Treatment of onychomycosis in an era of antifungal resistance: Role for antifungal stewardship and topical antifungal agents.

A growing body of literature has marked the emergence and spread of antifungal resistance among species of Trichophyton, the most prevalent cause of toenail and fingernail onychomycosis in the United States and Europe. We review published data on rates of oral antifungal resistance among Trichophyton species; causes of antifungal resistance and methods to counteract it; and in vitro data on the role of topical antifungals in the treatment of onychomycosis. Antifungal resistance among species of Trichophyton against terbinafine and itraconazole-the two most common oral treatments for onychomycosis and other superficial fungal infections caused by dermatophytes-has been detected around the globe. Fungal adaptations, patient characteristics (e.g., immunocompromised status; drug-drug interactions), and empirical diagnostic and treatment patterns may contribute to reduced antifungal efficacy and the development of antifungal resistance. Antifungal stewardship efforts aim to ensure proper antifungal use to limit antifungal resistance and improve clinical outcomes. In the treatment of onychomycosis, critical aspects of antifungal stewardship include proper identification of the fungal infection prior to initiation of treatment and improvements in physician and patient education. Topical ciclopirox, efinaconazole and tavaborole, delivered either alone or in combination with oral antifungals, have demonstrated efficacy in vitro against susceptible and/or resistant isolates of Trichophyton species, with low potential for development of antifungal resistance. Additional real-world long-term data are needed to monitor global rates of antifungal resistance and assess the efficacy of oral and topical antifungals, alone or in combination, in counteracting antifungal resistance in the treatment of onychomycosis.

Number of Affected Nails Is the Primary Determinant of Efinaconazole 10% Solution Usage for Onychomycosis.

Good adherence to treatment is necessary for the successful treatment of onychomycosis and requires that an appropriate amount of medication be prescribed. Most prescriptions for efinaconazole 10% solution, a topical azole antifungal, are for 4 mL per month but there are no data on patient factors or disease characteristics that impact how much medication is needed. Data from two phase 3 studies of efinaconazole 10% solution for the treatment of toenail onychomycosis were pooled and analyzed to determine monthly medication usage based on the number of affected toenails, percent involvement of the target toenail, body mass index (BMI), and sex. Participants with two or more affected nails required, on average, >4 mL of efinaconazole per month, with increasing amounts needed based on the number of nails with onychomycosis (mean: 4.39 mL for 2 nails; 6.36 mL for 6 nails). In contrast, usage was not greatly impacted by target toenail involvement, BMI, or sex. Together, these data indicate that the number of affected nails should be the major consideration when determining the monthly efinaconazole quantity to prescribe. J Drugs Dermatol. 2024;23(2):110-112.    doi:10.36849/JDD.7676.

Therapeutic Recommendations for the Treatment of Toenail Onychomycosis in the US.

BACKGROUND: Onychomycosis affects around 14% of individuals in North America and Europe and is undertreated. Treatment is challenging as toenail growth can take 12–18 months, the nail plate may prevent drug penetration, and disease recurrence is common. National guidelines/consensus documents on onychomycosis diagnosis and treatment were last published more than 5 years ago and updated medical guidance is needed. METHODS: This document aims to provide recommendations for the diagnosis and pharmaceutical treatment of toenail onychomycosis following a roundtable discussion with a panel of dermatologists, podiatrists, and a microbiologist specializing in nail disease. RESULTS: There was a general consensus on several topics regarding onychomycosis diagnosis, confirmatory laboratory testing, and medications. Onychomycosis should be assessed clinically and confirmed with microscopy, histology, and/or culture. Terbinafine is the primary choice for oral treatment and efinaconazole 10% for topical treatment. Efinaconazole can also be considered for off-label use for maintenance to prevent recurrences. For optimal outcomes, patients should be counseled regarding treatment expectations as well as follow-up care and maintenance post-treatment. CONCLUSIONS: This article provides important updates to previous guidelines/consensus documents to assist dermatologists and podiatrists in the diagnosis and treatment of toenail onychomycosis. J Drugs Dermatol. 2021;20(10):1076-1084. doi:10.36849/JDD.6291.

Onychomycosis Diagnosis and Management: Perspectives from a Joint Dermatology-Podiatry Roundtable.

Onychomycosis prevalence is expected to rise as the population ages and the prevalence of diabetes, peripheral vascular disease, and other significant risk factors rise. Until recently, treatment options were limited due to safety concerns with oral antifungals and low efficacy with available topical agents. Efinaconzole and tavaborole were approved by the FDA in 2014 for onychomycosis treatment and provide additional effective topical treatment options for patients with mild-to-moderate disease. Dermatologists and podiatrists both regularly treat onychomycosis, yet there are striking differences between specialties in approach to diagnosis and treatment. In order to explore these differences a joint dermatology-podiatry roundtable of onychomycosis experts was convened. Although it has little effect on mycologic cure, debridement may be a valuable adjunct to oral or topical antifungal therapy, especially in patients with greater symptom burden. However, few dermatologists incorporate debridement into their treatment plans and referral to podiatry may be appropriate for some of these patients. Furthermore, podiatrists may be better equipped to manage patients with concurrent diabetes or peripheral vascular disease and elderly patients who are unable to maintain proper foot hygiene. Once cure is achieved, lifestyle and hygiene practices, maintenance/prophylactic onychomycosis treatment, and proactive tinea pedis treatment in patients and family members may help to maintain patients' cured status.

A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers.

BACKGROUND: The role of hyperbaric oxygen (HBO2) for the treatment of diabetic foot ulcers (DFUs) has been examined in the medical literature for decades. There are more systematic reviews of the HBO2/DFU literature than there have been randomized controlled trials (RCTs), but none of these reviews has resulted in a clinical practice guideline (CPG) that clinicians, patients and policy-makers can use to guide decision-making in everyday practice. METHODS: The Undersea and Hyperbaric Medical Society (UHMS), following the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, undertook this systematic review of the HBO2 literature in order to rate the quality of evidence and generate practice recommendations for the treatment of DFUs. We selected four clinical questions for review regarding the role of HBO2 in the treatment of DFUs and analyzed the literature using patient populations based on Wagner wound classification and age of the wound (i.e., acute post-operative wound vs. non-healing wound of 30 or more days). Major amputation and incomplete healing were selected as critical outcomes of interest. RESULTS: This analysis showed that HBO2 is beneficial in preventing amputation and promoting complete healing in patients with Wagner Grade 3 or greater DFUs who have just undergone surgical debridement of the foot as well as in patients with Wagner Grade 3 or greater DFUs that have shown no significant improvement after 30 or more days of treatment. In patients with Wagner Grade 2 or lower DFUs, there was inadequate evidence to justify the use of HBO2 as an adjunctive treatment. CONCLUSIONS: Clinicians, patients, and policy-makers should engage in shared decision-making and consider HBO2 as an adjunctive treatment of DFUs that fit the criteria outlined in this guideline. The current body of evidence provides a moderate level of evidence supporting the use of HBO2 for DFUs. Future research should be directed at improving methods for patient selection, testing various treatment protocols and improving our confidence in the existing estimates.

Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes.

OBJECTIVE: To evaluate efficacy, safety, and tolerability efinaconazole topical solution, 10% in diabetic patients with onychomycosis. METHODS: A post-hoc analysis of 112 patients, aged 29-70 years, randomized to receive efinaconazole topical solution, 10% or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. RESULTS: Mycologic cure rates (OC) were significantly greater with efinaconazole (56.5% and 56.3% in diabetic and non-diabetic patients respectively) compared to vehicle (P=0.016 and P<0.001, respectively). The primary end point, complete cure, was also greater for efinaconazole (13.0% and 18.8%, respectively vs 3.7% and 4.7%). Treatment success (percent affected target toenail ≤10%) for efinaconazole was 40.8% and 47.7%, respectively vs 18.5% and 18.2% with vehicle. There was no statistically significant difference between the diabetic and non-diabetic populations for any efficacy endpoint. Adverse events associated with efinaconazole were local site reactions and clinically similar to vehicle. CONCLUSIONS: Once daily efinaconazole topical solution, 10% may provide a useful topical option in the treatment of diabetic patients with onychomycosis.

The Peer Review System: A Journal Editor's 30-Year Perspective.

The peer review system has become the standard by which scientific articles are refereed. Unfortunately, even from its beginnings in the mid-1800s it has been fraught with difficulties. Potential reviewers are volunteers who may be inundated with requests to review yet these reviews take considerable time and effort. There is little motivation to complete a review causing significant delays in the publication process. There may be biases unintentionally built into the system between reviewers, authors, editors, and journals. Attempts to overcome these biases by various blinding schemes have been met with limited success. Finally, the recent advent of Artificial Intelligence has the potential to completely upend the system, for good or bad.

Dermatophytomas in Onychomycosis: A Scoping Review of Prevalence, Diagnosis, and Treatment.

BACKGROUND: Dermatophytoma, also described as a longitudinal streak/spike, is a form of onychomycosis that presents as yellow/white streaks or patches in the subungual space, with dense fungal masses encased in biofilm. This scoping review of the literature was conducted to address a general lack of information about the epidemiology, pathophysiology, and treatment of dermatophytomas in onychomycosis. METHODS: A search was performed in the PubMed and Embase databases for the terms "longitudinal spike" or "dermatophytoma." Outcomes of interest were definition, prevalence, methods used for diagnosis, treatments, and treatment efficacy. Inclusion and exclusion of search results required agreement between two independent reviewers. RESULTS: Of a total of 51 records, 37 were included. Two reports provided the first unique definitions/clinical features of dermatophytomas. Overall, many descriptions were found, but one conclusive definition was lacking. Prevalence data were limited and inconsistent. The most frequently mentioned diagnostic techniques were clinical assessment, potassium hydroxide/microscopy, and fungal culture/mycology. Oral terbinafine and topical efinaconazole 10% were the most frequently mentioned treatments, followed by topical luliconazole 5% and other oral treatments (itraconazole, fluconazole, fosravuconazole). In studies with five or more patients without nail excision, cure rates were highest with efinaconazole 10%, which ranged from 41% to 100% depending on the clinical and/or mycologic assessment evaluated. Other drugs with greater than or equal to 50% cure rates were topical luliconazole 5% (50%), oral fosravuconazole (57%), and oral terbinafine (67%). In studies that combined oral terbinafine treatment with nail excision using surgical or chemical (40% urea) methods, cure rates ranged from 50% to 100%. CONCLUSIONS: There is little published information regarding dermatophytomas in onychomycosis. More clinical research and physician education are needed. Although dermatophytomas have historically been considered difficult to treat, the efficacy data gathered in this scoping review have demonstrated that newer topical treatments are effective, as are oral antifungals in combination with chemical or surgical methods.

Parenteral Vancomycin in the Treatment of MRSA-Associated Diabetic Foot Infections: An Unnecessary Risk.

Diabetic foot infections (DFIs) are a common and costly complication of diabetes. Soft tissue and bone infections in DFIs frequently lead to amputation and/or sepsis which can be costly for both the patient and the healthcare system. Staphylococcus aureus is the most commonly identified causative agent in DFIs, and people with diabetes may have an increased risk of infection with methicillin-resistant Staphylococcus aureus (MRSA). In addition to increased susceptibility to severe infection, MRSA in DFIs is associated with high rates of treatment failure, morbidity, and hospitalization costs meaning appropriate treatment is a high priority. While hospitalized patients are usually treated with intravenous (IV) vancomycin, this can be costly in terms of inpatient stays, staffing costs, and adverse events. For example, vancomycin-associated acute kidney injury not only delays hospital discharge and increases costs but is also a particular concern for patients with diabetes who already have an increased risk of kidney problems. Vancomycin-resistant strains of S. aureus have also been identified, which means that alternative treatment options may need to be explored. Treatment alternatives to IV vancomycin, including oral antibiotics, have been shown to provide similar efficacy, with reduced costs, outpatient or home-based administration, and with fewer serious adverse effects. Although infectious disease specialists often use IV vancomycin alone, or in combination, as a first-line therapeutic option, they are increasingly seeing the value of outpatient or at-home oral antibiotics as an alternative. This manuscript reviews the evidence for true costs of vancomycin therapy for MRSA-associated DFIs and examines the alternatives.

All Feet on Deck: The Role of Podiatry During the COVID-19 Pandemic: Preventing Hospitalizations in an Overburdened Health-Care System, Reducing Amputation and Death in People with Diabetes.

The coronavirus disease of 2019 pandemic is driving significant change in the health-care system and disrupting the best practices for diabetic limb preservation, leaving large numbers of patients without care. Patients with diabetes and foot ulcers are at increased risk for infections, hospitalization, amputations, and death. Podiatric care is associated with fewer diabetes-related amputations, emergency room visits, hospitalizations, length-of-stay, and costs. However, podiatrists must mobilize and adopt the new paradigm of shifts away from hospital care to community-based care. Implementing the proposed Pandemic Diabetic Foot Triage System, in-home visits, higher acuity office visits, telemedicine, and remote patient monitoring can help podiatrists manage patients while reducing the coronavirus disease of 2019 risk. The goal of podiatrists during the pandemic is to reduce the burden on the health-care system by keeping diabetic foot and wound patients safe, functional, and at home.

Topical autologous blood clot therapy: consensus panel recommendations to guide use in the treatment of complex wound types.

The etiology of acute and chronic wounds goes beyond those often reported in the literature, including those with exposed structures, those in which the entire wound bed cannot be visualized, and patients who are not candidates for typical standard of care. Treatment options for these patients may be limited. TABCT is a viable option for these complex wound types and is not hindered by logistical, procedural, or patient factors. A consensus panel of providers with extensive experience in treatment of these wound types was convened to develop consensus recommendations on the use of TABCT in specific complex wound types. Four consensus statements were defined for TABCT use in patients who cannot undergo sharp or extensive debridement, as a protective barrier to prevent further bacterial ingress, in patients with wounds in which the entire wound bed cannot be safely visualized, and in wounds with exposed tendon and/or bone. Consensus panel recommendations show that TABCT application assists in maintenance of a moist wound healing environment, autolytic debridement, recruitment and delivery of factors essential for wound healing, prevention of pathogen entry, and ability to completely fill wound voids that cannot be fully visualized. Additional advantages of TABCT use are its cost-effectiveness, ease of access, minimal related complications, and proven clinical efficacy.

Executive summary: 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections.

Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs.

2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections.

Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs.

Topical autologous blood clot therapy: an introduction and development of consensus panel to guide use in the treatment of complex wound types.

Complex or hard-to-heal wounds can be acute or chronic; the complexity is based on patient-specific local, systemic, and psychosocial factors. Use of autologous tissue can be a significant adjunct to wound closure. Grafts and flaps are the most common autologous tissue used in wound reconstruction. However, patient factors, wound size, and exposed structures may preclude using these methods as primary or even secondary closure techniques. Alternative autologous tissue therapies include those derived from adipose, epidermis or dermis, bone marrow, and blood. Limitations of these treatment modalities include access-related difficulty, cost, creation of a secondary donor site, use of singular or limited cell types, and sparse or contradictory evidence basis of their efficacy of use. A panel of providers experienced in wound care and surgical wound management was convened to create a series of publications on the use of topical autologous blood clot therapy (TABCT) in the treatment of complex wounds. This publication, the first in a series, provides an evidence basis of the gap between definition and treatment of complex wounds, an overview of the use of autologous therapies in these wounds, and the science behind TABCT. The development of a consensus panel for decision pathways and recommendations for TABCT use in specific complex wound types are also discussed. Subsequent articles will provide consensus recommendations on the use of TABCT in full-thickness wounds with exposed tendon and/or bone and undermining or tunneling wounds, in wounds in patients who are nonsurgical candidates, in those who cannot undergo sharp debridement, in patients with arterial wounds who have been maximally revascularized, and in those with transsphincteric anal fistula. This article provides a foundation of knowledge and describes the plan for consensus panel decision pathways and recommendation development of use of TABCT in the treatment of specific complex wound types.

Medical therapy of diabetic foot infections.

Diabetic foot infections are a common and often serious problem, accounting for a greater number of hospital bed days than any other complication of diabetes. Despite advances in both antibiotic therapy and surgical management, these infections continue to be a major risk factor for amputations of the lower extremity. Although a number of wound size and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific for infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic foot infections, including the first severity scale specific for these infections. The following year, the Infectious Diseases Society of America (IDSA) published their Diabetic Foot Infection Guidelines. In this article, we review some of the critical points from the Executive Summary of the IDSA document and provide a commentary following each issue to update the reader on any pertinent changes that have occurred since the publication of the original document in 2004. The importance of a multidisciplinary limb salvage team, apropos this special joint issue of the American Podiatric Medical Association and the Society for Vascular Surgery, cannot be overstated.

A Standardized Approach to Evaluating Lower Extremity Chronic Wounds Using a Checklist.

As the population ages and more people live with diabetes, obesity, and vascular disease, chronic wounds have become more prevalent. Increasingly, wound care falls into the hands of clinicians who may be new to the specialty. To facilitate a better understanding of wounds and to ensure all integral items for best outcomes are considered, an interprofessional panel of wound care experts developed a checklist to aid in lower extremity wound identification, assessment, evaluation, and potential complication recognition. This checklist focuses on an evidence-based approach to obtaining a medical history, evaluating the wound, determining the etiology, and assessing perfusion, edema, infection, and neurologic status. The goal of this fundamental evaluation tool is to help the clinician move towards the next steps in optimizing patient care. Evidence-based support for each item on the checklist is reviewed and detailed for clinician reference.

Onychomycosis: diagnosis and definition of cure.

Until now, there has been no agreement on criteria defining resolution of onychomycosis. Most published reports use clinical and mycological cure, which comprises a completely normal-appearing nail plate, and negative nail culture and microscopy results, as the end point for defining success of therapeutic intervention. Reported here is the definition of onychomycosis, which delineates both primary and secondary criteria for diagnosis of onychomycosis and identifies clinical and laboratory parameters to define a resolved fungal nail infection. Onychomycosis cure is defined by the absence of clinical signs or the presence of negative nail culture and/or microscopy results with one or more of the following minor clinical signs: (1) minimal distal subungual hyperkeratosis; and (2) nail-plate thickening. Clinical signs indicative of persistent onychomycosis at the end of the observation period include (1) white/yellow or orange/brown streaks or patches in or beneath the nail plate; and (2) lateral onycholysis with subungual debris. Although nail appearance will usually continue to improve after cessation of therapy, the nails may have a persistent abnormal appearance even in cases where treatment has been effective.