BACKGROUND.Candida auris has demonstrated the ability to colonize the skin of hospitalized patients, possibly contributing to nosocomial spread. OBJECTIVE. The objective was to determine whether two novel transdermal agents could clear skin colonization established by C. aurisMETHODS. A murine skin colonization model was first optimized and then used to test fungal burden reduction following treatment with 1% terbinafine or 1% clotrimazole in a proprietary Advanced Penetration Technology formulation (APT™). RESULTS. Both treatments significantly reduced fungal burden compared to control groups. CONCLUSION. These novel agents show promise as a topical means of preventing skin colonization by C. auris.

Use of broad-spectrum antibiotics (e.g., doxycycline, minocycline) significantly alters the gut and skin microbiome leading to dysbiosis, resulting in microbial imbalance and has been associated with exacerbation of inflammation. Sarecycline was developed as the first narrow-spectrum tetracycline-class antibiotic to treat acne. Narrow-spectrum antibiotics are hypothesized to cause minimal interference with endogenous gastrointestinal (GI) tract microbiota, thereby maintaining innate microbial diversity. To examine the breadth of this effect, a panel of microorganisms that reflect the diversity of the gut microbiome were evaluated with sarecycline compared to the broad-spectrum minocycline using in vitro susceptibility testing and time-kill assays. Sarecycline had a lower minimum inhibitory concentration (MIC) against 3 out of 4 isolates from Actinobacteria phylum, 10 out of 12 isolates from Bacteroidetes, and 5 out of 7 isolates from the Firmicutes. Furthermore, sarecycline was less active against E. coli, and significantly less active against P. freudenreichii when compared to minocycline. Against fungi, sarecycline showed less activity against 4 representative Candida species. Time-kill curves for E. coli and C. tropicalis showed significantly less activity against E. coli for sarecycline compared to minocycline at all time-points (p-values <0.05). Similarly, sarecycline was significantly less effective in inhibiting C. tropicalis compared to minocycline at 20 and 22 hours exposure. Overall, sarecycline showed reduced antimicrobial activity against 79% of gut microflora tested compared to minocycline, suggesting that it has less potential to cause dysbiosis. Further in vivo testing is warranted.

Coating or dipping inflatable penile prosthesis (IPP) into antibiotic solutions is a well-established practice during implantation. More recently there has been a trend towards dipping prosthetics in additional antimicrobial solutions (i.e. antifungals), along with local anesthetics. There is insufficient evidence to support this practice in a controlled setting with previous studies being conducted with limited species, antibiotic solutions, or repetitions of the experiment.

Candida auris has been shown to have a high risk of skin colonization in hospitalized patients, possibly contributing to nosocomial spread. In a guinea pig skin model, animals were evaluated for clinical appearance, tissue fungal burden, histology, and pharmacokinetics. Oral dosing with 10 mg/kg ibrexafungerp (IBX) reduced the severity of lesions and significantly reduced the C. auris fungal burden in infected animals compared with untreated controls.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata Susceptibility of clinical strains to Ibrexafungerp was determined by microdilution and time kill assays. The MIC range against wild type strains was 1-2 μg/mL. IBX was also active against the majority of echinocandin-resistant strains. Time kill studies showed a 4 to 6-log reduction in growth at concentrations of 0.25 to 4 μg/ml at 24 and 48 hr.

Probiotics in various combinations and in various forms have become popular supplements for establishing and maintaining gut health. However, commercial products vary in the effectiveness of their specific probiotic strains and the ability of these strains to survive the acidic environment of the stomach. A novel probiotic, manufactured by BIOHM, LLC, has a unique formulation of Saccharomyces boulardii, Lactobacillus acidophilus, L. rhamnosus, and Bifidobacterium breve, in combination with amylase, which has been developed to re-balance the bacterial and fungal population of the human gastrointestinal tract and combat digestive biofilms formed by pathogenic bacteria and fungi. Our data shows that these strains have the ability to survive the acidic environment when taken within 30 minutes of meal, a factor that is vital to ensure probiotic effectiveness.

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.

Central line associated bloodstream infections (CLABSIs) are increasingly recognized to be associated with intralumenal microbial biofilms, and effective measures for the prevention and treatment of BSI remain lacking. This report evaluates a new commercially developed antimicrobial catheter lock solution (ACL) containing trimethoprim (5 mg/ml) and ethanol (25%) and CA-EDTA 3% for activity against bacterial and fungal biofilms using in vitro and in vivo (rabbit) catheter biofilm models. Biofilms were formed with bacterial (seven different species including vancomycin-resistant enterococcus, VRE) or fungal ( C . albicans ) species on catheter materials. Biofilm formation was evaluated by quantitative culture (colony forming units, CFUs) and scanning electron microscopy (SEM). Treatment with ACL inhibited growth of adhesion phase biofilms in vitro after 60 min (VRE) or 15 min (all others), while mature biofilms were eradicated after exposure for 2 or 4 h, compared to control. Similar results were observed for drug-resistant bacteria. In the catheterized rabbit model, when compared against heparinized saline control, ACL lock therapy significantly reduced the catheter bacterial (3.49 ± 0.75 vs. 0.03 ± 0.06 log CFU/catheter, respectively; P = 0.001) and fungal burden (2.48 ± 1.60 vs. 0.55 ± 1.19 log CFU/catheter segment, respectively; P = 0.012). SEM also demonstrated eradication of bacterial and fungal biofilms in vivo on catheters exposed to ACL, while vigorous biofilms were observed on untreated control catheters. Our results demonstrate that ACL was efficacious against both adhesion phase and mature biofilms formed by bacteria and fungi in vitro as well as in vivo .

ABSTRACT Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non- fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 μg/ml) compared with the activities of amphotericin B (MIC 90 = 8 μg/ml) and voriconazole (MIC 90 = 2 μg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

Background: Dermatophytosis, including onychomycosis, causes significant discomfort and affects patient quality-of-life. More effective therapies are needed. Echinocandin antifungals have been used clinically for over 15 years but not for treatment of dermatophytosis, as current echinocandins are limited to IV administration. CD101 is a novel echinocandin with stability that enables non-IV formulation. The aim of this study was to evaluate subcutaneous (SQ) CD101 in the treatment of Trichophyton mentagrophytes (TM) dermatophytosis in a GP model. Methods: Male albino GPs (weighing 400-450 g) were clipped, shaved and skin-abraded. GPs were inoculated with 107 conidia of TM ATCC 24953 and randomized into 5 groups (n=10/group). Starting on the day of inoculation, treatments were given on days 1 and 8 as follows: CD101 10 mg/kg, 20 mg/kg or 40 mg/kg SQ; terbinafine (TERB) 10 mg/kg PO as a positive control; and a vehicle control (VC). On day 12 postchallenge, clinical and mycological evaluations were performed. Results: Clinical Efficacy: As expected, VC guinea pigs showed hair loss and ulcerated, scaly skin. Percent efficacies for CD101 10, 20 and 40 mg/kg were 90.5, 94.2 and 98.4%, respectively, and 76.8% for TERB 10 mg/kg. All treatment groups showed significant efficacy compared with the VC (P < 0.001). Mycological Efficacy: The VC behaved as expected having the highest average fungal positive hairs. Percent efficacies for CD101 10, 20 and 40 mg/kg were 80.9, 82.9 and 98.5%, respectively, and 54.2% for TERB 10 mg/kg. All treatment groups showed significant efficacy compared with the VC (P < 0.001). The CD101–treated groups showed significant efficacy compared with the TERB –treated group (P≤0.001). Conclusions: All CD101-treated groups showed significant clinical and mycological efficacy compared with the VC and the TERB –treated group. Our findings demonstrate that CD101 dosed once weekly possesses potent mycological and clinical efficacy in a GP model of dermatophytosis.

ABSTRACT The treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, the in vivo efficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with a P value of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding.

ABSTRACT Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction ( P < 0.001) and improvement in clinical scores ( P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly ( P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

ABSTRACT The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC ( n = 400) and the minimum fungicidal concentration (MFC) ( n = 300). Additionally, we examined the potential for resistance development in dermatophytes ( n = 4) following repeated exposure to ME1111. Our data show that the MIC 90 of ME1111 against dermatophyte strains was 0.25 μg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC 90 s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 μg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes.

ABSTRACT The development of a topical agent that would strengthen the nail, improve the natural barrier, and provide better drug penetration to the nail bed is needed. In this study, we examined the effects of a hydroxypropyl chitosan (HPCH)-based nail solution using a bovine hoof model. Following application of the nail solution, changes in the hardness of the hoof samples were measured using the Vickers method. Tensile and flexural strengths were tested by stretching or punching the samples, respectively. The ultrastructure was examined using scanning electron microscopy (SEM), and samples stained with periodic acid-Schiff (PAS) stain were used to determine the fungal penetration depth. The comparators included 40% urea and 70% isopropyl alcohol solutions. The HPCH nail solution increased hoof sample hardness in comparison to the untreated control sample (mean, 22.3 versus 19.4 Vickers pyramid number [HV]). Similarly, the HPCH solution increased the tensile strength (mean, 33.07 versus 28.42 MPa) and flexural strength (mean, 183.79 versus 181.20 MPa) compared to the untreated control. In contrast, the comparators had adverse effects on hardness and strength. SEM showed that the HPCH solution reduced the area of sample crumbling following abrasion compared to the untreated control (7,418 versus 17,843 pixels), and the PAS-stained images showed that the HPCH solution reduced penetration of the dermatophyte hyphae (e.g., penetration by Trichophyton mentagrophytes was <25 μm at day 9 versus 275 μm in the untreated control). Unlike chemicals normally used in cosmetic treatments, repeated application of the HPCH nail solution may help prevent the establishment of new or recurring fungal nail infection.

The in vivo efficacy of terbinafine was compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Topical antifungal treatment commenced three days post-infection, and each agent was applied once daily for seven consecutive days. Upon completion of the treatment period, evaluations of clinical and mycological efficacies were performed, as was scanning electron microscopy (SEM) analyses. Data showed that while all tested antifungals demonstrated significant mycological efficacy in terms of eradicating the fungi over untreated control, terbinafine and luliconazole showed superior clinical efficacy compared to lanoconazole (P-values < 0.001 & 0.003, respectively). Terbinafine demonstrated the highest clinical percent efficacy. SEM analysis revealed hairs from terbinafine and lanoconazole-treated animals had near complete clearance of fungi, while samples from luliconazole-treated animals were covered with debris and few conidia. This study demonstrates that, in general, terbinafine possessed similar efficacy to lanoconazole and luliconazole in the treatment of dermatophytosis. Terbinafine tended to have superior clinical efficacy compared to the azoles tested, although this difference was not statistically significant against luliconazole. This apparent superiority may be due to the fungicidal activity of terbinafine compared to the fungistatic effect of the other two drugs.

Staphylococcus aureus is found in a wide variety of habitats, including human skin, where many strains are commensals that may be clinically significant or contaminants of food. A number of factors contribute to the virulence of S. aureus, including deoxyribonuclease (DNase), catalase, lipases, and hemolysins. However, the most notable virulence factors are the enterotoxins. Staphylococcal food poisoning results from consumption of one or more preformed enterotoxins resulting in symptoms of intoxication. In clinical and food settings, S. aureus is found within a high density of other microflora, requiring selective bacteriological media for isolation and enumeration. However, due to sublethal stress placed on food contaminants, including S. aureus during processing, direct detection/enumeration using selective media may underestimate the level of contamination. One option for recovering sublethally injured organisms is an approach using selective agar overlays, a method shown to be effective for coliforms and other common pathogens. This inexpensive variation on the common standard plate count means for enumeration of bacteria in food improves detection sensitivity for cells that may be sublethally injured or stressed from food processing treatments. Therefore, implementation of this as a means for more accurately determining the microbiological quality of foods is met with low cost and general acceptance for smaller food processing operations. The application of this technique, however, has not been largely explored for specific Gram-positive pathogens such as S. aureus, but is perhaps warranted owing to the increasing number of characterized enterotoxins from these strains.

OBJECTIVES The objective of this study was to compare the activity of aminocandin, a new echinocandin with broad-spectrum activity against Candida spp., with that of amphotericin B, caspofungin and fluconazole, in an immunocompetent murine model of haematogenously disseminated candidiasis caused by a fluconazole-resistant Candida albicans. METHODS Mice were infected with a fluconazole-resistant strain of C. albicans and treated with aminocandin 5 and 10 mg/kg intravenously (iv) once and twice weekly, amphotericin B 0.5 mg/kg iv every other day for 5 days, fluconazole 20 mg/kg orally (po) once a day for 5 days and caspofungin 0.5 mg/kg intraperitoneally (ip) once daily for 5 days. RESULTS Treatment with aminocandin, given iv twice a week, resulted in 100% survival. Further, the tissue fungal burden of the aminocandin group was equivalent to that of amphotericin B (administered every other day) and caspofungin (administered daily). CONCLUSIONS Aminocandin may be an effective addition to the arsenal of antifungal compounds for the treatment of candidiasis caused by fluconazole-resistant C. albicans.

The Bhopal tragedy was a defining moment in the history of the chemical industry. On December 3, 1984, a runaway reaction within a methyl isocyanate storage tank at the Union Carbide India Limited pesticide plant released a toxic gas cloud that killed thousands and injured hundreds of thousands. After Bhopal, industrial chemical plants became a major public concern. Both the public and the chemical industry realized the necessity of improving chemical process safety.Bhopal served as a wake-up call. To prevent the same event from occurring in the United States, many legislative and industrial changes were invoked-one of which was formation of the U.S. Chemical Safety and Hazard Investigation Board (CSB). The ultimate goal of CSB is to use the lessons learned and recommendations from its investigations to achieve positive change within the chemical industry-preventing incidents and saving lives.Although it seems clear that the lessons learned at Bhopal have improved chemical plant safety, CSB investigations indicate that the systemic problems identified at Bhopal remain the underlying causes of many incidents. These include:center dot Lack of awareness of reactive hazards.center dot Lack of management of change.center dot Inadequate plant design and maintenance.center dot Ineffective employee training.center dot Ineffective emergency preparedness and community notification.center dot Lack of root cause incident investigations and communication of lessons learned.The aim of this paper is to present common themes from recent cases investigated by CSB and to discuss how these issues might be best addressed in the future.This paper has not been independently approved by the Board and is published for general informational purposes only. Any material in the paper that did not originate in a Board-approved report is solely the responsibility of the authors and does not represent an official finding, conclusion, or position of the Board. (c) 2005 Elsevier Ltd. All rights reserved.

Dermatophytoses are known to cause considerable discomfort, cosmetic problems and financial loss that have been recognized as a significant health concern worldwide. Since currently available antifungal agents have limitations in their efficacy, new agents are being developed. This study was undertaken to optimize an in vivo model of experimental dermatophytosis for evaluation of the efficacy of antifungal compounds. Guinea pigs were infected with different inocula of T. mentagrophytes to establish dermatophytosis. The optimal conditions for dermatophytosis in guinea pigs were found to be an inoculum size of 1 x 10(7) fungal cells applied on abraded skin. After optimization, animals were treated with oral or topical formulations of terbinafine. The optimized guinea pig model was found to be highly reproducible, and useful in the primary screening and evaluation of the anti-dermatophytic efficacy of topical and oral formulations of antifungal agents.