Understanding symptoms and management of skin disorders

It is estimated that at any one time about 25 per cent of the population has a skin problem that could benefit from medical care. Skin diseases can be physically disabling, disfiguring, painful, intensely irritating and distracting. Relatively few skin diseases are life-threatening, but they can all have severe psychological, physical and social effects.     

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL_CRs) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL_CRs of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL_CRs of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC_τ) was computed as dose/CL. The probability of achieving an AUC_τ/MIC ratio of ≥219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC_τ/MIC ratio of ≥219 for MIC values as high as 2 mg/liter. For patients with CL_CRs of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC_0–24 (AUC from 0 to 24 h) and AUC_24–48 intervals for MICs of ≤1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC_0–24 and AUC_24–48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.     

Understanding the principles of suturing minor skin lesions

Suturing has been used as a method of primary wound closure for centuries. Despite the introduction of other methods of wound closure such as staples, tissue glue, and adhesive skin-closure strips, it has remained a popular and effective choice. This article looks at the principles of suturing minor skin lesions in adults, wound assessment and choosing a method of closure, basic suturing technique, and when to remove sutures.     

Iclaprim: a differentiated option for the treatment of skin and skin structure infections

ABSTRACT

Introduction: Iclaprim is a selective bacterial dihydrofolate reductase (DHFR) inhibitor. Although there are alternative options for the treatment of acute bacterial skin and skin structure infections (ABSSSI), iclaprim is differentiated from other available antibiotics.

Areas covered: Iclaprim is under clinical development for ABSSSI. This review summarizes the mechanism of action, pharmacokinetics, microbiology, clinical development program, and the differentiation of iclaprim from other antibiotics.

Expert commentary: Iclaprim has a different mechanism of action (DHFR inhibitor) compared to most other antibiotics, is active and rapidly bactericidal against Gram-positive pathogens including antibiotic-resistant pathogens, and suppresses bacterial exotoxins (alpha hemolysin, Panton Valentine leukocidin, and toxic shock syndrome toxin-1). Compared to trimethoprim, iclaprim has lower MIC_90s, can be given without a sulfonamide, overcomes select trimethoprim resistance, and does not cause hyperkalemia. Iclaprim is administered as a fixed dose, does not require dose adjustment in renally-impaired or obese patients, and was not associated with nephrotoxicity in the Phase 3 pivotal REVIVE studies. Iclaprim represents a novel, alternative option for the treatment of severe skin and skin structure infections due to Gram-positive bacteria, particularly in patients at risk of acute kidney injury.     

Ceftobiprole: a new cephalosporin for the treatment of skin and skin structure infections

Ceftobiprole is among the first of a new generation of cephalosporins with activity against aerobic Gram-negative bacilli, which extends to cefepime-sensitive Pseudomonas aeruginosa, and activity against Gram-positive organisms, which includes methicillin-resistant Staphylococcus aureus. Ceftobiprole is currently undergoing evaluation by the US FDA for the treatment of complicated skin and skin structure infections, with a decision pending further evaluation of study site monitoring. It is also being evaluated for the treatment of community-acquired and healthcare-associated pneumonia. Two Phase III multicenter trials have demonstrated noninferiority in complicated skin and skin structure infections when tested against vancomycin in primarily Gram-positive bacterial infections, and when tested against vancomycin plus ceftazidime in Gram-positive and Gram-negative bacterial infections. It is well tolerated, with the most common side effects being nausea and dysgeusia. Ceftobiprole is likely to prove useful as an empiric as well as directed monotherapy in patients with complicated skin and skin structure infections, in which both Gram-positive pathogens including methicillin-resistant S. aureus and Gram-negative pathogens including cefepime-sensitive P. aeruginosa may be involved.     

Telavancin (VIBATIV) for the treatment of complicated skin and skin structure infections

Methicillin-resistant Staphylococcus aureus has emerged as a major causative pathogen in complicated skin and skin structure infections (cSSSIs). Unfortunately, treatment failure with vancomycin has been increasingly reported. Over the past decade, several alternative antimicrobial agents have been studied and approved for the treatment of cSSSIs. One such agent is the lipoglycopeptide telavancin, which was approved by the US FDA 2009. Given its dual mechanism of action, telavancin is characterized by a highly bactericidal activity and low potential for resistance selection. In addition, in clinical trials, it was efficacious and safe in the treatment of cSSSI. The purpose of this review is to give a background overview of telavancin, highlighting its microbiological, pharmacokinetic and pharmacodynamics characteristics, to summarize the available evidence for its use in the treatment of cSSSIs, and to provide an updated evaluation of its safety profile.     

Management of bacterial skin and skin structure infections with polymicrobial etiology

Introduction: Skin and Soft Tissue Infections (SSTIs) are some of the most commonly occurring bacterial infections, with a wide range of possible etiological pathogens and a considerable variety of clinical presentations and severity; from mild to severe life-threatening infections. Several classifications have been proposed based on a specific variable, such as anatomical localization, skin extension, progression rate, clinical presentation, severity, and etiological agent.

Areas covered: The last criteria allows the differentiation of SSTIs as monomicrobial and polymicrobial. Among them, especially those infections with a long lasting or chronic course can be sustained by multiple microbial etiology. Most polymicrobial SSTIs can be included in the following: diabetes foot infections (DFIs), pressure ulcers infection, burn infection, and infected chronic ulcers.

Expert commentary: The medical management of these infections comprises the administration of wide a spectrum antibiotic, taking into consideration the frequent occurrence of multidrug resistant microorganisms as responsible agents. An appropriate deep tissue specimen for microbiological examination is a very important issue, especially for polymicrobial infections, sometimes permitting the distinction between real pathogens and contaminants avoiding more complex antibiotic treatments. This aspect must be strongly emphasized, as frequently superficial swabs remain the specimen of choice because they are easy to obtain.     

Tedizolid for treatment of acute bacterial skin and skin structure infections

Tedizolid is a newly approved drug of the oxazolidinone class. It has high in vitro activity against Gram-positive bacteria, including multidrug-resistant strains. Peak plasma concentration of tedizolid is obtained within 3 h of oral dosing (PO), with high bioavailability. Tedizolid is mostly metabolized via the liver, and is excreted in feces in the form of a sulfate conjugate. Tedizolid 200 mg taken once daily demonstrated non-inferior efficacy and a good safety profile in patients with acute bacterial skin and skin structure infections. Results of two pivotal Phase III clinical trials showed that 6 days of 200 mg tedizolid PO or sequential intravenous (IV)/PO once-daily treatment was non-inferior to 10 days of 600 mg linezolid PO or sequential IV/PO twice-daily treatment at 48–72 h (primary end point) and at the test-of-cure in patients with acute bacterial skin and skin structure infections. The Phase II and Phase III trials also demonstrated that tedizolid was well tolerated.     

Dalbavancin (BI-387) for the treatment of complicated skin and skin structure infection

In the era of increasing antibiotic resistance, development of new agents that could provide therapeutic options for difficult to treat pathogens is vital. Dalbavancin is a new lipoglycopeptide recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections. A derivative of the older glycopeptide class, chemical structure alterations resulted in a molecule with a similar mechanism of action, however, with a comparatively increased activity as reflected by organism MICs. These modifications also resulted in an antibiotic with distinctive properties that allow for once-weekly dosing in the treatment of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and drug resistant Streptococcus spp. As the first of these long acting compounds, understanding the pharmacokinetic and pharmacodynamic properties of agents like dalbavancin is essential for determining a place in therapy.     

The problem of complicated skin and skin structure infections: the need for new agents

Complicated skin and skin structure infections (cSSSIs) continue to pose a significant clinical challenge. The most frequent cause of these infections is Staphylococcus aureus, although other organisms, including Streptococcus pyogenes and, in certain circumstances, Enterobacteriaceae, are also involved. The relentless increase in methicillin resistance among S. aureus isolated in hospitals throughout the world has made it important to provide coverage for these organisms when treating cSSSIs in hospitals. More recently, however, there has been a striking increase in methicillin resistance among staphylococci isolated from infections acquired in the community, particularly in the USA. As a result, previous recommendations for empirical therapy of these important infections are now outdated. The papers in this Supplement detail the properties of a new broad-spectrum cephalosporin that has activity against MRSA and is, thus, an outstanding candidate for empirical therapy of cSSSIs. The papers included provide data on the in vitro activity, pharmacokinetics and pharmacodynamics as well as the clinical efficacy of ceftaroline fosamil, which is a welcome addition to our therapeutic armamentarium against cSSSIs.     

Topical antibiotic treatment for uncomplicated skin and skin structure infections: review of the literature

Uncomplicated skin infections account for almost 200 million physician-office visits in the USA annually. Treating these infections is estimated to cost in excess of US$350 million each year. The primary etiology of these infections is Staphylococcus aureus, over 60% of which is estimated to be methicillin resistant across the USA. Therapeutic options include incision and drainage in combination with antimicrobial therapy, which may be oral, topical or occasionally parenteral. Because the effectiveness of the current oral options, such as β-lactams and other classes, is being eroded due to acquired resistance, older, untested agents such as trimethoprim–sulfamethoxazole or clindamycin are often being used. Thus, topical approaches may offer effective, localized, well-tolerated alternatives to the systemic regimen. However, their value in the management of uncomplicated skin infections is not yet clearly defined. This literature review discusses various topical antibiotic treatment options for uncomplicated skin infections, including over-the-counter and prescribed regimens.     

Understanding platelet function through signal transduction

Platelets are activated by a number of stimuli resulting in the expression and/or activation of surface receptors, secretion of vasoactive substances, adhesion, aggregation, and finally thrombus formation. These events are propagated by a process known as transmembrane signaling, which relays the activating signal from the platelet membrane (eg, von Willebrand Factor binding to glycoprotein Ib) to the inside of the platelet which then serves to activate the platelet via a cascade of biochemical interactions. Inhibition of these transmembrane signaling molecules with a variety of available inhibitors or antagonists can in many cases prevent the platelet from becoming activated. An awareness of the mechanisms involved in platelet transmembrane signaling and the recent availability of new reagents to inhibit signaling may provide us with additional means to prevent platelet activation and perhaps even ameliorate the platelet storage lesion. This review will provide an introduction to the field of platelet transmembrane signaling and give an overview of some of the platelet signaling mechanisms that are relevant to transfusion medicine.     

Pharmacokinetics of cefonicid in patients with skin and skin structure infections.

The disposition of cefonicid (2 g intravenously every 24 h) was assessed in 15 patients with skin and skin structure infections. Trough and peak concentrations in serum were measured on two successive days to verify the attainment of steady state; and 1 trough and 12 postdose values of the concentration in serum were collected on the following day. Cefonicid concentrations in serum were determined by high-performance liquid chromatography. The cefonicid serum concentration versus time profile after intravenous infusion was clearly biexponential in all patients. The terminal elimination half-life determined by nonlinear regression analysis was 4.63 +/- 1.49 h (mean +/- standard deviation). The steady-state volume of distribution and total body clearance were 0.12 +/- 0.04 liter/kg and 0.369 +/- 0.110 ml/min per kg, respectively. These results are comparable to parameters derived from previous studies in noninfected normal volunteers. Thus, the disposition of cefonicid is not altered in patients with severe skin and skin structure infections.     

组织工程化皮肤重建皮肤功能的研究进展

随着组织工程学的兴起和发展,组织工程化皮肤的研究有可能成为解决这一难题的有效途径。自从Rheinwald和Green成功建立表皮细胞培养方法以来,表皮培养的技术方法有了很大改进;胶原海绵、无细胞异体或异种真皮基质等真皮替代物的研究使复合皮的建立成为可能;干细胞的研究、基因转染在皮肤组织工程学中的应用将使组织工程化皮肤的研究更加成熟;组织工程化皮肤的生产和应用,使其成为第一个商品化的、也时目前成功应用的组织工程化产品,并且可能成为皮肤缺损后愈合时间短、愈合后效果好、瘢痕轻的创面愈合方法,以达到皮肤结构和功能的恢复。     

Steady-state pharmacokinetics of fleroxacin in patients with skin and skin structure infections.

Steady-state pharmacokinetics of oral fleroxacin were studied in six males who had skin or skin structure infections and who were receiving 400 mg of fleroxacin once a day. Blood samples (n = 10) and total urine output were collected during a 24-h dosing interval. Fleroxacin concentrations in serum and urine were determined by high-performance liquid chromatography. The maximum concentration in serum and the time to achieve that maximum were 6.2 +/- 2.2 micrograms/ml and 0.94 +/- 0.62 h, respectively. The absorption half-life, alpha half-life, beta half-life, apparent steady-state volume of distribution, apparent total body clearance, and renal clearance were 0.56 +/- 0.37 h, 0.78 +/- 0.51 h, 10.56 +/- 1.40 h, 0.85 +/- 0.31 liters/kg, 129.2 +/- 19.6 ml/min, and 53.3 +/- 16.7 ml/min, respectively. Fleroxacin disposition in this patient population was similar to that in noninfected volunteers with normal renal function.