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Local delivery of soluble interleukin-6 receptors to improve the outcome of alpha-toxin producing Staphylococcus aureus infection in mice.

Staphylococcal alpha-toxin enhances interleukin (IL)-6 secretion in mice infected with Staphylococcus aureus. The role of alpha-toxin-induced IL-6 secretion in host defense has not been sufficiently clarified. In the present study, IL-6 signaling was transiently regulated using soluble IL-6 receptors (sIL-6R) to investigate the role of IL-6 in the early stage of abdominal S. aureus infection. In mice challenged with bacteria producing high alpha-toxin levels, the local delivery of sIL-6R was effective in improving the survival rate, the resolution of neutrophilia and the bacteria clearance. Mice that had received sIL-6R and survived showed high levels of IL-6, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha. In contrast, mice that died in spite of the delivery of sIL-6R showed high levels of interferon (IFN)-gamma and IL-1alpha and low TNF-alpha level. When the effect of soluble gp130, a sIL-6R antagonist, was examined, the number of neutrophils increased significantly and the MCP-1 level decreased significantly, compared to the group that received sIL-6R alone; the number of viable bacteria also tended to increase as a result of the inhibition of IL-6 signaling. The cellular phosphotyrosine level in alpha-toxin-treated macrophages was reduced in cultures supplemented with recombinant IL-6 in vitro. These results suggest that IL-6 enhances bactericidal activity and reduces the number of immune cells that are activated abnormally through the regulation of inflammatory cytokines during the early stage of infection in alpha-toxin producers.

Animals↗

Klebsiella pneumoniae and Staphylococcus aureus infection in mice: difference in uremia and ammoniagenesis.

Lethal infections by Staphylococcus aureus and Klebsiella pneumoniae were compared for kidney-related effects in mice. K. pneumoniae caused uremia and an increase in blood ammonia that could reach 2.5 times normal. These events did not occur in mice inoculated with S. aureus. Use of germfree animals indicated that most of the increase in ammonia arose from the gut, presumably due to greater availability of urea and ureolysis. Injected ornithine restored blood ammonia to nearly normal levels and extended survival.

Ammonia↗

[Epidemiology and prevention of Staphylococcus aureus infections during hemodialysis].

Staphylococcus aureus is the pathogen most often isolated from blood during bacteraemic episodes in haemodialysis patients (42%). The pathophysiology of these infections is discussed and a prophylactic strategy is proposed. Nasal carriage of S. aureus, found in 42% of haemodialysis patients, plays a major role in its cutaneous dissemination and hence in the risk of infection by this microorganism. Long-term use of nasal mupirocin in haemodialysis patients with nasal carriage of S. aureus (t.i.d. for 3 to 5 days, followed by once a week) led to a decrease in the yearly incidence of S. aureus bacteraemia from 0.097 to 0.024 (p < 0.01). Tolerance was excellent. This chemoprophylaxis results in substantial savings. When applied as proposed (only nasal application), the long-term use of mupirocin only very rarely leads to the emergence of mupirocin-resistance in S. aureus (1 case in 165 patient-years).

Arteriovenous Shunt, Surgical↗

[Risk factors and treatment of methicillin-resistant Staphylococcus aureus infections].

METICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS INFECTIONS (MRSA): The maintenance of a catheter in febrile neutropenic patients with MRSA bacteremia is justified, except when the latter persists 2 to 3 days after the initiation of treatment. Prior administration of fluoroquinolones (levofloxacine or ciprofloxacine) is a risk factor significantly associated with the isolation of MRSA. Meticillin resistance is not a factor of mortality in HIV-infected patients exhibiting S. aureus bacteremia. Surveillance blood cultures represent a simple method for identifying patients at high risk of secondary foci. INFECTIONS WITH GLYCOPEPTIDE-INTERMEDIATE MRSA (HETERO-GISA): In liver transplant recipients, the risk of acquiring a hetero-GISA is not associated with prior MRSA infection nor prior glycopeptide treatment. It is significantly associated with the occurrence of an infectious episode in the weeks preceding the transplant and with the administration of beta-lactams during the previous two months. Mortality is not increased in patients with hetero-GISA. NEW ANTIBIOTICS: Linezolide and quinupristine-dalfopristine are new agents available for the treatment of MRSA infection. Other antibiotics under development have demonstrated their activity: lipopeptides (daptomycin), semi-synthetic glycopeptides (oritavancin, dalbavancin), glycylglycines (tigecyclin), carbapenems (CP5609), and cephalosphorins (LB 11058). ANTIBIOTIC COMBINATIONS: Various studies have shown that antibiotic combinations must be used with care in the treatment of MRSA and GISA infections (glycopeptide intermediate strains) because of the antagonism between molecules belonging to different families.

Anti-Bacterial Agents↗

Staphylococcus lugdunensis: an emerging cause of ventriculoperitoneal shunt infections.

Staphylococcus lugdunensis, a coagulase-negative staphylococcus first described in 1988, has gained recognition as an organism with considerable pathogenic capability in adults. In contrast to the indolent presentation characteristic of other coagulase-negative staphylococci, S. lugdunensis infections resemble the aggressive behavior of Staphylococcus aureus. Although the organism has been isolated from a wide variety of infections in adults, it is a very rare cause of pediatric infections. We describe the first two pediatric patients who developed ventriculoperitoneal shunt infections caused by S. lugdunensis. These cases suggest that coagulase-negative staphylococci should be identified to the species level and that, if S. lugdunensis is identified, greater morbidity compared to that associated with other coagulase-negative staphylococcal shunt infections should be anticipated. A longer course of therapy is recommended for S. lugdunensis infections.

Adolescent↗

Transcription of clumping factor A in attached and unattached Staphylococcus aureus in vitro and during device-related infection.

Staphylococcus aureus is one of the pathogens most frequently isolated in device-related infections. S. aureus is equipped with surface-associated proteins promoting specific binding to matrix molecules. Clumping factor A (ClfA, encoded by clfA) mediates adhesion to fibrinogen. Whereas the contribution of ClfA to pathogenicity is well documented, the influence of different growth and host parameters on gene activity is unclear. To elucidate this question, we investigated clfA transcript levels in an animal model of device-related infection and in planktonic and sessile bacteria grown in vitro. Specific mRNA from the S. aureus strains Newman, Reynolds, and RN6390 was quantified by LightCycler reverse transcription-PCR. In vitro, clfA transcript levels were low in the early logarithmic growth phase, but a clear increase was observed after the late logarithmic phase. Quantities of clfA transcripts were four to six times higher in the planktonic than in the sessile bacterial subpopulations grown to the stationary phase. During infection, in strains Newman and Reynolds levels of clfA transcripts in exudates accumulating in the infected devices were lower than those in the bacteria grown in vitro to stationary phase. clfA mRNA levels in the exudates increased during the initial phase of infection and remained constant after 96 h postinoculation. In contrast to the in vitro results, quantities of clfA transcripts in the unattached bacteria of the exudates never exceeded the level of clfA transcripts in the sessile bacteria attached to glass beads. However, a clear increase in clfA quantities in the sessile bacteria was observed late in infection after 144 h. In conclusion, maximal clfA transcript levels are reached late during growth in vitro and in vivo.

Animals↗

Clinical and microbiological characteristics of 28 patients with Staphylococcus schleiferi infection.

The aim of this study was to analyse the clinical and microbiological characteristics of a series of patients with infection by Staphylococcus schleiferi. Seventy-one isolates were recovered from 36 patients between January 1993 and June 1999 at a tertiary care centre in northern Spain. There were 28 patients with well-documented clinical data. Infection was more frequent in men (89.3%), and more than half of the patients had some degree of immunosuppression, mainly malignant neoplasms. Infection was nosocomial in 22 cases and community-acquired in the remaining cases. Staphylococcus schleiferi was frequently associated with wound infections, mainly surgical-site infections, although unusual types of infections were detected. Infection-related mortality was low. This study highlights the importance of careful identification of Staphylococcus schleiferi in the clinical microbiology laboratory. Due to the documented association of Staphylococcus schleiferi with clinical infections in humans, any isolates of this organism should be assumed to be pathogenic, unless proven otherwise.

Adult↗

Prostaglandin E2 modulates monocyte MHC-II (Ia) suppression in biomaterial infection.

Staphylococcus epidermidis biomaterial infection is associated with local cellular immune suppression measured by a depressed monocyte (M phi) Ia expression. The purpose of this study was to define the effect of proinflammatory mediators on Ia expression and bacterial clearance in experimental biomaterial infection. A 1-cm-long Dacron tube graft, sterile or colonized with Staphylococcus epidermidis (1 x 10(7) cfu/ml2), was implanted in Swiss-Webster mice. Perigraft fluid was collected at 7, 10, 14, and 28 days and assayed by enzyme-linked immunoassays for tumor necrosis factor alpha (TNF alpha), interleukin (IL)-I alpha, IL-4, IL-10, and prostaglandin E2 (PGE2). Grafts were sonicated and plated for quantitative growth. In vivo effector inhibitions was accomplished with anti-TNF alpha, anti-IL-1 alpha antibodies (7 micrograms/24 hr), or indomethacin (50 micrograms/24 hr) via an Alzet 7-day microinfusion pump. M phi Ia expression was determined by flow cytometry. A significant elevation of TNF alpha, IL-1 alpha, and PGE2 was found during the first 10 days in the infected compared with sterile (P < or = 0.05) grafts and correlated with maximal Ia suppression. Neither IL-4 nor IL-10 was significantly different in the sterile or infected perigraft fluid. Indomethacin completely prevented M phi Ia suppression, while anti-IL-1 alpha only partially (94%) prevented M phi Ia suppression with a corresponding decrease in PGE2 production in infected grafts. Anti-TNF alpha increased PGE2 production by 189% and was associated with depressed M phi Ia expression. Indomethacin treatment improved mean graft-adherent bacterial clearance by 54% at 7 days and 75% at 28 days compared with control (not significant). Interleukin-1 alpha but not TNF alpha increases PGE2 production which modulates M phi Ia suppression. To improve treatment of biomaterial infections, local immunomodulation of PGE2 and IL-1 alpha is promising.

Animals↗

Staphylococcus aureus small colony variants, electron transport and persistent infections.

Staphylococcus aureus can mutate to form a sub-population of bacteria known as small colony variants (SCVs). These bacteria have a characteristic phenotype defined by slow growth, the lack of pigment, an altered pattern of carbohydrate utilization, and a reduction in toxin production. This complex phenotype can be explained by deficiencies in electron transport. In clinical isolates, the most common mutations that affect electron transport are in the operons encoding menaquinone or heme biosynthesis. These isolates are responsible for persistent antibiotic resistant infections. The clinical presentation of these infections is readily explained by a reduction electron transport. SCVs survive within host cells, increasing the instances of recurrent infections and have a novel mechanism of resistance based upon their altered trans-membrane potential. Additionally, SCVs provide a connection between energy metabolism and toxin production. This link may operate through the bacteria responding to altered levels of NADH and ATP. A more complete understanding of these signaling pathways may provide new targets for the development of drugs to ameliorate staphylococcal virulence and disease.

Adenosine Triphosphate↗

[Use of nasal mupirocin for Staphylococcus aureus: effect on nasal carriers and nosocomial infections].

Staphylococcus aureus is the agent of community-acquired and nosocomial infections. Twenty to 35% of the population permanently carries it in the nose and oropharynx, and additional 50%, carries it intermittently. Topical calcium mupirocin is an antibacterial agent against Staphylococcus aureus recommended to eradicate nasal and hand colonization in patients and health care workers. The prevalence of nasal S. aureus was determined in patients undergoing cardiovascular surgery. In addition, the effect of mupirocine on the number of carriers and rate of nosocomial infections was evaluated. An experimental prospective study was undertaken with two groups of patients: one treated with mupirocin (n = 96), and the other without treatment (n = 95). Tests for presence of nasal S. aureus and nosocomial infections were conducted in all patients. A 34% prevalence of S. aureus carriers was found. A decrease of the prevalence was found in both treated (87%) and untreated patients (33%), but in significantly different proportions (p = 0.0002, RR = 0.22, 95%CI = 0.09-0.054). This result demonstrated the effectiveness of a mupirocin treatment program to decrease numbers of nasal carriers. With regard to nosocomial infection, S. aureus prevalence was 3.6%, occurring mostly in control patients (6 of 7). Total nosocomial infection prevalence was 17.3%, evenly distributed in treated and untreated patients. This suggested that mupirocin use did not decrease the number of nosocomial infections.

Administration, Intranasal↗

Penetration of clindamycin into experimental Staphylococcus aureus infections.

Inactivation of clindamycin at the site of experimental infection with Staphylococcus aureus was studied using rabbits with plastic capsules implanted in the peritoneal cavity. The mean percentage penetration of bioactive clindamycin (concentration in capsule divided by simultaneous concentration in serum times 100) into infected and noninfected capsules was 30.4 per cent and 13.0 per cent, respectively. In contrast, the mean penetration of radiolabeled clindamycin into infected capsules was 38.4 per cent. These findings indicate that the observed loss of bioactivity in infected capsules is due to intracapsular inactivation of clindamycin and not to an alteration in capsular permeability. Biologic inactivation of clindamycin was not evident after in vitro incubation of the drug with Staphylococcus aureus. These results suggest that the observed loss of bioactivity may be due to chemical modification by enzymes in the inflammatory exudate or to binding of the antibiotic to tissue components.

Animals↗

Personal hygiene and methicillin-resistant Staphylococcus aureus infection.

Methicillin-resistant Staphylococcus aureus (MRSA) infections outside the healthcare setting are an increasing concern. We conducted a case-control study to investigate an MRSA outbreak during 2002-2003 in a Missouri prison and focused on hygiene factors. Information on sociodemographic characteristics, medical history, and hygiene practices of study participants was collected by interview and medical record review. Logistic regression was used to evaluate MRSA infection in relation to hygiene factors individually and as a composite hygiene score; potential confounding factors were controlled. Selected MRSA isolates were analyzed by pulsed-field gel electrophoresis (PFGE). MRSA infection was significantly associated with a low composite hygiene score. Transmission among prison inmates appeared to be responsible for this outbreak. PFGE analysis showed that isolates were indistinguishable and associated with community-onset MRSA infections in other US prisons. Improving hygiene practices and environmental conditions may help prevent and interrupt future MRSA outbreaks in prison settings.

Adult↗

Impact of an aggressive infection control strategy on endemic Staphylococcus aureus infection in liver transplant recipients.

BACKGROUND: Methicillin-resistant Staphylococcus aureus has emerged as a leading pathogen in transplant recipients and has become endemic in many institutions where transplantation is performed. The role of active surveillance programs based on the detection of colonization in the prevention of S. aureus infection in liver transplant recipients has not been defined. METHODS: A total of 47 consecutive patients who underwent liver transplantation during 1996-1999 were compared with 97 patients who received a liver transplant during 2000-2004 after implementation of an intensive intervention program that included use of surveillance cultures to detect nasal and rectal colonization, use of cohorting and contact isolation precautions, and decolonization with intranasal mupirocin therapy. RESULTS: The rate of new acquisition of S. aureus colonization of nares after transplantation decreased from 45.6% (21 of 46 patients) during the preintervention period to 9.9% (9 of 91 patients) during the postintervention period (P<.001). An increased length of hospital stay (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P<.002) was associated with new carriage acquisition, and transplantation during the postintervention period (odds ratio, 0.21; 95% confidence interval, 0.08-0.51; P<.001) was independently protective against new carriage. The rate of infection due to S. aureus decreased from 40.4% (19 of 47 patients) during the preintervention period to 4.1% (4 of 97 patients) during the postintervention period (P<.001), and the rate of bacteremia decreased from 25.5% (12 of 47 patients) to 4.1% (4 of 97 patients), respectively (P<.001). Overall, S. aureus infections occurred more frequently among patients with new carriage than among patients who were carriers at the time of transplantation (P<.001) or patients who were noncarriers (P<.001). CONCLUSIONS: Use of active surveillance cultures to detect colonization and implementation of targeted infection control interventions proved to be effective in curtailing new acquisition of S. aureus colonization and in decreasing the rate of S. aureus infection that was endemic in our population of liver transplant recipients.

Cohort Studies↗

Effects of tissue-type plasminogen activator on Staphylococcus epidermidis--infected plasma clots as a model of infected endocardial vegetations.

The ability of tissue-type plasminogen activator (t-PA) to enhance the effect of antibiotics in the treatment of bacterial endocarditis was studied using plasma clots infected with Staphylococcus epidermidis as a model of infected endocardial vegetations. A concentration-dependent lysis of the infected plasma clots was induced by t-PA, as shown by the decrease in the weight of the clots, a decrease in the amount of incorporated 125I fibrin, as well as the release of staphylococci from the clots into the incubation fluid. The addition of cloxacillin to the incubation medium in various concentrations led to a concentration-dependent decrease of the number of S. epidermidis in the clots. The presence of t-PA did not enhance the antibacterial effect of cloxacillin. It is concluded that the lysis induced by t-PA might enhance the effect of treatment of endocarditis by reducing the size of endocardial vegetations but not by enhancement of the effect of antibiotics on the bacteria embedded in the vegetations.

Animals↗