I.C.J.W. Bowler

Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study.

Summary Background Patients born outside the UK have contributed to a 20% rise in the UK’s tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. Methods We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. Findings Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100 000 population per year in Oxfordshire, compared with 3·5 cases per 100 000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2–2·9]; p=0·009), social risk factors (4·4 [2·0–9·4]; p<0·0001), and be part of a local transmission cluster (4·8 [1·6–14·8]; p=0·006). Interpretation Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised.

Real-Time Genomic Epidemiological Evaluation of Human Campylobacter Isolates by Use of Whole-Genome Multilocus Sequence Typing

ABSTRACT Sequence-based typing is essential for understanding the epidemiology of Campylobacter infections, a major worldwide cause of bacterial gastroenteritis. We demonstrate the practical and rapid exploitation of whole-genome sequencing to provide routine definitive characterization of Campylobacter jejuni and Campylobacter coli for clinical and public health purposes. Short-read data from 384 Campylobacter clinical isolates collected over 4 months in Oxford, United Kingdom, were assembled de novo. Contigs were deposited at the pubMLST.org/campylobacter website and automatically annotated for 1,667 loci. Typing and phylogenetic information was extracted and comparative analyses were performed for various subsets of loci, up to the level of the whole genome, using the Genome Comparator and Neighbor-net algorithms. The assembled sequences (for 379 isolates) were diverse and resembled collections from previous studies of human campylobacteriosis. Small subsets of very closely related isolates originated mainly from repeated sampling from the same patients and, in one case, likely laboratory contamination. Much of the within-patient variation occurred in phase-variable genes. Clinically and epidemiologically informative data can be extracted from whole-genome sequence data in real time with straightforward, publicly available tools. These analyses are highly scalable, are transparent, do not require closely related genome reference sequences, and provide improved resolution (i) among Campylobacter clonal complexes and (ii) between very closely related isolates. Additionally, these analyses rapidly differentiated unrelated isolates, allowing the detection of single-strain clusters. The approach is widely applicable to analyses of human bacterial pathogens in real time in clinical laboratories, with little specialist training required.

Relation between lymphopenia and bacteraemia in UK adults with medical emergencies

Aims: To determine the relevance of lymphopenia to the diagnosis of bacteraemia in patients admitted with medical emergencies, relative to peripheral blood white cell count and neutrophilia. Patients/Methods: A two year cohort study carried out in a teaching hospital in Oxford, UK of 21 495 consecutive adult emergency admissions to general medical or infectious disease wards. Full blood data were available in 21 372 cases; 41 cases with extreme full blood count results (neutrophil count, > 75 × 109/litre; lymphocyte count, > 10 × 109/litre) were excluded, leaving 21 331 cases for analysis. The association between the admission lymphocyte and neutrophil counts and the risk of bacteraemia was assessed. Results: Neutrophilia and lymphopenia were both associated with bacteraemia. Lymphopenia was the better predictor in this cohort. Both neutrophilia and lymphopenia were more predictive of bacteraemia than the total white blood cell count. Conclusions: Both lymphocyte and neutrophil counts, rather than total white blood cell count, should be considered in adult medical admissions with suspected bacteraemia.

A Longitudinal 6-Year Study of the Molecular Epidemiology of Clinical Campylobacter Isolates in Oxfordshire, United Kingdom

ABSTRACT Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST-283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity (P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST-460, ST-464, and ST-607) were associated with ciprofloxacin resistance (P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally.

Bacteraemia prediction in emergency medical admissions: role of C reactive protein

Aim: To define the contribution made by C reactive protein (CRP) measurement to bacteraemia prediction in adults with medical emergencies in the UK. Methods: This two year cohort study involved 6234 patients admitted as emergency cases to the acute medical or infectious diseases services of the Oxford Radcliffe Hospitals, in whom blood cultures were taken on arrival. The main outcome measures were bacteraemia risk associated with admission CRP concentrations, lymphocyte counts, and neutrophil counts. Results: The quantitative associations between CRP concentration, admission lymphocyte count, and neutrophil count were defined. Risk of bacteraemia rose continuously as the CRP increased: no “cutoff” value was evident. Models examining combinations of CRP, neutrophil count, and lymphocyte count were developed and validated using a split sample technique. CRP contributed to a model including lymphocyte and neutrophil counts, but its effect was small. CRP alone performed no better than either a model combining lymphopenia and neutrophilia, or than lymphopenia alone. Conclusions: In patients with acute medical emergencies who are suspected of bacteraemia clinically, CRP concentrations, although associated with bacteraemia, have a limited role in bacteraemia prediction.

Risk factors for recurrence after Staphylococcus aureus bacteraemia. A retrospective matched case–control study

OBJECTIVES We sought to identify risk factors for recurrence of Staphylococcus aureus bacteraemia (SAB) by auditing compliance with guidelines on its treatment in our hospital. METHODS We retrospectively identified patients over the preceding 8 years whose SAB had recurred, matching each to a control patient with non-recurrent SAB. RESULTS 40/1870 patients with SAB had suffered recurrent disease (2.1%), 33 of whom were available for study. Where 2, 4 and 6 weeks of intravenous therapy were recommended, 78%, 29% and 25% of patients received it, and there was no association with recurrence. Glycopeptide use in patients with methicillin sensitive SAB (MSSA) was significantly associated with recurrence (p=0.015). Where the source of the bacteraemia was a peripheral venous catheter the odds of recurrence were less than where an SAB originated at another site (p=0.047). All patients with SAB in whom a central venous catheter was not removed suffered recurrence. CONCLUSIONS We found the recurrence rate after SAB was low despite poor compliance with guidelines on treatment duration. Glycopeptide therapy for MSSA bacteraemia was more likely to result in recurrent SAB than beta-lactam therapy. Recurrence was significantly less likely in patients where the source of the SAB was a peripheral line than in those with another source.

Microbiological diagnosis of prosthetic joint infections: a prospective evaluation of four bacterial culture media in the routine laboratory

The diagnosis of prosthetic joint infection (PJI) in the routine microbiology laboratory is labour-intensive, but semi-automated methods may be appropriate. We prospectively compared four microbiological culture methods on samples taken at prosthetic joint revision surgery. Automated BACTEC blood culture bottles and cooked meat enrichment broth were the most sensitive methods (87% and 83%, respectively, as compared with fastidious anaerobic broth (57%) and direct plates (39%)); all were highly specific (97-100%). To our knowledge, this is the first prospective study aimed at comparing culture methods in routine use in UK clinical laboratories for the diagnosis of PJI.

Impact of a clonal outbreak of extended-spectrum β-lactamase-producing Klebsiella pneumoniae in the development and evolution of bloodstream infections by K. pneumoniae and Escherichia coli: an 11 year experience in Oxfordshire, UK

OBJECTIVES The objectives of this study were: (i) to describe an outbreak of multidrug-resistant Klebsiella pneumoniae in our population; (ii) to identify the potential source of this outbreak by examining antibiotic resistance trends in urocultures; (iii) to evaluate the contribution of this outbreak to resistance patterns over time in the two commonest Gram-negative blood culture isolates, namely K. pneumoniae and Escherichia coli; and (iv) to assess risk factors for multidrug resistance and the impact of this resistance on mortality and length of stay. METHODS We searched Microbiology and Patient Administration Service databases retrospectively and describe resistance trends in E. coli and K. pneumoniae bloodstream infections (BSIs) in Oxfordshire, UK, over an 11 year period. RESULTS An outbreak of a multidrug-resistant, CTX-M-15 extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae clone was identified and shown by multilocus sequence typing to belong to a novel sequence type designated ST490. This was associated with a sporadic change in resistance rates in K. pneumoniae BSIs with rates of multidrug resistance (defined as resistance to three or more antibiotic classes) reaching 40%. A case-control study showed prior antibiotic exposure as a risk factor for infection with this organism. During the same time period, rates of ESBL-producing Klebsiella spp. isolated from urocultures increased from 0.5% to almost 6%. By contrast, the rate of multidrug resistance in E. coli rose more steadily from 0% in 2000 to 10% in 2010. CONCLUSIONS Changes in resistance rates may be associated with outbreaks of resistant clones in K. pneumoniae. Changing resistance patterns may affect important health economic issues such as length of stay.

Ciprofloxacin-resistant campylobacteriosis in the UK.

misses an important point regarding the potential of nutritional interventions to prevent pre-eclampsia.Steegers and colleagues state that an evidence-based review found no relation between calcium supple-mentation and risk reduction for pre-eclampsia, but that some reduction might be seen in populations that are calcium defi cient. The review cited was a US Food and Drug Administration (FDA) assessment

Streptococcus mutans infective endocarditis complicated by vertebral discitis following dental treatment without antibiotic prophylaxis.

We report what we believe is the first reported case of Streptococcus mutans endocarditis complicated by vertebral discitis. The case is particularly interesting and topical as it occurred in a patient with pre-existing cardiac valvular disease who had recently had a dental procedure without antibiotic prophylaxis following a dramatic shift in the UK guidelines.