Fluconazole and propolis co-encapsulated in chitosan nanoparticles for the treatment of vulvovaginal candidiasis in a murine model.

Vulvovaginal candidiasis (VVC) is a fungal infection caused mainly by Candida albicans. The treatment of VVC with azoles has been impaired due to the increased cases of resistance presented by this pathogen. The aim of the present study was to investigate the antifungal activity of mucoadhesive chitosan nanoparticles encapsulating both green propolis and fluconazole for topical use in the treatment of VVC. The nanoparticles were prepared by the ionic gelation method, resulting in a size of 316.5 nm containing 22 mg/kg of green propolis and 2.4 mg/kg of fluconazole. The nanoparticles were non-toxic in vitro using red blood cells or in vivo in a Galleria mellonella toxicity model. The treatment of female BALB/c mice infected by C. albicans ATCC 10231 with topical nanoparticles co-encapsulating fluconazole and green propolis was effective even using a fluconazole amount 20 times lower than the amount of miconazole nitrate 2% cream. Considering that the mucoadhesive property of chitosan, which is known to allow a prolonged retention time of the compounds at the mucous epithelia, the antifungal potential of the phenols and flavonoids present in green propolis may have favored the effectiveness of this treatment. These results indicate that this formulation of topical use for fluconazole associated with green propolis can be used as a promising approach to therapy for the treatment of VVC, thus contributing to reducing the development of resistance to azoles.

Vulvovaginal candidiasis is a fungal infection for which we search for alternatives for its treatment. Thus, a nanoparticle formulation based on fluconazole and green propolis was developed. These nanoparticles were tested, and we obtained adequate results in laboratory tests.

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis.

Candida glabrata has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.

Efficacy of a medical grade honey formulation (L-Mesitran) in comparison with fluconazole in the treatment of women with recurrent vulvovaginal candidiasis: protocol for a randomised controlled trial (HONEY STUDY).

INTRODUCTION: Recurrent vulvovaginal candidiasis (RVVC) affects up to 9% of women worldwide. This amount is expected to increase due to lifestyle changes, increased fungal resistance and biofilm formation. Treatment options are limited and in 57% of the cases, relapses occur within 12 months after starting fluconazole therapy (golden standard). The pathogenesis of RVVC is multifactorial and includes fungal biology, the vaginal microenvironment and the immune system. Fluconazole is antimicrobial and effective in inducing short-term remission but a long-term cure is hard to achieve. Medical grade honey (MGH) has antimicrobial, protective, antioxidative and immunomodulatory activity and may therefore be a good alternative treatment. This study aims to investigate the clinical cure rate and long-term efficacy of MGH compared with fluconazole in patients with RVVC. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled trial (Maastricht University Medical Centre+ and Zuyderland Medical Centre). A total of 252 eligible women will be randomly assigned to the fluconazole group (control) or the MGH group (L-Mesitran, treatment). The primary objective is to investigate the mycological cure rate after 1 month assessed through a vaginal culture. Secondary objectives are the clinical cure rate regarding symptoms, the prophylactic activity after 6 months of maintenance therapy and the number of relapses within 12 months. Moreover, information about side effects, discomfort and quality of life will be collected with the use of questionnaires. ETHICS AND DISSEMINATION: Ethical approval from the Medical Ethics Review Committee of the academic hospital Maastricht/University Maastricht has been obtained (NL 73974.068.21, V.7 on 8 February 2022). Additional approval was obtained from the Ethics Committee of the Zuyderland Medical Centre Heerlen (Z2021141 on 4 March 2022). The first patient was randomised on 22 August 2022. Results will be made available to researchers and healthcare professionals via conferences, meetings and peer-reviewed international publications. TRIAL REGISTRATION NUMBER: NCT05367089.

Azole resistance in Candida auris: mechanisms and combinatorial therapy.

Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first-line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.

[New opportunities for complex treatment of oropharyngeal candidiasis in HIV-infected patients in the later stages of the disease].

Treatment of recurrent oropharyngeal candidiasis (OPC) in HIV-infected patients is a serious clinical problem due to the emergence of resistant Candida strains, the risk of invasive disease, and high economic costs, which warrants the need for new treatment regimens. AIM: To improve the treatment regimen of OPC in the later stages of HIV infection by combining the complex herbal medicinal product Tonsilgon® N with fluconazole and evaluate the effectiveness of this combination. MATERIALS AND METHODS: A comparative randomized clinical study included 65 patients divided into observation and comparison groups, receiving fluconazole plus Tonsilgon® H and fluconazole monotherapy, respectively, for 7 days. On days 1 and 8, the severity of OPC clinical signs was assessed using a visual analog scale. The secretory immunoglobulin A in saliva was measured as a criterion for changing the level of local mucosal protection of the oral cavity and pharynx. CONCLUSION: This treatment regimen for oropharyngeal candidiasis in patients with HIV infection in the later stages of the disease (IVB-IVC) with fluconazole and Tonsilgon® N is effective, which is confirmed by a significantly more pronounced regression of clinical signs (pM-U<0.01), as well as an increase in the level of secretory immunoglobulin A in the oral fluid (from 0.62±0.33 g/L to 0.81±0.18 g/L; p<0.05).

[Mechanism of n-butanol alcohol extract of Baitouweng Decoction in treatment of vulvovaginal candidiasis based on negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis].

This study aimed to explore the mechanism of n-butanol alcohol extract of Baitouweng Decoction(BAEB) in the treatment of vulvovaginal candidiasis(VVC) in mice based on the negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis. In the experiment, female C57BL/6 mice were divided randomly into the following six groups: a blank control group, a VVC model group, high-, medium-, and low-dose BAEB groups(80, 40, and 20 mg·kg~(-1)), and a fluconazole group(20 mg·kg~(-1)). The VVC model was induced in mice except for those in the blank control group by the estrogen dependence method. After modeling, no treatment was carried out in the blank control group. The mice in the high-, medium-, and low-dose BAEB groups were treated with BAEB at 80, 40, and 20 mg·kg~(-1), respectively, and those in the fluconazole group were treated with fluconazole at 20 mg·kg~(-1). The mice in the VVC model group received the same volume of normal saline. The general state and body weight of mice in each group were observed every day, and the morphological changes of Candida albicans in the vaginal lavage of mice were examined by Gram staining. The fungal load in the vaginal lavage of mice was detected by microdilution assay. After the mice were killed, the degree of neutrophil infiltration in the vaginal lavage was detected by Papanicolaou staining. The content of inflammatory cytokines interleukin(IL)-1ß, IL-18, and lactate dehydrogenase(LDH) in the vaginal lavage was tested by enzyme-linked immunosorbent assay(ELISA), and vaginal histopathology was analyzed by hematoxylin-eosin(HE) staining. The expression and distribution of NLRP3, PKCδ, pNLRC4, and IL-1Ra in vaginal tissues were measured by immunohistochemistry(IHC), and the expression and distribution of pNLRC4 and IL-1Ra in vaginal tissues were detected by immunofluorescence(IF). The protein expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by Western blot(WB), and the mRNA expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by qRT-PCR. The results showed that compared with the blank control group, the VVC model group showed redness, edema, and white secretions in the vagina. Compared with the VVC model group, the BAEB groups showed improved general state of VVC mice. As revealed by Gram staining, Papanicolaou staining, microdilution assay, and HE staining, compared with the blank control group, the VVC model group showed a large number of hyphae, neutrophils infiltration, and increased fungal load in the vaginal lavage, destroyed vaginal mucosa, and infiltration of a large number of inflammatory cells. BAEB could reduce the transformation of C. albicans from yeast to hyphae. High-dose BAEB could significantly reduce neutrophil infiltration and fungal load. Low-and medium-dose BAEB could reduce the da-mage to the vaginal tissue, while high-dose BAEB could restore the damaged vaginal tissues to normal levels. ELISA results showed that the content of inflammatory cytokines IL-1ß, IL-18, and LDH in the VVC model group significantly increased compared with that in the blank control group, and the content of IL-1ß, IL-18 and LDH in the medium-and high-dose BAEB groups was significantly reduced compared with that in the VVC model group. WB and qRT-PCR results showed that compared with the blank control group, the VVC model group showed reduced protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues of mice and increased protein and mRNA expression of NLRP3. Compared with the VVC model group, the medium-and high-dose BAEB groups showed up-regulated protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues and inhibited protein and mRNA expression of NLRP3 in vaginal tissues. This study indicated that the therapeutic effect of BAEB on VVC mice was presumably related to the negative regulation of NLRP3 inflammasome by promoting PKCδ/NLRC4/IL-1Ra axis.

Predominance of non-Candida albicans species oral colonisation among patients on anticancer therapy: findings from a cross-sectional study in Tanzania.

OBJECTIVES: This study aimed to determine the oral carriage prevalence of Candida species and identify factors associated with the carriage of Candida species among patients with cancer on treatment. DESIGN: A hospital-based cross-sectional study. SETTING: The study was conducted at a tertiary-level cancer hospital Ocean Road Cancer Institute (ORCI), Dar es Salaam, Tanzania. PARTICIPANTS: We enrolled 196 participants who consented to join the study. Oral swabs were collected from all participants and inoculated onto Sabouraud dextrose agar supplemented with 50 mg/mL gentamicin and 50 mg/mL chloramphenicol, and chromogenic agar for phenotypic identification of Candida species. PRIMARY OUTCOME: The study reported the high prevalence of oral carriage of Candida species among patients with cancer on treatment at the tertiary-level cancer hospital in Dar es Salaam, Tanzania. RESULTS: A total of 196 participants were enrolled in the study. The overall oral carriage of Candida species was 37.8% (74/196). The prevalence was higher among patients undergoing chemotherapy and radiotherapy (44.4%) than those in monotherapy (13.3% chemotherapy, 20% radiotherapy). Candida krusei was the most common isolated species, 48.6% (36/74). Head and neck (adjusted OR (aOR) 15.09, 95% CI 3.05 to 74.59, p=0.00), gastrointestinal (aOR 14.14, 95% CI 2.25 to 88.63, p=0.00) malignancies and diabetes (aOR 3.18, 95% CI 1.03 to 9.77, p=0.04) were factors independently associated with oral carriage of Candida species. CONCLUSION: The oral carriage of Candida species among patients with cancer receiving treatment at ORCI is high, mainly due to C. krusei species. This is alarming since C. krusei has intrinsic resistance to fluconazole, a common antifungal agent used to manage adult fungal infections. Therefore, efforts should be put into conducting regular check-ups for such opportunistic pathogens as they can lead to subsequent infections. Furthermore, studies conducted to determine the antifungal profile of the causative agents are warranted since different causative agents might have different profiles.

Mechanism of n-butanol alcohol extract of Baitouweng Decoction in treatment of vulvovaginal candidiasis based on negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis / 中国中药杂志

This study aimed to explore the mechanism of n-butanol alcohol extract of Baitouweng Decoction(BAEB) in the treatment of vulvovaginal candidiasis(VVC) in mice based on the negative regulation of NLRP3 inflammasome via PKCδ/NLRC4/IL-1Ra axis. In the experiment, female C57BL/6 mice were divided randomly into the following six groups: a blank control group, a VVC model group, high-, medium-, and low-dose BAEB groups(80, 40, and 20 mg·kg~(-1)), and a fluconazole group(20 mg·kg~(-1)). The VVC model was induced in mice except for those in the blank control group by the estrogen dependence method. After modeling, no treatment was carried out in the blank control group. The mice in the high-, medium-, and low-dose BAEB groups were treated with BAEB at 80, 40, and 20 mg·kg~(-1), respectively, and those in the fluconazole group were treated with fluconazole at 20 mg·kg~(-1). The mice in the VVC model group received the same volume of normal saline. The general state and body weight of mice in each group were observed every day, and the morphological changes of Candida albicans in the vaginal lavage of mice were examined by Gram staining. The fungal load in the vaginal lavage of mice was detected by microdilution assay. After the mice were killed, the degree of neutrophil infiltration in the vaginal lavage was detected by Papanicolaou staining. The content of inflammatory cytokines interleukin(IL)-1β, IL-18, and lactate dehydrogenase(LDH) in the vaginal lavage was tested by enzyme-linked immunosorbent assay(ELISA), and vaginal histopathology was analyzed by hematoxylin-eosin(HE) staining. The expression and distribution of NLRP3, PKCδ, pNLRC4, and IL-1Ra in vaginal tissues were measured by immunohistochemistry(IHC), and the expression and distribution of pNLRC4 and IL-1Ra in vaginal tissues were detected by immunofluorescence(IF). The protein expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by Western blot(WB), and the mRNA expression of NLRP3, PKCδ, pNLRC4, and IL-1Ra was detected by qRT-PCR. The results showed that compared with the blank control group, the VVC model group showed redness, edema, and white secretions in the vagina. Compared with the VVC model group, the BAEB groups showed improved general state of VVC mice. As revealed by Gram staining, Papanicolaou staining, microdilution assay, and HE staining, compared with the blank control group, the VVC model group showed a large number of hyphae, neutrophils infiltration, and increased fungal load in the vaginal lavage, destroyed vaginal mucosa, and infiltration of a large number of inflammatory cells. BAEB could reduce the transformation of C. albicans from yeast to hyphae. High-dose BAEB could significantly reduce neutrophil infiltration and fungal load. Low-and medium-dose BAEB could reduce the da-mage to the vaginal tissue, while high-dose BAEB could restore the damaged vaginal tissues to normal levels. ELISA results showed that the content of inflammatory cytokines IL-1β, IL-18, and LDH in the VVC model group significantly increased compared with that in the blank control group, and the content of IL-1β, IL-18 and LDH in the medium-and high-dose BAEB groups was significantly reduced compared with that in the VVC model group. WB and qRT-PCR results showed that compared with the blank control group, the VVC model group showed reduced protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues of mice and increased protein and mRNA expression of NLRP3. Compared with the VVC model group, the medium-and high-dose BAEB groups showed up-regulated protein and mRNA expression of PKCδ, pNLRC4, and IL-1Ra in vaginal tissues and inhibited protein and mRNA expression of NLRP3 in vaginal tissues. This study indicated that the therapeutic effect of BAEB on VVC mice was presumably related to the negative regulation of NLRP3 inflammasome by promoting PKCδ/NLRC4/IL-1Ra axis.

Pseudomonas Synergizes with Fluconazole against Candida during Treatment of Polymicrobial Infection.

Polymicrobial infections are challenging to treat because we don't fully understand how pathogens interact during infection and how these interactions affect drug efficacy. Candida albicans and Pseudomonas aeruginosa are opportunistic pathogens that can be found in similar sites of infection such as in burn wounds and most importantly in the lungs of CF and mechanically ventilated patients. C. albicans is particularly difficult to treat because of the paucity of antifungal agents, some of which lack fungicidal activity. In this study, we investigated the efficacy of anti-fungal treatment during C. albicans-P. aeruginosa coculture in vitro and co-infection in the mucosal zebrafish infection model analogous to the lung. We find that P. aeruginosa enhances the activity of fluconazole (FLC), an anti-fungal drug that is fungistatic in vitro, to promote both clearance of C. albicans during co-infection in vivo and fungal killing in vitro. This synergy between FLC treatment and bacterial antagonism is partly due to iron piracy, as it is reduced upon iron supplementation and knockout of bacterial siderophores. Our work demonstrates that FLC has enhanced activity in clinically relevant contexts and highlights the need to understand antimicrobial effectiveness in the complex environment of the host with its associated microbial communities.

Competition for Iron during Polymicrobial Infections May Increase Antifungal Drug Susceptibility-How Will It Impact Treatment Options?

Interaction between microbes may influence antimicrobial susceptibility of one or more of the microbes, with studies pointing to increased resistance in these scenarios. Hattab et al. provided a novel perspective by identifying synergism between fluconazole and bacterial antagonism in the context of Candida albicans-Pseudomonas aeruginosa co-infection. Further research is required to translate these findings to the clinical setting, especially in the era of increasing antifungal resistance.

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis.

Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5-diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

Sodium houttuyfonate enhances the mono-therapy of fluconazole on oropharyngeal candidiasis (OPC) through HIF-1α/IL-17 axis by inhibiting cAMP mediated filamentation in Candida albicans-Candida glabrata dual biofilms.

Candida albicans and Candida glabrata are two common opportunistic fungi that can be co-isolated in oropharyngeal candidiasis (OPC). Hypha is a hallmark of the biofilm formation of C. albicans, indispensable for the attachment of C. glabrata, which is seldom in mycelial morphology. Increasing evidence reveals a hypoxic microenvironment in interior fungal biofilms, reminding of a fact that inflammation is usually accompanied by oxygen deprivation. As a result, it is assumed that the disaggregation of hypha-mediated hypoxia of biofilms might be a solution to alleviate OPC. Based on this hypothesis, sodium houttuyfonate (SH), a well-identified traditional herbal compound with antifungal activity, is used in combination with fluconazole (FLU), a well-informed synthesized antimycotics, to investigate their impact on filamentation in C. albicans and C. glabrata dual biofilms and the underlying mechanism of their combined treatment on OPC. The results show that compared with the single therapy, SH plus FLU can inhibit the hyphal growth in the mixed biofilms in vitro, decrease the fungal burden of oral tissues and internal organs, restore mucosal epithelial integrity and function, and reduce hypoxic microenvironment and inflammation in a mice OPC model. The possible mechanism of the combined therapy of SH plus FLU can be attributed to the regulation of HIF-1α/IL-17A axis through direct abrogation of the dual Candida biofilm formation. This study highlights the role of HIF-1α/IL-17A axis and the promising application of SH as a sensitizer of conventional antifungals in the treatment of OPC.

Paeonol enhances treatment of fluconazole and amphotericin B against oropharyngeal candidiasis through HIF-1α related IL-17 signaling.

Oropharyngeal candidiasis (OPC) is an oral infection mainly caused by Candida albicans, a dimorphic human opportunistic pathogen that can proliferate and invade the superficial oral epithelium using its hyphae. The filamentation of C. albicans is a hallmark of biofilm formation, accompanied by the occurrence of a hypoxic microenvironment. Paeonol (PAE) is a traditional medicine with multiple properties. In a previous study, we demonstrated the synergism of PAE plus Fluconazole (FLU) or Amphotericin B (AmB) against C. albicans in vitro and in vivo. This study aimed to explore the therapeutic mechanisms of drug combinations on OPC. In an established OPC mouse model, the culture of hypoxia was observed by calcofluor white and hypoxyprobe staining. The expression and levels of IL-17 signaling-associated genes and proteins (IL-17A and IL-23) were evaluated in tissue homogenates and EC109 cells. The results show that compared with the single therapy, PAE plus FLU or AmB can decrease fungal burden, restore mucosal integrity, and reduce the hypoxic microenvironment and inflammation in the OPC mice. Relative to infected mice, the drug combinations can also rectify the abnormal expression of hypoxia inducible factor (hif)-1α, il-17a, and il-23 mRNA. Meanwhile, compared with the infected EC109 cells treated with a single drug, PAE plus FLU or AmB significantly inhibited the mRNA and protein expression of HIF-1α, IL-17A, and IL-23. Taken together, the possible mechanism of PAE plus FLU or AmB can be attributed to the regulation of hypoxia-associated IL-17 signaling in OPC treatment.

Therapeutic drug monitoring guided fluconazole therapy in a patient with cholangitis sepsis.

Candida and other fungal species play an increasing role in nosocomial infections, including cholangitis and cholangiosepsis. Early diagnosis and prompt treatment are essential in successful patient outcomes. Fluconazole is an antifungal of choice in fluconazole-sensitive Candida infections. Little information is known about the fluconazole biliary excretion. Decreased tissue penetration may be one of the possible causes of treatment failure. Due to favorable pharmacokinetics, therapeutic drug monitoring of this antifungal has not been recommended routinely. In the presented case we report the successful therapeutic drug monitoring-guided fluconazole treatment in a patient with cholangitis and cholangiosepsis caused by fluconazole-sensitive Candida spp.

Lay abstract A successful fluconazole treatment of Candida cholangitis based on therapeutic drug monitoring, is described in our case study. Unlike other azole antimycotic agents, fluconazole is not considered a desirable candidate for therapeutic drug monitoring. However, as shown in our case study, a fixed dosage regimen might not lead to adequate fluconazole exposure in every patient and a personalized dosing regimen might be useful in the achievement of adequate fluconazole exposure and the successful treatment of Candida infection.

The liquid Kangfuxin (KFX) has efficient antifungal activity and can be used in the treatment of vulvovaginal candidiasis in mice.

Vulvovaginal candidiasis (VVC) is an infectious disease caused mainly by Candida albicans. Kangfuxin (KFX) is a traditional Chinese medicine preparation made from Periplaneta americana extracts, which promotes wound healing and enhances body immunity and also acts as an antifungal agent. Here, we evaluated the effect of KFX in the treatment of VVC in vitro and in vivo. The minimum inhibitory concentration (MIC50 ) of KFX against C. albicans ranged from 7·65 to 20·57%. In addition, KFX was more efficient than fluconazole (FLC) in inhibiting the drug-resistant C. albicans, and the effect was more intense after 8 h. The KFX treatment also exhibited good activity in vivo. It restored the body weight and reduced the vulvovaginal symptoms in mice induced with VVC. It downregulated the expression of the hyphae-related gene, HWP1, thus inhibiting the growth and development of C. albicans hyphae. It also increased the number of neutrophils and promoted the secretion of interleukin-17A (IL-17A); however, the levels of interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) decreased in mice with VVC. We deduce that KFX effectively treats vaginal candidiasis in two ways: by inhibiting the growth and development of mycelia to reduce colonization of C. albicans and by promoting the secretion and release of IL-17A and neutrophils in high numbers to fight C. albicans infection. This study provides a theoretical basis for the use of KFX for the clinical treatment of VVC.

Immune-mediated membranous nephropathy: Long term fluconazole usage caused podocyte autophagy.

The primary consequences of membranous nephropathy (MN) are the development of nephrotic syndrome including hypogammaglobulinemia, the increased infectious risk, the loss of protein-bound vitamin D, and, above all, an elevated thromboembolic incidence of up to 50% in severe proteinuria patients. Membrane nephropathy may be either idiopathic or primary, not recognized (70%-80%) or secondary (20%-30%) to pathological sicknesses such as hepatitis B, systemic lupus erythematosus, malignancies, and side-effects of medicines. The immunological responses in MN involve multiple components: immunoglobulin G (IgG), long-escaped antigens, and the membrane attachment complex, formed by the supplement to form C5b-9. In general, IgG4 is the most significant IgG subclass deposited in idiopathic membranous nephropathic disease but fluctuating IgG1 levels also are linked with immunological deposits. In contrast, IgG1, IgG2, and IgG3 deposition are greater than IgG4 deposition in secondary nephropathy. Fluconazole is a synthetic antifungal triazole that is often used. It is well tolerated in general and has never been identified as a cause of nephropathies. We report on the development of MN caused by fluconazole therapy that could potentiate podocyte autophagy.

Comparação da ação entre o antifúngico fluconazol e o óleo essencial de Melaleuca Alternifolia sobre amostras de leveduras do gênero Candida / Comparison of the action between the antifungal fluconazole and the essential oil of Melaleuca Alternifolia on samples of yeasts of the genus Candida

As onicomicoses são doenças causadas por fungos que acometem a pele, unhas e pelos, existindo diferentes formas clínicas e ocasionado por diversos agentes etiológicos. Os agentes causadores mais frequentes das onicomicoses são classificados como dermatófitos, não dermatófitos e leveduras. Dentre as leveduras destaca-se os fungos do gênero Candida, caracterizada como leveduriforme, em condições normais se apresentam como colonizantes, comensais e são consideradas oportunistas. A Candida albicans é a levedura mais comum de ser encontrada e está possui relatos de resistência ao fluconazol. A presença desta resistência representa um grande desafio terapêutico, pela escassez de alternativas no tratamento. Por conta disso muitas pessoas acabam optando por métodos alternativos para o controle deste tipo de infecção, um exemplo seria a aplicação de óleos essenciais naturais puros com ação combatente de microrganismos. O óleo essencial de Melaleuca, teve atividade antifúngica relatada por vários estudos usando diversas combinações de compostos originados da planta, mas sua aplicação mais comum é do óleo puro diluído. Porém os estudos aprofundando do quanto este composto possui de ação bactericida e antifúngica, comparados a medicamentos sintéticos, são escassos, mas sabe-se que com o uso frequente e correto do óleo ocasiona uma ação satisfatória. Objetivo geral foi descrever o efeito do óleo de Melaleuca sobre amostras de Candida albicans (ATT 90028) e Candida krusei (ATT 6258) comparando ao uso de Fluconazol.Método: Foi desenvolvida uma pesquisa qualitativa de caráter exploratório do uso tópico do óleo de Melaluca sobre Candida albicans (ATT 90028) e Candida krusei (ATT 6258) comparando com o antifúngico Fluconazol em método de difusão de disco.Os halos formados nos testes foram positivos para o Fluconazol, já para o óleo essencial de Melaleuca não constatando que a comparação por igual não é válida.

Onychomycosis are diseases caused by fungi that affect the skin, nails and hair, with different clinical forms and caused by different etiological agents. The most frequent causative agents of onychomycosis are classified as dermatophytes, non-dermatophytes and yeasts. Among the yeasts, the fungi of the genus Candida stand out, characterized as yeast, under normal conditions they present themselves as colonizers, commensals and are considered opportunistic. Candida albicans is the most common yeast to be found and has been reported to be resistant to fluconazole. The presence of this resistance represents a major therapeutic challenge, due to the scarcity of alternatives in the treatment. Because of this, many people end up opting for alternative methods to control this type of infection, an example would be the application of pure natural essential oils with microorganism-fighting action. Melaleuca essential oil has had antifungal activity reported by several studies using various combinations of compounds originating from the plant, but its most common application is as a diluted pure oil. However, the in-depth studies of how much this compound has bactericidal and antifungal action, compared to synthetic drugs, are scarce, but it is known that with the frequent and correct use of the oil it causes a satisfactory action. General objective was to describe the effect of Melaleuca oil on samples of Candida albicans (ATT 90028) and Candida krusei (ATT 6258) comparing to the use of Fluconazole. Method: A qualitative exploratory research was carried out on the topical use of Melaluca oil on Candida albicans (ATT 90028) and Candida krusei (ATT 6258) comparing it with the antifungal Fluconazole in a disc diffusion method. The halos formed in the tests were positive for Fluconazole, as for the essential oil of Melaleuca, not finding that the comparison is not valid.

Successful fluconazole combined with caspofungin treatment of candida bloodstream infection in preterm infant: A case report.

RATIONALE: Candida bloodstream infection continues to be a significant cause of mortality in premature infants. Amphotericin B has been recommended as the primary treatment; however, its use is limited due to drug-induced nephrotoxicity and amphotericin B-resistant candidemia. PATIENT CONCERNS: The gestational age was 29 (+6) weeks, and birth weight was 1760 g. DIAGNOSIS: The infant was diagnosed with Candida parapsilosis bloodstream infection. INTERVENTIONS: Fluconazole, 12 mg/kg/day, combined with caspofungin (loading dose 3 mg/kg, at a maintenance dose of 2 mg/kg every 24 h) therapy was administered to premature infant with Candida bloodstream infection. When fluconazole or caspofungin was used to treat Candida bloodstream infection in preterm infants, the blood cultures of the infant remained positive for Candida parapsilosis. OUTCOMES: All persistent candidemia resolved on fluconazole combined with caspofungin therapy. There were no adverse effects, hepatotoxicity, nephrotoxicity, anemia, or thrombocytopenia. LESSONS: Fluconazole combined with caspofungin successfully treated Candida bloodstream infection in premature infants at 29 + 6 weeks' gestational age, but large-scale clinical trials are required.

Efficacy of Voriconazole, Isavuconazole, Fluconazole, and Anidulafungin in the Treatment of Emerging Candida auris Using an Immunocompromised Murine Model of Disseminated Candidiasis.

Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo. MICs for anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 µg/ml, respectively. Significant in vivo efficacy was observed in the anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to that in the untreated group (P values of <0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacies against C. auris, whereas isavuconazole did not show significant in vivo activity.

Multiple facial candidal abscesses after self-administered acupuncture in a patient with undiagnosed diabetes mellitus: a case report.

BACKGROUND: Facial abscess caused by Candida albicans infection is a rare condition even in immunocompromised patients, and only a few cases have been reported. To our knowledge, this is the first case of multiple facial candidal abscesses caused by self-administered acupuncture in an undiagnosed diabetes mellitus patient. CASE PRESENTATION: A 57-year-old woman who had self-acupuncture treatment 2 weeks previously, presented with a 1-week history of progressive left eyelid swelling, erythema, and pain. Despite the antibiotic treatment, the lesion progressed. Surgical incision and drainage was performed and Candida albicans was isolated from the obtained pus culture. The patient was diagnosed with type 2 diabetes mellitus based on a random serum glucose level of 350 mg/dl and 9.2% HbA1c. The abscess resolved after seven incision and drainage cycles and 4 weeks of intravenous fluconazole treatment with an appropriate control of diabetes mellitus. CONCLUSION: Unusual organisms and underlying immunocompromised condition should be suspected in cases of recurrent abscess showing an inadequate response to antibiotic treatment.