Search PubMed⌕ Search

Biomedical subjects

Dennis L Stevens

Publications and source records attributed to Dennis L Stevens.

16 recordsLinked to original sources
PubMed2006

Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Extracellular protein toxins contribute to the pathogenesis of a wide variety of Staphylococcus aureus infections. The present study investigated the effects that cell-wall active antibiotics and protein-synthesis inhibitors have on transcription and translation of genes for Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin 1, in both methicillin-sensitive and methicillin-resistant S. aureus. Subinhibitory concentrations of nafcillin induced and prolonged mRNA for Panton-Valentine leukocidin, alpha-toxin, and toxic-shock syndrome toxin 1 and increased toxin production. In contrast, clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes. These results suggest (1) that protein-synthesis inhibition is an important consideration in the selection of antimicrobial agents to treat serious infections caused by toxin-producing gram-positive pathogens and (2) that, by inducing and enhancing toxin production, inadvertent use of beta-lactam antibiotics to treat methicillin-resistant S. aureus infections may contribute to worse outcomes.

Acetamides↗
PubMed2006

Identification and characterization of bicistronic speB and prsA gene expression in the group A Streptococcus.

Severe, invasive group A streptococcal infections have reemerged worldwide, and extracellular toxins, including streptococcal pyrogenic exotoxin B (SpeB), have been implicated in pathogenesis. The genetic regulation of SpeB is not fully understood, and the mechanisms involved in the processing of the protoxin to its enzymatically active form have not been definitively established. The present work demonstrated that the genes encoding SpeB (speB) and a peptidyl-prolyl isomerase (prsA) constitute an operon with transcription initiated from two promoters upstream of speB. Further, the speB-prsA operon was transcribed as a bicistronic mRNA. This finding is in contrast to the generally accepted notion that speB is transcribed only as a monocistronic gene. In addition, prsA has its own promoter, and transcription from this promoter starts in early log phase, prior to the transcription of speB. Genomic disruption of prsA decreased the production of enzymatically active SpeB but not the level of the pro-SpeB zymogen. Taken together, these results demonstrate that prsA is required for production of fully mature, enzymatically active SpeB.

Aged↗
PubMed2006

Group A streptococcal myonecrosis: increased vimentin expression after skeletal-muscle injury mediates the binding of Streptococcus pyogenes.

Necrotizing fasciitis and myonecrosis caused by invasive infection with group A streptococci (GAS) are life-threatening conditions that have reemerged worldwide. Half of all GAS myonecrosis cases have no known portal of entry; yet, for unknown reasons, infection becomes established precisely at the site of a prior, nonpenetrating minor injury, such as a muscle strain. We hypothesized that GAS establishes infection by binding to surface molecules that are up-regulated on injured skeletal-muscle cells. Here, we isolated and identified vimentin as the major skeletal-muscle GAS-binding protein. Furthermore, we found that vimentin expression was up-regulated on injured skeletal-muscle cells in vitro and was expressed in muscle tissues from a patient with GAS myonecrosis who died of streptococcal toxic shock syndrome. These findings provide a molecular mechanism to explain the development of severe GAS soft-tissue infections at the sites of prior minor muscle trauma. This understanding may provide a basis for novel preventive strategies or therapies for patients with this devastating infection.

Amino Acid Sequence↗
PubMed2006

Evaluation of an intervention designed to decrease the rate of nosocomial methicillin-resistant Staphylococcus aureus infection by encouraging decreased fluoroquinolone use.

OBJECTIVE: Society for Health Care Epidemiology guidelines recommend decreasing the use of fluoroquinolone antibiotics in institutions where methicillin-resistant Staphylococcus aureus (MRSA) is endemic. We evaluated whether an intervention to limit fluoroquinolone use was associated with a lower rate of nosocomial MRSA infection and summarized changes in antibiotic use, changes in other variables potentially correlated with a lower rate of MRSA infection, and rates of nosocomial infections due to other pathogens. DESIGN: Single-center quasi-experimental design. A time series of nosocomial MRSA infections was measured at monthly intervals from July 2001 through June of 2004; there were 80 MRSA infections recorded. Segmented regression analysis (ie, quasi-Poisson generalized linear models) was used to evaluate variables possibly associated with the nosocomial MRSA infection rate. SETTING: An 87-bed Veterans Affairs teaching hospital with an extended-care facility. INTERVENTION: A physician-directed computer-generated intervention designed to limit the use of fluoroquinolone antibiotics was initiated, and institutional changes in antibiotic use and nosocomial MRSA infection rates were tracked. RESULTS: After the intervention, fluoroquinolone use decreased by approximately 34%, and levofloxacin use decreased by approximately 50%. Decreased fluoroquinolone use was offset by increased cephalosporin, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole use. The nosocomial MRSA infection rate decreased from 1.37 to 0.63 episodes per 1,000 patient-days after the study intervention (P=.02). Coagulase-negative Staphylococcus and Enterococcus infection rates also decreased. However, the rate of infection with gram-negative organisms increased. The rate of MRSA infection was positively correlated with levofloxacin use (P=.01) and azithromycin use (P=.08), whereas it was negatively correlated with summer season (P=.05). In a subsequent model, the rate of MRSA infection was negatively correlated with the study intervention (P=.04). CONCLUSION: Reduction in the institutional use of fluoroquinolones may be associated with a lower nosocomial MRSA infection rate.

Cross Infection↗
PubMed2006

The role of vancomycin in the treatment paradigm.

Vancomycin was introduced in the United States in 1956 as a possible treatment for infections due to penicillin-resistant Staphylococcus aureus, but it was not used widely because of toxicity and the nearly simultaneous development of semisynthetic antibiotics and cephalosporins. Thus, its main indication was the treatment of serious gram-positive infections in penicillin-allergic patients. For susceptible strains of S. aureus, vancomycin was more rapidly bactericidal than penicillin, nafcillin, or cefazolin, and, in a rabbit model of S. aureus endocarditis, sterilization of vegetations was more rapid with vancomycin. In clinical practice, however, nafcillin remained the treatment of choice for staphylococcal bacteremia, largely because it had failure rates of only 4%. With the appearance of methicillin-resistant S. aureus and coagulase-negative staphylococci, vancomycin became the drug of choice for these infections. Recently, the efficacy of vancomycin has been questioned because of vancomycin's increasing minimum inhibitory concentrations among staphylococci, poor tissue penetration, and apparently slower bacterial killing than previously was recognized.

Anti-Bacterial Agents↗
PubMed2005

Vascular dysfunction and ischemic destruction of tissue in Streptococcus pyogenes infection: the role of streptolysin O-induced platelet/neutrophil complexes.

Rapid tissue destruction in group A streptococcal (GAS) necrotizing fasciitis/myonecrosis often necessitates extensive debridement to ensure survival. The mechanisms responsible for this fulminant process remain unknown; we hypothesized that toxin-induced ischemia contributes to necrosis. In a rat model, Doppler flowmetry was used to measure local blood flow at the site of the intramuscular injection of exotoxins from an invasive M-type 1 GAS, which caused a rapid, dose-dependent decrease in perfusion that was irreversible at the highest toxin concentration tested. Videomicroscopic results revealed that blood flow was impeded by occlusive intravascular cellular aggregates. Flow-cytometric results confirmed that GAS toxins induced the coaggregation of platelets and neutrophils, that this activity was attributable to streptolysin O, and that platelet/neutrophil complex formation was largely mediated by platelet P-selectin (CD62P). Strategies that target platelet adherence molecules may prevent vascular occlusion, maintain tissue viability, and reduce the need for amputation in necrotizing GAS infections.

Animals↗
PubMed2004

Immunization with the C-Domain of alpha -Toxin prevents lethal infection, localizes tissue injury, and promotes host response to challenge with Clostridium perfringens.

Clostridium perfringens gas gangrene is characterized by rapid tissue destruction, impaired host response, and, often, death. Phospholipase C (alpha -toxin) is the virulence factor most responsible for these pathologies. The present study investigated the efficacy of active immunization with the C-terminal domain of alpha -toxin (Cpa247-370) in a murine model of gas gangrene. Primary end points of the study were survival, progression of infection, and tissue perfusion. Secondary end points, which were based on findings of histologic evaluation of tissues, included the extent of tissue destruction and microvascular thrombosis, as well as the magnitude of the tissue inflammatory response. Survival among C-domain-immunized animals was significantly greater than that among sham-immunized control animals. Furthermore, immunization with the C-domain localized the infection and prevented ischemia of the feet. Histopathologic findings demonstrated limited muscle necrosis, reduced microvascular thrombosis, and enhanced granulocytic influx in C-domain-immunized mice. We conclude that immunization with the C-domain of phospholipase C is a viable strategy for the prevention of morbidity and mortality associated with C. perfringens gas gangrene.

Animals↗
PubMed2004

A review of linezolid: the first oxazolidinone antibiotic.

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.

Acetamides↗
PubMed2003

Activation of platelet gpIIbIIIa by phospholipase C from Clostridium perfringens involves store-operated calcium entry.

Clostridium perfringens gas gangrene is characterized by rapid tissue destruction, and amputation remains the single best treatment. Previous studies have demonstrated that tissue destruction follows C. perfringens phospholipase C (PLC)-induced, platelet gpIIbIIIa-mediated formation of occlusive intravascular platelet/leukocyte aggregates. In this study, the intracellular signaling events leading to activation of gpIIbIIIa by PLC were investigated. PLC activated surface expressed gpIIbIIIa and mobilized gpIIbIIIa from internal stores. Chelation of intracellular calcium or inhibition of store-operated calcium entry each blocked PLC-induced activation of gpIIbIIIa, whereas inhibition of protein kinase C was without effect. Thus, PLC initiates an "inside-out" signaling cascade that begins with depletion of internal calcium stores, is sustained by an influx of calcium through store-sensitive channels, and culminates in the functional activation of gpIIbIIIa. These findings suggest that calcium-channel blockade and strategies targeting gpIIbIIIa may prevent vascular occlusion, maintain tissue viability, and provide an alternative to radical amputation for patients with gas gangrene.

Blood Platelets↗
PubMed2002

The role of clostridial toxins in the pathogenesis of gas gangrene.

Clostridium perfringens gas gangrene is, without a doubt, the most fulminant necrotizing infection that affects humans. In victims of traumatic injury, the infection can become well established in as little as 6-8 h, and the destruction of adjacent healthy muscle can progress several inches per hour despite appropriate antibiotic coverage. Shock and organ failure are present in 50% of patients and, among these, 40% die. Despite modern medical advances and intensive-care regimens, radical amputation remains the single best life-saving treatment. Over the past century, much has been learned about the pathogenesis of this disease, and novel therapies are on the horizon for patients with this devastating infection.

Bacterial Toxins↗
PubMed2002

Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.

Linezolid, the first available member of a new antibiotic class, the oxazolidinones, is broadly active against gram-positive bacteria, including drug-resistant strains. In this randomized, open-label trial, hospitalized adults with known or suspected methicillin-resistant Staphylococcus aureus (MRSA) infections were treated with linezolid (600 mg twice daily; n=240) or vancomycin (1 g twice daily; n=220) for 7-28 days. S. aureus was isolated from 53% of patients; 93% of these isolates were MRSA. Skin and soft-tissue infection was the most common diagnosis, followed by pneumonia and urinary tract infection. At the test-of-cure visit (15-21 days after the end of therapy), among evaluable patients with MRSA, there was no statistical difference between the 2 treatment groups with respect to clinical cure rates (73.2% of patients in the linezolid group and 73.1% in the vancomycin group) or microbiological success rates (58.9% in the linezolid group and 63.2% in the vancomycin group). Both regimens were well tolerated, with similar rates of adverse events.

Acetamides↗