Efficacy and safety of Lactobacillus plantarum P 17630 strain soft vaginal capsule in vaginal candidiasis: a randomized non-inferiority clinical trial.

OBJECTIVE: To investigate the non-inferiority of efficacy and tolerability of Lactobacillus plantarum P 17630 soft vaginal capsules compared to the antifungal therapy with miconazole nitrate 400 mg soft vaginal capsules in patients with symptomatic vulvovaginal infection due to Candida. PATIENTS AND METHODS: Adult women with vulvovaginal candidiasis were randomized to either L. plantarum P17630 100,000,000 CFU soft vaginal capsules by vaginal route each day for 3 or 6 consecutive days or miconazole nitrate 400 mg soft vaginal capsule. Visual Analog Scale (VAS) scores for vaginitis symptoms were used, and vaginal fluid interleukin 6 (IL6) was dosed. The study was registered in EudraCT database (code LPP17630-C-018; number: 2018-003095-12). RESULTS: 200 patients were included in the study. The mean VAS scores for vaginitis symptoms were progressively reduced in both treatment groups at each visit, without significant difference between groups (p>0.05 for each symptom, at each time point). The efficacy of L. plantarum and the reference medicinal product was maintained at follow-up (day 21). The mean concentration of IL-6 decreased from visit 1 to visit 3 in both groups without a significant difference (p>0.05). No adverse events were reported. CONCLUSIONS: L. plantarum P17630 100,000,000 CFU soft vaginal capsules are effective and safe for treating vaginal candidiasis without the concomitant use of an antifungal product, which rules out the risk of antimicrobic resistance. The long-term effect on vaginal microflora may add the possibility of reducing the risk of recurrences.

Miconazole for the treatment of vulvovaginal candidiasis. In vitro, in vivo and clinical results. Review of the literature.

At concentrations achieved following systemic administration, the primary effect of imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase, a microsomal cytochrome P450 (CYP) enzyme. Imidazoles and triazoles impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-α-methyl sterols. The synthetic imidazole miconazole is additionally able to increase intracellular reactive oxygen species, at least in part through inhibition of fungal catalase and peroxidase. This unique feature of miconazole is probably the basis for its fungicidal activity in C. albicans, in addition to the fungistatic mode of action. Studies show that miconazole is superior to nystatin treatment and demonstrate its impact as one of the best options in managing vulvovaginal candidiasis. Regarding recurrent vulvovaginal candidiasis, several new drugs are currently developed to ensure effective treatment also for this group of patients.

The Efficacy of Kundur (Boswellia serrata Roxb. Ex Colebr.) in Vulvovaginal Candidiasis: A Randomized Control Trial.

Context: Kundur, Boswellia serrata Roxb. ex Colebr., is prescribed by Unani (Greco-Arab) scholars clinically under conditions similar to vulvovaginal candidiasis (VVC) and has been supported by recent pharmacological studies, but scientific evidence is scarce. Objectives: The study intended to investigate the drug's scientific parameters and to compare its efficacy and safety to that of Miconazole nitrate (2% w/w) in treatment of VVC. Design: The research team designed a randomized controlled trial (RCT). Setting: The RCT was performed in the Department of Ilmul Qabalat wa Amraze Niswan at Luqman Unani Medical College Hospital and Research Center in Vijaypura, India, between November 2018 and March 2020. Participants: Participants were 40 married women, aged 18 to 45 years, who had been clinically examined and diagnosed with VVC. Interventions: Participants were randomly allocated to the Boswellia serrata (Kundur) group, the intervention group (n = 20), or to the miconazole group, the control group (n = 20). The Kundur group took a one-gram tablet of Kundur as a vaginal insert every day at bedtime for 21 days, while the control group used vaginal suppositories with 100 mg of miconazole (2% w/w) every day at bedtime for seven days. Outcome Measures: The primary outcome measures were changes: (1) in vulval itching (pruritus), (2) in vaginal discharge, (3) in painful urination (dysuria), (4) in recurrent genital pain (dyspareunia), and (5) in quality of life (QoL). The secondary outcome measures were mycological clearing on a potassium hydroxide (KOH) test and a per-speculum pelvic examination for the presence or absence of curdy discharge, vulval erythema, and vulval swelling. Results: The response to the intervention was greater than that of the control in reducing pruritus vulvae and vaginal discharge. However, both drugs were equally effective in improving the rest of the parameters, including QoL. Conclusion: The VVC symptoms were equally and significantly improved in both the intervention and the control groups, and Boswellia serrata Roxb. ex Colebr. was shown to be efficacious in the management of VVC. Further studies with a rigorous design and larger sample size are needed to reinforce scientific evidence.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-κB pathway and iNOS production.

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

Topical azole treatments for otomycosis.

BACKGROUND: Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used. OBJECTIVES: To evaluate the benefits and harms of topical azole treatments for otomycosis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow-up of two weeks was required. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution). A. Topical azoles versus placebo None of the studies assessed this comparison. B. Topical azoles versus no treatment None of the studies assessed this comparison. C. One type of topical azole versus another type of topical azole i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole) Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low-certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles. One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low-certainty evidence). Clotrimazole may result in little or no difference in mycological resolution at two weeks follow-up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low-certainty evidence) or in other (less serious) adverse events at two weeks follow-up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low-certainty evidence). ii) Bifonazole cream versus bifonazole solution One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow-up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low-certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low-certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low-certainty evidence). AUTHORS' CONCLUSIONS: We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non-serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.

Pharyngeal haematoma and partial airway obstruction caused by interaction between warfarin and topical miconazole gel.

A man in his 70s on warfarin attended the emergency department three times over a 24-hour period, complaining of a sore throat, neck swelling and difficulty swallowing. He was initially diagnosed with pharyngitis, given antibiotics and discharged home, which was reconfirmed on the second attendance after an episode of haemoptysis. On the third, he was diagnosed with a pharyngeal haematoma causing partial airway obstruction and admitted to critical care. His international normalised ratio (INR) was reported initially as unreadable by the laboratory, then eventually came back as >20. After a thorough medication history, he said that he had recently been prescribed topical miconazole oromucosal gel by his dentist for oral candidiasis, which had interacted with the warfarin to cause this life-threatening haematoma.

Antimycotic Treatment of Oral Candidiasis in Warfarin Users.

PURPOSE: Azole antimycotics and nystatin oral solution are used to treat oral candidiasis. Azoles inhibit cytochrome (CYP) P450-dependent metabolism of warfarin, which could increase the anticoagulant effect of warfarin. Nystatin is not expected to interfere with warfarin metabolism, but current data are conflicting. With this study, we aimed to explore the potential drug-drug interactions between warfarin and azole antimycotics used in the treatment of oral candidiasis, that is, systemic fluconazole, miconazole oral gel, and nystatin oral solution. METHODS: By linking clinical data on international normalized ratio (INR) measurements with administrative data on filled prescriptions of warfarin and antimycotics during 2000-2015, we explored INR changes in warfarin users relative to initiation of systemic fluconazole (n = 413), miconazole oral gel (n = 330), and nystatin oral solution (n = 399). RESULTS: We found a significant increase in mean INR of 0.83 (95% confidence interval [CI] 0.61-1.04) and 1.27 (95% CI 0.94-1.59) following initiation of systemic fluconazole and miconazole oral gel, respectively. Also, the proportion of patients experiencing an INR-value above 5 was increased after initiation of fluconazole (from 4.3% to 15.3%) and miconazole (from 5.5% to 30.1%). INR was unaffected by initiation of nystatin oral solution (mean change 0.08; 95% CI -0.10 to 0.25). CONCLUSION: Initiation of systemic fluconazole and miconazole oral gel was associated with increased INR in warfarin users. A similar association was not found for nystatin oral solution, which thus appears to be the safest alternative when treating oral candidiasis in warfarin users.

PRISM study: Comparison of a nystatin-neomycin-polymyxin B combination with miconazole for the empirical treatment of infectious vaginitis.

OBJECTIVE: An empirical treatment of infectious vaginitis is justified because of its multiple etiologies, the frequent uncertainty of clinical diagnosis and limits of microbiological analysis. Our aim was to comparatively investigate nystatin-neomycin-polymyxin B combination (NNP, Polygynax®) and miconazole. PATIENTS AND METHODS: In this European multicenter, double-blind PRISM trial, participating women presenting with infectious vaginitis were randomized to receive one vaginal capsule containing either NNP for 12 days or miconazole for 3 days followed by 9 days of placebo. RESULTS: The clinical success rate was higher in the NNP group (n=302) than the miconazole group (n=309), with a difference between groups close to statistical significance (91.1% vs. 86.7%, P=0.0906). The risk of treatment failure was 36% lower in the NNP group (odds ratio, 0.64; 95% confidence interval, 0.38-1.07). Vaginal burning on Day 2 and vaginal discharge on Day 4 were significantly less intense in the NNP group than in the miconazole group (39.1 vs. 42.3, P=0.031 and 34.6 vs. 37.6, P=0.031, respectively). Adverse drug reactions were reported by 1.2% and 2.1% of patients in the NNP and miconazole group respectively, with the ratio of adverse drug reactions relative to total adverse events significantly higher in the miconazole group (20.3% vs. 6.9%, P=0.022). CONCLUSION: The widespread use of NNP for several decades and its good efficacy and safety profile, as well as the frequent diagnostic uncertainties due to the various pathogens sustain the initiation of this broad-spectrum empirical treatment in infectious vaginitis.

Morbidity and mortality associated with the interaction of miconazole oral gel and warfarin.

Oral candidiasis is a frequently encountered oral fungal infection which can be treated with systemic and topical antifungal agents. Warfarin is a widely used oral anticoagulant. The interaction of miconazole oral gel and warfarin, causing potentiation of anticoagulant activity, has been documented over many years with evidence of occurrence in multiple settings and is a significant patient safety risk. This dangerous interaction remains underappreciated by dentists, doctors, pharmacists and patients, with resulting significant morbidity and mortality still occurring. This paper reports on recent developments concerning this interaction, and the important patient safety issues involved. In situations where topical treatment for oral candidiasis is indicated, nystatin should be prescribed instead of miconazole oral gel in patients taking warfarin, unless close monitoring and titration of the anticoagulant effect is undertaken.

Effect of Incorporation of Antifungal Agents on the Ultimate Tensile Strength of Temporary Soft Denture Liners.

PURPOSE: To investigate the ultimate tensile strength of temporary soft denture liners modified by minimum inhibitory concentrations (MICs) of antifungal agents for Candida albicans biofilm (SC5314) determined in previous microbiological research. MATERIALS AND METHODS: Dumbbell-shaped specimens (n = 7) with a central cross-sectional area of 6 × 3 × 33 mm were produced by Softone and Trusoft, without (control) or with incorporation of drugs in powder form at MICs for C. albicans biofilm (per g of material powder): nystatin (0.032 g), chlorhexidine diacetate (0.064 g), ketoconazole (0.128 g), miconazole (0.256 g), and itraconazole (0.256 g). After plasticization, specimens were immersed in distilled water at 37°C for 24 hours, 7 or 14 days, and then tested in tension in a universal testing machine at 40 mm/min. Data of tensile strength (MPa) and elongation percentage (%) were submitted to 3-way ANOVA and Tukey's test (α = 0.05). RESULTS: At the end of 14 days, the tensile strength for both materials was significantly lower in the groups modified by miconazole and itraconazole compared to the other groups (p < 0.0001), which showed no significant difference between them (p > 0.05). After 7 and 14 days in water, miconazole and itraconazole added into both materials resulted in significantly lower elongation percentages compared to the other antifungal agents and control (p < 0.0001), which were similar to each other (p > 0.05). CONCLUSIONS: The addition of the nystatin, chlorhexidine, and ketoconazole at MICs for C. albicans biofilm resulted in no harmful effects on the tensile strength and elongation percentage of the temporary soft denture liner materials up to 14 days.

[Pharmacokinetic drug interaction between miconazole mucoadhesive tablet and tacrolimus: About 3 case-reports in transplant patients]. / Interaction pharmacocinétique entre la forme mucoadhésive de miconazole et le tacrolimus : à propos de 3 observations cliniques chez des patients greffés.

Loramyc® is a mucoadhesive tablet of miconazole, indicated for the treatment of oropharyngeal candidiasis in immunocompromised patients. Miconazole, as others azole antifungals, is known for its potent inhibitory properties of cytochromes P450 enzymes and P-glycoprotein (P-gp). Inhibition of cytochromes P450 enzymes and P-gp can produce pharmacokinetic drug interaction. Immunosuppressive agents, such as calcineurin inhibitors (tacrolimus, cyclosporine) are substrates of cytochromes P450 3A4 and P-gp. Nevertheless, the impact of systemic absorption of miconazole mucoadhesive tablet has not been investigated by the laboratory before regulatory approval. No recommendation currently exists in case of co-prescription of Loramyc® and immunosuppressive agents which are counter-indicated as a matter of principle. Herein, we present 3 cases of transplanted patients, requiring miconazole mucoadhesive tablet, who presented a tacrolimus overdose. These cases illustrate that of therapeutic drug monitoring is feasible in order to prevent the occurrence of overdoses and adverse reactions related.

Topical Antimycotics for Oral Candidiasis in Warfarin Users.

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.

Warfarin and Drug Interactions: Prescribing Vigilance.

A patient taking warfarin presented to the Oral Medicine Clinic at Liverpool University Dental Hospital, having been prescribed metronidazole and miconazole by his general dental practitioner (GDP) for his oral mucosal problem. He subsequently developed bruising on his torso following mild trauma. Having read the drug information leaflet provided with his metronidazole and miconazole, he noted the potential drug interactions between these and warfarin. He therefore stopped his warfarin. The details of this case are outlined, and the potential for significant drug interactions with warfarin are highlighted. The need for dental practitioners to be vigilant concerning drug interactions is emphasized, together with the importance of CPD in relation to drug prescribing. CPD/CLINICAL RELEVANCE: This case report, which is of relevance to all dental practitioners, highlights the importance of up-to-date medical and drug histories and the continuing awareness of potential drug interactions. In this case, patient intervention after checking drug information leaflets prevented serious consequences. The importance and potentially serious consequences of significant drug interactions needs to be understood.

Efficacy and safety of miconazole for oral candidiasis: a systematic review and meta-analysis.

The objective of this study is to assess the efficacy and safety of miconazole for treating oral candidiasis. Twelve electronic databases were searched for randomized controlled trials evaluating treatments for oral candidiasis and complemented by hand searching. The clinical and mycological outcomes, as well as adverse effects, were set as the primary outcome criteria. Seventeen trials were included in this review. Most studies were considered to have a high or moderate level of bias. Miconazole was more effective than nystatin for thrush. For HIV-infected patients, there was no significant difference in the efficacy between miconazole and other antifungals. For denture wearers, microwave therapy was significantly better than miconazole. No significant difference was found in the safety evaluation between miconazole and other treatments. The relapse rate of miconazole oral gel may be lower than that of other formulations. This systematic review and meta-analysis indicated that miconazole may be an optional choice for thrush. Microwave therapy could be an effective adjunct treatment for denture stomatitis. Miconazole oral gel may be more effective than other formulations with regard to long-term results. However, future studies that are adequately powered, large-scale, and well-designed are needed to provide higher-quality evidence for the management of oral candidiasis.