Microneedle-based arrays - Breakthrough strategy for the treatment of bacterial and fungal skin infections.

Currently, fungal and bacterial skin infections rank among the most challenging public health problems due to the increasing prevalence of microorganisms and the development of resistance to available drugs. A major issue in treating these infections with conventional topical medications is the poor penetration through the stratum corneum, the outermost layer of the skin. The concept of microneedles seems to be a future-proof approach for delivering drugs directly into deeper tissues. By bypassing the skin barrier, microneedle systems allow therapeutic substances to reach deeper layers more efficiently, significantly improving treatment outcomes. Nonetheless, the primary challenges regarding the effectiveness of microneedles involve selecting the appropriate size and shape, along with polymer composition and fabrication technology, to enable controlled and efficient drug release. This review offers a comprehensive overview of the latest knowledge on microneedle types and manufacturing techniques, highlighting their potential effectiveness in treating bacterial and fungal skin infections. It includes updated statistics on infection prevalence and provides a detailed examination of common bacterial and fungal diseases, focusing on their symptoms, causative species, and treatment methods. Additionally, the review addresses safety considerations, regulatory aspects, and future perspectives for microneedle-based therapeutic systems. It also underscores the importance of industrialization and clinical translation efforts, emphasizing the significant potential of microneedle technology for advancing medical applications.

Pharmacokinetics and pharmacodynamics of intravenous delafloxacin in healthy subjects: model-based dose optimization.

Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.

Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET).

BACKGROUND: The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens. METHODS: TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection. RESULTS: In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles. CONCLUSIONS: TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit. CLINICAL TRIALS REGISTRATION: NCT03137173.

Furunculosis and its complications: A cause of morbidity in renal transplant recipients: A retrospective observational study from Sindh Institute of Urology and Transplantation Karachi.

Furunculosis in renal transplant recipients may be associated with increased morbidity. With the aim to study the presentation, morbidity, and risk factors for furunculosis, this observational study was conducted at the Sindh Institute of Urology and Transplantation, between January to December 2014. All patients with furuncles or abscesses were included. The clinical presentation and risk factors were recorded. A morbidity scale of 0 and 1 was made on the basis of hospital stay for ≥7 days, bacteraemia, large abscesses and repeated furunculosis. Out of 38 patients, 29 (76%) had large abscesses and 9 (24%) had furuncles, with gluteal region being the most common site. Twelve (32%) had severe disease; 29 (76%) had morbidity scale of ≥1. High dose immunosuppression was significantly associated with severe disease while repeated furunculosis had significantly more risk factors. Furunculosis is a severe disease with high morbidity in renal transplant recipients and more studies are needed on skin colonisation and preventive strategies.

Features and associated factors of bacterial skin infections in hospitalized patients with pemphigus: a single-center retrospective study.

BACKGROUND: Infections were the primary cause of death (34.3-55.5%) in patients with pemphigus. Skin was usually the origin of infections. The study aimed to explore features and associated factors of bacterial skin infections (BSIs) in inpatients with pemphigus. METHODS: One hundred and seventy-seven inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records. Then, we retrieved the clinical and laboratory data to explore the characteristics and associated factors of BSIs. RESULTS: Of patients enrolled, pemphigus vulgaris (PV, n = 142) and pemphigus foliaceus (PF, n = 9) were most common, followed by pemphigus erythematosus (PE, n = 25) and pemphigus vegetans (Pveg, n = 1). Eighty-seven of 177 (49.2%) inpatients developed BSIs, and they had a longer length of stay compared with inpatients without BSIs (median: 18.9 vs. 14.1 days, p = 0.008). Staphylococcus aureus was the most common bacteria (71.3%, 62/87) and highly resistant to penicillin (91.9%, 57/62). Higher levels of anti-Dsg1 autoantibodies (> 124.2 U/mL) (p < 0.001, odds ratio [OR] = 3.564, 95% confidence interval [CI]: 1.784-7.123) and anti-Dsg3 autoantibodies (> 169.5 U/mL) (p = 0.03, OR = 2.074, 95% CI: 1.084-3.969) were underlying risk factors of BSIs when analyzed by binary regression analysis. As for Gram's stain of bacteria, females had a lower rate of Gram-positive infections (p = 0.03). Patients using oral antibiotics (p = 0.05) had a higher rate of Gram-negative infections. Inpatients who were hospitalized in other hospitals within 2 weeks before the current admission had a higher rate of Gram-negative and co-infections (p = 0.03). CONCLUSIONS: Inpatients with pemphigus had a high incidence of BSIs. Some factors were associated with the susceptibility of BSIs and bacterial species.

Thymoquinone-Loaded Polymeric Films and Hydrogels for Bacterial Disinfection and Wound Healing.

The purpose of this study was to synthesize and characterize novel biocompatible topical polymeric film and hydrogel systems that have the potential to deliver the antibacterial agent thymoquinone (TQ) directly to the skin target site to manage the local wound infection and thereby wound healing. The polyvinyl pyrrolidone (PVP) matrix-type films containing TQ were prepared by the solvent casting method. In vitro skin permeation studies on human cadaver skin produced a mean flux of 2.3 µg TQ/cm2/h. Human keratinocyte monolayers subjected to a scratch wound (an in vitro wound healing assay) showed 85% wound closure at day 6 in the TQ group (100 ng/mL TQ) as compared to 50% in the vehicle control group (p = 0.0001). In a zone-of-inhibition (ZOI) assay, TQ-containing films and hydrogels completely wiped out Staphylococcus aureus in 10 cm diameter Tryptic Soy Agar plates while 500 µg/mL gentamicin containing filters gave 10 mm of ZOI. In an ex vivo model, TQ-containing films eradicated bacterial colonization on human cadaver skin. Furthermore, in a full-thickness wound infection model in mice, TQ-containing films showed significant activity in controlling Staphylococcus aureus infection, thereby disinfecting the skin wound. In summary, TQ-containing PVP films and hydrogels developed in this study have the potential to treat and manage wound infections.

Skin Infections Caused by Staphylococcus aureus.

Staphylococcus aureus is the most common pathogen involved in skin infections worldwide, regardless of the patient's age, the climate or geographical area. The main skin clinical manifestations can be linked to a few toxins produced by the bacteria, which give rise to a rich and varied clinical spectrum. Panton Valentine leucocidin, exfoliatins, enterotoxins and toxin shock syndrome toxin 1 are the main toxins involved in most dermatological manifestations associated with S. aureus. Other less frequent cutaneous manifestations can occur in endocarditis, bacteraemia. Currently, the most important event is worldwide emergence of community-acquired S. aureus resistant to methicillin (CA-MRSA), mainly causing skin infections.

Retrospective Real-World Evaluation of Outcomes in Patients with Skin and Soft Structure Infections Treated with Tedizolid in an Outpatient Setting.

INTRODUCTION: Outcomes data for patients who received tedizolid for acute bacterial skin and skin-structure infections (ABSSSIs) are scant. We provide a real-world analysis of economic and clinical outcomes following tedizolid use in the outpatient setting. METHODS: This retrospective study of adults with skin infections treated with tedizolid (index period: 1 July 2014-31 May 2016) used data from the Optum Research and Impact National Benchmark databases. RESULTS: Ninety-one patients received tedizolid for the treatment of skin infections (with complications, n = 18; without complications, n = 73). Some patients had > 1 complication and infection site. Among patients with complications, pre-index complications during the [index date - 30] through [index date + 1] period included osteomyelitis (44.4%), septicemia (44.4%), and prosthetic joint/device/graft infection (16.7%). For the [index date - 7] through [index date + 1] period, the infection site included abscesses (55.6%) and chronic ulcers (38.9%). Mean (standard deviation [SD]) days supplied for the index tedizolid claim was 6.8 (2.3) days. Healthcare resource utilization (HCRU) during the 30-day post-index period included ≥ 1 ambulatory visit (100.0%), ≥ 1 emergency department (ED) visit (16.7%), and ≥ 1 hospitalization (22.2%). Median 30-day post-index all-cause costs were $11,098 [lower quartile (Q1), $5688; upper quartile (Q3), $16,246; mean (SD), $14,637 ($11,435)]. Among patients without complications, the pre-index infection site from ([index date - 7] through [index date + 1]) included abscesses (60.3%), chronic ulcers (37.0%), and cellulitis (2.7%). Mean (SD) days supplied for the index tedizolid claim was 6.6 (2.5) days. Thirty-day post-index HCRU included ≥ 1 ambulatory visit (91.8%), ≥ 1 ED visit (17.8%), and ≥ 1 hospitalization (5.5%). Median 30-day post-index all-cause costs were $3230 (Q1, $2345; Q3, $6847; mean [SD], $6898 [$11,129]). CONCLUSIONS: Patients treated with tedizolid in the outpatient setting experienced a short duration of therapy, low hospital admission, and modest post-index HCRU indicators, suggesting its utility for outpatient therapy of ABSSSIs.

Pharmacokinetics of Tedizolid and Pseudoephedrine Administered Alone or in Combination in Healthy Volunteers.

Therapeutic doses of tedizolid phosphate, an oxazolidinone antibiotic, lack monoamine oxidase inhibition in vivo, potentially resulting in an improved safety profile versus other oxazolidinones. This randomized, double-blind, placebo-controlled, 2-period, 2-sequence, crossover, phase 1 study (NCT01577459) assessed the potential for pharmacokinetic (PK) interactions between tedizolid and pseudoephedrine. Eighteen healthy volunteers (age: 18⁻45 years) were block-randomized to 1 of 2 treatment sequences containing 2 treatment periods (tedizolid phosphate or placebo once daily for 4 days; single dose of pseudoephedrine 60 mg on day 5) separated by a 2-day washout. Median time to maximum plasma concentration for tedizolid and pseudoephedrine ranged from 3 to 4 h, regardless of treatment coadministration. Steady-state tedizolid had no effect on the PK of pseudoephedrine; geometric mean ratio and 90% confidence interval remained within the no-effect 0.8 to 1.25 boundaries. The maximum observed concentration of tedizolid decreased by approximately 14% when pseudoephedrine was coadministered; no changes in the area under the plasma concentration-time curve or the minimum observed plasma concentration occurred. All adverse events (AEs) were mild, and there were no serious AEs or study drug discontinuations. No meaningful PK interactions occurred between tedizolid and pseudoephedrine, and tedizolid was well tolerated when administered in conjunction with pseudoephedrine.

Return of the tetracyclines: omadacycline, a novel aminomethylcycline antimicrobial.

Omadacycline is a novel aminomethylcycline antimicrobial agent that is available in both oral and intravenous formulations. The distinguishing structural characteristics of omadacycline from other tetracyclines allow for its continued antimicrobial activity in the presence of traditional tetracycline resistance mechanisms (efflux pumps and ribosomal protection proteins). Omadacycline has been found to have potent activity against antibiotic-resistant pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended spectrum beta-lactamase-producing Escherichia coli and multidrug-resistant Streptococcus pneumoniae. Currently available data indicate that omadacycline is generally well tolerated with the most common adverse effects being gastrointestinal symptoms. Omadacycline seems to be a promising new agent for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Studies for the treatment of cystitis in adult females are currently underway, and future results of these studies will further help delineate the antibacterial role of omadacycline.

Tigeciclina en infecciones de piel y tejidos blandos complicadas / Tigecycline in complicated skin and soft-tissue infection

Objetivo: evaluar la mejor evidencia actual disponible para generar recomendaciones con respecto a la efectividad y seguridad del uso de tigeciclina en adultos con infección de piel y tejidos blandos (IPTB). Materiales y métodos: se realizó una revisión sistemática de la literatura, seleccionando los metaanálisis y experimentos clínicos controlados (ECCs), los cuales se valoraron utilizando la herramienta SIGN (Scottish Intercollegiate Guidelines Network.), con el fin de generar tablas de evidencia según GRADE de los estudios de tigeciclina en la indicación de IPTB, para posteriormente utilizar un proceso Delphi modificado para calificar las diferentes recomendaciones. Resultados: la revisión sistemática se incluyeron 9 metaanálisis que incluyeron 5 estudios clínicos aleatorizados con 1873 pacientes, y de ellos 952 asignados al brazo de tigeciclina, no mostró inferioridad frente a los comparadores en curación clínica (RR= 0.76 IC95% 0,57 - 1.03), curación microbiológica (RR= 0.92 IC95% 0,61 - 1.38), eventos adversos serios RR 1,41 (IC95%0,97 a 2,35), ni mortalidad RR 1,9 (IC95%0,84 a 4,3). La tigeciclina puede relacionarse con mayor frecuencia de eventos adversos leves de origen gastrointestinal. Conclusión: en pacientes adultos con IPTB, se considera que el uso de tigeciclina en monoterapia en pacientes no críticamente enfermos es equivalente en eficacia a otras opciones terapéuticas antimicrobianas. Se debe considerar especialmente como terapia de ajuste en pacientes con infecciones polimicrobianas.

Objective: To assess current best evidence available to generate recommendations regarding the effectiveness and safety of tigecycline use in adults with skin and soft-tissue infections (SSTIs). Materials and methods: A systematic review of the literature was conducted by selecting meta-analyzes and controlled clinical trials (CCTs), which were assessed using the SIGN tool (Scottish Intercollegiate Guidelines Network) in order to generate evidence tables according to GRADE of studies of tigecycline in the SSTIs indication, and then using a modified Delphi Method to score the different recommendations. Results: Nine meta-analyzes were included compounded by five randomized clinical trials with a sample size of 1873 patients, where 952 patients were assigned to tigecycline. The group of patients with tigecycline showed no inferiority to the comparator in clinical cure (RR = 0.76 95% CI 0.57 - 1.03), microbiologic cure (RR = 0.92 95% CI 0.61 - 1.38), serious adverse events RR 1, 41 (95% CI 0.97 to 2.35) or mortality RR 1.9 (95% CI 0.84 to 4.3). Tigecycline may be related to increased frequency of minor adverse events of gastrointestinal origin. Conclusion: In adult patients with SSTIs, it is considered that the use of tigecycline in monotherapy in non-critically ill patients is equivalent in effectiveness to other antimicrobial treatment options. It should be especially considered as an adjustment therapy in patients with polymicrobial infections.

Skin Infections due to Bacteria in Solid Organ Transplant Recipients: A Review.

Though there is an abundance of information on cutaneous malignancies in transplant recipients, cutaneous infections in solid organ transplant recipients (SOTRs) are underrepresented in the dermatological literature. Our paper provides a comprehensive review of bacterial cutaneous infections within the solid organ transplant population. Cutaneous bacterial infections may lead to significant morbidity and even mortality in this immunosuppressed population. Thus, it is to the benefit of both dermatologists and other transplant care providers to better understand and recognize the features of cutaneous bacterial infections in SOTRs. This paper can aid providers in promptly identifying, diagnosing, and treating bacterial skin infections. This review discusses the diagnosis and treatment of the following bacterial species: Staphylococcus, Streptococcus, Pseudomonas aeruginosa, Escherichia coli, Nocardia, Mycobacteria, and Bartonella henselae.

[SEIP-AEPAP-SEPEAP consensus document on the aetiology, diagnosis and treatment of bacterial skin infections in out-patients]. / Documento de consenso SEIP-AEPAP-SEPEAP sobre la etiología, el diagnóstico y el tratamiento de las infecciones cutáneas bacterianas de manejo ambulatorio.

Skin infections are a common cause for dermatological consultations in the paediatric setting. A review is presented of the clinical manifestations, diagnosis and treatment of the main bacterial skin infections, as well as the diagnosis and treatment of super-infected puncture and bite wounds. The most prevalent bacteria in skin infections are Staphylococcus aureus and Streptococcus pyogenes. Treatment is usually empirical, since microbiological studies are only recommended under certain circumstances or lack of improvement with common therapies. Superficial skin infections can be treated with local antiseptics or antibiotics (mupirocin or fusidic acid). Systemic treatment is usually reserved for patients with extensive or severe disease or with other risk factors. Systemic treatment depends on the suspected infecting bacteria, with penicillin, amoxicillin, amoxicillin-clavulanic acid and first or second generation cephalosporin being the most frequently used drugs. Due to the low incidence of community-acquired methicillin-resistant infection by S. aureus in Spain, the use of clindamycin or co-trimoxazole is only recommended after severe disease, relapses or a clear epidemiological background.