Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases : a pooled analysis of primary data from three studies across international settings

Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause infections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0·01) and the percent of household members aged <18 years (P < 0·01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission.

Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass

Objective:

The SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) gene has been shown to be differentially expressed in the hypothalamus of lean versus obese Israeli sand rats (Psammomys obesus), and is suspected of having a role in regulating food intake. The purpose of this study was to assess the role of genetic variation in SGIP1 in human disease.
Subjects:

We performed single-nucleotide polymorphism (SNP) genotyping in a large family pedigree cohort from the island of Mauritius. The Mauritius Family Study (MFS) consists of 400 individuals from 24 Indo-Mauritian families recruited from the genetically homogeneous population of Mauritius. We measured markers of the metabolic syndrome, including diabetes and obesity-related phenotypes such as fasting plasma glucose, waist:hip ratio, body mass index and fat mass.
Results:

Statistical genetic analysis revealed associations between SGIP1 polymorphisms and fat mass (in kilograms) as measured by bioimpedance. SNP genotyping identified associations between several genetic variants and fat mass, with the strongest association for rs2146905 (P=4.7 × 10−5). A strong allelic effect was noted for several SNPs where fat mass was reduced by up to 9.4% for individuals homozygous for the minor allele.
Conclusions:

Our results show association between genetic variants in SGIP1 and fat mass. We provide evidence that variation in SGIP1 is a potentially important determinant of obesity-related traits in humans.

Community onset staphylococcus aureus infections in Melbourne

Objective: To investigate the relative importance of methicillin resistant Staphylococcus aureus (MRSA) in the community in Melbourne by describing circulating S. aureus strains and infection characteristics.

Methods: Patients with any community-onset S. aureus infection were identified via clinical specimens submitted to a community-based pathology service in 2006. The referring doctors confirmed community onset and defined site and severity of each infection. Patient isolates were characterised by antibiotic resistance subtype and presence of the Panton-Valentine leukocidin gene (pvl).

Results: Between April and September 2006, 2,094 S. aureus isolates were processed. Of these, 133 (6.4%) were multiresistant MRSA (mMRSA) and 110 (5.3%) were resistant to less than 3 non-betalactam antibiotics (non-multiresistant MRSA or nmMRSA). We followed-up all nmMRSA (34) and mMRSA (15) confirmed community-onset infections, and a random subset of eligible patients with MSSA infections (57), for whom clinical data were available from referring doctors (82% response).

The majority of isolates were from skin infections (99/106), but drainage was performed in less than one third of cases (29/99). Antibiotics were prescribed for 89% (95%CI: 82, 94) of infections. The isolates were resistant to the prescribed antibiotic 100% of the time for mMRSA infections and 80% for nmMRSA. Those with infections caused by MRSA had on average one additional visit to their doctor compared with MSSA infections.

Ten nmMRSA clones were identified, including one new pvl positive nmMRSA. Of the 29 nmMRSA isolates, 14 were pvl positive (48%; 95%CIs: 30%, 66%) compared with 16% of MSSA and 0% mMRSA.

Patients with an infection caused by pvl positive strains (23) were younger ((mean age 23 years (95%CI: 16, 30) compared with the 55 years (95%CI: 50, 61)). Infection site also varied with presence of pvl; more pvl positive infections were found in the axilla (17.9% compared with 0%) and head and neck (35.7% compared with 8.2%), and less for the leg or foot (21.4% compared with 55.7%).

Conclusions: We estimate that 3.5% of community-onset S. aureus infections in Melbourne in 2006 were caused by MRSA, and 70 to 90% of patients with MRSA infections were treated initially with antibiotics to which their isolate was resistant. pvl positive isolates of S. aureus were associated with younger age and axillary or head and neck infections.

Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins.

BACKGROUND: Using multinational collections of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from infective endocarditis (IE) and soft tissue infections (STIs), we sought to (1) validate the finding that S. aureus in clonal complex (CC) 30 is associated with hematogenous complications and (2) test the hypothesis that specific genetic characteristics in S. aureus are associated with infection severity. METHODS: IE and STI isolates from 2 cohorts were frequency matched by geographic origin. Isolates underwent spa typing to infer CC and multiplex polymerase chain reaction for presence of virulence genes. RESULTS: 114 isolate pairs were genotyped. IE isolates were more likely to be CC30 (19.5% vs 6.2%; P = .005) and to contain 3 adhesins (clfB, cna, map/eap; P < .0001 for all) and 5 enterotoxins (tst, sea, sed, see, and sei; P ≤ .005 for all). CC30 isolates were more likely to contain cna, tst, sea, see, seg, and chp (P < .05 for all). CONCLUSIONS: MSSA IE isolates were significantly more likely to be CC30 and to possess a distinct repertoire of virulence genes than MSSA STI isolates from the same region. The genetic basis of this association requires further study.

A hybrid approach to selecting susceptible single nucleotide polymorphisms for complex disease analysis

An increasingly popular and promising way for complex disease diagnosis is to employ artificial neural networks (ANN). Single nucleotide polymorphisms (SNP) data from individuals is used as the inputs of ANN to find out specific SNP patterns related to certain disease. Due to the large number of SNPs, it is crucial to select optimal SNP subset and their combinations so that the inputs of ANN can be reduced. With this observation in mind, a hybrid approach - a combination of genetic algorithms (GA) and ANN (called GANN) is used to automatically determine optimal SNP set and optimize the structure of ANN. The proposed GANN algorithm is evaluated by using both a synthetic dataset and a real SNP dataset of a complex disease.

Community-onset Staphylococcus aureus infections presenting to general practices in South-eastern Australia

Community-acquired Staphylococcus aureus infections are a public health concern, yet little is known about infections that do not present to hospital. We identified community-onset S. aureus infections via specimens submitted to a community-based pathology service. Referring doctors confirmed eligibility and described infection site, severity and treatment. Isolates were characterized on antibiotic resistance, PFGE, MLST/SCCmec, and Panton–Valentine leukocidin (PVL), representing 106 community-onset infections; 34 non-multiresistant methicillin-resistant S. aureus (nmMRSA) (resistant to <3 non-β-lactam antibiotics), 15 multiply antibiotic-resistant MRSA (mMRSA) and 57 methicillin-sensitive S. aureus (MSSA). Most (93%) were skin and soft tissue infections. PVL genes were carried by 42% of nmMRSA isolates [95% confidence interval (CI) 26–61] and 15% of MSSA (95% CI 8–28). PVL was associated with infections of the trunk, head or neck (56·4% vs. 24·3%, P= 0·005) in younger patients (23 vs. 52 years, P< 0·001), and with boils or abscesses (OR 8·67, 95% CI 2·9–26·2), suggesting underlying differences in exposure and/or pathogenesis.

Changes in physical activity following a genetic-based internet-delivered personalized intervention: randomized controlled trial (Food4Me)

Background: There is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown. Objective: The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention.

Methods: The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no).

Results: At baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts.

Conclusions: No association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change.

Risk factors, microbiological findings and outcomes of necrotizing fasciitis in New Zealand: a retrospective chart review

Background
The incidence and mortality from necrotizing fasciitis (NF) are increasing in New Zealand (NZ). Triggered by a media report that traditional Samoan tattooing was causing NF, we conducted a chart review to investigate the role of this and other predisposing and precipitating factors and to document NF microbiology, complications and interventions in NZ.

Methods
We conducted a retrospective review of 299 hospital charts of patients discharged with NF diagnosis codes in eight hospitals in NZ between 2000 and 2006. We documented and compared by ethnicity the prevalence of predisposing and precipitating conditions, bacteria isolated, complications and interventions used.

Results
Out of 299 charts, 247 fulfilled the case definition. NF was most common in elderly males. Diabetes was the most frequent co-morbid condition, followed by obesity. Nearly a quarter of patients were taking non-steroidal anti-inflammatory drugs (NSAID). Traditional Samoan tattooing was an uncommon cause. Streptococcus pyogenes and Staphylococcus aureus were the two commonly isolated bacteria. Methicillin-resistant Staphylococcus aureus was implicated in a relatively small number of cases. Shock, renal failure, coagulation abnormality and multi-organ dysfunction were common complications. More than 90% of patients underwent surgical debridement, 56% were admitted to an intensive care unit (ICU) and slightly less than half of all patients had blood product transfusion. One in six NF cases had amputations and 23.5% died.

Conclusion
This chart review found that the highest proportion of NF cases was elderly males with co-morbidities, particularly diabetes and obesity. Tattooing was an uncommon precipitating event. The role of NSAID needs further exploration. NF is a serious disease with severe complications, high case fatality and considerable use of health care resources.

Synthesis of norbornane bisether antibiotics via silver-mediated alkylation

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).

Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese

Cytochrome P450 (CYP2B6) is an important enzyme that metabolizes more than eight compounds and about 3.0% of therapeutic drugs. The genetic polymorphisms of CYP2B6 have earlier been studied in Caucasian, Japanese and Korean, but the data are lacking for Han Chinese. The aim of this study was to investigate the frequencies of allelic variants of CYP2B6 in healthy Han Chinese and compare with those in other ethnic groups reported in the literature. Polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) method was used to test the five common non-synonymous single nucleotide polymorphisms (SNPs) of CYP2B6 gene, namely, 64C > T, 516G > T, 777C > A, 785A > G and 1459C > T in unrelated healthy Han Chinese (n = 193). The study demonstrated that the frequencies of 64C > T, 516G > T, 777C > A, 785A > G and 1459C > T SNPs in Han Chinese were 0.03, 0.21, 0, 0.28 and 0.003, respectively. The frequencies of all five SNPs tested in female were higher than those in male, but the statistical difference was insignificant (P > 0.05). Compared to the data reported in the literature, the frequencies of common CYP2B6 allelic variants in Chinese are similar to those of other Asian populations including Japanese and Korean, but markedly different from those in Caucasians. These results indicate the presence of marked ethnic difference in CYP2B6 SNP frequencies between Chinese and Caucasian. Further studies are required to explore the impact of these SNPs of CYP2B6 gene on the clinical response (efficacy and toxicity) to drugs that are substrates for CYP2B6 in patients.

Neisseria meningitidis and Neisseria gonorrhoeae are differently adapted in the regulation of denitrification: single nucleotide polymorphisms that enable species-specific tuning of the aerobic–anaerobic switch

The closely related pathogenic Neisseria species N. meningitidis and N. gonorrhoeae are able to respire in the absence of oxygen, using nitrite as an alternative electron acceptor. aniA (copper-containing nitrite reductase) is tightly regulated by four transcriptional regulators: FNR (fumarate and nitrate reductase), NarP, FUR (Ferric uptake regulator) and NsrR. The four regulators control expression of aniA in N. meningitidis by binding to specific and distinct regions of the promoter. We show in the present study that FUR and NarP are both required for the induction of expression of aniA in N. meningitidis, and that they bind adjacent to one another in a non-co-operative manner. Activation via FUR/NarP is dependent on their topological arrangement relative to the RNA polymerase-binding site. Analysis of the sequence of the aniA promoters from multiple N. meningitidis and N. gonorrhoeae strains indicates that there are species-specific single nucleotide polymorphisms, in regions predicted to be important for regulator binding. These sequence differences alter both the in vitro DNA binding and the promoter activation in intact cells by key activators FNR (oxygen sensor) and NarP (which is activated by nitrite in N. meningitidis). The weak relative binding of FNR to the N. gonorrhoeae aniA promoter (compared to N. meningitidis) is compensated for by a higher affinity of the gonococcal aniA promoter for NarP. Despite containing nearly identical genes for catalysing and regulating denitrification, variations in the promoter for the aniA gene appear to have been selected to enable the two pathogens to tune differentially their responses to environmental variables during the aerobic–anaerobic switch.

Validation and development of a clinical prediction rule in clinically suspected community-acquired pneumonia

To develop a mathematical model to predict the probability of having community-acquired pneumonia and to evaluate an already developed prediction rule that has not been validated in a clinical scenario.

Adherence to therapeutic guidelines for patients with community-acquired pneumonia in Australian hospitals

Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality, particularly in elderly patients, and is associated with a considerable economic burden on the healthcare system. The combination of high incidence and substantial financial costs necessitate accurate diagnosis and appropriate management of patients admitted with CAP. This article will discuss the rates of adherence to clinical guidelines, the use of severity scoring tools and the appropriateness of antimicrobial prescribing for patients diagnosed with CAP. The authors maintain that awareness of national and hospital guidelines is imperative to complement the physicians' clinical judgment with evidence-based recommendations. Increased use of pneumonia severity assessment tools and greater adherence to therapeutic guidelines will enhance concordant antimicrobial prescribing for patients with CAP. A robust and multifaceted educational intervention, in combination with antimicrobial stewardship programs, may enhance compliance of CAP guidelines in clinical practice in Australia.