scholarly journals In VitroandIn VivoAssessment of Dermatophyte Acquired Resistance to Efinaconazole, a Novel Triazole Antifungal

2014 ◽  
Vol 58 (8) ◽  
pp. 4920-4922 ◽  
Author(s):  
Atsushi Iwata ◽  
Yoko Watanabe ◽  
Naomichi Kumagai ◽  
Maria Katafuchi-Nagashima ◽  
Keita Sugiura ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Trichophyton Rubrum ◽  
Acquired Resistance ◽  
Continuous Exposure ◽  
Experimental Conditions ◽  
Resistance Development ◽  
Content Type ◽  
Induce Resistance ◽  
Nail Infection

ABSTRACTEfinaconazole is a novel triazole antifungal drug for the topical treatment of onychomycosis, a nail infection caused mainly by dermatophytes. We assessed the potential of efinaconazole to induce resistance in dermatophytes by continuous exposure ofTrichophyton rubrumstrains to efinaconazolein vitro(12 passages) and in a guinea pig onychomycosis model (8 weeks). There was no evidence of efinaconazole resistance development in the tested strains under the experimental conditions used.

scholarly journals Ciclopirox and Efinaconazole Transungual Permeation, Antifungal Activity, and Proficiency To Induce Resistance in Trichophyton rubrum

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Daniela Monti ◽  
Diletta Mazzantini ◽  
Silvia Tampucci ◽  
Alessandra Vecchione ◽  
Francesco Celandroni ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Trichophyton Rubrum ◽  
Nail Plate ◽  
Content Type ◽  
Nail Bed ◽  
Antimycotic Activity ◽  
Frequent Relapses ◽  
Induce Resistance ◽  
Over Time

ABSTRACT Onychomycosis is a nail fungal infection, mostly caused by dermatophytes. The treatment efficacy is impaired by difficulties of reaching effective drug levels at the site of infection; frequent relapses occur after cessation of antifungal therapy. The aim of the study was to compare two commercial products containing ciclopirox or efinaconazole for antimycotic activity and antifungal drug resistance. A study of permeation and penetration through bovine hoof membranes, as a nail model, was performed to evaluate the antimycotic activity of permeates against clinical isolates of selected fungi, and the frequency of spontaneous in vitro Trichophyton rubrum-resistant strains was assessed by broth microdilution assays. The results suggest that ciclopirox creates a depot in the nail, leading to a gradual release of the drug over time with action on both the nail plate and bed. Conversely, efinaconazole, mildly interacting with nail keratin, mainly exerts its antifungal activity in the nail bed. However, in the case of T. rubrum, the antifungal activities of the drugs in the nail plate seem comparable. Finally, efinaconazole showed a potential for induction of resistance in T. rubrum, which may limit its efficacy over time. Ciclopirox did not show any potential to induce resistance in T. rubrum and appears endowed with a more complete activity than efinaconazole in the management of onychomycosis as the nail keratin is a substrate for the growth of fungal cells, and the availability of drug in large concentration just in the nail bed may not be sufficient to guarantee the complete eradication of pathogens.

scholarly journals Comparison ofIn VitroAntifungal Activities of Efinaconazole and Currently Available Antifungal Agents against a Variety of Pathogenic Fungi Associated with Onychomycosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1610-1616 ◽  
Author(s):  
William J. Jo Siu ◽  
Yoshiyuki Tatsumi ◽  
Hisato Senda ◽  
Radhakrishnan Pillai ◽  
Takashi Nakamura ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Trichophyton Rubrum ◽  
Yeast Species ◽  
Pathogenic Fungi ◽  
Trichophyton Mentagrophytes ◽  
Antifungal Drugs ◽  
Content Type ◽  
Comprehensive Survey ◽  
Nail Infection

ABSTRACTOnychomycosis is a common fungal nail infection in adults that is difficult to treat. Thein vitroantifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates ofTrichophyton rubrum,Trichophyton mentagrophytes, andCandida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs againstT. rubrumandT. mentagrophytesranged from ≤0.002 to 0.06 μg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 μg/ml, respectively. Efinaconazole MICs against 105C. albicansisolates ranged from ≤0.0005 to >0.25 μg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 μg/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13T. rubrumtoenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active againstTrichophyton,Microsporum,Epidermophyton,Acremonium,Fusarium,Paecilomyces,Pseudallescheria,Scopulariopsis,Aspergillus,Cryptococcus,Trichosporon, andCandidaand compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

scholarly journals MBX-500, a Hybrid Antibiotic withIn VitroandIn VivoEfficacy against Toxigenic Clostridium difficile

2012 ◽  
Vol 56 (9) ◽  
pp. 4786-4792 ◽  
Author(s):  
Michelle M. Butler ◽  
Dean L. Shinabarger ◽  
Diane M. Citron ◽  
Ciarán P. Kelly ◽  
Sofya Dvoskin ◽  
...  
Keyword(s):  
Weight Gain ◽  
Clostridium Difficile ◽  
Severe Disease ◽  
Normal Weight ◽  
New Drugs ◽  
Hamster Model ◽  
Resistance Development ◽  
Content Type

ABSTRACTClostridium difficileinfection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, thein vitroandin vivoefficacies of MBX-500 were explored against the Gram-positive anaerobe,C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

scholarly journals Imipenem/Cilastatin/Relebactam Alone and in Combination against Pseudomonas aeruginosa in the In Vitro Pharmacodynamic Model

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Iris H. Chen ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Resistance Development ◽  
Content Type ◽  
Combination Studies ◽  
The Mean ◽  
Combined Drugs

ABSTRACT Combination therapy may enhance imipenem/cilastatin/relebactam’s (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were −2.52 ± 0.49, −1.49 ± 0.49, −1.15 ± 0.67, and −0.61 ± 0.10 log10 CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24-h CFU reductions ranging from −2.62 to −4.67 log10 CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving −0.51- to −3.33-log10 CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.

scholarly journals Silicon Phthalocyanine 4 Phototoxicity in Trichophyton rubrum

2014 ◽  
Vol 58 (6) ◽  
pp. 3029-3034 ◽  
Author(s):  
Minh Lam ◽  
Matthew L. Dimaano ◽  
Patricia Oyetakin-White ◽  
Mauricio A. Retuerto ◽  
Jyotsna Chandra ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Trichophyton Rubrum ◽  
Therapeutic Option ◽  
Age Related Macular Degeneration ◽  
Noninvasive Treatment ◽  
Content Type ◽  
Age Related ◽  
Wide Range ◽  
Silicon Phthalocyanine

ABSTRACTTrichophyton rubrumis the leading pathogen that causes long-lasting skin and nail dermatophyte infections. Currently, topical treatment consists of terbinafine for the skin and ciclopirox for the nails, whereas systemic agents, such as oral terbinafine and itraconazole, are also prescribed. These systemic drugs have severe side effects, including liver toxicity. Topical therapies, however, are sometimes ineffective. This led us to investigate alternative treatment options, such as photodynamic therapy (PDT). Although PDT is traditionally recognized as a therapeutic option for treating a wide range of medical conditions, including age-related macular degeneration and malignant cancers, its antimicrobial properties have also received considerable attention. However, the mechanism(s) underlying the susceptibility of dermatophytic fungi to PDT is relatively unknown. As a noninvasive treatment, PDT uses a photosensitizing drug and light, which, in the presence of oxygen, results in cellular destruction. In this study, we investigated the mechanism of cytotoxicity of PDTin vitrousing the silicon phthalocyanine (Pc) 4 [SiPc(OSi(CH3)2(CH2)3N(CH3)2)(OH)] inT. rubrum. Confocal microscopy revealed that Pc 4 binds to cytoplasmic organelles, and upon irradiation, reactive oxygen species (ROS) are generated. The impairment of fungal metabolic activities as measured by an XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) assay indicated that 1.0 μM Pc 4 followed by 670 to 675 nm light at 2.0 J/cm2reduced the overall cell survival rate, which was substantiated by a dry weight assay. In addition, we found that this therapeutic approach is effective against terbinafine-sensitive (24602) and terbinafine-resistant (MRL666) strains. These data suggest that Pc 4-PDT may have utility as a treatment for dermatophytosis.

scholarly journals Contribution of Resistance-Nodulation-Division Efflux Pump OperonsmeU1-V-W-U2-Xto Multidrug Resistance of Stenotrophomonas maltophilia

2011 ◽  
Vol 55 (12) ◽  
pp. 5826-5833 ◽  
Author(s):  
Chao-Hsien Chen ◽  
Chiang-Ching Huang ◽  
Tsao-Chuen Chung ◽  
Rouh-Mei Hu ◽  
Yi-Wei Huang ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Type Systems ◽  
Resistant Mutant ◽  
Multidrug Resistant ◽  
Content Type ◽  
Membrane Fusion Protein ◽  
Resistance Nodulation Division

ABSTRACTKJ09C, a multidrug-resistant mutant ofStenotrophomonas maltophiliaKJ, was generated byin vitroselection with chloramphenicol. The multidrug-resistant phenotype of KJ09C was attributed to overexpression of a resistance nodulation division (RND)-type efflux system encoded by an operon consisting of five genes:smeU1,smeV,smeW,smeU2, andsmeX. Proteins encoded bysmeV,smeW, andsmeXwere similar to the membrane fusion protein, RND transporter, and outer membrane protein, respectively, of known RND-type systems. The proteins encoded bysmeU1andsmeU2were found to belong to the family of short-chain dehydrogenases/reductases. Mutant KJ09C exhibited increased resistance to chloramphenicol, quinolones, and tetracyclines and susceptibility to aminoglycosides; susceptibility to β-lactams and erythromycin was not affected. The expression of thesmeU1-V-W-U2-Xoperon was regulated by the divergently transcribed LysR-type regulator genesmeRv. Overexpression of the SmeVWX pump contributed to the acquired resistance to chloramphenicol, quinolones, and tetracyclines. Inactivation ofsmeVandsmeWcompletely abolished the activity of the SmeVWX pump, whereas inactivation ofsmeXalone decreased the activity of the SmeVWX pump. The enhanced aminoglycoside susceptibility observed in KJ09C resulted from SmeX overexpression.

scholarly journals Mycobacterial Esx-3 Requires Multiple Components for Iron Acquisition

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
M. Sloan Siegrist ◽  
Magnus Steigedal ◽  
Rushdy Ahmad ◽  
Alka Mehra ◽  
Marte S. Dragset ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Iron Acquisition ◽  
Multiple Reaction Monitoring ◽  
Protein Export ◽  
Secretion Systems ◽  
Experimental Conditions ◽  
Content Type ◽  
Type Vii Secretion ◽  
Wide Range

ABSTRACT The type VII secretion systems are conserved across mycobacterial species and in many Gram-positive bacteria. While the well-characterized Esx-1 pathway is required for the virulence of pathogenic mycobacteria and conjugation in the model organism Mycobacterium smegmatis, Esx-3 contributes to mycobactin-mediated iron acquisition in these bacteria. Here we show that several Esx-3 components are individually required for function under low-iron conditions but that at least one, the membrane-bound protease MycP3 of M. smegmatis, is partially expendable. All of the esx-3 mutants tested, including the ΔmycP 3ms mutant, failed to export the native Esx-3 substrates EsxH ms and EsxG ms to quantifiable levels, as determined by targeted mass spectrometry. Although we were able to restore low-iron growth to the esx-3 mutants by genetic complementation, we found a wide range of complementation levels for protein export. Indeed, minute quantities of extracellular EsxH ms and EsxG ms were sufficient for iron acquisition under our experimental conditions. The apparent separation of Esx-3 function in iron acquisition from robust EsxG ms and EsxH ms secretion in the ΔmycP 3ms mutant and in some of the complemented esx-3 mutants compels reexamination of the structure-function relationships for type VII secretion systems. IMPORTANCE Mycobacteria have several paralogous type VII secretion systems, Esx-1 through Esx-5. Whereas Esx-1 is required for pathogenic mycobacteria to grow within an infected host, Esx-3 is essential for growth in vitro. We and others have shown that Esx-3 is required for siderophore-mediated iron acquisition. In this work, we identify individual Esx-3 components that contribute to this process. As in the Esx-1 system, most mutations that abolish Esx-3 protein export also disrupt its function. Unexpectedly, however, ultrasensitive quantitation of Esx-3 secretion by multiple-reaction-monitoring mass spectrometry (MRM-MS) revealed that very low levels of export were sufficient for iron acquisition under similar conditions. Although protein export clearly contributes to type VII function, the relationship is not absolute.

scholarly journals In VitroAntifungal Activity of Naftifine Hydrochloride against Dermatophytes

2013 ◽  
Vol 57 (9) ◽  
pp. 4369-4372 ◽  
Author(s):  
M. Ghannoum ◽  
N. Isham ◽  
A. Verma ◽  
S. Plaum ◽  
A. Fleischer ◽  
...  
Keyword(s):  
Developed Countries ◽  
Microsporum Canis ◽  
Test Panel ◽  
Resistance Development ◽  
Epidermophyton Floccosum ◽  
Content Type ◽  
Development Of Resistance ◽  
Time Kill ◽  
Dose Dependent

ABSTRACTThe incidence of superficial dermatophytoses is high in developed countries, and there remains a need for effective topical antifungals. In this study, we evaluated thein vitroantifungal activity of naftifine hydrochloride, the active ingredient in naftifine hydrochloride cream and gel 1% and 2%, against dermatophytes. The MICs and minimum fungicidal concentrations (MFCs) of naftifine hydrochloride against 350 clinical strains, includingTrichophyton rubrum,T. mentagrophytes,T. tonsurans,Epidermophyton floccosum, andMicrosporum canis, were determined using the CLSI methodology. Subsets from this test panel were subsequently tested in a time-kill assay at 0.125×, 0.25×, 0.5×, and 1× the MFC for each isolate. CFU counts were performed over a period of 48 h of incubation. Additionally, in order to determine the potential for resistance development, six strains were subjected to 15 serial passages in concentrations higher than the MIC for each strain. MICs were determined following each passage. The MIC range against the dermatophyte isolates tested was 0.015 to 1.0 μg/ml, with naftifine hydrochloride being fungicidal against 85% of theTrichophytonspecies. The time-kill assay showed dose-dependent activity, with the greatest reduction in the numbers of CFU corresponding to the highest drug concentration. There was no increase in MIC for any strains following repeated exposure to naftifine hydrochloride. Naftifine hydrochloride demonstrated potent activity against all dermatophytes tested, and none of the isolates within this test panel demonstrated the potential for the development of resistance. Thus, future clinical studies of naftifine hydrochloride against dermatophytes may be warranted for the treatment of superficial dermatophytoses.

scholarly journals Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Csaba Papp ◽  
Katica Kocsis ◽  
Renáta Tóth ◽  
László Bodai ◽  
Jesse R. Willis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid ◽  
Candida Parapsilosis ◽  
Hot Spot ◽  
Abiotic Stress Tolerance ◽  
Acquired Resistance ◽  
Cross Resistance ◽  
First Line ◽  
Content Type

ABSTRACT Candida species are a major cause of life-threatening bloodstream infections worldwide. Although Candida albicans is responsible for the vast majority of infections, the clinical relevance of other Candida species has also emerged over the last twenty years. This shift might be due in part to changes in clinical guidelines, as echinocandins became the first line of therapeutics for the treatment. Candida parapsilosis is an emerging non-albicans Candida species that exhibits lower susceptibility levels to these drugs. Candida species frequently display resistance to echinocandins, and the mechanism for this is well-known in C. albicans and Candida glabrata, where it is mediated by amino acid substitutions at defined locations of the β-1,3-glucan synthase, Fks1p. In C. parapsilosis isolates, Fks1p harbors an intrinsic amino acid change at position 660 of the hot spot 1 (HS1) region, which is thought to be responsible for the high MIC values. Less is known about acquired substitutions in this species. In this study, we used directed evolution experiments to generate C. parapsilosis strains with acquired resistance to caspofungin, anidulafungin, and micafungin. We showed that cross-resistance was dependent on the type of echinocandin used to generate the evolved strains. During their characterization, all mutant strains showed attenuated virulence in vivo and also displayed alterations in the exposure of inner cell wall components. The evolved strains harbored 251 amino acid changes, including three in the HS1, HS2, and HS3 regions of Fks1p. Altogether, our results demonstrate a direct connection between acquired antifungal resistance and virulence of C. parapsilosis. IMPORTANCE Candida parapsilosis is an opportunistic fungal pathogen with the ability to cause infections in immunocompromised patients. Echinocandins are the currently recommended first line of treatment for all Candida species. Resistance of Candida albicans to this drug type is well characterized. C. parapsilosis strains have the lowest in vitro susceptibility to echinocandins; however, patients with such infections typically respond well to echinocandin therapy. There is little knowledge of acquired resistance in C. parapsilosis and its consequences on other characteristics such as virulence properties. In this study, we aimed to dissect how acquired echinocandin resistance influences the pathogenicity of C. parapsilosis and to develop explanations for why echinocandins are clinically effective in the setting of acquired resistance.

scholarly journals Synergistic Efficacy of β-Lactam Combinations againstMycobacterium abscessusPulmonary Infection in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Acquired Resistance ◽  
Mycobacterium Abscessus ◽  
The Novel ◽  
Content Type ◽  
Treatment Regimens ◽  
Chronic Lung Diseases ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Inhibitor Combination

ABSTRACTMycobacterium abscessusis an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinicalM. abscessusisolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several β-lactams againstM. abscessusin vitro; however, these combinations have never been tested in an animal model ofM. abscessuspulmonary disease. We utilized a recently developed murine system of sustainedM. abscessuslung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual β-lactam combinations and one β-lactam/β-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log10reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).

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