the absence of a random allocation method, the implementation of the allocation concealment, or the implementation of the blind law, which leads to existence of varying degrees of bias and risk.

Our findings underscore the notion that antifungal drugs are effective in the treatment of VVC, and flucon-azole appeared to be the best drug for the treatment of VC according to our analysis. However, due to the low quality of the included studies, this conclusion needs to be further confirmed by high-quality research with a large sample.