David M. Young

Telavancin Versus Vancomycin for the Treatment of Complicated Skin and Skin-Structure Infections Caused by Gram-Positive Organisms

BACKGROUND Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. METHODS We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged > or = 18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). RESULTS A total of 1867 patients were randomized and received > or = 1 dose of study medication. In the clinically evaluable population, at 7-14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, -2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, -1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, -0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. CONCLUSIONS Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.

Randomized, Double-Blind, Placebo-Controlled Trial of Cephalexin for Treatment of Uncomplicated Skin Abscesses in a Population at Risk for Community-Acquired Methicillin-Resistant Staphylococcus aureus Infection

ABSTRACT Empirical use of beta-lactam antibiotics, the preferred agents for treating uncomplicated skin and soft tissue infections, may no longer be appropriate for these infections because of the increasing prevalence of community strains of methicillin-resistant Staphylococcus aureus (MRSA). Retrospective studies, however, suggest that outcomes are good even when beta-lactams are used. We conducted a randomized, double-blind trial of 166 outpatient subjects comparing placebo to cephalexin at 500 mg orally four times for 7 days after incision and drainage of skin and soft tissue abscesses. The primary outcome was clinical cure or failure 7 days after incision and drainage. S. aureus was isolated from 70.4% of abscess cultures. Of the isolates tested 87.8% were MRSA, 93% of which were positive for Panton-Valentine leucocidin genes. Clinical cure rates were 90.5% (95% confidence interval, 0.82 to 0.96) in the 84 placebo recipients and 84.1% (95% confidence interval, 0.74 to 0.91) in the 82 cephalexin recipients (difference in the two proportions, 0.0006; 95% confidence interval, −0.0461 to 0.0472; P = 0.25). The 90.5% cure rate observed in the placebo arm and 84.1% cure rate observed in the cephalexin arm provide strong evidence that antibiotics may be unnecessary after surgical drainage of uncomplicated skin and soft tissue abscesses caused by community strains of MRSA.

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

ABSTRACT Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

Sustained expression of Hif-1α in the diabetic environment promotes angiogenesis and cutaneous wound repair

Impaired wound healing in diabetic patients is associated with deficiencies in the production of factors involved in cell proliferation and migration, such as vascular endothelial growth factor. However, it remains unclear how the transcriptional regulation of the genes encoding these factors is affected by the diabetic environment. Hypoxia‐inducible factor‐1α (Hif‐1α), the regulatory subunit of the Hif‐1 transcription factor, plays an important role in activating many of these genes. Therefore, we tested whether Hif‐1α function is impaired in the diabetic wound environment and whether restoring Hif‐1 function improves wound healing. Here, we show that Hif‐1α protein levels are dramatically reduced in wounds of leptin receptor‐deficient diabetic mice compared with nondiabetic littermates. Reduction in Hif‐1α levels results in decreased DNA‐binding activity and in decreased expression of several Hif‐1 target genes, including vascular endothelial growth factor, heme oxygenase‐1, and inducible nitric oxide synthase. Furthermore, we demonstrate that sustained expression of Hif‐1α in leptin receptor‐deficient diabetic wounds restores expression of these factors, enhances angiogenesis, and significantly accelerates wound healing. Taken together, these results suggest that Hif‐1α function plays a significant role in wound healing and reduced levels of Hif‐1α may contribute to impaired healing.

Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism

Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother–pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2+/− dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups’ USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pups interaction with its mother strongly influences the pups vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.

HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair

Wound repair requires both the recruitment and coordination of numerous cell types including inflammatory cells, fibroblasts, endothelial and epithelial cells. Each cell type has a distinct set of cell behavior such as formation of granulation tissue and basement membrane, migration, proliferation and redifferentiation. These processes are dependent on cell-cell and cell-ECM signaling, intracellular signal transduction cascades, and ultimately, changes in gene transcription. We have investigated the role of the transcription factor HOXA3 in wound repair and angiogenesis. Here we show that HOXA3 increases endothelial cell migration, induces angiogenesis in vivo, and leads to increased expression of the matrix metalloproteinase-14 (MMP-14) and urokinase-type plasminogen activator receptor (uPAR) genes in endothelial cells in culture and in vivo in response to injury. We find that HOXA3 gene expression is upregulated during wound healing in angiogenic endothelial cells and keratinocytes, and that HOXA3 is not induced in genetically diabetic mice that have impaired angiogenesis and wound repair. We demonstrate that gene transfer of HOXA3 into diabetic mouse wounds leads to dramatic improvements in both angiogenesis and wound closure. In addition, we show that HOXA3 promotes migration of endothelial cells and keratinocytes in a uPAR-dependent manner. Together these findings illustrate how the morphoregulatory protein, HOXA3 can facilitate tissue remodeling via coordinated changes in both epithelial and endothelial cell gene expression and behavior in adult tissues during wound repair.

HoxD3 Accelerates Wound Healing in Diabetic Mice

Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections

BACKGROUND Skin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear. METHODS We enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment. RESULTS A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups. CONCLUSIONS We found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.).

Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity

Rapamycin, a specific inhibitor for mTOR complex 1, is an FDA-approved immunosuppressant for organ transplant. Recent developments have raised the prospect of using rapamycin to treat cancer or diabetes and to delay aging. It is therefore important to assess how rapamycin treatment affects glucose homeostasis. Here, we show that the same rapamycin treatment reported to extend mouse life span significantly impaired glucose homeostasis of aged mice. Moreover, rapamycin treatment of lean C57B/L6 mice reduced glucose-stimulated insulin secretion in vivo and ex vivo as well as the insulin content and beta cell mass of pancreatic islets. Confounding the diminished capacity for insulin release, rapamycin decreased insulin sensitivity. The multitude of rapamycin effects thus all lead to glucose intolerance. As our findings reveal that chronic rapamycin treatment could be diabetogenic, monitoring glucose homeostasis is crucial when using rapamycin as a therapeutic as well as experimental reagent.

HoxD3 expression and collagen synthesis in diabetic fibroblasts

Diabetic wound healing is characterized by deficiencies in both growth factor and collagen production. We have observed that expression of homeobox D3 (HoxD3), a collagen‐inducing transcription factor, and expression of collagen are reduced in an established animal model of diabetic wound repair, the leptin‐deficient diabetic (db/db) mouse. We sought to evaluate whether the diminished expression of collagen and HoxD3 would be maintained once fibroblasts were removed from the diabetic wound environment. Fibroblasts were isolated from both wild‐type and diabetic animals and expression of HoxD3 and collagen assessed. We found that when removed from the diabetic wound environment, HoxD3 and type I collagen expression are increased in diabetic fibroblasts when compared to wild‐type fibroblasts. The increase in type I collagen is not related to increased production or activation of transforming growth factor‐β1. However, when the diabetic fibroblasts are cultured in a 3D collagen matrix, expression of type I collagen and HoxD3 is markedly reduced and reflects the pattern of gene expression observed in the in vivo diabetic wound environment. Thus, although diabetic fibroblasts can regain the capacity to express high levels of collagen and HoxD3 once removed from the diabetic wound environment, culturing cells in the presence of a 3D collagen matrix is sufficient to revert these fibroblasts to their previous nonsynthetic state. (WOUND REP REG 2003;11:474–480)