Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

Introduction: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach.

Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included.

Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.     

Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria

Introduction: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii.

Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included.

Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.     

Pharmacokinetic drug evaluation of tedizolid for the treatment of skin infections

Introduction: Tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Although tedizolid shares many similar properties with linezolid, another oxazolidinone used to treat ABSSSI, the two antibiotics have several key differences.

Areas covered: This review provides a detailed summary of the overall pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of tedizolid for the treatment of ABSSSI.

Expert opinion: Compared to other antibiotics used for ABSSSI, tedizolid has several advantages. Tedizolid has a long half-life, allowing for once daily dosing. Tedizolid also has broad spectrum of activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Coagulase-negative Staphylococci, and Enterococci – including isolates demonstrating resistance to linezolid. It is available in both oral and intravenous formulations, and, has outstanding oral bioavailability, allowing for oral-step down therapy. There is also some evidence that, tedizolid has fewer significant interactions with serotonin reuptake inhibitors or monoamine oxidase inhibitors than linezolid. Finally, thrombocytopenia may occur less often with tedizolid than linezolid. However, these benefits must be weighed against the financial cost of tedizolid and the availability of alternative antibiotic choices.     

Shaving effects on percutaneous penetration: clinical implications

Context: Human/animal shaving biology.

Objective: To assess the effect of shaving on percutaneous penetration and skin function.

Methods: We screened 500+publications in Pub Med, Scopus, Cochrane Library and pertinent journals out of which only 17 were deemed relevant. Terms for searches included shaving and skin, percutaneous penetration and shaving, skin absorption and shaving, absorption of dyes and shaving, skin penetration, effects of shaving and absorption, shave and dyes, axillary shaving and stratum corneum, shaving and breast cancer, shaving and infections, etc.

Result: Shaving appears to have an exaggerated effect on percutaneous absorption; however, some studies do not support this evidence.

Conclusion: Shaving enhances percutaneous penetration of some chemicals; however this effect is species and chemical specific. Further investigations of chemicals of varying physio-chemical properties are mandated before a generalized theory can be promulgated.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

An evaluation of tedizolid for the treatment of MRSA infections

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA)is a common pathogen in acute bacterial skin and soft tissue infections (ABSSSIs), nosocomial pneumonia, bacteremia, endocarditis, as well as diabetic foot, bone, and joint infections.

Areas covered: This review summarizes the randomized controlled trials that evaluated the clinical efficacy of tedizolid in ABSSSIs, which is currently the only United States Food and Drug Administration-labeled indication for tedizolid.

Expert opinion: Tedizolid has several potential advantages over linezolid including once-daily dosing, shorter duration of therapy, and increased tolerability. However, its cost will likely limit its adoption for ABSSSIs with MRSA because other oxazolidinone antibiotics are available in less costly generic versions. Tedizolid is also currently being investigated for its use in other MRSA infections including nosocomial pneumonia as well as diabetic foot, bone, and joint infections and tedizolid’s use in these disease states appears more promising. Potential indications for future clinical investigation of tedizolid’s efficacy and safety include bacteremia and meningitis.     

An update on emerging therapies for urinary tract infections

Introduction: Urinary tract infections (UTIs) are the most common healthcare-acquired infections, and are associated with high morbidity and mortality. Worldwide use of antibiotics has led to a significant rise in resistant uropathogens emanating from both hospitals and communities. The huge concern of multidrug resistance (MDR) has led the Food and Drug Administration (FDA) to encourage drug companies to invest in the development of new antibiotics.

Area covered: In this review we summarized data on already approved antibiotics, and selected emerging therapies that are currently in phase II and III trials with emphasis on complicated urinary tract infections (cUTIs). We performed our search using PubMed, ClinicalTrials.gov, Google Scholar and Pharmaprojects.

Expert opinion: Efficacious antimicrobials are needed to overcome MDR organisms. There are several dugs in initial and later stages of development, but most of them lack full spectrum of activity against some Gram-negative organisms, particularly against MDR Pseudomonas aeruginosa. Better understanding of the pathogenesis of UTI and genetic engineering of pathogens can provide new drugs to combat resistance in the future.     

Treatment of chlamydial infections: 2014 update

Introduction: Chlamydiae are obligate intracellular bacterial pathogens whose entry into mucosal epithelial cells is required for intracellular survival and subsequent growth. The life cycle of Chlamydia spp. and the ability to cause persistent, often subclinical infection, has major ramifications for diagnosis and treatment of Chlamydia trachomatis and C. pneumoniae infections in humans.

Areas covered: This paper reviews the current literature on the antimicrobial susceptibilities and treatment of genital infections due to C. trachomatis and respiratory infections due to C. pneumoniae published since 2011.

Expert opinion: Chlamydiae are susceptible to antibiotics that interfere with DNA and protein synthesis, including tetracyclines, macrolides and quinolones, which are the compounds that have been most extensively studied and used for treatment of human infection. Since our original review was published in 2011, there have been some major advances in diagnostic tests for C. trachomatis and the introduction of the first FDA-approved test for the detection of C. pneumoniae in respiratory samples. However, the options for treating chlamydial infections have largely remained the same. There are a small number of new drugs currently in preclinical development and early clinical trials that may have a role in the treatment of chlamydial infections.     

Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials

Introduction: Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options.

Areas covered: An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed.

Expert opinion: The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting.     

Solid lipid nanoparticles and nanostructured lipid carrier-based nanotherapeutics in treatment of psoriasis: a comparative study

Background: The present work focuses on the development of ultra-small solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) encapsulating cyclosporine and calcipotriol, further incorporated into gel, increasing their penetration through the skin.

Research design and methods: Developed SLN and NLC were characterized regarding particle size, zeta potential, %entrapment efficiency and dispersed into carbopol 934P-NF gel. Gel was further characterized for rheological behavior and spreadability. Ex vivo dermatokinetic by tape stripping method, in vitro efficacy on HaCaT cell lines and in vivo efficacy on imiquimod induced psoriatic model in mice were evaluated.

Results: Ultra-small (size<100 nm) particles were formed with high entrapment efficiency and spherical morphology. Ex vivo dermatokinetic studies revealed deeper and confined drug penetration of lipid formulation gel in epidermal layers as compared to free drug. In vitro study on HaCaT cell lines depicted higher uptake and high efficacy owing to decrease in cell viability for NLC. The anti-psoriatic efficacy in BALB/c mice (evaluated on basis of cytokine levels and skin morphology) highlighted potential of drug-loaded NLC significantly higher as compared to drug loaded SLN and marketed formulation Betagel.

Conclusions: The study demonstrated that NLC gel had higher efficacy in psoriatic management and hold promise for further exploration.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.     

European and Russian physician awareness of best management approaches for infections due to antibiotic-resistant Gram-negative bacteria

Objectives: The rapid spread of infections due to antibiotic-resistant, Gram-negative bacteria in Europe and surrounding regions requires a heightened level of awareness among physicians within their practice settings.

Methods: We surveyed 800 physicians who treat these infections across France, Germany, Spain, Italy, and Russia to assess their awareness of best management approaches.

Results: We found that more than two-thirds do not consider themselves highly aware of best management practices. The respondents are facing these resistant infections as evidenced by the antibiotics they report using and their stated interest in newer agents. Respondents indicated that precious time is lost waiting for culture results, but also said they will need more information about accuracy, use, and costs for adopting rapid molecular testing.

Conclusions: The survey further identified the need for treatment guidelines and clinical decision support tools that can be applied at the bedside.     

Pharmacokinetic drug evaluation of dalbavancin for the treatment of skin infections

Introduction: Acute bacterial skin and skin structure infections (ABSSIs), defined as a bacterial infection of the skin with a lesion size area of at least 75 cm, are a leading cause of hospital admission and ambulatory care visits worldwide. Dalbavancin is a lipoglycopeptide antibiotic recently approved by the United States Food and Drug Administration (FDA) and by European Medicines Agency (EMA) for ABSSSIs. The authors review and provide updates of efficacy and safety by several studies on dalbavancin.

Areas covered: A PubMed search was performed for relevant literature. We especially focused our attention on pharmacokinetics.

Expert opinion: Dalbavancin provides an important new therapy for management of ABSSI, maintaining a spectrum of activity similar to vancomycin against gram-positive organisms. Use of dalbavancin, with its 1-week-shot treatment, consist in a reduction of the length of hospital stay or in a reduction of hospital admissions, with important cost savings.     

Clinical cosmeceutical repurposing of melatonin in androgenic alopecia using nanostructured lipid carriers prepared with antioxidant oils

Background: The present work aims to formulate nanostructured lipid carriers (NLCs) exhibiting high skin deposition and high inherent antioxidant potential to repurpose the use of melatonin hormone and some antioxidant oils in the treatment of androgenic alopecia (AGA).

Research design and methods: NLCs were characterized for their size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Their merits were clinically tested on patients suffering from AGA by calculating the degree of improvement, conduction of hair pull test, histometric assessment, and dermoscopic evaluation.

Results: Results revealed that melatonin NLCs showed nanometer size, negatively charged surface, high entrapment efficiency, and high anti-oxidant potential, in addition to sustained release for 6 h. Furthermore, NLCs displayed good storage stability and they were able to increase the skin deposition of melatonin 4.5-folds in stratum corneum, 7-folds in epidermis, and 6.8-folds in the dermis compared to melatonin solution. Melatonin NLCs displayed more clinically desirable results compared to the melatonin solution in AGA patients, manifested by increased hair density and thickness and decreased hair loss.

Conclusions: The aforementioned system was shown to be a very promising treatment modality for AGA, which is worthy of futuristic experimentation.     

Ethnomedicinal uses,phytochemistry and pharmacological aspects of the genus Premna: a review

Context: The genus Premna (Lamiaceae), distributed throughout tropical and subtropical Asia, Africa, Australia and the Pacific Islands, is used in folk medicine primarily to treat inflammation, immune-related diseases, stomach disorders, wound healing, and skin diseases.

Objectives: This review exhaustively gathers available information on ethnopharmacological uses, phytochemistry, and bioactivity studies on more than 20 species of Premna and critically analyzes the reports to provide the perspectives and directions for future research for the plants as potential source of drug leads and pharmaceutical agents.

Methods: A literature search was performed on Premna species based on books of herbal medicine, major scientific databases including Chemical Abstract, Pubmed, SciFinder, Springerlink, Science Direct, Scopus, the Web of Science, Google Scholar, and ethnobotanical databases.

Results: More than 250 compounds have been isolated and identified from Premna species, comprising of diterpenoids, iridoid glycosides, and flavonoids as the most common secondary metabolites, followed by sesquiterpenes, lignans, phenylethanoids, megastigmanes, glyceroglycolipids, and ceramides. Many in vitro and in vivo studies have been conducted to evaluate the biological and pharmacological properties of the extracts, and isolated compounds of Premna species with antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antihyperglycaemia, and cytotoxic activities.

Conclusion: The bioactive compounds responsible for the bioactivities of most plants have not been well identified as the reported in vivo pharmacological studies were mostly carried out on the crude extracts. The isolated bioactive components should also be further subjected to more preclinical studies and elaborate toxicity study before clinical trials can be pursued.     

Advances in pharmacotherapeutic management of common skin diseases in neonates and infants

Introduction: neonatal and infantile skin diseases are frequently encountered in the clinical practice and represent worldwide a socioeconomic issue. They encompass a wide range of acquired or congenital conditions, including infections, vascular lesions and inflammatory diseases and can present with different degrees of severity, leading in some cases to dramatic complications.

Areas covered: In this paper we report the most recent evidences on the management of some common skin diseases in neonates and infants. Hemangiomas, viral, fungal and bacterial infections, omphalitis, atopic and seborrhoeic dermatitis, napkin disease will be treated and discussed.

Expert opinion: The majority of the dermatologic alterations in neonates are physiological, transient and do not require any treatment, thus the parents can be reassured about the good prognosis. However, in some cases, serious conditions must be excluded. In particular neonatal and infantile infections should be promptly recognized and properly managed, to avoid severe complications. The therapeutic options include traditional and, although few, innovative medical treatments, which will be carefully taken into consideration by the expert Dermatologists and Paediatricians.     

A review on phytochemical and pharmacological properties of Litsea coreana

Context: Litsea coreana H. Lév. (Lauraceae) is used as an ethnic herb or beverage in China. Substantial studies indicate that it contains a variety of compounds and shows diverse bioactivities with no toxicity.

Objective: This review analyzes and summarizes the ethnopharmacological applications, phytochemistry, and pharmacological activities and molecular mechanisms of L. coreana.

Methods: Related literature (from 1998 to 2016) was obtained and compiled via searching databases including Scopus, Web of Science, Google Scholar, CNKI and PubMed. Keywords (Litsea coreana, hawk tea, eagle tea and laoying cha) were used to select the articles.

Results: Studies indicate that L. coreana contains characteristic polysaccharides, polyphenols, essential oils, and numerious flavonoids, which exhibit remarkable bioactivities, such as hepatoprotection, hyperglycaemia, anti-inflammation, antioxidation and antibacterial, through multiple molecular mechanisms.

Conclusion: This paper provides a systematic review on the phytochemicals and pharmacological activities of L. coreana which should be useful for further study and application of this medicinal herb.     

Echinacea biotechnology: advances,commercialization and future considerations

Context: Plants of the genus Echinacea (Asteraceae) are among the most popular herbal supplements on the market today. Recent studies indicate there are potential new applications and emerging markets for this natural health product (NHP).

Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.

Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.

Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.

Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities.     

Fractional laser-assisted topical delivery leads to enhanced,accelerated and deeper cutaneous 5-fluorouracil uptake

Background: Topical 5-Fluorouracil (5-FU) exhibits suboptimal efficacy for non-melanoma skin cancer, attributed to insufficient intracutaneous penetration. This study investigates the impact of ablative fractional laser (AFXL) at different laser-channel depths on cutaneous 5-FU pharmacokinetics and biodistribution.

Methods: In vitro porcine skin underwent AFXL-exposure using a fractional 10,600 nm CO₂-laser, generating microscopic ablation zones (MAZ) reaching the dermoepidermal junction (MAZ-ED), superficial-(MAZ-DS), or mid-dermis(MAZ-DM). 5-FU in AFXL-exposed and control skin was measured in Franz diffusion cells at 4 and 24 hours (n = 55). HPLC quantified 5-FU in full-thickness skin, specific skin depths of 100μm-1500μm, and transcutaneous receiver-compartments. Qualitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) visualized 5-FU in selected samples.

Results: Overall, AFXL enhanced and accelerated 5-FU uptake versus unexposed controls, with increased accumulation in deep skin layers (p < 0.01). While total, 24-hour 5-FU uptake in control skin was 0.096 mg/cm³ (0.19% of applied concentration), AFXL delivered up to 4.707 mg/cm³ (MAZ-DM; 9.41% uptake, 49-fold enhancement) (p = 0.002; 24 hours). Indicating accelerated delivery, 5-FU in laser-exposed samples at 4 hours was at least 10-fold that of 24-hour controls (p = 0.002). Deeper laser-channels increased delivery throughout the skin (MAZ-ED vs. MAZ-DM; p<0.01). MALDI-MSI confirmed enhanced, accelerated, deeper and more uniform 5-FU distribution after AFXL versus controls.

Conclusions: AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers.