Antifungal Activity Of Itraconazole Research Articles

A study to assess the efficacy of oral itraconazole as an add-on to steroids in allergic fungal rhinosinusitis in a tertiary care hospital

Background: Allergic fungal rhinosinusitis (AFRS) is a distinct type of chronic polypoid rhinosinusitis that affects atopic individuals. The incidence worldwide ranges from 5% to 10%, with geographic variation in epidemiology. It imposes a significant negative impact on quality of life, concomitantly generating socioeconomic losses. Failure to remove all sinus disease increases the likelihood of relapse; thus, the best outcome is achieved through coordinated medical-surgical care. The antifungal activity of itraconazole in addition to standard steroid therapy may provide greater relief to patients with AFRS following functional endoscopic sinus surgery (FESS) by decreasing the chances of recurrence and long-term use of steroids. Therefore, this study has been taken up. Aim and Objectives: The aims and objectives of the study are to evaluate the efficacy of oral itraconazole as an add-on to the standard steroid therapy in allergic fungal rhinosinusitis from baseline to 6 weeks. Materials and Methods: This study was conducted among 60 patients who underwent FESS and were administered medications postoperatively. The efficacy was measured by the sinonasal outcome test-20 score, the nasal endoscopic grade, and the Lund and Mackay score from baseline to 6 weeks. Continuous data were analyzed using the unpaired t-test, repeated measure analysis of variance, and paired t-test, whereas categorical data were analyzed using the Chi-square test. Results: Comparable efficacy was observed between the group treated with standard steroids alone and the group receiving a combination of standard steroids and itraconazole. No significant improvement was seen with oral itraconazole as an add-on therapy when compared with standard steroids at the end of 6 weeks. Conclusion: Oral itraconazole as an add-on therapy will reduce the chances of recurrence such as steroids, but in this study, there was no statistically significant reduction. The disease has a long natural course, and further follow-up is needed to establish the importance of itraconazole.

Assessment Swot on Performance of Micronized Itraconazole against Candida albicans and Aspergillus niger for Superior Health Security

Background: Antifungal medication is used in adults to indulge infections caused by fungi. This includes infections in any part of the body including the lungs, mouth or throat, toenails, or fingernails. The widespread fungal pathogens causing stern insidious infections surrounded by immuno compromised patients are Candida albicans and Aspergillus niger. Itraconazole, is an antifungal medication used to treat a number of fungal infections. Itraconazole undergoes rapid metabolism to form hydroxyitraconazole, which also contributes to the anti-fungal activity exhibited by the parent compound. In the present study the assessment of plain Itraconazole and micronized Itraconazole material for increasing health safety and its biological evaluation by using Candida albicans and Aspergillus niger was reported.
 Methods: The determination of particle size of the micronized material which is a very fine powder and its characteristics was carried out by Dynamic light scattering(DLS) and Scanning Electron Microscopy(SEM).Structural identification was done by UV-spectroscopy and Fourier transform Infrared spectroscopy(FT-IR).
 Results: An active pharma ingredient having antifungal activity was selected and micronized using Microniser to reduce the particle size as small as possible. The product antifungal activity was reviewed between untreated material(large particle size, 200 microns) and reduced particle size(micro particles, 2.72 microns). Size reduction showed an increased efficiency of antifungal activity
 Conclusion: The antifungal activity of Itraconazole can be enhanced if the coarse large particles are micronized to significantly (>70 folds) smaller particles.

Dissolving microneedle-mediated dermal delivery of itraconazole nanocrystals for improved treatment of cutaneous candidiasis

The administration of conventional dosage forms of itraconazole (ITZ) for cutaneous candidiasis treatment is limited by its poor aqueous solubility and the deep location ofCandida albicans(CA) in this disease. In the present work, we developed a nanocrystal (NC) form of ITZ, which was incorporated into dissolving microneedles (MNs) to facilitate skin delivery of ITZ into the infection site. The NCs were prepared by media milling with an ultra-small-scale device using Pluronic®F127 as a stabiliser. The antifungal activity of ITZ was enhanced by NC formulations (MIC value of 2.5 μg/ml), compared to a coarse dispersion of ITZ (MIC value of >2560 μg/ml). The formulation of ITZ into NCs increased dissolution rate by 3-fold. Furthermore, the dissolving MNs containing ITZ-NCs exhibited better dermatokinetic profiles, compared to needle-free patches and conventional creams containing ITZ-NCs. Importantly, the antifungal activity in anex vivocandidiasis infection model exhibited that the CA viability declined by up to 100% after 48 h of administration. These studies have verified the concept that the incorporation of ITZ-NCs into dissolving MNs can offer an effective approach for cutaneous candidiasis treatment.

303 Comparison of Antifungal Activities of Efinaconazole and Conventional Antifungal Agents against Dermatophytes and Yeasts

As growing the number of aging population and immunocompromised patients, there has been an increase in patients with skin fungal infections. Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans are known as the key pathogen of superficial dermatomycosis. Although itraconazole, terbinafine, amorolfine, and ciclopirox have been used for the treatment of these infections, they have limitation due to the drug side effects and lack of efficacy. In 2014, the Food and Drug Administration approved efinaconazole as a novel antifungals particular in onychomycosis. However, there has not been studied about the efficacy of efinazonazole for specific strains yet. So, we analyzed the antifungal activities of efinaconazole against T. rubrum, T. mentagrophytes, and C.albicans and compared with the antifungal activities of itraconazole, terbinafine, amorolfine, and ciclopirox in vitro. 63 strains of T. rubrum, 59 strains of T. mentagrophytes and 50 strains of C. albicans were isolated from patient with onychomycosis and tinea pedis. The antifungal activities of efinaconazole, itraconazole, terbinafine, amorolfine and ciclopirox were compared using minimal inhibitory concentration (MIC). The MIC range of efinaconazole was 0.001-0.125 μg / mL for T. rubrum, 0.0005-0.125 μg / mL for T. mentagrophytes and 0.0002-0.002 μg / mL for C. albicans. It was the lowest MIC among the antifungal agents used in this study. For most evaluated antifungal agents, a significant number of resistant strains were observed. The MICs of efinaconazole showed relatively small standard deviations. These results suggest that efinaconazole resistant strains did not appear. In summary, efinaconazole can be considered as a new alternative antifungal agent that goes beyond the limits of traditional antifungal agents.

Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans

Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC-triggered cell death, cell viability was examined using the ROS scavenger N-acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans.

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR34/L98H- and TR46/Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014.

We employed an endpoint genotyping method to update the prevalence rate of positivity for the TR34/L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) and the TR46/Y121F/T289A mutation (a 46-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with substitutions at codons Y121 and T289) among clinical Aspergillus fumigatus isolates obtained from different regions of Iran over a recent 5-year period (2010 to 2014). The antifungal activities of itraconazole, voriconazole, and posaconazole against 172 clinical A. fumigatus isolates were investigated using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. For the isolates with an azole resistance phenotype, the cyp51A gene and its promoter were amplified and sequenced. In addition, using a LightCycler 480 real-time PCR system, a novel endpoint genotyping analysis method targeting single-nucleotide polymorphisms was evaluated to detect the L98H and Y121F mutations in the cyp51A gene of all isolates. Of the 172 A. fumigatus isolates tested, the MIC values of itraconazole (≥16 mg/liter) and voriconazole (>4 mg/liter) were high for 6 (3.5%). Quantitative analysis of single-nucleotide polymorphisms showed the TR34/L98H mutation in the cyp51A genes of six isolates. No isolates harboring the TR46/Y121F/T289A mutation were detected. DNA sequencing of the cyp51A gene confirmed the results of the novel endpoint genotyping method. By microsatellite typing, all of the azole-resistant isolates had genotypes different from those previously recovered from Iran and from the Dutch TR34/L98H controls. In conclusion, there was not a significant increase in the prevalence of azole-resistant A. fumigatus isolates harboring the TR34/L98H resistance mechanism among isolates recovered over a recent 5-year period (2010 to 2014) in Iran. A quantitative assay detecting a single-nucleotide polymorphism in the cyp51A gene of A. fumigatus is a reliable tool for the rapid screening and monitoring of TR34/L98H- and TR46/Y121F/T289A-positive isolates and can easily be incorporated into clinical mycology algorithms.

Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability.

The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 μg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 μg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 μm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.

In vitro skin penetration and antimycotic activity of itraconazole loaded niosomes: Various non-ionic surfactants

The main objective of the present study was to explore different types of surfactants for formulating itraconazole (ITZ) loaded niosomes to improve its skin penetration. These surfactants vary in number and nature of the alkyl chains. The prepared niosomes were characterized in terms of particle size, surface charge, entrapment efficiency, skin penetration and antifungal activity. Brij (BR) 35 niosomes exhibited largest size, while the smallest size was observed in case of Spans and Tweens with tri-alkyl chains. The entrapment efficiency (EE%) of niosomes made of unsaturated alkyl chain surfactants was less than that one with saturated alkyl chain. Furthermore, tri-alkyl chains of niosomes showed higher EE% compared to mono-alkyl chain. Regarding skin permeation, Spans niosomes showed enhancement permeation of ITZ compared to ITZ solution; however, it was less in magnitude than that of Tweens. The niosomes made of tri-alkyl chains tend to accumulate more in stratum corneum (SC) and stripped skin with low amount of ITZ in receptor fluid. The highest amount of ITZ reached receptor fluid was observed in Tween 80 and 60 niosomes. The antifungal activity of ITZ was not compromised when ITZ being loaded into niosomes. It could be concluded that niosomes drug delivery systems are promising carriers for cutaneous targeted delivery of ITZ.

The role of oxidative and nitrosative bursts caused by azoles and amphotericin B against the fungal pathogen Cryptococcus gattii

Although the most accepted mechanisms of action of amphotericin B and azoles are related to ergosterol, it is possible that these drugs have other effects on the fungal cell. In the present study, the role of endogenous reactive oxygen species (ROS) and peroxynitrite produced by azoles and amphotericin B in the fungus Cryptococcus gattii were examined. We studied distinct parameters to evaluate the effect of oxidative and nitrosative stresses induced by these drugs in C. gattii cells: lipid peroxidation, ergosterol content, ROS and peroxynitrite production, enzymatic activity of the antioxidant system and the in vitro interaction of antifungal drugs with a peroxidase inhibitor, a superoxide dismutase inhibitor and a peroxynitrite scavenger. The data demonstrated that itraconazole led to ROS formation and lipid peroxidation in C. gattii cells in the early stages of the treatment; this did not occur with fluconazole. This phenomenon strongly increased the activities of enzymes of the antioxidant system. These results were confirmed by synergism observed between the catalase inhibitor and itraconazole. Amphotericin B caused lipid peroxidation in C. gattii cells through a greatly enhanced production of oxidative and nitrosative radicals with increased peroxidase activity. These data were confirmed by the synergism between the catalase/superoxide dismutase inhibitors and amphotericin B. In addition, the effect of this antifungal was antagonized by the peroxynitrite scavenger. Oxidative and nitrosative bursts play an important role in the antifungal activity of itraconazole and amphotericin B against C. gattii.

Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a-1h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans- stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the anti-angiogenic and anti-fungal activities of itraconazole.

Antifungal Activity of Itraconazole and Voriconazole against Clinical Isolates Obtained from Animals with Mycoses

Animal mycosis, particularly deep mycosis, is one of the most challenging conditions encountered by veterinarians. Pathogens causing mycotic infections in animals include fungi such as Cryptococcus neoformans, Candida spp., and Aspergillus spp. The antifungal drugs used for the treatment of deep mycoses in animals as well as humans are polyenes and azoles. However, the sensitivity of clinical isolates obtained from animals toward these drugs has rarely been assayed. In this study, the antifungal activities of itraconazole and voriconazole against clinical isolates of C. neoformans, Candida spp., and A. fumigatus isolated from animals with mycoses were examined using the broth microdilution method performed according to the guidelines provided by the Clinical and Laboratory Standards Institute. The minimum inhibitory concentrations (MICs) of itraconazole toward the C. neoformans, Candida spp., and A. fumigatus isolates were 0.125 - 1, 0.125 - 2, and 0.25 - 2 microg/ml, respectively, and those of voriconazole were 0.0625 - 0.5, < or =0.0313 - 0.0625, and 0.0625 - 1 microg/ml, respectively. The results of the MIC analyses implied that the fungal isolates obtained from infected animals exhibit an equivalent degree of susceptibility to itraconazole and voriconazole, as is observed in the case of isolates obtained from humans. The appropriate antifungal therapeutic strategy for the treatment of mycoses in animals must be selected taking into consideration the host immune status and organ function as well as the in vitro sensitivity of the pathogens to antifungal drugs.

Terbinafine susceptibility patterns for onychomycosis-causative dermatophytes and Scopulariopsis brevicaulis

The in vitro antifungal activity of terbinafine against 521 clinical isolates of seven species of dermatophytes, including four onychomycosis-causative species, as well as five Scopulariopsis brevicaulis isolates was determined by a modified Clinical and Laboratory Standards Institute microdilution method. Results showed a high antifungal activity of terbinafine against all dermatophyte isolates (geometric minimal inhibitory concentration (MIC) = 0.026 μg/mL; concentration inhibiting 50% of mycological growth (MIC 50) = 0.03 μg/mL; and concentration inhibiting 90% of mycological growth (MIC 90) = 0.06 μg/mL). The geometric mean MICs against onychomycosis-causative dermatophyte species was lower (0.024 μg/mL) than the global MIC. However, the in vitro activity of terbinafine against S. brevicaulis was considerably lower (geometric mean MIC = 1.38 μg/mL) in comparison with dermatophytes. The antifungal activity of itraconazole was lower than that of terbinafine against these fungi. These data confirm the high in vitro antifungal activity of terbinafine against dermatophytes, under standardised conditions.

In vitro susceptibility testing of dermatophytes isolated from pediatric cases in Nigeria against five antifungals

The antifungal activities of itraconazole, ketoconazole, fluconazole, terbinafine and griseofulvin were tested by broth microdilution methods against 71 isolates of dermatophytes isolated from Nigerian children. Most drugs were very active against all the dermatophytes and the MIC 90 ranged from 0.03 to 8.0 microg/mL. This appears to be the first documented data on the antifungal susceptibility testing of isolates of dermatophytes from Nigerian children.

In Vitro Susceptibilities of Clinical Isolates of Candida Species, Cryptococcus neoformans , and Aspergillus Species to Itraconazole: Global Survey of 9,359 Isolates Tested by Clinical and Laboratory Standards Institute Broth Microdilution Methods

The in vitro activity of itraconazole was determined against 7,299 isolates of Candida spp., 1,615 isolates of Cryptococcus neoformans, and 445 isolates of Aspergillus spp. obtained from over 200 medical centers worldwide. Itraconazole was active against all Candida spp. (96% of MICs were < or =1 microg/ml) with the exception of C. glabrata (77% of MICs were < or =1 microg/ml). Itraconazole inhibited 94% of C. krusei and 84% of other fluconazole-resistant Candida species, exclusive of C. glabrata, at a MIC of < or =1 microg/ml. Itraconazole was not active against fluconazole-resistant isolates of C. glabrata. Only modest activity was seen against C. neoformans (80% of MICs were < or =1 microg/ml); however, itraconazole showed excellent activity against Aspergillus spp. (94% of MICs were < or =1 microg/ml). These results provide an update on the antifungal activity of itraconazole against major opportunistic fungal pathogens. In light of the new intravenous formulation of itraconazole these data suggest that this agent remains a viable systemically active antifungal agent.

Antifungal activity of itraconazole and terbinafine in human stratum corneum: A comparative study

Background: The evaluation of antifungal agents by in vitro and animal experiments cannot predict clinical efficacy with certainty. New models are needed to assess and compare antifungal activity. Objective: We compared on human stratum corneum ex vivo the antifungal activity and lingering effect of 200 mg itraconazole daily and twice daily, and 250 mg/day terbinafine. Methods: Three groups of 10 healthy volunteers entered the open comparative trial. Results were evaluated in a blinded manner. Cyanoacrylate skin surface strippings (CSSS) were taken from the back and superficial dermatome skin samples (SDSS) were taken from plantar skin at days 0, 1, 3, 7, 8, 10, 14, 21, 28, and 35. Spores or yeasts of selected fungi ( Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, and Candida albicans) were deposited and cultured on the CSSS and SDSS. The 1-week fungal growth on CSSS and SDSS was assessed over time by computerized image analysis to derive the inhibitory effect of the oral antifungal agents administered. Fungitoxic activity was also assessed by the use of 2-day cultures on CSSS followed by a transfer to Sabouraud medium. Results: Comparable antifungal activity against dermatophytes was found for all three regimens. Itraconazole at both dosages was always significantly more active than terbinafine against C. albicans on CSSS and SDSS. Overall, 200 mg itraconazole twice daily appeared to be more fungitoxic than 250 mg/day terbinafine and 200 mg/day itraconazole. Conclusion: The ex vivo culture of fungi on human stratum corneum is very similar to the in vivo situation. Both itraconazole and terbinafine display high antidermatophyte activity. Faster onset and longer posttherapy activity were demonstrated in the itraconazole treatment groups. Terbinafine had marginal activity against C. albicans in this model.

Pharmacokinetic optimisation of oral antifungal therapy.

The range of oral antifungal therapy has been expanded recently by the introduction of itraconazole, and terbinafine. These agents have a broader spectrum of activity than griseofulvin and flucytosine, and induce less liver toxicity than ketoconazole. Treatment with these agents may be optimised by application of pharmacokinetic principles. Griseofulvin, ketoconazole and itraconazole should be administered with food to ensure adequate absorption. Maximal absorption of griseofulvin is achieved by administration of the drug as a solid solution in polyethylene glycol. Absorption of azole antifungal agents is impaired by high gastric pH, which is observed in some patients with acquired immunodeficiency syndrome. It is also impaired by frequent vomiting, which commonly occurs in patients with neutropenia. Furthermore, antacids, H2-antagonists and sucralfate interfere with absorption of ketoconazole. The newer oral antifungals are more slowly eliminated and associated with less pronounced drug interactions than ketoconazole. As with ketoconazole, itraconazole and fluconazole influence cyclosporin metabolism. These effects are of clinical relevance and necessitate cyclosporin dosage reduction. However, the cyclosporin dosage reduction required during coadministration of itraconazole and fluconazole (50 to 55%) is less than that required when ketoconazole is concomitantly administered (85%). Monitoring of cyclosporin concentrations during coadministration with these agents is necessary to avoid nephrotoxicity. Drug monitoring is also advisable when phenytoin, carbamazepine or rifampicin (rifampin) are administered concomitantly with azoles, due to a mutual influence on drug metabolism. The antifungal activity of itraconazole is not related exclusively to free drug concentrations. Therefore, the low protein binding of fluconazole does not place this agent at an advantage over itraconazole in the treatment of fungal meningitis. However, terbinafine may be superior to itraconazole for the treatment of tinea unguium, another recalcitrant fungal disease, because terbinafine more rapidly penetrates the nail plate. During repeated use, itraconazole concentrations increase slowly in the nail plate. Steady-state concentrations are reached in the stratum corneum only after several weeks' administration. Following cessation of treatment, terbinafine, itraconazole and ketoconazole concentrations in keratinised tissues decline slowly. This allows a short duration of drug treatment. Some clinical trials suggest that low concentrations of flucytosine, griseofulvin and itraconazole are associated with treatment failure. Flucytosine-induced myelotoxicity also appears to be concentration dependent. This adverse reaction may be caused by fluorouracil (which is produced by metabolism of flucytosine by enterobacillary flora in the gut) rather than by the parent compound.