ABSTRACT Tedizolid phosphate is approved for the treatment of acute bacterial skin and skinstructureinfection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200 mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6 days or 600 mg of linezolid, i.v./p.o. twice daily for 10 days. The primary endpoint was early clinical response rate at 48 to 72 h. Secondary end- points included programmatic and investigator-assessed outcomes at end-of-therapy (EOT) and posttherapy evaluation (PTE) visits. Safety was also evaluated. In the intent-to-treat (ITT) population, 75.3% of tedizolid-treated patients and 79.9% of linezolid-treated patients were early responders (treatment difference, – 4.6%; 95% conﬁdence interval [CI], –11.2, 2.2). After exclusion of patients who never received the study drug (tedizolid, n ⫽ 8; linezolid, n ⫽ 1; modiﬁed ITT), comparable early re- sponse rates were observed (tedizolid, 77.4%; linezolid, 80.1%; treatment difference, –2.7%; 95% CI, –9.4, 3.9). Secondary endpoints showed high and similar clinical suc- cess rates in the ITT and clinically evaluable (CE) populations at EOT and PTE visits (e.g., CE-PTE for tedizolid, 90.4%; for linezolid, 93.5%). Both drugs were well toler- ated, and no death occurred. Eight patients experienced phlebitis with tedizolid while none did with linezolid; hence, drug-related treatment-emergent adverse events were reported in a slightly higher proportion in the tedizolid (20.9%) arm than in the linezolid arm (15.8%). The study demonstrated that tedizolid in a primar- ily Asian population was an efﬁcacious and well-tolerated treatment option for ABSSSI patients. (This study has been registered at ClinicalTrials.gov under registra- tion no. NCT02066402.)
Phase 3, international, multicenter, randomized, double- blind, comparative clinical trials are considered the gold standard for establishing efficacy of antibiotics used for treatment of patients with complicated skin and skinstructureinfection (cSSSI). Although “efficacy” is estab- lished in this study design, it is often difficult to generate quantitative economic or “effectiveness” inferences be- tween treatments in such trials. Making the leap from the comparative efficacy to the comparative effectiveness of an antibiotic used to treat cSSSI is complex and chal- lenging. For example, studies have clearly shown that hospital length of stay (LOS) is the primary driver of the cost of treating patients with cSSSI [1, 2]. However, it is difficult to make direct LOS comparisons from registra- tional trials because of their structured nature and ex- plicit requirements (i.e., fixed duration of therapy, lack of an oral step-down therapy option during the primary treatment period). Furthermore, evaluating comparative effectiveness requires relaxation of certain parameters included in the design of traditional randomized clin- ical trials (RCTs), such as patient inclusion and exclu- sion criteria, monitoring, and restrictions on the use of both the experimental intervention and the comparator agent [3, 4].
Overall, the majority of hospitalizations were related to cellulitis/erysipelas (32.8% to 63.4%) followed by abscess (16.6% to 41.9%), and other subtypes (2.1% to 49.7%; Table 2). Cellulitis/erysipelas was the most frequent type of infection for patients with a primary diagnosis across all provinces (55.8% to 63.4%) and for patients with a second- ary diagnosis in Ontario, Alberta/British Columbia, and the Canadian Prairie (47.3% to 58.0%). In all provinces, infections categorized as “other” occurred more frequently among patients with a secondary diagnosis than among those with a primary diagnosis. In the total cohort, the majority of infections involved a limb (62.7% to 73.8%), followed by the trunk (16.6% to 26.8%). The most common comorbid conditions were diabetes mellitus (42.5% to 72.2%), renal disease (9.1% to 21.5%), and congestive heart failure (5.1% to 17.4%). The distribution of comorbidity burden differed slightly depending on whether the patient had a primary or secondary diagnosis. The majority of the patients across the samples had zero or one comorbidity; however, among patients with a secondary diagnosis, a higher proportion of patients had two or more comorbidities.
Oritavancin (previously LY333328) is a newly introduced glycopeptide whose history dates back to 1996, when Eli Lilly and Company submitted to the US Food and Drug Administration (FDA) an Investigational New Drug Application, following which, several Phase I, II, and III studies were initiated, mainly bacteremia and skin and skinstructureinfection studies (Figure 1). Then, in 2002, the Investigational New Drug Application was transferred to InterMune, Incorporated, but clinical trials were halted due to infusion-related adverse events in previous trials. Targanta Therapeutics Corporation acquired oritavancin in 2006 and demonstrated that injection-site phlebitis was a side effect frequently observed with most glycopeptides. In 2008, Targanta presented a New Drug Application for oritavancin as an intravenous formulation given once daily for 3 to 7 days for the treatment of complicated skin and soft tissue infections. Oritavancin has since been studied in two Phase III trials, the results of which have been recently published and show oritavancin to be noninferior to vancomycin in skin infections. The current proposed therapeutic use of oritavancin is for the treatment of acute bacterial skin and skinstructure infections (ABSSSIs) caused by susceptible Gram-positive bacteria.
skin after transplantation, TESSs at 5, 9, 14, and 21 days were collected before grafting for western blot analysis of their expression of various differentiation markers, p63, and markers of cell apoptosis (Fig. 6a). The expres- sion of the basal cell marker keratin 5 (K5) was not dif- ferent among the 4 groups, but the expression of the suprabasal marker keratin 1 (K1) was significantly en- hanced with increased culture time in vitro. Importantly, TESS-5d expressed a much higher level of p63, which is crucial for the initiation of epithelial stratification and the maintenance of basal keratinocyte proliferation, compared with the other groups. The expression of p63 was downregulated with increased culture time in vitro (Fig. 6a, b), which was consistent with the in vivo results of p63 staining (Fig. 3c, g). Finally, the expression of cleaved Caspase-3 (C-Caspase-3) was increased with a longer culture time, indicating the activation of cellular apoptosis during the in vitro culture (Fig. 6a), while the activated form of Pro-Caspase-3 (Total Caspase-3) was significantly increased, and the level of Pro-Caspase-3 was reduced correspondingly (Fig. 6a, b). This was fur- ther confirmed by qRT-PCR analysis of the expression of the apoptotic markers p21 and Bax, whose expression was increased in late-stage TESSs, and the expression of Bcl-2, an anti-apoptotic gene, was decreased in late-stage TESSs (Fig. 6c). These results suggested that early-stage TESSs contain more undifferentiated cells with higher expression levels of p63 and fewer apoptotic cells com- pared to late-stage TESSs.
A number of S. aureus vaccines have reached clinical trials, all of which were composed of a single target antigen that was designed to induce neutralising and opsonising antibodies , and although these vaccines produced robust humoral immunity, and proved efficacious in pre-clinical models, they did not prevent or attenuate infection in clinical trials . The failure of these immunization strategies to confer protection in humans would suggest that antibodies alone are not sufficient to provide protection against S. aureus. This is somewhat unsurprising, as B cell deficiencies in humans and mice do not result in an increased frequency or severity of S. aureus disease [5–7]. There is increasing evidence that T cells, in particular T helper (Th) cells, have an important role in the immune response to S. aureus . It is now widely accepted that protection against S. aureus requires a robust T cell response, in particular Th1 and Th17 cells, which are critical for controlling phagocytic cell responses and thus facilitating bacterial clearance [4,8]. Interestingly, it has been shown that model vaccines can actually confer protection against S. aureus infection in the complete absence of antibodies provided there is a robust T cell response [7,9]. Patients suffering from a range of conditions that affect Th cells are at greater risk of developing S. aureus infections [6,10–12]. Autosomal dominant hyper-IgE syndrome (AD-HIES) patients are susceptible to recurrent staphylococcal skin and lung abscesses . AD-HIES results in impaired Th17 cell development, however, CD4 + T cells retain the ability to differentiate into other subsets of Th cells . Interestingly, these patients are not more susceptible to S. aureus bloodstream infection, suggesting that Th17 responses are particularly important during skin and respiratory site infections, but may be less important during systemic infection. Similarly, mice deficient in interleukin-17A (IL-17A) and IL-17F showed
Abstract: Tedizolid phosphate is the first once-daily oxazolidinone approved by the United States Food and Drug Administration for the treatment of acute bacterial skin and skinstructure infections (ABSSSI). It is more potent in vitro than linezolid against methicillin-resistant Staphy- lococcus aureus (MRSA) and other gram-positive pathogens causing ABSSSI, even retaining activity against some linezolid-resistant strains. Tedizolid is approximately 90% protein bound, leading to lower free-drug concentrations than linezolid. The impact of the effect of food, renal or hepatic insufficiency, or hemodialysis on tedizolid’s pharmacokinetic have been evaluated, and no dosage adjustment is needed in these populations. In animal and clinical studies, tedizolid’s effect on bacterial killing is optimized by the free-drug area under the curve to minimum inhibi- tory concentration ratio (fAUC/MIC). The 200 mg once-daily dose is able to achieve the target fAUC/MIC ratio in 98% of simulated patients. Two Phase III clinical trials have demonstrated the noninferiority of tedizolid 200 mg once daily for 6 days to linezolid 600 mg twice daily for 10 days. In vitro, animal, and clinical studies have failed to demonstrate that tedizolid inhibits monoamine oxidase to a clinically relevant extent. Tedizolid has several key advantages over linezolid including once daily dosing, decreased treatment duration, minimal interaction with serotonergic agents, possibly associated with less adverse events associated with the impairment of mitochondrial protein synthesis (eg, myelosuppression, lactic acidosis, and peripheral/optic neuropathies), and retains in vitro activity against linezolid-resistant gram-positive bacteria. Economic analyses with tedizolid are needed to describe the cost-effectiveness of this agent compared with other options used for ABSSSI, particularly treatment options active against MRSA.
Inclusion criteria: Patients were included in the primary trial if they had signs or symptoms of a cSSSI involving deep tissues and at least two of the following: purulent drainage, erythema, swelling or induration, tenderness or pain, and local warmth. In addition, patients had at least one sign of systemic infection, such as fever, hypoten- sion, increased white blood cell count (≥10,000 mm 3 ), or more than 15% immature neutrophils regardless of the
3. destructive infections require treatment in an inpa- tient setting. failure to remove necrotic, infected tissue and drain purulent collections increases the risk of amputation. the goal is to relieve the puru- lent infection via operative debridement and to re- move infected tissue. this is the most secure way to prevent an imminent amputation. Especially in case of very advanced infections, it is important to rule out a phlegmonous infection of the plantar fascia in the differential diagnosis. In case of osteitis with joint involvement, only a limited resection is indi- cated. the initial debridement must be performed independently of the status of arterial circulation with revascularisation postponed until sepsis is con- trolled.
Although most cSSSIs are caused by Gram-positive cocci, there is a difference in the organisms isolated from CA-cSSSIs and HA-cSSSIs, such as MRSA. In addition, some of the Gram-negative bacteria are common isolates from HA-cSSSIs. It is best to use this parameter as a guide for initial antimicrobial therapy options, especially if a Gram stain report is not available or is delayed. Infection with Streptococcus species usually respond favorable to standard semisynthetic penicillin or early generation cephalosporins. However, if the patient is allergic to penicillin and because the group A streptococci are showing resistance to erythromycin, a lincosamide such as clindamycin could be used. Because of increasing resistance to these drugs, it might be best to use drugs from antimicrobial classes that have different foci (eg, cell-wall inhibition, protein synthesis inhibition) in combination. 19,93
Linezolid is currently approved by the US Food and Drug Administration for the treatment of complicated skin and skinstructure infections and nosocomial pneumonia caused by susceptible pathogens, including MRSA. Much debate exists whether linezolid should be considered the drug of choice for MRSA pneumonia on the basis of two retrospective analyses of pooled data from randomized trials comparing linezolid and vancomycin for nosocomial pneumonia [50,51]. In these retrospective analyses, linezolid therapy was associated with increased survival, but one limitation is that vancomycin may have been dosed inadequately, leading to suboptimal concentrations. A randomized, double-blind trial is underway in an effort to either confirm or refute these findings in hospitalized patients with nosocomial pneumonia due to MRSA. Linezolid should also be considered for necrotizing infections, including skin lesions, fasciitis, and pneumonia caused by CA-MRSA as it has been hypothesized that antibiotics with the ability to inhibit protein synthesis may demonstrate efficacy against susceptible toxin-producing strains . Recent guidelines  recommend against the use of linezolid as empiric therapy for catheter-related blood stream infections (CRBSIs) as one study  comparing vancomycin and linezolid for empiric therapy of complicated skin and soft tissue infections and CRBSI found a trend toward increased mortality in the linezolid group when performing a Kaplan-meier analysis of the intent-to-treat population. In the primary analysis of this study, linezolid was found to be non-inferior to the control group, and a subgroup analysis of patients with MRSA bacteremia showed improved outcomes in the linezolid group . Linezolid is recommended as an alternative agent for CRBSI due to MRSA in this same guideline . Safety concerns that sometimes limit the use of this agent include the association of serotonin toxicity and thrombocytopenia .
The present study demonstrates that cSSSI due to pvl-posi- tive MRSA is significantly more likely to be cured than cSSSI due to MRSA not containing this gene. This finding persisted when the analysis was adjusted for patient comorbidity as well as for infection type, severity, and surgical intervention. The results of this study validate previous observations for patients with cSSSI (2) and bacteremia (15) and are also consistent with a recent study showing that the presence of pvl did not ad- versely influence the outcome of uncomplicated SSSI (10). Taken together, these results clearly indicate that factors other than the simple presence of pvl determine the clinical outcome of cSSSI caused by MRSA.
Our study had several limitations. First, our study focused by design on patients with S. aureus HAP, while most prior reports that link PVL with pneumonia involved community-acquired S. aureus necrotizing pneumonia (15, 16). Thus, our findings would not apply to community-acquired S. aureus necrotizing pneumo- nia. This is an important distinction because of the prior health status of the infected individuals, i.e., those with community- acquired S. aureus necrotizing pneumonia were typically other- wise healthy, whereas patients with S. aureus HAP had risk factors for infection (and were thus highly susceptible to infection). Pre- viously existing susceptibility of the HAP patients to infection could in part explain the finding that there was no significant association between clinical outcome and presence or absence of putative virulence genes (Table 3). Such molecules might simply be unnecessary to cause infection in these immunocompromised patients. Second, the proportion of isolates harboring and ex- pressing PVL was low (⬍10%) and thus limited the statistical power of finding associations. Although we must remain cautious in the conclusions drawn from the present study, the fact that other investigators (33) have recently reported the same result strengthens its generalizability. Third, we evaluated alpha- hemolysin levels in vitro, and it remains unclear whether in vitro activity is a reflection of relative toxin production in vivo.
In order to provide a stable base for friction testing and improve the consistency of the sample thicknesses (Table 1), the synthetic substitute skin was used as a base layer for the dermis, human skin and TE skin tests. This was glued onto sand paper attached to the rig. The epidermis was tested too, in order to provide a comparison that might validate the use of synthetic skin as a base layer. For these studies different skin donors were tested (Table 1). Friction tests were carried out using a CETR-UMT 2 (Bruker) tribometer. The configuration used was a normally loaded probe (a 4 mm diameter stainless steel ball) being driven across the sample in a linear reciprocating fashion. The tests were completed at three different normal loads (5, 10 and 30 mN) at an average speed of 0.5 mm/s for six sliding cycles with a stroke of 10 mm (one cycle is twice the stroke). The normal load was stabilised for 20 s before testing. Figure 4 shows the measurement system which is composed of a double load cell (one for normal load and one for friction force). The kinetic coefficient of friction was calculated as the ratio between the friction force and the normal force. For each sample at least two repeats were carried out.
Microneedle administration is a minimally invasive technique. In current experimental studies, micron-sized silicon, metal, glass, and polymer microneedles have been manufactured. Microneedles for transdermal drug delivery have attracted more and more attention because it can provide with painless, minimally invasion and time-release drug delivery. However, it is difficult to produce a qualified microneedle with high mechanical strength, small trama, and good biocompatibility. Silicon microneedles have sufficient hardness, but they are brittle. While polymer microneedles are soft to insert into the skin and tend to buckle. How to effectively penetrate the microneedles into the skin has become a hot topic of research, and it is also an important research direction for the development of microneedle technology.
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated and hospital-associated strains, is a major cause of human morbidity and mortality. Treatment options have become limited due to the emergence of MRSA strains with decreased sensitiv- ity to vancomycin, which has long been the first-line therapy for serious infections. This has prompted the search for novel antibiotics that are efficacious against MRSA. Linezolid, an oxazolidinone class of antibiotic, was approved by the Food and Drug Administration in 2000 for treatment of MRSA infections. Since then, there have been a multitude of clinical trials and research studies evaluating the effectiveness of linezolid against serious infections, including pneumonia (both community- and hospital-acquired), skin and soft-tissue infections such as diabetic foot ulcers, endocarditis, osteomyelitis, prosthetic devices, and others. The primary aim of this review is to provide an up-to-date evaluation of the clinical evidence for using linezolid to treat MRSA infections, with a focus on recently published studies, including those on nosocomial pneumonia. Other objectives are to analyze the cost-effectiveness of linezolid compared to other agents, and to review the pharmokinetics and pharmacodynamics of linezolid, emphasizing the most current concepts.
Abstract - Fuselage buckling of a stiffened composite cylinder is a very complex phenomenon that involves complex interactions between the skin and the stiffeners. Considering different configurations of the skin and stiffener, different types of buckling failure modes and failure loads are observed in stiffened cylinders. In this work failure modes and the buckling loads of stiffened composite cylinders under uniaxial loading condition is investigated by using analytical and experimental approaches. Initially, a developed model for buckling problem of an isogrid stiffened composite cylinder. In these models the stiffness contributions of the stiffeners is computed by analyzing the moment and force effect of the stiffener on the unit cell. The equivalent stiffness of the stiffener/shell panel is computed by superimposing the stiffness contribution of the stiffeners and the shell. Once the equivalent stiffness parameter is determined for the whole panel buckling load is calculated using the energy method. A 3-D finite-elements model was also built which takes into consideration the exact geometric configuration and the orthotropic properties of the stiffeners and the shell. Based on finite-elements model, a discussion is made on the different buckling failure modes observed. The results of these three types of analysis methods are compared and comments are made on the reliability of the analytical models developed and finally a parametric study was carried out and general conclusions were drawn regarding the optimum configurations of the different parameters of the grid-stiffened cylinder.
Previous studies have revealed the primary structure of type I and II procollagen α1 chain in some fishes (Saito et al., 2001; Hwang et al., 2006; Zhang et al., 2016). We cloned the cDNA for PBT procollagen α1 (I) (Tanaka et al., 2014) and predicted that the PBT procollagen α1 (I) might contain high numbers of Gly-Gly sequences (Gly- Gly and Gly-Gly-Gly) in the triple-helical region. The number of Gly-Gly sequences in PBT procollagen α1 (I) was 14, whereas the number in zebrafish, rainbow trout, and torafugu were 4, 22, and 11, respectively. Since Gly is the smallest amino acid, the Gly-Gly sequence likely con- tributes to the partial skew in the triple helix structure and the decrease in thermal stability. While the PBT pro- collagen α1 (I) contains a high number of Gly-Gly se- quence, it is not the highest among fish procollagen α1 (I) reported previously. Thus, further rationalization for the low thermal stability of PBT skin collagen is required. In addition, two Ser residues (1253 and 1270) that play a crucial role in the interactions of the procollagen α chains (Dion and Myers, 1987) were not found in the C-terminal region of the PBT procollagen α1 (I) chain. This indicated that PBT collagen might easily accrue distortion in its protein structure, which might contribute to its low de- naturation temperature. PBT possesses delicate skin, which renders handling difficult during rearing this species. The primary structure of the PBT skin collagen could possibly explain the sensitive nature of its skin.