DAXXIFYTM (DaxibotulinumtoxinA-Lanm) for Injection, for Intramuscular Use.

DAXXIFYTM (daxibotulinumtoxinA-lanm) for intramuscular injection was recently approved for temporary improvement in the appearance of the moderate to severe glabellar lines (GLs) associated with corrugator and/or procerus muscle activity in adult patients. DaxibotulinumtoxinA for Injection (DAXI) includes a purified 150-kDA botulinum toxin Type A (BoNTA) formulated with a novel peptide excipient that is positively charged and helps to bind the neurotoxin to negatively charged neuronal membrane for a longer duration. The effectiveness of DAXI was evaluated in two phase 3 trials, SAKURA 1 and SAKURA 2, using a randomized, double-blind, placebo-controlled design. The primary endpoint (treatment success) was a composite clinical outcome (investigator and subjects) of ≥2-point improvement in severity of GLs at week 4. In SAKURA 1, the treatment success was 74% (148/201) in subjects treated with DAXI and 0% in subjects treated with placebo. In SAKURA 2, the treatment success was 74% (152/205) in subjects treated with DAXI and 0% in subjects treated with placebo. An open-label study, SAKURA 3, included 2,691 participants, who underwent three consecutive treatment cycles. These individuals were recruited from either SAKURA 1 or SAKURA 2 trials, or were new to the study and received DAXI. Treatment success proportions were 73.2%, 77.7%, and 79.6% across the three consecutive treatment cycles. The recommended dose is 40 units for the Glabellar-complex divided in traditional five intramuscular injections at five injection sites (medial and lateral corrugator bilaterally and one injection in the procerus muscle).

Antifungal resistance in dermatophytes - review of the epidemiology, diagnostic challenges and treatment strategies for managing Trichophyton indotineae infections.

INTRODUCTION: There is an increasing number of reports of Trichophyton indotineae infections. This species is usually poorly responsive to terbinafine. AREAS COVERED: A literature search was conducted in May 2024. T.indotineae infections detected outside the Indian subcontinent are generally associated with international travel. Reports of local spread are mounting.As a newly identified dermatophyte species closely related to the T. mentagrophytes complex with limited genetic and phenotypic differences, there is an unmet need to develop molecular diagnosis for T. indotineae. Terbinafine has become less effective as a first-line agent attributed to mutations in the squalene epoxidase gene (Leu393Phe, Phe397Leu). Alternative therapies include itraconazole for a longer time-period or a higher dose (200 mg/day or higher). Generally, fluconazole and griseofulvin are not effective. In some cases, especially when the area of involvement is relatively small, topical non-allylamine antifungals may be an option either as monotherapy or in combination with oral therapy. In instances when the patient relapses after apparent clinical cure then itraconazole may be considered. Good antifungal stewardship should be considered at all times. EXPERT OPINION: When both terbinafine and itraconazole are ineffective, options include off-label triazoles (voriconazole and posaconazole). We present four patients responding to these newer triazoles.

Ringworm (dermatophytosis, tinea) is a fungal infection of the skin, hair and nails that is commonly seen by primary and secondary healthcare providers. An estimated 20­25% of the global population is affected by this condition. In Europe and the United States, tineas are often treated empirically using over-the-counter medications, which can increase the risk of resistance development.While antifungal resistance is not a new problem, this topic has garnered the attention of physicians and researchers in recent years due to an outbreak from South Asia caused by a new pathogen known as Trichophyton indotineae. In this review, we summarize the global prevalence, diagnosis methods, antifungal resistance profile and treatment options for T. indotineae. Currently, most cases outside of South Asia are linked to international travel, there is evidence suggesting local person-to-person transmission and transmission via animal contact. One hurdle to surveilling the spread of this pathogen is the requirement of complex molecular diagnosis, tackling this challenge will require the development of newer assays.Terbinafine, a widely available antifungal drug, is becoming less effective owing to resistance mutations of the squalene epoxidase gene. Itraconazole has shown effectiveness, especially with a higher dose and a longer treatment duration. There is a significant risk of T. indotineae infections becoming chronic with episodes of relapse. When both terbinafine and itraconazole fail, newer agents such as posaconazole and voriconazole can be considered. Combination therapy using oral and topical medications should also be considered.

Spevigo® (Spesolimab-Sbzo) Injection for the Treatment of Generalized Pustular Psoriasis.

Spevigo® (spesolimab-sbzo) injection was recently approved for the treatment of generalized pustular psoriasis (GPP) in adults aged 18- 75 years. Spesolimab, a monoclonal antibody, binds to the interleukin-36 (IL-36) receptor and prevents its activation by IL-36 cytokines, leading to reduced inflammation, skin lesions, and flares. In a randomized placebo-controlled, phase 2 study (Effisayil-1, NCT03782792), 53 patients were randomized to spesolimab (n = 35) and placebo (n = 18) to evaluate the effect of a one-time 900-mg dose of spesolimab versus placebo against GPP flares. The primary endpoint was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (no visible pustules) and the key secondary endpoint was the GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1. The primary endpoint was achieved by 54% (19/35) of patients in the spesolimab group and 6% (1/18) of patients in the placebo group. The key secondary endpoint was achieved by 43% (15/35) of patients in the spesolimab group and 11% (2/18) of patients in the placebo group. In the first week, adverse events (mild to severe) were reported in 66% (22/35) of patients in the spesolimab group and 56% (10/18) in the placebo group.

Libtayo® (Cemiplimab-rwlc) Injection for Intravenous Use.

Libtayo® (cemiplimab-rwlc) injection for intravenous use was recently approved by the US Food and Drug Administration (FDA) for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC), both being the advanced stages of BCC. In the past, it was approved by the FDA for the treatment of metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC), both being the advanced stages of CSCC. Cemiplimab is a monoclonal antibody that works by blocking the programmed death-1 pathway. In two open-label, single-arm, phase 2 studies, cemiplimab was investigated for the treatment of advanced stages of BCC (study 1620, NCT03132636) and advanced stages of CSCC (study 1540, NCT02760498). The primary endpoint was objec-tive response rate (ORR) per independent central review. In the study 1620, both mBCC and laBCC received cemiplimab 350 mg every 3 weeks. ORR was 21% (6/28) and 31% (26/84) in the mBCC and laBCC groups, respectively. In the study 1520, mCSCC was divided into two groups: one receiving cemiplimab 350 mg every 3 weeks (Q3W) and another receiving 3-mg/kg cemiplimab every 2 weeks (Q2W); the third group, laCSCC, received cemiplimab 3 mg/kg every 2 weeks. ORR was 41% (23/56) in the Q3W group, 49% (29/59) in the Q2W group, and 44% (34/78) in the laCSCC group. An acceptable safety profile and antitumor activity was discovered in patients treated with cemiplimab. The recommended dosage for cemiplimab to treat advanced stages of BCC and CSCC is 350 mg every 3 weeks administered intravenously over 30 min.

Global prevalence of onychomycosis in general and special populations: An updated perspective.

BACKGROUND: Onychomycosis is a chronic nail disorder commonly seen by healthcare providers; toenail involvement in particular presents a treatment challenge. OBJECTIVE: To provide an updated estimate on the prevalence of toenail onychomycosis. METHODS: We conducted a literature search using PubMed, Embase and Web of Science. Studies reporting mycology-confirmed diagnoses were included and stratified into (a) populations-based studies, and studies that included (b) clinically un-suspected and (c) clinically suspected patients. RESULTS: A total of 108 studies were included. Based on studies that examined clinically un-suspected patients (i.e., with or without clinical features suggestive of onychomycosis), the pooled prevalence rate of toenail onychomycosis caused by dermatophytes was 4% (95% CI: 3-5) among the general population; special populations with a heightened risk include knee osteoarthritis patients (RR: 14.6 [95% CI: 13.0-16.5]), chronic venous disease patients (RR: 5.6 [95% CI: 3.7-8.1]), renal transplant patients (RR: 4.7 [95% CI: 3.3-6.5]), geriatric patients (RR: 4.7 [95% CI: 4.4-4.9]), HIV-positive patients (RR: 3.7 [95% CI: 2.9-4.7]), lupus erythematosus patients (RR: 3.1 [95% CI: 1.2-6.3]), diabetic patients (RR: 2.8 [95% CI: 2.4-3.3]) and hemodialysis patients (RR: 2.8 [95% CI: 1.9-4.0]). The prevalence of onychomycosis in clinically suspected patients was significantly higher likely due to sampling bias. A high degree of variability was found in a limited number of population-based studies indicating that certain pockets of the population may be more predisposed to onychomycosis. The diagnosis of non-dermatophyte mould onychomycosis requires repeat sampling to rule out contaminants or commensal organisms; a significant difference was found between studies that performed single sampling versus repeat sampling. The advent of PCR diagnosis results in improved detection rates for dermatophytes compared to culture. CONCLUSION: Onychomycosis is an underrecognized healthcare burden. Further population-based studies using standardized PCR methods are warranted.

An update on antifungal resistance in dermatophytosis.

INTRODUCTION: The reports of resistance to antifungal agents used for treating onychomycosis and other superficial fungal infections are increasing. This rise in antifungal resistance poses a public health challenge that requires attention. AREAS COVERED: This review explores the prevalence of dermatophytes and the current relationship between dermatophyte species, their minimum inhibitory concentrations (MICs) for terbinafine (an allylamine) and itraconazole (an azole), and various mutations prevalent in these species. The most frequently isolated dermatophyte associated with resistance in patients with onychomycosis and dermatophytosis was T. mentagrophytes. However, T. indotineae emerged as the most prevalent isolate with mutations in the SQLE gene, exhibiting the highest MIC of 8 µg/ml for terbinafine and MICs of 8 µg/ml and ≥ 32 µg/ml for itraconazole.Overall, the most prevalent SQLE mutations were Phe397Leu, Leu393Phe, Ala448Thr, Phe397Leu/Ala448Thr, and Lys276Asn/Leu415Phe (relatively recent). EXPERT OPINION: Managing dermatophyte infections requires a personalized approach. A detailed history should be obtained including details of travel, home and occupational exposure, and clinical examination of the skin, nails and other body systems. Relevant testing includes mycological examination (traditional and molecular). Additional testing, where available, includes MIC evaluation and detection of SQLE mutations. In case of suspected terbinafine resistance, itraconazole or voriconazole (less commonly) should be considered.

XdemvyTM (Lotilaner Ophthalmic Solution) 0.25% Topical Solution for the Treatment of Demodex Blepharitis.

XdemvyTM (lotilaner ophthalmic solution) 0.25% topical solution was recently approved for the treatment of Demodex blepharitis in adults aged ≥18 years. As an antiparasitic agent, lotilaner selectively inhibits gamma-aminobutyric acid chloride channels specific to the parasite and induces spastic paralysis, leading to death of Demodex blepharitis mites. In two randomized, double-masked, vehicle-controlled, multi-center, phase-3 clinical trials (Saturn-1 and Satuirn-2), lotilaner 0.25% topical solution was investigated for the treatment of Demodex blepharitis. Patients were assigned to receive either lotilaner 0.25% topical solution or vehicle (solution that did not contain lotilaner as an active ingredient) twice daily for 6 weeks. On day 43, lotilaner group demonstrated primary efficacy in achieving collarette cure ([collarette grade 0], Saturn-1: study group 44% [92/209], vehicle 7.4% [15/204]; Saturn-2: study group 56% [108/193], vehicle 12.5% [25/200]). Secondary efficacy was achieved by eradication of mite ([0 mite/lash], Saturn-1: study group 67.9% [142/209], vehicle 17.6% [36/304]; Saturn-2: study group 51.8% [99/193], vehicle 14.6% [29/200]), composite cure ([grade 0 collarette as well as grade 0 erythema], Saturn-1: study group 13.9% [29/209], vehicle 1.0% [2/204]; Saturn-2: study group 19.2% [37/193], vehicle 4% [8/200]), and erythema cure ([grade 0 erythema], study group 19.1% [40/209], vehicle 6.9% [14/204]; Saturn-2: study group 31.1% [60/193], vehicle 9.0% [18/199]). The adverse events were mild, with the most common being pain at instillation site. The recommended regimen for lotilaner 0.25% solution is one drop in each eye twice daily for 6 weeks.

Characterization and synergy studies of Caudoviricete Escherichia phage FS2B infecting multi-drug resistant uropathogenic Escherichia coli isolates / Estudios de caracterización y sinergia del fago FS2B de Caudoviricete Escherichia que infecta aislados de Escherichia coli uropatógena multirresistente

Escherichia coli is one of the most common causes of urinary tract infections. However, a recent upsurge in antibiotic resistance among uropathogenic E. coli (UPEC) strains has provided an impetus to explore alternative antibacterial compounds to encounter this major issue. In this study, a lytic phage against multi-drug-resistant (MDR) UPEC strains was isolated and characterized. The isolated Escherichia phage FS2B of class Caudoviricetes exhibited high lytic activity, high burst size, and a small adsorption and latent time. The phage also exhibited a broad host range and inactivated 69.8% of the collected clinical, and 64.8% of the identified MDR UPEC strains. Further, whole genome sequencing revealed that the phage was 77,407 bp long, having a dsDNA with 124 coding regions. Annotation studies confirmed that the phage carried all the genes associated with lytic life cycle and all lysogeny related genes were absent in the genome. Further, synergism studies of the phage FS2B with antibiotics demonstrated a positive synergistic association among them. The present study therefore concluded that the phage FS2B possesses an immense potential to serve as a novel candidate for treatment of MDR UPEC strains.(AU)

Effectiveness and safety of oral terbinafine for dermatophyte distal subungual onychomycosis.

INTRODUCTION: Terbinafine has been a cornerstone in dermatophyte infection treatment. Despite its global efficacy, the emergence of terbinafine resistance raises concerns, requiring ongoing vigilance. AREAS COVERED: This paper focuses on evaluating the efficacy and safety of terbinafine in treating dermatophyte toenail infections. Continuous and pulse therapies, with a 24-week continuous regimen and a higher dosage of 500 mg/day have demonstrated superior efficacy to the FDA approved regimen of 250 mg/day x 12 weeks. Pulse therapies, though showing comparable effectiveness, present debates with regards to their efficacy as conflicting findings have been reported. Safety concerns encompass hepatotoxicity, gastrointestinal, cutaneous, neurologic, hematologic and immune adverse-effects, and possible drug interactions, suggesting the need for ongoing monitoring. EXPERT OPINION: Terbinafine efficacy depends on dosage, duration, and resistance patterns. Continuous therapy for 24 weeks and a dosage of 500 mg/day may enhance outcomes, but safety considerations and resistance necessitate individualized approaches. Alternatives, including topical agents and alternative antifungals, are to be considered for resistant cases. Understanding the interplay between treatment parameters, adverse effects, and resistance mechanisms is critical for optimizing therapeutic efficacy while mitigating resistance risks. Patient education and adherence are vital for early detection and management of adverse effects and resistance, contributing to tailored and effective treatments.

Characterization and synergy studies of Caudoviricete Escherichia phage FS2B infecting multi-drug resistant uropathogenic Escherichia coli isolates.

Escherichia coli is one of the most common causes of urinary tract infections. However, a recent upsurge in antibiotic resistance among uropathogenic E. coli (UPEC) strains has provided an impetus to explore alternative antibacterial compounds to encounter this major issue. In this study, a lytic phage against multi-drug-resistant (MDR) UPEC strains was isolated and characterized. The isolated Escherichia phage FS2B of class Caudoviricetes exhibited high lytic activity, high burst size, and a small adsorption and latent time. The phage also exhibited a broad host range and inactivated 69.8% of the collected clinical, and 64.8% of the identified MDR UPEC strains. Further, whole genome sequencing revealed that the phage was 77,407 bp long, having a dsDNA with 124 coding regions. Annotation studies confirmed that the phage carried all the genes associated with lytic life cycle and all lysogeny related genes were absent in the genome. Further, synergism studies of the phage FS2B with antibiotics demonstrated a positive synergistic association among them. The present study therefore concluded that the phage FS2B possesses an immense potential to serve as a novel candidate for treatment of MDR UPEC strains.

Navigating fungal infections and antifungal stewardship: drug resistance, susceptibility testing, therapeutic drug monitoring and future directions.

Antifungal stewardship refers to the rational use of antifungal agents. Historically, in some instances, the misuse or overuse of antifungal agents has predisposed patients to an elevated risk of systemic side-effects and treatment resistance, as well as increased healthcare costs. Superficial mycoses, such as onychomycosis, are sometimes treated without any diagnostic testing and is associated with a high likelihood of self-diagnosis and self-treatment, potentially leading to the emergence of resistance against commonly used antifungals like terbinafine. Practitioners need to ensure that a proper clinical diagnosis is backed up by appropriate testing. This may include the traditional light microscopy and culture; additionally, molecular techniques (such as polymerase chain reaction, terbinafine gene mutational analysis) and antifungal susceptibility testing are considerations as appropriate. The choice of antifungal agent should be guided by what is the standard of care in the location where the clinician practices as well as more broadly state and national prescription patterns. Recently, reports of treatment resistance concerning both superficial and deep fungal infections have added another layer of difficulty to clinical practice. This review aims to explore the phenomenon of antifungal drug resistance, and highlights the importance of adopting antifungal stewardship programs. We provide an overview of treatment resistance and mechanisms of resistance reported thus far in dermatophytes. Challenges of performing antifungal susceptibility testing and therapeutic drug monitoring are discussed, as well as principles, recommendations and future directions of antifungal stewardship programs.

YCANTHTM (Cantharidin) Topical Solution.

YCANTHTM (cantharidin) topical solution has been approved recently for the treatment of molluscum contagiosum (MC) in children (aged ≥2 years) and adults. It works by activating serine proteases that lead to blistering and inflammation, promoting shedding of infected cells and viral clearance. In two phase-3, randomized, double-blind, vehicle-controlled trials of similar design, VP-102 (a drug-device combination, containing cantharidin 0.7% w/v and inactive ingredients, such as gentian violet, acetone, and denatonium benzoate, administered with an applicator) was investigated for the treatment of MC. VP-102 and vehicle were applied topically once every 21 days until complete clearance of lesions was observed, or for up to four treatments. Cantharidin demonstrated efficacy in achieving the primary outcome, at day 84/visit 4 (Cantharidin Application in Molluscum Patients [CAMP-1], VP-102: 46% [73/160], vehicle: 18% [19/106]; and CAMP-2, VP-102: 54% [81/150], vehicle: 13% [15/112]). Common adverse events were mild to moderate, such as lesions at the site of application, pruritus, and pain. The recommended regimen of cantharidin topical solution is its application once every 21 days until complete clearance of lesions is observed, or up to four treatments.

Antibiotic resistance in agriculture: Perspectives on upcoming strategies to overcome upsurge in resistance.

Antibiotic resistance is a massive problem rising constantly and spreading rapidly since the past decade. The major underlying mechanism responsible for this problem is an overuse or severe misuse of antibiotics. Regardless of this emerging global threat, antibiotics are still being widely used, not only for treatment of human infections, but also to a great extent in agriculture, livestock and animal husbandry. If the current scenario persists, we might enter into a post-antibiotic era where drugs might not be able to treat even the simplest of infections. This review discusses the current status of antibiotic utilization and molecular basis of antibiotic resistance mechanisms acquired by bacteria, along with the modes of transmittance of the resultant resistant genes into human pathogens through their cycling among different ecosystems. The main focus of the article is to provide an insight into the different molecular and other strategies currently being studied worldwide for their use as an alternate to antibiotics with an overall aim to overcome or minimize the global problem of antibiotic resistance.

Whole genome sequencing data of Klebsiella aerogenes isolated from agricultural soil of Haryana, India.

Klebsiella aerogenes, is a Gram-negative bacterium, which was previously known as Enterobacter aerogenes. It is present in all environments such as water, soil, air and hospitals; and is an opportunistic pathogen that causes several types of infections. As compared to other clinically important pathogens included in the ESKAPE category (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), the pangenome and population structure of Klebsiella aerogenes is still poorly understood. For the present study, the bacterial sample was isolated from agricultural soils of Haryana, India. With an aim to identify the occurrence of multi-drug resistance genes in the agricultural field soil bacterial isolate, whole genome sequencing (WGS) of the bacteria was performed; and the antibiotic resistance causing genes, along with the genes responsible for other major functions of the cell; and the different Single Nuceotide Polymorphisms (SNPs) and Insertions and deletions (InDels) were identified. The data presented in this manuscript can be reused by researchers as a reference for determining the antibiotic resistance genes that could be present in different bacterial isolates, and it would also help in determination of functions of various other genes present in other genomes of Klebsiella species.