Secular trends in nosocomial bloodstream infections: antibiotic-resistant bacteria increase the total burden of infection.

BACKGROUND: It is unknown whether rising incidence rates of nosocomial bloodstream infections (BSIs) caused by antibiotic-resistant bacteria (ARB) replace antibiotic-susceptible bacteria (ASB), leaving the total BSI rate unaffected. METHODS: We investigated temporal trends in annual incidence densities (events per 100 000 patient-days) of nosocomial BSIs caused by methicillin-resistant Staphylococcus aureus (MRSA), ARB other than MRSA, and ASB in 7 ARB-endemic and 7 ARB-nonendemic hospitals between 1998 and 2007. RESULTS: 33 130 nosocomial BSIs (14% caused by ARB) yielded 36 679 microorganisms. From 1998 to 2007, the MRSA incidence density increased from 0.2 to 0.7 (annual increase, 22%) in ARB-nonendemic hospitals, and from 3.1 to 11.7 (annual increase, 10%) in ARB-endemic hospitals (P = .2), increasing the incidence density difference between ARB-endemic and ARB-nonendemic hospitals from 2.9 to 11.0. The non-MRSA ARB incidence density increased from 2.8 to 4.1 (annual increase, 5%) in ARB-nonendemic hospitals, and from 1.5 to 17.4 (annual increase, 22%) in ARB-endemic hospitals (P < .001), changing the incidence density difference from -1.3 to 13.3. Trends in ASB incidence densities were similar in both groups (P = .7). With annual increases of 3.8% and 5.4% of all nosocomial BSIs in ARB-nonendemic and ARB-endemic hospitals, respectively (P < .001), the overall incidence density difference of 3.8 increased to 24.4. CONCLUSIONS: Increased nosocomial BSI rates due to ARB occur in addition to infections caused by ASB, increasing the total burden of disease. Hospitals with high ARB infection rates in 2005 had an excess burden of BSI of 20.6 per 100 000 patient-days in a 10-year period, mainly caused by infections with ARB.

Monitoring Clostridium difficile infection in an acute hospital: prevalence or incidence studies?

BACKGROUND: Surveillance of Clostridium difficile infection (CDI) is an essential component of a CDI preventative programme. AIMS: The aim of this study was to evaluate two methods of CDI surveillance. METHODS: Prevalence of CDI, antibiotic use and associated co-morbidity was assessed weekly on two wards over 6 weeks. In addition, CDI incidence surveillance was performed on all new CDI cases over a 13-week period. Cases were assessed for CDI risk factors, disease severity, response to treatment and outcome at 6 months. RESULTS: Clostridium difficile infection prevalence was 3.5% (range 2.9-6.1%) on the medical ward and 1.1% (range 0-3.5%) on the surgical ward. Patients on the medical ward were older and more likely to be colonised with MRSA; however, recent antibiotic use was more prevalent among surgical patients. Sixty-one new CDI cases were audited. Patients were elderly (mean age 71 years) with significant co-morbidity (median age adjusted Charlson co-morbidity score 5). CDI ribotypes included 027 (29 cases) 078 (5) and 106 (4). Eight patients developed severe CDI, seven due to 027. Antibiotic use was common with 56% receiving three or more antibiotics in the preceding 8 weeks. Twenty-four patients had died at 6 months, five due to CDI. CONCLUSION: Clostridium difficile infection prevalence gives a broad overview of CDI and points to areas that require more detailed surveillance and requires little time. However, patient-based CDI incidence surveillance provides a more useful analysis of CDI risk factors, disease and outcome for planning preventative programmes and focusing antibiotic stewardship efforts.

A 12-year review of Staphylococcus aureus bloodstream infections in haemodialysis patients: more work to be done.

Staphylococcus aureus bloodstream infections (BSI) are a significant cause of morbidity and mortality in haemodialysis patients. This study describes a 12-year retrospective review of S. aureus BSI in a large haemodialysis centre in a tertiary referral hospital. The overall rate of S. aureus BSI was 17.9 per 100 patient-years (range 9.7-36.8). The rate of meticillin-resistant S. aureus (MRSA) BSI was 5.6 per 100 patient-years (range 0.9-13.8). Infective complications occurred in 11% of episodes, the most common being infective endocarditis (7.6%). Ten percent of patients died within 30 days of S. aureus being isolated from blood. Most cases of S. aureus BSI (83%) were related to vascular catheters. The provision of lower-risk vascular access, such as arteriovenous fistulae, and reduced use of intravascular catheters should be priorities in all haemodialysis units. Where alternative vascular access cannot be established, interventions to reduce the risk of catheter-related infections should be implemented to reduce morbidity and mortality in this vulnerable patient group.

Inhibition of human lung carcinoma cell growth by apoptosis induction using Semliki Forest virus recombinant particles.

We have utilised cell cultures and growth of tumours in nude mice to assess further the potential of the Semliki Forest virus (SFV) vector as a cancer therapy agent. This vector is a transient RNA-based expression vector, and we have previously shown that SFV and its derived vector can induce p53-independent apoptosis by expression of the nonstructural region of the virus genome. Apoptosis induction is therefore an inherent property of the vector and is not dependent on heterologous gene expression. SFV recombinant suicide particles (rSFV) were shown to induce apoptosis in H358a cells, which are human non-small cell lung carcinoma cells deleted in p53. EGFP-expressing rSFV also inhibited the growth of developing H358a spheroids. Direct injection of rSFV into H358a tumours subcutaneously implanted as xenografts in nu/nu mice inhibited tumour growth, and in some cases caused complete regression. It is concluded that tumour growth suppression induced by rSFV was due to apoptosis induction and that the vector has an inherent cell death-promoting and antitumour activity. These results, as well as previous work by other authors on targeting and immune stimulation using alphavirus vectors, indicate that SFV recombinant particles in particular have considerable potential for further exploitation as a cancer therapy agent.

The protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGF-beta1) up-regulation and increased prostaglandin E2 (PGE2) production.

Polyunsaturated fatty acids are known to affect the immune response and administration of the omega-6 fatty acid linoleic acid has been reported to be beneficial in multiple sclerosis (MS) and EAE. In this study we have investigated the effects of oral feeding of plant lipid rich in the omega-6 fatty acid gamma-linolenic acid from Borago officinalis on acute and relapse disease and the immune response in EAE using SJL mice. EAE was induced by an encephalitogenic peptide (92-106) of myelin oligodendrocyte glycoprotein (MOG), and mice were fed the plant lipid daily from 7 days after EAE induction to assess the effects on acute disease and from day 25 to assess the effects on disease relapse. The clinical incidence and histological manifestations of acute EAE, and the clinical relapse phase of chronic relapsing EAE (CREAE) were markedly inhibited by omega-6 fatty acid feeding. A significant increase in the production of TGF-beta1 in response to concanavalin A (Con A) at day 13 and a significant increase in TGF-beta1 and PGE2 to Con A, PPD and MOG peptide (92-106) at day 21 were detected in spleen mononuclear cells from fatty acid-fed mice. There was no difference in interferon-gamma, IL-4 and IL-2 production between the fatty acid-fed and control groups. Significantly higher TGF-beta mRNA expression was found in the spleens of omega-6 fatty acid-fed mice at day 21. There were no differences in spleen cell proliferative response to Con A, PPD and MOG peptide (92-106). Biochemical analysis of spleen cell membrane fatty acids revealed significant increases in the eicosanoid precursor fatty acids dihomo-gamma-linolenic acid and arachidonic acid in response to gamma-linolenic acid feeding, indicating rapid metabolism to longer chain omega-6 fatty acids. These results show that oral feeding of gamma-linolenic acid-rich plant lipid markedly affects the disease course of acute EAE and CREAE and is associated with an increase in cell membrane long chain omega-6 fatty acids, production of PGE2 and gene transcription and, on activation, secretion of TGF-beta1.

A recombinant Semliki Forest virus particle vaccine encoding the prME and NS1 proteins of louping ill virus is effective in a sheep challenge model.

This study has examined the efficacy following intramuscular administration of a recombinant Semliki Forest virus (rSFV) vaccine, encoding the prME and NS1 proteins of louping ill virus (LIV), in sheep. Administration of rSFV-LIV vaccine resulted in transient detection at the injection site and draining lymph node only and no dissemination to distal sites. In addition, the recombinant vaccine offered complete protection against subcutaneous challenge with LIV, and partial protection following intranasal administration of LIV. Protected animals had no pathological changes normally associated with LIV infection, and had developed high antibody titres. In contrast, the two animals not protected exhibited classical clinical signs and neuropathological lesions of LIV infection. These findings indicate that rSFV-based vaccines have the potential to be developed as effective prototype vaccines for LIV.

Transient virus infection and multiple sclerosis.

Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS in which autoimmunity to myelin plays a role in pathogenesis. The epidemiology of MS indicates that it may be triggered by a virus infection before the age of adolescence, but attempts to associate a specific virus with MS have produced equivocal results. Many studies of the aetiology of MS have postulated that a persistent virus infection is involved, but transient virus infection may provide a plausible alternative mechanism that could explain many of the inconsistencies in MS research. The most studied animal model of MS is chronic relapsing experimental autoimmune encephalomyelitis (CREAE), which is induced in susceptible animals following injection of myelin components. While CREAE cannot provide information on the initiating factor for MS, it may mimic disease processes occurring after an initial trigger that may involve transient virus infection. The disease process may comprise separate triggering and relapse phases. The triggering phase may involve sensitisation to myelin antigens as a result of damage to oligodendrocytes or molecular mimicry. The relapse phase could be similar to CREAE, or alternatively relapses may be induced by further transient virus infections which may not involve infection of the CNS, but which may involve the recrudescence of anti-myelin autoimmunity. Although current vaccines have a high degree of biosafety, it is suggested that the measles-mumps-rubella vaccine in particular could be modified to obviate any possibility of triggering anti-myelin autoimmunity.

Semliki Forest virus-based vaccines: persistence, distribution and pathological analysis in two animal systems.

This study has examined the persistence, distribution and pathological changes following intramuscular administration of Semliki Forest virus (SFV) vaccine vectors in mice and chickens. Administration of recombinant SFV RNA particles showed persistence at the injection site of mice up to 7 days, transient detection in secondary lymphoid organs and no dissemination to distal sites. In contrast, administration of a layered SFV DNA/RNA vector and a conventional standard naked DNA vector resulted in long-term persistence at the injection site, plasmid DNA being detected at 8 months post-inoculation in mice. Plasmid DNA was found distributed throughout the body, and tissues distal from the site of injection were positive up to 3 months. A similar pattern was observed in chickens. Mild pathological changes were observed at the injection site only, and plasmid DNA or recombinant RNA was not detected in mouse foetuses. These findings indicate that SFV-based vectors have the potential to be developed as safe vaccines.