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Lynn Zechiedrich - One of the best experts on this subject based on the ideXlab platform.
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Sugar and iron: Toward understanding the antibacterial effect of Ciclopirox in Escherichia coli
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:New antibiotics are needed against antibiotic-resistant gram-negative bacteria. The repurposed antifungal drug, Ciclopirox, equally blocks antibiotic-susceptible or multidrug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates, indicating that it is not affected by existing resistance mechanisms. Toward understanding how Ciclopirox blocks growth, we screened E. coli mutant strains and found that disruption of genes encoding products involved in galactose salvage, enterobacterial common antigen synthesis, and transport of the iron binding siderophore, enterobactin, lowered the minimum inhibitory concentration of Ciclopirox needed to block growth of the mutant compared to the isogenic parent strain. We found that Ciclopirox induced enterobactin production and that this effect is strongly affected by the deletion of the galactose salvage genes encoding UDP-galactose 4-epimerase, galE, or galactose-1-phosphate uridylyltransferase, galT. As disruption of ECA synthesis activates the regulation of capsular synthesis (Rcs) phosphorelay, which inhibits bacterial swarming and promotes biofilm development, we test whether Ciclopirox prevents activation of the Rcs pathway. Sub-inhibitory concentrations of Ciclopirox increased swarming of the E. coli laboratory K12 strain BW25113 but had widely varying effects on swarming or surface motility of clinical isolate E. coli, A. baumannii, and K. pneumoniae. There was no effect of Ciclopirox on biofilm production, suggesting it does not target Rcs. Altogether, our data suggest Ciclopirox-mediated alteration of lipopolysaccharides stimulates enterobactin production and affects bacterial swarming.
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Sub-inhibitory concentrations of Ciclopirox increase swarming of E. coli strain BW25113.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data. Bacterial cultures were dotted on the surface of LB Eiken agar containing various concentrations of Ciclopirox. (b) Swarming on agar containing 2.5 or 5 μg/mL Ciclopirox was normalized relative to swarming on agar without Ciclopirox. (c) Area of swarming motility for E. coli grown without or with 5 μg/mL Ciclopirox or 5 μg/mL 1,10-phenanthroline, as well as without or with 1,000 μM FeCl3, to examine combinatory effects. Student’s t-tests were used to assess statistical significance (*p < 0.05; **p < 0.005).
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Sub-inhibitory concentrations of Ciclopirox increase P. aeruginosa swarming.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data of P. aeruginosa strain ATTC 27853 swarming after ~18 or ~42 hours. Yellow indicates pyoverdine production; bluish-green indicates pyocyanin production. (b) Quantification of swarming motility in cm2. A Student’s t-test was used to assess significance of swarming with Ciclopirox compared to the absence of Ciclopirox (* p < 0.05, **p < 0.005).
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Ciclopirox does not increase swarming or biofilm production in Rcs effector deletion strains.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsA strain (b) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsB strain (c) An MTT assay was used to assess absorbance at 560 nm, indicative of biofilm production, for the parent E. coli strain BW25113 and the ΔrcsA or ΔrcsB deletion mutant strains. Student’s t-tests were used to assess significance (* p < 0.05, ** p < 0.005).
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Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae
2013Co-Authors: Kimberly M. Carlson-banning, Yongcheng Song, Andrew Chou, Zhen Liu, Richard J. Hamill, Lynn ZechiedrichAbstract:Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, Ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of Ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that Ciclopirox, at 5–15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, Ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher Ciclopirox concentrations to completely block growth. To determine how Ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive Ciclopirox concentrations. We found that Ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ΔgalU, ΔgalE, ΔrfaI, or ΔrfaB mutant strains all have lower Ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that Ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that Ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to Ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make Ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens.
Xiaoying Hui - One of the best experts on this subject based on the ideXlab platform.
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in vitro human onychopharmacokinetic and pharmacodynamic analyses of me1111 a new topical agent for onychomycosis
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Natsuki Kubotaishida, Naomi Takeimasuda, Kaori Kaneda, Yu Nagira, Tsubasa Chikada, Masahiro Nomoto, Yuji Tabata, Sho Takahata, Kazunori Maebashi, Xiaoying HuiAbstract:ME1111 is a novel antifungal agent currently under clinical development as a topical onychomycosis treatment. A major challenge in the application of topical onychomycotics is penetration and dissemination of antifungal agent into the infected nail plate and bed. In this study, pharmacokinetic/pharmacodynamic parameters of ME1111 that potentially correlate with clinical efficacy were compared with those of marketed topical onychomycosis antifungal agents: efinaconazole, tavaborole, Ciclopirox, and amorolfine. An ME1111 solution and other launched topical formulations were applied to an in vitro dose model for 14 days based on their clinical dose and administration. Drug concentrations in the deep layer of the nail and within the cotton pads beneath the nails were measured using liquid chromatography-tandem mass spectrometry. Concentrations of ME1111 in the nail and cotton pads were much higher than those of efinaconazole, Ciclopirox, and amorolfine. Free drug concentrations of ME1111 in deep nail layers and cotton pads were orders of magnitude higher than the MIC90 value against Trichophyton rubrum (n = 30). Unlike other drugs, the in vitro antifungal activity of ME1111 was not affected by 5% human keratin and under a mild acidic condition (pH 5.0). The in vitro antidermatophytic efficacy coefficients (ratio of free drug concentration to MIC90s against T. rubrum) of ME1111, as measured in deep nail layers, were significantly higher than those of efinaconazole, tavaborole, Ciclopirox, and amorolfine (P < 0.05). This suggests that ME1111 has excellent permeation of human nails and, consequently, the potential to be an effective topical onychomycosis treatment.
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Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers
Drug Development and Industrial Pharmacy, 2014Co-Authors: Farhaan Hafeez, Xiaoying Hui, Marc Selner, Bert Rosenthal, Howard I. MaibachAbstract:AbstractContext: Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected.Objective: This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [14C]-Ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial Ciclopirox nail lacquer using the in vitro finite dose model.Materials and methods: The penetration rate of Ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed.Results: After a multiple day treatment, cumulative concentrations of Ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial Ciclopirox lacquer (p < 0.001) a...
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in vitro penetration of a novel oxaborole antifungal an2690 into the human nail plate
Journal of Pharmaceutical Sciences, 2007Co-Authors: Xiaoying Hui, Stephen J Baker, Ronald C Wester, Sherry Barbadillo, Anne K Cashmore, Virginia Sanders, Karin M Hold, Tsutomu Akama, Yongkang Zhang, Jacob J PlattnerAbstract:Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, Ciclopirox. AN2690 has superior penetration compared to Ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.
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Ciclopirox delivery into the human nail plate
Journal of Pharmaceutical Sciences, 2004Co-Authors: Xiaoying Hui, Ronald C Wester, Sherry Barbadillo, Christine M Lee, Bhiku Patel, Mitchel Wortzmman, Eugene H Gans, Howard I. MaibachAbstract:The human nail penetration of the antifungal Ciclopirox was determined for marketed gel containing 0.77% of Ciclopirox, an experimental gel containing 2% of Ciclopirox, and a marketed lacquer containing 8% of Ciclopirox. After 14 days dosing, unabsorbed drug remaining on the surface, drug within the infection-prone area, and the amount that had penetrated through the nail were determined. Ciclopirox delivery into and through the nail was significantly greater from the marketed gel, than from either the experimental gel or the nail lacquer (p < 0.05). In addition, the surface nail contained more unabsorbed drug from the lacquer. Further, the drug penetrating into and through the nail was also greater from the marketed gel, leading to a higher Calculated Efficacy Coefficient for the marketed gel, than from the marketed lacquer or the experimental gel. The formulation plays an important role in the enhancement of Ciclopirox permeation into and through the human nail plate, and the concentration of Ciclopirox in the formulation was not a factor in determining penetration.
Kimberly M. Carlson-banning - One of the best experts on this subject based on the ideXlab platform.
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Sugar and iron: Toward understanding the antibacterial effect of Ciclopirox in Escherichia coli
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:New antibiotics are needed against antibiotic-resistant gram-negative bacteria. The repurposed antifungal drug, Ciclopirox, equally blocks antibiotic-susceptible or multidrug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates, indicating that it is not affected by existing resistance mechanisms. Toward understanding how Ciclopirox blocks growth, we screened E. coli mutant strains and found that disruption of genes encoding products involved in galactose salvage, enterobacterial common antigen synthesis, and transport of the iron binding siderophore, enterobactin, lowered the minimum inhibitory concentration of Ciclopirox needed to block growth of the mutant compared to the isogenic parent strain. We found that Ciclopirox induced enterobactin production and that this effect is strongly affected by the deletion of the galactose salvage genes encoding UDP-galactose 4-epimerase, galE, or galactose-1-phosphate uridylyltransferase, galT. As disruption of ECA synthesis activates the regulation of capsular synthesis (Rcs) phosphorelay, which inhibits bacterial swarming and promotes biofilm development, we test whether Ciclopirox prevents activation of the Rcs pathway. Sub-inhibitory concentrations of Ciclopirox increased swarming of the E. coli laboratory K12 strain BW25113 but had widely varying effects on swarming or surface motility of clinical isolate E. coli, A. baumannii, and K. pneumoniae. There was no effect of Ciclopirox on biofilm production, suggesting it does not target Rcs. Altogether, our data suggest Ciclopirox-mediated alteration of lipopolysaccharides stimulates enterobactin production and affects bacterial swarming.
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Sub-inhibitory concentrations of Ciclopirox increase swarming of E. coli strain BW25113.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data. Bacterial cultures were dotted on the surface of LB Eiken agar containing various concentrations of Ciclopirox. (b) Swarming on agar containing 2.5 or 5 μg/mL Ciclopirox was normalized relative to swarming on agar without Ciclopirox. (c) Area of swarming motility for E. coli grown without or with 5 μg/mL Ciclopirox or 5 μg/mL 1,10-phenanthroline, as well as without or with 1,000 μM FeCl3, to examine combinatory effects. Student’s t-tests were used to assess statistical significance (*p < 0.05; **p < 0.005).
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Sub-inhibitory concentrations of Ciclopirox increase P. aeruginosa swarming.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data of P. aeruginosa strain ATTC 27853 swarming after ~18 or ~42 hours. Yellow indicates pyoverdine production; bluish-green indicates pyocyanin production. (b) Quantification of swarming motility in cm2. A Student’s t-test was used to assess significance of swarming with Ciclopirox compared to the absence of Ciclopirox (* p < 0.05, **p < 0.005).
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Ciclopirox does not increase swarming or biofilm production in Rcs effector deletion strains.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsA strain (b) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsB strain (c) An MTT assay was used to assess absorbance at 560 nm, indicative of biofilm production, for the parent E. coli strain BW25113 and the ΔrcsA or ΔrcsB deletion mutant strains. Student’s t-tests were used to assess significance (* p < 0.05, ** p < 0.005).
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Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae
2016Co-Authors: Kimberly M. Carlson-banning, Andrew Chou, Zhen Liu, Richard J. Hamill, Yongcheng SongAbstract:Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, Ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of Ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that Ciclopirox, at 5–15 mg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, Ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher Ciclopirox concentrations to completely block growth. To determine how Ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive Ciclopirox concentrations. We found that Ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, DgalU, DgalE, DrfaI, or DrfaB mutant strains all have lower Ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactos
Yongcheng Song - One of the best experts on this subject based on the ideXlab platform.
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Sugar and iron: Toward understanding the antibacterial effect of Ciclopirox in Escherichia coli
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:New antibiotics are needed against antibiotic-resistant gram-negative bacteria. The repurposed antifungal drug, Ciclopirox, equally blocks antibiotic-susceptible or multidrug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates, indicating that it is not affected by existing resistance mechanisms. Toward understanding how Ciclopirox blocks growth, we screened E. coli mutant strains and found that disruption of genes encoding products involved in galactose salvage, enterobacterial common antigen synthesis, and transport of the iron binding siderophore, enterobactin, lowered the minimum inhibitory concentration of Ciclopirox needed to block growth of the mutant compared to the isogenic parent strain. We found that Ciclopirox induced enterobactin production and that this effect is strongly affected by the deletion of the galactose salvage genes encoding UDP-galactose 4-epimerase, galE, or galactose-1-phosphate uridylyltransferase, galT. As disruption of ECA synthesis activates the regulation of capsular synthesis (Rcs) phosphorelay, which inhibits bacterial swarming and promotes biofilm development, we test whether Ciclopirox prevents activation of the Rcs pathway. Sub-inhibitory concentrations of Ciclopirox increased swarming of the E. coli laboratory K12 strain BW25113 but had widely varying effects on swarming or surface motility of clinical isolate E. coli, A. baumannii, and K. pneumoniae. There was no effect of Ciclopirox on biofilm production, suggesting it does not target Rcs. Altogether, our data suggest Ciclopirox-mediated alteration of lipopolysaccharides stimulates enterobactin production and affects bacterial swarming.
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Sub-inhibitory concentrations of Ciclopirox increase swarming of E. coli strain BW25113.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data. Bacterial cultures were dotted on the surface of LB Eiken agar containing various concentrations of Ciclopirox. (b) Swarming on agar containing 2.5 or 5 μg/mL Ciclopirox was normalized relative to swarming on agar without Ciclopirox. (c) Area of swarming motility for E. coli grown without or with 5 μg/mL Ciclopirox or 5 μg/mL 1,10-phenanthroline, as well as without or with 1,000 μM FeCl3, to examine combinatory effects. Student’s t-tests were used to assess statistical significance (*p < 0.05; **p < 0.005).
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Sub-inhibitory concentrations of Ciclopirox increase P. aeruginosa swarming.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Representative data of P. aeruginosa strain ATTC 27853 swarming after ~18 or ~42 hours. Yellow indicates pyoverdine production; bluish-green indicates pyocyanin production. (b) Quantification of swarming motility in cm2. A Student’s t-test was used to assess significance of swarming with Ciclopirox compared to the absence of Ciclopirox (* p < 0.05, **p < 0.005).
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Ciclopirox does not increase swarming or biofilm production in Rcs effector deletion strains.
2019Co-Authors: Zachary C. Conley, Kimberly M. Carlson-banning, Ashley G. Carter, Alejandro De La Cova, Yongcheng Song, Lynn ZechiedrichAbstract:(a) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsA strain (b) Bacteria swarming in 0, 2.5, or 5 μg/mL Ciclopirox for the ΔrcsB strain (c) An MTT assay was used to assess absorbance at 560 nm, indicative of biofilm production, for the parent E. coli strain BW25113 and the ΔrcsA or ΔrcsB deletion mutant strains. Student’s t-tests were used to assess significance (* p < 0.05, ** p < 0.005).
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Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae
2016Co-Authors: Kimberly M. Carlson-banning, Andrew Chou, Zhen Liu, Richard J. Hamill, Yongcheng SongAbstract:Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, Ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of Ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that Ciclopirox, at 5–15 mg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, Ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher Ciclopirox concentrations to completely block growth. To determine how Ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive Ciclopirox concentrations. We found that Ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, DgalU, DgalE, DrfaI, or DrfaB mutant strains all have lower Ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactos
Aditya K Gupta - One of the best experts on this subject based on the ideXlab platform.
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topical therapy for toenail onychomycosis an evidence based review
American Journal of Clinical Dermatology, 2014Co-Authors: Aditya K Gupta, Deanne Daigle, Kelly A FoleyAbstract:Managing toenail onychomycosis with topical treatments is challenging. It is difficult for topical medication to penetrate the nail plate, and this is reflected in lower cure rates with topical treatment than with oral treatment. However, oral medications may not be suitable for some patients, because of drug interactions; therefore, topical treatments are critical in managing the disease in certain patient populations. This paper reviews the quality and content of the scientific literature on topical treatments for toenail onychomycosis. PubMed, Ovid (Medline and Embase), Scopus, Cochrane library, and clinicaltrials.gov databases were searched for original clinical reports of topical monotherapy for microscopy and/or culture-confirmed toenail onychomycosis in adults. Studies were evaluated using an onychomycosis study quality scale, which was based on the CONSORT guidelines. Twenty-five publications (28 studies) were identified and met the inclusion criteria. Thirteen studies scored high ratings on the quality scale. These were randomized controlled trials or randomized comparative trials. Low-quality studies were nonrandomized, open studies that prevented statistical analysis. Most studies reported clinical and mycological cure. The most variation was observed with reporting outcomes of clinical improvement. Amorolfine, Ciclopirox, tavaborole, and efinaconazole produced clinical and mycological cure in patients with mild to moderate toenail onychomycosis (<50–65 % nail involvement), with efinaconazole showing the highest rates. Treatments were generally applied daily for 24–48 weeks, with longer treatment and follow-up showing better outcomes. Topical treatment with amorolfine, Ciclopirox, tavaborole, or efinaconazole is appropriate for cases of mild to moderate toenail onychomycosis due to dermatophyte or mixed dermatophyte/Candida infection.
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therapies for the treatment of onychomycosis
Clinics in Dermatology, 2013Co-Authors: Aditya K Gupta, Maryse Paquet, Fiona SimpsonAbstract:Onychomycosis treatments include nail avulsion and debridement by chemical or surgical procedures, topical and oral antifungals, and device-based therapies. The advantages, disadvantages, and limitations of the different types of treatments—including the most commonly prescribed topical (Ciclopirox) and oral (terbinafine, itraconazole, and fluconazole) treatments for onychomycosis caused by dermatophytes, non-dermatophyte molds, and yeasts—are reviewed. Safety and efficacy data for the healthy adult population and for special populations such as children and diabetic patients have confirmed the importance of proper mycological diagnosis before the initiation of therapy as well as the evaluation of the risks and benefits of the different treatments.
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evaluation of microdilution and disk diffusion methods for antifungal susceptibility testing of dermatophytes
Medical Mycology, 2007Co-Authors: Jagpal Singh, Muhammad Zaman, Aditya K GuptaAbstract:A total of 63 dermatophyte strains belonging to 6 species (Trichophyton rubrum (16), T. mentagrophytes (16), T. tonsurans (20), T. violaceum (2), Microsporum canis (7), and Epidermophyton floccosum (2)) were tested for their in vitro susceptibility to a range of antifungal drugs using disk diffusion and Clinical Laboratory Standards Institute M38-A (CLSI, formerly NCCLS) broth microdilution methods. The antifungals used were Ciclopirox (CIC), terbinafine (TER), griseofulvin (GRE), fluconazole (FLC), itraconazole (ITR), posaconazole (POS), and ravuconazole (RAV). In the broth microdilution assay terbinafine was found to have the highest activity followed by ravuconazole, posaconazole, Ciclopirox, itraconazole, griseofulvin and fluconazole. In the disk diffusion assay terbinafine produced the largest inhibition zone diameters (IZDs) on Dermasel agar media followed by ravuconazole, griseofulvin, posaconazole, and itraconazole. A significant correlation was not observed between the minimum inhibitory concentrations (MICs) and IZDs, but some correlations were observed for POS, RAV, and TER (correlation coefficients r=-0.507, -0.249, -0.267, P<0.05, respectively). MICs obtained by the microdilution method with ITR and GRE did not correlate with IZDs obtained in disk diffusion assays in this study. The Ciclopirox (20 microg/disk) and fluconazole (25 microg/disk) did not produce well defined inhibition zone diameters on Dermasel agar medium.
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in vitro susceptibility testing of Ciclopirox terbinafine ketoconazole and itraconazole against dermatophytes and nondermatophytes and in vitro evaluation of combination antifungal activity
British Journal of Dermatology, 2003Co-Authors: Aditya K Gupta, Yatika KohliAbstract:Summary Background With the development of newer antifungal agents with activity against both yeasts and filamentous fungi, there is an increased need to develop and standardize in vitro assays that will evaluate the activity of antimycotics against filamentous fungi. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different antimycotics, which in turn may clarify the reasons for lack of clinical response or serve as an effective therapy for patients with chronic infection. Objectives To determine the in vitro susceptibility of fungal organisms to Ciclopirox, terbinafine, ketoconazole and itraconazole and to evaluate the in vitro activity and mode of interaction of Ciclopirox in combination with either terbinafine or itraconazole. Materials and methods In the minimum inhibitory concentration (MIC) study 133 strains were evaluated, including dermatophytes (110 strains; 98 from Trichophyton spp.), Candida spp. (14 strains) and nondermatophyte moulds (nine strains). In vitro susceptibility testing was conducted in microbroth dilutions based on the National Committee for Clinical Laboratory Standards (NCCLS) M27-A proposed standard. The testing MIC ranges were 0·003–2 μg mL−1 for Ciclopirox and terbinafine, and 0·06–32 μg mL−1 for itraconazole and ketoconazole. For inoculum preparation, dermatophytes were grown on Heinz oatmeal cereal agar slants. Inoculum suspensions of dermatophytes were diluted in RPMI 1640 (Sigma-Aldrich) with the desired final concentration being 2–5 × 103 c.f.u. mL−1. Once inoculated, the microdilution plates were set up according to the NCCLS M27-A method, incubated at 35 °C, and read visually following 7 days of incubation. For azole agents, the MIC was the lowest concentration showing 80% growth inhibition; for terbinafine and Ciclopirox, the MIC was the lowest concentration showing 100% growth inhibition. In the synergy studies, 29 strains from nondermatophyte species were evaluated using a checkerboard microdilution method. The concentrations tested were: 0 and 0·06–32 μg mL−1 for itraconazole, and 0 and 0·003–4 μg mL−1 for both terbinafine and Ciclopirox. Modes of interaction between drugs were classified as synergism, additivism, antagonism or indifference based on fractional inhibitory concentration index values (FIC index). Synergism was defined as an FIC index of ≤ 0·50, additivity as an FIC index of ≤ 1·0, and antagonism as an FIC index of ≥ 2·0. The drug combination was interpreted as indifferent if neither of the drugs had any visible effect on the presence of the other drug. Results In the MIC study, the dermatophyte MIC values (μg mL−1) (mean ± SEM) were: Ciclopirox (0·04 ± 0·02), terbinafine (0·04 ± 0·23), itraconazole (2·28 ± 7·42) and ketoconazole (0·83 ± 1·99). The yeast MIC values (μg mL−1) (mean ± SEM) were: Ciclopirox (0·05 ± 0·02), terbinafine (1·77 ± 0·58), itraconazole (0·18 ± 0·27) and ketoconazole (0·56 ± 0·60). The non-dermatophyte fungi MIC values (μg mL−1) (mean ± SEM) were: Ciclopirox (1·04 ± 2·62), terbinafine (1·04 ± 0·95), itraconazole (17·87 ± 16·75) and ketoconazole (10·69 ± 13·09). In the synergy study, with Ciclopirox in combination with terbinafine, mainly a synergistic or additive reaction was observed; there were no cases of antagonism. For Ciclopirox in combination with itraconazole, there were some instances of additivism or synergism, with indifference in the majority of instances; there were no cases of antagonism. Conclusions In vitro susceptibility testing indicates that Ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and other nondermatophytes. Terbinafine is extremely potent against dermatophytes. In vitro evaluation of activity of Ciclopirox and terbinafine suggests many instances of synergy or additivism; for Ciclopirox and itraconazole there may be indifference, synergy or additivism.
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treatment of dermatophyte toenail onychomycosis in the united states a pharmacoeconomic analysis
Journal of the American Podiatric Medical Association, 2002Co-Authors: Aditya K GuptaAbstract:This study attempted to determine the cost-effectiveness of therapies for dermatophyte toenail onychomycosis in the United States in 2001. The antimycotic agents evaluated were Ciclopirox 8% nail lacquer and the oral agents terbinafine, itraconazole (pulse), itraconazole (continuous), fluconazole, and griseofulvin. A treatment algorithm for the management of onychomycosis was developed, and a meta-analysis was carried out to determine the average mycologic and clinical response rates for the various agents. The cost of the regimen was figured as the sum of the costs of drug acquisition, medical management, and management of adverse effects. The expected cost of management and disease-free days were determined, and a sensitivity analysis was conducted. It was concluded that Ciclopirox 8% nail lacquer, which has recently become available in the larger size of 6.6 mL, is a cost-effective agent for the management of toenail onychomycosis.