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The Cochrane Database of Systematic... May 2021Otomycosis 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... (Meta-Analysis)
Meta-Analysis
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Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials.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.
Topics: Administration, Topical; Adult; Antifungal Agents; Bias; Child; Clotrimazole; Cycloheptanes; Fluconazole; Humans; Imidazoles; Miconazole; Otomycosis; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34033120
DOI: 10.1002/14651858.CD009289.pub2 -
BMC Microbiology Jan 2022This study was aimed to determine the potency of Minocycline (MIN) and azoles, including itraconazole (ITR), voriconazole (VOR) and posaconazole (POS) against...
BACKGROUND
This study was aimed to determine the potency of Minocycline (MIN) and azoles, including itraconazole (ITR), voriconazole (VOR) and posaconazole (POS) against Scedosporium and Lomentospora species.
RESULTS
This study revealed that MIN exhibited no significant antifungal activity against any of the tested strains, whereas in vitro combination of MIN with ITR, VOR or POS showed satisfactory synergistic effects against 8 (80%), 1 (10%), and 9 (90%) strains, respectively. Moreover, combined use of MIN with azoles decreased the minimum inhibitory concentration (MIC) range from 5.33-16 μg/ml to 1-16 μg/ml for ITR, from 0.42-16 μg/ml to 0.21-16 μg/ml for VOR, and from 1.33-16 μg/ml to 0.33-16 μg/ml for POS. Meanwhile, no antagonistic interactions were observed between the above combinations. The G. mellonella infection model demonstrated the in vivo synergistic antifungal effect of MIN and azoles.
CONCLUSIONS
The present study demonstrated that combinations between MIN and azoles lead to synergistic antimicrobial effects on Scedosporium and Lomentospora species, while showing a potential for overcoming and preventing azole resistance.
Topics: Animals; Antifungal Agents; Ascomycota; Azoles; Drug Resistance, Fungal; Drug Synergism; Humans; Larva; Microbial Sensitivity Tests; Minocycline; Moths; Scedosporium
PubMed: 35016611
DOI: 10.1186/s12866-021-02433-6 -
PloS One 2017Several controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We conducted a systematic literature review of studies evaluating the efficacy and toxicity associated with azole therapy for tegumentary leishmaniasis.
METHODOLOGY
PRISMA guidelines for systematic reviews and the Cochrane manual were followed, and the review methodology was registered (PROSPERO; CRD42016048668). Sources included the EMBASE, Web of Science, MEDLINE, LILACS, and IBECS databases along with a manual search of references from evaluated studies. Additional resources such as Google Scholar and clinicaltrials.gov were also searched. We included all studies reporting cure rate after cutaneous or mucosal leishmaniasis treatment with systemic azole drugs, regardless of their design. R software was used to estimate global rates of success and adverse events with each drug. The main outcome of interest was clinical cure, defined as complete re-epithelialization of all lesions.
RESULTS
A total of 37 studies involving 1259 patients that reported outcomes after fluconazole (9), ketoconazole (14) and itraconazole (15) treatments were included. Only 14 (38%) were randomized controlled trials (RCT). The pooled azole final efficacy rate was 64% (CI95%: 57-70%) for all studies and 60% (CI95%: 50-70%) (p = 0.41) if only RCTs studies were considered. Twenty-four studies were conducted in the Old World and 13 studies in the Americas. The final efficacy rate according to New and Old World were 62% (CI95%: 43-77%) and 66% (CI95%: 58-73%), respectively. The final efficacy rate of azoles according to species were 89% (CI95%: 50-98%) for L. mexicana; 88% for L. infantum (CI95%: 27-99%); 80% for L. donovani; 53% (CI95%: 29-76%) for L. major; 49% for L. braziliensis (CI95%: 21-78%); and 15% (CI95%: 1-84%) for L. tropica. The cure rates were similar among the fluconazole, ketoconazole and itraconazole group arms (p = 0.89), specifically 61% (CI95%: 48-72%), 64% (CI95%: 44-80%) 65% (CI95%: 56-72%), respectively. Adverse events during fluconazole, itraconazole and ketoconazole therapy were reported in 7% (CI95%: 3-14%), 12% (CI95% 8-19%) and 13% (CI95%: 6-29%) of treated patients, respectively, without difference among them (p = 0.35). This systematic review included studies with small samples and both non-comparative and non-randomized studies and the main limitation was the low quality of the available studies.
CONCLUSIONS
Available evidence suggests that fluconazole, ketoconazole and itraconazole have similar and modest efficacy rates for tegumentary leishmaniasis treatment. There is insufficient evidence to support the exclusive use of azole therapy as a single agent for leishmaniasis treatment.
Topics: Administration, Cutaneous; Administration, Mucosal; Antifungal Agents; Azoles; Databases, Factual; Humans; Itraconazole; Ketoconazole; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous
PubMed: 29016694
DOI: 10.1371/journal.pone.0186117 -
Mycopathologia Apr 2023Malassezia pachydermatis is part of the normal skin microbiota of various animal species but under certain circumstances becomes an opportunistic pathogen producing...
Malassezia pachydermatis is part of the normal skin microbiota of various animal species but under certain circumstances becomes an opportunistic pathogen producing otitis and dermatitis. Commonly these Malassezia diseases are effectively treated using azoles. However, some cases of treatment failure have been reported. Alterations in the ERG11 gene have been associated with in vitro azole resistance in M. pachydermatis. In the present study, in vitro antifungal susceptibility of 89 different strains of M. pachydermatis isolated from different animal species and health status was studied. The susceptibility to fluconazole (FLZ), itraconazole (ITZ), ketoconazole and amphotericin B was tested by a disk diffusion method and 17 strains were also subjected to an ITZ E-test. Mueller-Hinton supplemented with 2% glucose and methylene blue was used as culture medium in both susceptibility assays. Multilocus sequence typing was performed in 30 selected strains using D1D2, ITS, CHS2 and β-tubulin genes. Also, ERG11 gene was sequenced. The four antifungals tested were highly effective against most of the strains. Only two strains showed no inhibition zone to antifungals and a strain showed an increased MIC to ITZ. The study of the ERG11 sequences revealed a high diversity of DNA sequences and a total of 23 amino acid substitutions, from which only two have been previously described. Also, three deleterious substitutions (A302T, G459D and G461D) previously associated with azole resistance in this yeast were recovered. A correlation between certain genotypes and ERG11 mutations was observed. Some of the ERG11 mutations recovered were correlated with a reduced susceptibility to azoles.
Topics: Animals; Antifungal Agents; Azoles; Malassezia; Ketoconazole; Itraconazole; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 36495417
DOI: 10.1007/s11046-022-00696-9 -
Molecular and Cellular Endocrinology Mar 2021The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct... (Review)
Review
The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.
Topics: Animals; Antifungal Agents; Azoles; Drug Monitoring; Humans; Mineralocorticoids; Syndrome
PubMed: 33484741
DOI: 10.1016/j.mce.2021.111168 -
Science Advances Jul 2023Using a citizen science approach, we identify a country-wide exposure to aerosolized spores of a human fungal pathogen, , that has acquired resistance to the...
Using a citizen science approach, we identify a country-wide exposure to aerosolized spores of a human fungal pathogen, , that has acquired resistance to the agricultural fungicide tebuconazole and first-line azole clinical antifungal drugs. Genomic analysis shows no distinction between resistant genotypes found in the environment and in patients, indicating that at least 40% of azole-resistant infections are acquired from environmental exposures. Hotspots and coldspots of aerosolized azole-resistant spores were not stable between seasonal sampling periods. This suggests a high degree of atmospheric mixing resulting in an estimated per capita cumulative annual exposure of 21 days (±2.6). Because of the ubiquity of this measured exposure, it is imperative that we determine sources of azole-resistant to reduce treatment failure in patients with aspergillosis.
Topics: Humans; Aspergillus fumigatus; Citizen Science; Drug Resistance, Fungal; Aspergillosis; Antifungal Agents; Azoles
PubMed: 37478175
DOI: 10.1126/sciadv.adh8839 -
Antimicrobial Agents and Chemotherapy Aug 2020Infections caused by have caused worldwide concern, especially when they are associated with increasing echinocandin and azole resistance. In this study, we analyzed...
Infections caused by have caused worldwide concern, especially when they are associated with increasing echinocandin and azole resistance. In this study, we analyzed the molecular mechanisms of azole and echinocandin resistance in isolates obtained from hospitalized patients in Japan from 1997 to 2019. All isolates were checked phenotypically for resistance and genotypically for mutations in , , hot spot 1 (HS1), HS2, and HS3 of , and HS1 and HS2 of , and all isolates were genotyped by multilocus sequence typing (MLST). Interestingly, 32.6% of the isolates were resistant to caspofungin, and 4.7% were resistant to micafungin. The isolates showed low rates of resistance to azoles, ranging from 2.3% to 9.3%, and only 4.7% of the isolates were non-wild type for flucytosine susceptibility. For the first time in Japan, 4.7% of the isolates were identified as multidrug-resistant strains. Nonsynonymous mutations in , including two novel mutations associated with azole resistance, were identified in 39.5% of the isolates, and a single nonsynonymous mutation was identified in Nine isolates from the same patient harbored nonsynonymous mutations in HS1 of , and a single isolate harbored a single nonsynonymous mutation in HS1 of MLST genotyping revealed 13 different sequence types (STs), with 3 new STs, and ST7 was the most prevalent among the patients (35%) and was associated with high resistance rates. Our results are of crucial clinical concern, since understanding the molecular mechanisms underlying fungal resistance is imperative for guiding specific therapy for efficient patient treatment and promoting strategies to prevent epidemic spread.
Topics: Antifungal Agents; Azoles; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Humans; Japan; Microbial Sensitivity Tests; Multilocus Sequence Typing; Mutation
PubMed: 32571826
DOI: 10.1128/AAC.00783-20 -
Journal of Global Antimicrobial... Mar 2021Candida albicans is a yeast that causes fungal infections with high mortality and is typically resistant to azole drugs. To overcome this resistance, we explored the...
OBJECTIVES
Candida albicans is a yeast that causes fungal infections with high mortality and is typically resistant to azole drugs. To overcome this resistance, we explored the combined use of oridonin (ORI) and three azole drugs, namely fluconazole (FLC), itraconazole (ITR) and voriconazole (VOR). Azole-resistant C. albicans strains were obtained from cancer patients and the reversal of drug resistance in these strains was investigated.
METHODS
The synergistic antifungal activity of ORI and azole drugs was measured by checkerboard microdilution and time-kill assays. The resistance reversal mechanisms, namely inhibition of drug efflux and induction of apoptosis, were investigated by flow cytometry. Expression levels of the efflux pump-related genesCDR1 and CDR2 were assessed by RT-qPCR.
RESULTS
The efflux pump inhibition assay with ORI showed that the minimum inhibitory concentrations (MICs) of FLC (128-fold), ITR (64-fold) and VOR (250-fold) decreased significantly. Upregulation of genes encodingCDR1 and CDR2 was confirmed in the resistant strain. The sensitising effect of ORI on FLC in the treatment of C. albicans also included the promotion of apoptosis.
CONCLUSION
We demonstrated that combining azoles with ORI exerted potent synergism and that ORI could promote sensitisation to azoles in azole-resistantC. albicans. The discovery that ORI can effectively inhibit drug efflux and promote apoptosis may provide new insights and therapeutic strategies to overcome increasing azole resistance in C. albicans.
Topics: Azoles; Candida albicans; Diterpenes, Kaurane; Drug Resistance, Fungal; Humans
PubMed: 33513441
DOI: 10.1016/j.jgar.2020.10.025 -
Molecules (Basel, Switzerland) Jan 2019Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility... (Review)
Review
Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These -alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of -alkynyl azoles mirrors that of the more extensively studied -alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these -alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of -alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting -alkynyl azoles in synthesis.
Topics: Alkynes; Amides; Azoles; Biological Products; Catalysis; Cyclization; Molecular Structure; Oxidation-Reduction; Polymers
PubMed: 30682796
DOI: 10.3390/molecules24030422 -
Antimicrobial Agents and Chemotherapy Dec 2020The EUCAST EDef 9.3.2 procedure recommends visual readings of azole and amphotericin B MICs against spp. Visual determination of MICs may be challenging. In this work,...
The EUCAST EDef 9.3.2 procedure recommends visual readings of azole and amphotericin B MICs against spp. Visual determination of MICs may be challenging. In this work, we aim to obtain and compare visual and spectrophotometric MIC readings of azoles and amphotericin B against isolates. A total of 847 isolates ( [ = 828] and cryptic species [ = 19]) were tested against amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole using the EUCAST EDef 9.3.2 procedure. Isolates were classified as susceptible or resistant/non-wild type according to the 2020 updated breakpoints. The area of technical uncertainty for the azoles was defined in the updated breakpoints. Visual and spectrophotometric (fungal growth reduction of >95% compared to the control, read at 540 nm) MICs were compared. Essential (±1 2-fold dilution) and categorical agreements were calculated. Overall, high essential (97.1%) and categorical (99.6%) agreements were found. We obtained 100% categorical agreements for amphotericin B, itraconazole, and posaconazole, and consequently, no errors were found. Categorical agreements were 98.7 and 99.3% for voriconazole and isavuconazole, respectively. Most of the misclassifications for voriconazole and isavuconazole were found to be associated with MIC results falling either in the area of technical uncertainty or within one 2-fold dilution above the breakpoint. The resistance rate was slightly lower when the MICs were obtained by spectrophotometric readings. However, all relevant mutants were correctly classified as resistant. Spectrophotometric determination of azole and amphotericin B MICs against isolates may be a convenient alternative to visual endpoint readings.
Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Itraconazole; Microbial Sensitivity Tests; Voriconazole
PubMed: 33020164
DOI: 10.1128/AAC.01693-20