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Objectives To investigate the microbiological characteristics and clinical outcomes of patients with bloodstream infections (BSI) due to carbapenemase-producing Enterobacterales (CPE). Methods A multicentre retrospective service evaluation of patients with BSIs due to CPE admitted to six UK hospitals was conducted between 2011 and 2021. Multivariate analysis was used to identify factors predicting 30-day case fatality rate (CFR). Results There were 84 episodes of CPE-BSIs, 37 (44%) due to OXA-48, 35 (42%) to metallo-betalactamases (MBL) and 12 (14%) to KPC. 63% of patients were male with a median age of 64 years. Common organisms included Klebsiella spp. (61%), Escherichia coli (20%) and Enterobacter spp. (13%). Urinary devices were more often involved in OXA-48 BSIs (12/37; 32%) compared to infections caused by MBL and KPC (4/35; 11% and 1/12; 8%; p 0.046). In contrast, central venous catheters were more frequently present in KPC-BSIs (10/12; 92%) compared with OXA-48 and MBL (11/37; 30% and 20/35; 57%; p 0.002). Effective definitive antimicrobials were received by 72/84 (86%) patients – either empirically or following microbiology results – comprising monotherapy (32/72; 44%) or combination therapy (40/72; 56%). Overall, 30-day case fatality rate (CFR) was 38%. Sepsis or septic shock was associated with death [OR 3.81 (CI 1.19–12.14), p 0.024]. Conclusion CFR of CPE-BSI remains relatively high. We identified risks from urinary devices and intravenous catheters, but further larger studies are needed to characterise and compare the clinical and microbiological profile of BSIs due to different types of carbapenemases.

Objectives To assess the performance of T2Candida for the diagnosis of invasive candidiasis (IC) against gold standards of candidaemia or consensus IC definitions, and to evaluate the impact of T2Candida on antifungal drug prescribing. Methods A retrospective review was undertaken of all T2Candida (T2MR technology, T2 Biosystems) performed from October 2020 to February 2022. T2Candida performance was evaluated against confirmed candidaemia or against proven/probable IC within 48 hours of T2Candida, and its impact on antifungal drug prescriptions. Results T2Candida was performed in 61 patients, with 6 (9.8%) positive results. Diagnostic performance of T2Candida against candidaemia had a specificity of 85.7% and negative predictive value (NPV) of 96.8%. When comparing T2Candida results with consensus definitions of IC, the specificity and NPV of T2Candida was respectively 90% (54/60) and 98.2% (54/55) for proven IC, and 91.4% (53/58) and 96.4% (53/55) for proven/probable IC. Antifungals were initiated in three of six patients (50%) with a positive T2Candida result. Thirty-three patients were receiving empirical antifungals at the time of T2Candida testing, and a negative result prompted cessation of antifungals in 11 (33%) patients, compared with 6 (25%) antifungal prescriptions stopped following negative beta-d-glucan (BDG) testing in a control population (n = 24). Conclusions T2Candida shows high specificity and NPV compared with evidence of Candida bloodstream infection or consensus definitions for invasive Candida infection, and may play an adjunctive role as a stewardship tool to limit unnecessary antifungal prescriptions.

Objectives: An elevated serum (1-3)-β-D-glucan (BDG) concentration has high sensitivity for a diagnosis of Pneumocystis pneumonia (PCP) in people with HIV (PWH). At the current manufacturer-recommended positive threshold of 80 pg/mL (Fungitell), specificity for PCP is variable and other diagnostic tests are required. We evaluated the utility of serum BDG for diagnosis of suspected PCP in PWH at three inner-London hospitals to determine BDG concentrations for diagnosis and exclusion of PCP. Methods: From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG 400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG 400 pg/mL effectively confirm the diagnosis. Values 80–400 pg/mL should prompt additional diagnostic tests.

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.

Background Azithromycin resistance is emerging in typhoidal Salmonella. Confirmation of azithromycin MIC is the most frequent antibiotic susceptibility request made to the Gastrointestinal Bacteria Reference Unit (GBRU) laboratory in England by local diagnostic laboratories. Objectives (i) Determine concordance between local diagnostic and reference laboratory estimations of azithromycin MIC by gradient strip in Salmonella enterica serovars Typhi and Paratyphi. (ii) Consider causes of variation. Methods Isolates from patients with enteric fever attending a central London hospital between May 2011 and April 2019 were tested for azithromycin susceptibility using gradient strips, according to EUCAST methodology. Matched local diagnostic and reference laboratory estimations of azithromycin and ciprofloxacin (as a comparator) MICs were included; concordance in estimations was examined. Results Local diagnostic laboratory readings overestimated azithromycin MIC values compared with the reference laboratory, resulting in poor concordance in susceptibility/resistance attribution (concordant susceptibility interpretation in 8/19, κ = 0). In contrast, ciprofloxacin MIC estimation demonstrated superior concordance (concordant susceptibility interpretation in 16/17, κ = 0.85). None of the isolates was resistant to azithromycin at the reference laboratory and no known genes associated with azithromycin resistance were detected in any isolate using WGS. Conclusions Overestimation of azithromycin resistance is likely to be due to difficulty in interpreting the point of intersection of the ‘trailing edge’ with the gradient strip, used to determine MIC. We advise local diagnostic laboratories to review their experience and consider adopting a ‘second reader’ system to mitigate this.

The OVIVA study demonstrated noninferiority for managing bone and joint infections (BJIs) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJIs at our center would be eligible for oral antibiotics, saving a median (IQR) 19.5 IV-antibiotic days (8.5–37) and GBP 1234 (569–2594) per patient.

Objectives: Cystic neutrophilic granulomatous mastitis (CNGM) is a rare cause of destructive inflammatory breast disease which has been linked to the presence of lipophilic Corynebacteria which often show broad resistance to antibiotics. Antibiotic therapy is frequently utilised as an adjunct to surgical management however there is a lack of reported data on optimal antimicrobial strategies and recovery is often prolonged. Methods: We developed a management strategy in a tertiary infectious diseases unit to identify potential Corynebacteria-related CNGM pathology and took a targeted antibiotic-led approach to treatment. Clinical, laboratory, imaging, and therapeutic data were collected retrospectively from patients seen in our clinic between 2016-2020. Results: Thirteen patients were identified who met criteria for the diagnosis of CNGM. The mean age was 42.6 years and all patients were female. All had bacteriological evidence of Corynebacteria infection or granulomatous findings on histology. Microbiological evidence of Corynebacteria was present in 76.9%. Antibiotics were used as first line therapy in 92.6%, with a variety of agents used. Steroids were used as an adjunctive therapy in 53.8%. Most patients underwent surgical drainage or clinic-based aspiration of an abscess as part of their treatment. Eleven of thirteen patients (84.6%) experienced complete resolution of symptoms however recovery was protracted with a median time to resolution of >6 months. Conclusions: We present a case series of a rare clinical entity, CNGM, and highlight the outcomes of implementation of an antibiotic and infection service-led clinical approach in these patients.

A young previously healthy patient presented with sepsis and cavitating pneumonia. Campylobacter rectus was isolated from blood cultures and subsequent CT neck showed an internal jugular vein thrombosis. Treatment was with antibiotics, anticoagulation and supportive management. Lemierre’s syndrome is an infectious thrombophlebitis of the internal jugular vein. Although a rare diagnosis since the use of penicillin for treatment of acute pharyngitis, it is being reported with increasing frequency. Usually associated with Fusobacterium spp, we believe that this is the first reported case of Lemierre’s caused by C. rectus—an anaerobic member of the human oral cavity flora, usually associated with localised periodontal disease. The bacillus was isolated from blood during the acute presentation.

A 26-year-old man, returned to the UK having travelled extensively in Asia. He was referred with a 3-month history of distal leg ulceration following an insect bite while in Thailand. Despite multiple courses of oral antibiotics, he developed two adjacent ulcers. A wound swab isolated an organism identified as Burkholderia thailandensis. The histology of the skin biopsy was non-specific. A diagnosis of cutaneous melioidosis was made, based on clinical and microbiological grounds. The ulcers re-epithelialised on completion of intravenous ceftazidime followed by 3 months of high dose co-trimoxazole and wound care. Many clinical microbiology laboratories have limited diagnostics for security-related organisms, with the result that B. pseudomallei, the causative bacterium of melioidosis, may be misidentified. This case highlights the importance of maintaining high levels of clinical suspicion and close microbiological liaison in individuals returning from South-East Asia and northern Australia with such symptoms.

BACKGROUND Tuberculosis (TB) kills more people than any other infection, and new diagnostic tests to identify active cases are required. We aimed to discover and verify novel markers for TB in nondepleted plasma. METHODS We applied an optimized quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation combined with high-resolution mass spectrometry to study nondepleted plasma of 11 patients with active TB compared with 10 healthy controls. Prioritized candidates were verified in independent UK (n = 118) and South African cohorts (n = 203). RESULTS We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We analyzed the predominantly low–molecular weight subproteome, identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide FDR ≤ 1%, q ≤ 0.05). Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in 2 independent cohorts. Receiver operating characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP, and SAA1) exhibited discriminatory power in distinguishing TB from other respiratory diseases (AUC = 0.81). CONCLUSION We report the most comprehensive TB plasma proteome to date, identifying novel markers with verification in 2 independent cohorts, leading to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic triage test. FUNDING Colciencias, Medical Research Council, Innovate UK, NIHR, Academy of Medical Sciences, Program for Advanced Research Capacities for AIDS, Wellcome Centre for Infectious Diseases Research., Analysis of a comprehensive tuberculosis plasma proteome identified a 5-protein biosignature with potential to improve active tuberculosis diagnosis.

Background: Dependence upon azithromycin in the treatment of enteric fever is increasing, particularly with the emergence of Salmonella typhi strains with extended spectrum β-lactamase activity and the already high prevalence of quinolone resistance. Accurate determination of azithromycin susceptibility is crucial and underlined by recent reports of azithromycin resistance. We investigated concerns of discordance in azithromycin susceptibility estimation between local and reference laboratories. Methods: Retrospective audit of isolates from patients attending a central London hospital with enteric fever (May 2011-April 2019). Estimations of azithromycin and ciprofloxacin MICs by the local and reference laboratories were compared. Genomic data and laboratory practices were reviewed. Results: In isolates with matched clinical and reference laboratory MICs (n=19), there was poor inter-laboratory concordance: 5/19 MICs concordant (weighted κ = 0.190, adjusted for concordance within 1 log2 dilution); susceptibility interpretation concordant in 8/19 (κ=0). All isolates reported locally as resistant were found to be sensitive by the reference laboratory. No azithromycin resistance genes were detected. By contrast, for ciprofloxacin: 13/18 MIC gradient strip results concordant (weighted κ=0.823); susceptibility interpretation concordant in 17/18 (κ=0.85). Of the possible sources of variation identified, we believe that variable interpretation of “trailing edge” MIC estimation was key, mitigated in the reference laboratory by a “second reader” system. Conclusions: There is marked variation in azithromycin MIC gradient strip reporting between a local laboratory and the national reference laboratory, particularly over-reporting of resistance by the local laboratory. We would advise clinical laboratories to review their experience and consider adopting a “second reader” system.

Summary Background Staphylococcus aureus persistent bacteraemia is only vaguely defined and the effect of different durations of bacteraemia on mortality is not well established. Our primary aim was to analyse mortality according to duration of bacteraemia and to derive a clinically relevant definition for persistent bacteraemia. Methods We did a secondary analysis of a prospective observational cohort study at 17 European centres (nine in the UK, six in Spain, and two in Germany), with recruitment between Jan 1, 2013, and April 30, 2015. Adult patients who were consecutively hospitalised with monomicrobial S aureus bacteraemia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood-culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture. The primary outcome was 90-day mortality. Univariable and time-dependent multivariable Cox regression analysis were used to assess predictors of mortality. Duration of bacteraemia was defined as bacteraemic days under active antibiotic therapy counting the first day as day 1. Findings Of 1588 individuals assessed for eligibility, 987 were included (median age 65 years [IQR 51–75]; 625 [63%] male). Death within 90 days occurred in 273 (28%) patients. Patients with more than 1 day of bacteraemia (315 [32%]) had higher Charlson comorbidity index and sequential organ failure assessment scores and a longer interval from first symptom to first blood culture. Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteraemia, to 39% (85 of 218) with 2–4 days, 43% (30 of 69) with 5–7 days, and 36% (10 of 28) with more than 7 days of bacteraemia. Metastatic infections developed in 39 (6%) of 672 patients with 1 day of bacteraemia versus 40 (13%) of 315 patients if bacteraemia lasted for at least 2 days. The second day of bacteraemia had the highest HR and earliest cutoff significantly associated with mortality (adjusted hazard ratio 1·93, 95% CI 1·51–2·46; p Interpretation We suggest redefining the cutoff duration for persistent bacteraemia as 2 days or more despite active antibiotic therapy. Our results favour follow-up blood cultures after 24 h for early identification of all patients with increased risk of death and metastatic infection. Funding None.

A patient with well-controlled HIV-1 infection presented with fever and rigors, a widespread maculopapular rash, and severe generalised arthralgia. Sepsis of unknown aetiology was diagnosed, and treatment with broad-spectrum antimicrobials commenced. Following initial clinical improvement, a right knee septic arthritis developed. Microscopy and culture of the joint aspirate were negative for organisms but 16S rDNA PCR identified Neisseria meningitidis DNA, subsequently verified as capsular genogroup C, thus confirming a diagnosis of disseminated meningococcal sepsis with secondary septic arthritis.

Teicoplanin possesses several convenient properties for use in the delivery of outpatient parenteral antimicrobial therapy (OPAT) services. However, its use is not widespread and data on its efficacy in the OPAT setting are limited. Here we present a case series of patients undergoing OPAT care being treated by either teicoplanin-based (n = 107) or ceftriaxone-based (n = 191) antibiotic regimens. Clinical failure with teicoplanin occurred in five episodes of care (4.7%) compared with only two episodes of ceftriaxone-based OPAT care (1.0%). Teicoplanin-associated clinical failure was observed in 2 (33.3%) of 6 patients with Enterococcus infections compared with 3 (3.0%) of 101 patients with non-Enterococcus infections. Overall, there were four (2.9%) drug-related adverse events for teicoplanin and four (1.8%) for ceftriaxone, prompting a switch to teicoplanin in three patients. These findings support the continued use of teicoplanin in OPAT as well as its consideration in centres where it is not currently being offered.

United Kingdom guidelines recommend screening for and treatment of latent tuberculosis infection (LTBI) in HIV-positive patients at high risk of active tuberculosis (TB) disease, but implementation is suboptimal. We investigated potential missed opportunities to identify and treat LTBI among HIV-positive patients accessing a large HIV outpatient service in London. Case records of all adult patients attending our service for HIV care diagnosed with active TB between 2011 and 2015 were reviewed to determine whether they met criteria for LTBI screening and whether screening was undertaken. Twenty-five patients were treated for TB. Of 15 (60%) patients who started TB treatment ≥6 months after HIV diagnosis, 14 (93%) met UK guideline-recommended criteria for LTBI screening and treatment; only one (7%) had been screened for LTBI. Eight of these 15 (53%) patients had additional risk factors for TB which are not reflected in current UK guidelines. Of 15 patients treated for TB ≥6 months after diagnosis of HIV, 14 (93%) had not been screened for LTBI, suggesting missed opportunities for TB prevention. People living with HIV may benefit from a broader approach to LTBI screening which takes into account additional recognised TB risk factors and ongoing TB exposure.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FUNDING: UK National Institute for Health Research Health Technology Assessment.

This study aimed to determine whether there are seasonal changes in the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays, an interferon-gamma release assay widely used for the diagnosis of tuberculosis infection. Results of 31,932 QFT-GIT assays performed at a large independent, accredited diagnostic service provider in London, UK over a 4.5-year-period were analysed. The proportion of positive results was significantly lower in autumn (14.8%) than in spring (16.0%; p = 0.0366) and summer (17.5%; p < 0.0001), but similar to winter (15.2%; p = 0.4711). The proportion of indeterminate results was significantly higher in autumn (8.2%) than in spring (6.2%; p < 0.0001), summer (4.8%; p < 0.0001), and winter (6.2%; p < 0.0001). The highest proportions of indeterminate results were observed in October (8.4%) and November (8.8%), the lowest in June (4.5%). Our data show that significant seasonal variation occurs in the performance of QFT-GIT assays in a temperate climate setting. Potential underlying mechanisms, including host and environmental factors, are discussed.

Molecular diagnostic measurements are currently underpinned by the polymerase chain reaction (PCR). There are also a number of alternative nucleic acid amplification technologies, which unlike PCR, work at a single temperature. These ‘isothermal’ methods, reportedly offer potential advantages over PCR such as simplicity, speed and resistance to inhibitors and could also be used for quantitative molecular analysis. However there are currently limited mechanisms to evaluate their quantitative performance, which would assist assay development and study comparisons. This study uses a sexually transmitted infection diagnostic model in combination with an adapted metric termed isothermal doubling time (IDT), akin to PCR efficiency, to compare quantitative PCR and quantitative loop-mediated isothermal amplification (qLAMP) assays, and to quantify the impact of matrix interference. The performance metric described here facilitates the comparison of qLAMP assays that could assist assay development and validation activities.

The role of Xpert(®) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed.

Summary Objectives To establish the clinical reasons for inpatient admissions among injecting drug users. To determine the frequency of behavioural issues during their care and to estimate the financial implications of injecting drug use to the health service. Methods Retrospective cohort study at University College London Hospital. Clinical, laboratory and financial data were extracted from case notes and electronic records. The cost of each admission was compared to the income received for the period of care. Results 124 injecting drug users required 191 admissions between 2005 and 2009. Skin and soft tissue infections (58%) and pneumonia (18%) were the commonest reasons for admission. Bacteraemia at admission was often not accompanied by an inflammatory response. Exposure to HIV (4%), hepatitis B (49%) and C (84%) was common. Drug misuse (16%) during admission was frequent. The cost to the NHS of treating soft tissue infections in drug users was approximately £77 million per annum. After a median follow-up of 40 months, 10 patients (8%) had died. All deaths were attributable to drug use. Conclusions Bacterial and viral infections are largely responsible for the significant mortality and morbidity of injecting drug users presenting to secondary care. The financial burden to the NHS is substantial.

BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB. METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection. RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1–negative individuals, and 0.85 in HIV-1–infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1. CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever. FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR., Blood BATF2 transcripts provide a single biomarker for active tuberculosis and a novel four-gene transcriptional signature differentiates active TB from other infectious diseases with fever.

Background Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an important tool for the diagnosis and staging of lung cancer but its role in the diagnosis of tuberculous intrathoracic lymphadenopathy has not been established. The aim of this study was to describe the diagnostic utility of EBUS-TBNA in patients with intrathoracic lymphadenopathy due to tuberculosis (TB). Methods 156 consecutive patients with isolated intrathoracic TB lymphadenitis were studied across four centres over a 2-year period. Only patients with a confirmed diagnosis or unequivocal clinical and radiological response to antituberculous treatment during follow-up for a minimum of 6 months were included. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA. Demographic data, HIV status, pathological findings and microbiological results were recorded. Results EBUS-TBNA was diagnostic of TB in 146 patients (94%; 95% CI 88% to 97%). Pathological findings were consistent with TB in 134 patients (86%). Microbiological investigations yielded a positive culture of TB in 74 patients (47%) with a median time to positive culture of 16 days (range 3–84) and identified eight drug-resistant cases (5%). Ten patients (6%) did not have a specific diagnosis following EBUS; four underwent mediastinoscopy which confirmed the diagnosis of TB while six responded to empirical antituberculous therapy. There was one complication requiring an inpatient admission. Conclusions EBUS-TBNA is a safe and effective first-line investigation in patients with tuberculous intrathoracic lymphadenopathy.

Although typical published rates for periprosthetic joint infection are only about 1–2 % of all total joint arthroplasties, these infections have come to represent an increasingly significant burden on society. Financial estimates may be made for the economic loss associated with periprosthetic infection, but the personal cost of morbidity, whether psychological or physical, is often incalculable. This chapter examines the risk factors for development of periprosthetic infections, and discusses which of these factors are modifiable. By developing strategies that target those risks which are controllable, orthopaedic teams can seek to reduce periprosthetic joint infection rates to minimum levels. Risk factors may be considered as being either associated with individual patient characteristics or with the operative procedure itself and the environment in which it is performed. Risk reduction interventions will often require input from multidisciplinary teams, and the timing for interventions can be categorized as occurring in the pre-operative, immediate peri-operative or post-operative phases.

Pneumocystis pneumonia (PCP) is conventionally diagnosed by identifying Pneumocystis jirovecii in lower respiratory tract samples using cytochemical stains. Molecular diagnosis of PCP is potentially more sensitive.A study was undertaken to use an extensively optimised real-time polymerase chain reaction (PCR) using primers designed to hybridise with the P. jirovecii heat shock protein 70 (HSP70) gene to quantify P. jirovecii DNA in bronchoalveolar lavage (BAL) fluid from HIV-infected patients with and without PCP, and to compare this assay with conventional PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene sequence (mt LSU rRNA).Sixty-one patients had 62 episodes of PCP (defined by detection of P. jirovecii in BAL fluid by cytochemical stains and typical clinical presentation). Quantifiable HSP70 DNA was detected in 61/62 (range approximately 13-18,608 copies/reaction; median approximately 332) and was detectable but below the limit of quantification (approximately 5 copies/reaction) in 1/62. Seventy-one other patients had 74 episodes with alternative diagnoses. Quantifiable HSP70 DNA was detectable in 6/74 (8%) episodes (range approximately 6-590 copies/reaction; median approximately 14) and detectable but below the limit of quantification in 34/74 (46%). Receiver-operator curve analysis (cut-off10 copies/reaction) showed a clinical sensitivity of 98% (95% 91% to 100%) and specificity of 96% (95% CI 87% to 99%) for diagnosis of PCP. By contrast, clinical sensitivity of mt LSU rRNA PCR was 97% (95% CI 89% to 99%) and specificity was 68% (95% CI 56% to 78%).The HSP70 real-time PCR assay detects P. jirovecii DNA in BAL fluid and may have a diagnostic application. Quantification of P. jirovecii DNA by real-time PCR may also discriminate between colonisation with P. jirovecii and infection.

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.

We report a 72-year-old man on haemodialysis who presented with multiple abscesses on his lower legs. Routine bacterial culture of abscess pus was reported as 'sterile' after 48 h, leading to the suspicion of a mycobacterial infection. Skin biopsy taken for mycobacterial microscopy and culture isolated a heavy growth of Mycobacterium abscessus.

Objective To determine Mycoplasma genitalium infection and correlates among young women undergoing population-based screening or clinic-based testing for Chlamydia infection. Design Cross-sectional study. Setting National Chlamydia Screening Programme (NCSP) and two London sexually transmitted infection (STI) clinics. Participants 2441 women aged 15–64 years who participated in the NCSP and 2172 women who attended two London STI clinics over a 4-month period in 2009. Outcome measures (1) M genitalium prevalence in defined populations (%). (2) Age-adjusted ORs (aORs) for correlates of M genitalium infection. Results The overall frequency of M genitalium and Chlamydia trachomatis was 3% and 5.4%, respectively. Co-infection was relatively uncommon (0.5% of all women); however 9% of women with C trachomatis also had M genitalium infection. M genitalium was more frequently detected in swab than urine samples (3.9 vs 1.3%, p

Whether children with malarial anaemia should receive supplementation with iron or folic acid is uncertain. Therefore, the effects of supplementary treatment with iron or folic acid, given together with chloroquine or pyrimethamine-sulfadoxine (Fansidar ® ), has been assessed in 600 Gambian children with uncomplicated falciparum malaria. After one month, haematological recovery was significantly better in the group treated with Fansidar ® than in the chloroquine-treated group (difference in mean haemoglobin level = 0.54 g/dL, P = 0.01). Children who received iron had a significantly better response than those given placebo (differences in mean haemoglobin level after one month and at dry season follow-up = 0.70 g/dL, P = 0.006, and 0.81 g/dL, P = 0.001, respectively). Iron supplementation was not associated with increased prevalence of malaria. Supplementation with folic acid did not improve the haematological response but, among children who received Fansidar ® , the treatment failure rate was significantly higher among those given folic acid than among those given placebo. Thus, supplementation with iron, but not folic acid, improves haematological recovery without increasing susceptibility to malaria.

andtrimethoprim-sulfamethoxazole,� whicharetraditionallyfirst-lineagentsfor� thetreatmentofentericfever.�Themultid- rugresistancephenotypehasbecomecom- moninS. typhiand,�toalesserextent,�S. paratyphi� (ParryandThrelfall,� 2008)� and� thishasledtogreaterrelianceonother� agents,�particularlyfluoroquinolones.� Promisingresultswithciprofloxacin� suggestedthatitwasmoreeffectiveinthe� treatmentofuncomplicatedentericfever� inareaswithhighratesofmultidrugresist- ancesalmonellae� (Alametal,� 1995)� and� quinolonesalsohavesignificantlyreduced� failureratescomparedwithsomefirst-line� agentsinentericfevercausedbysuscepti- bleisolates� (Thaveretal,� 2008).� Unfortunately,� overthepastdecade,� iso- lateswithdecreasedciprofloxacinsuscepti- bilityhavebecomemorecommonandare� associatedwithtreatmentfailureand� relapse� (Chuangetal,� 2009).� Atthe� HospitalforTropicalDiseases,� London,� salmonellaewithdecreasedciprofloxacin�

A 62-year-old man presented to a district general hospital with a 4-week history of fever, drenching sweats, lethargy and intermittent thoracic back pain. Two weeks prior to onset, a pacemaker had been inserted for recurrent syncope secondary to carotid sinus hypersensitivity. His other past medical history included a permanent tracheostomy following resection of a laryngeal carcinoma 8 years previously, and ischaemic heart disease. The latter culminated in an acute coronary syndrome 7 months before the current presentation, for which primary angioplasty was undertaken with insertion of six drug-eluting coronary artery stents requiring dual antiplatelet therapy for at least 1 year. On admission , he was febrile at 38.5°C. There were no peripheral stigmata of infective endocarditis, auscultation of the pre-cordium identified no murmurs and the pacemaker site was not inflamed. Systemic examination was otherwise unremarkable, as were chest radiography and urinalysis. Transthoracic echocardiography demonstrated good systolic function, with no valvular regurgitation or pacemaker lead vegetations. In the absence of a clear septic focus, he was commenced on piperacillin–tazobactam. Blood tests showed haemoglobin of 11.6 g/dl, white cell count of 5.7 × 109 cells/l and platelet count of 52 × 109 cells/l. C-reactive protein (CRP) was elevated at 272 mg/l. Coagulation screen was normal. Multiple blood cultures were drawn, which grew methicillin-sensitive Staphylococcus aureus . Intravenous flucloxacillin and rifampicin were commenced. He was consequently transferred to the London Heart Hospital for further management. The pacemaker was explanted and there was marked clinical improvement. Nonetheless, despite antibiotic therapy he continued to have high-grade pyrexias, without diurnal variation, and elevated serum CRP concentrations. An extensive septic screen, including urine and blood cultures, chest radiographs and repeated transthoracic and transoesophageal echocardiograms revealed no abnormalities. Computed tomography (CT) scan of the thorax, abdomen and pelvis to identify any occult septic focus revealed a large infrarenal aortic aneurysm, as well …

Background Salmonella and Shigella species are pathogens of great medical and public health importance. However, laboratory identification of these organisms is time consuming. Using current standard laboratory algorithms, the vast majority of organisms submitted for serological typing with Salmonella -specific and Shigella -specific antisera are not clinically significant. Aims To assess the addition of the O -nitrophenyl-β-d-galactopyranoside (ONPG) test to the standard screening protocol for identification of Salmonella and Shigella species, and to describe a revised algorithm for the identification of these pathogens. Methods 71 non-lactose-fermenting isolates that were urease negative, indole negative, and produced acid and gas in triple sugar iron agar , with no H 2 S production in the agar, were tested for β-galactosidase activity using the ONPG test. The test results were read at half-hourly intervals over a 4 h incubation period in O 2 at 37°C. Results 42 isolates (59.2%) were found to be Hafnia alvei , of which 36 strains (85.7%) were ONPG positive. All 18 of the Enterobacter species (25.4%) were ONPG positive. Overall, about 79% of the ONPG-positive isolates were positive at the end of the first half-hour of incubation. The two pathogenic isolates obtained during this study were both identified as Salmonella enterica serovar Paratyphi A, and they were ONPG negative. Conclusions Incorporation of a 30 min ONPG test for non-lactose-fermenting organisms that are indole negative, urease negative, producers of acid and gas from glucose, oxidase negative and non-H 2 S gas producers eliminates the need for further serological testing of 79% of isolates, substantially improving the efficiency of the identification protocol.

Our current knowledge of the clinical characteristics of enteric fever is drawn mainly from population-based studies in disease-endemic countries, and there are limited data published on cases in returning travelers. We report the clinical characteristics of enteric fever in 92 travelers returning to London, United Kingdom. Salmonella typhi and S. paratyphi resulted in an almost indistinguishable clinical picture. Rose spots and relative bradycardia were found only in a few patients. A total of 91% of the patients had a normal leukocyte count, which was associated with a markedly increased level of alanine aminotransferase in 82%. A total of 57% of the S. typhi isolates had decreased susceptibility to ciprofloxacin and resistance to nalidixic acid; these isolates were from southern Asia. Thirty percent were multidrug resistant; all were from southern Asia and Nigeria. None of the paratyphoid isolates were multidrug resistant but rates of decreased susceptibility to fluoroquinolones were higher than in S. typhi (74%).

PURPOSE OF REVIEW Empyema is defined as pus in the thoracic cavity due to pleural space infection and has a multifactorial underlying cause, although a majority of them are post-bacterial pneumonia caused by tuberculosis or by infection following penetrating chest injuries or surgical procedures. It is still associated with significant morbidity and mortality in adults and children despite optimal management according to current guidelines. Historically, empyema management has been empirical, but more recent data are leading to more focused management guidelines. RECENT FINDINGS The number of therapeutic agents licensed for intrapleural use or undergoing clinical trials in the management of empyema continues to expand, although their use is currently controversial and probably best limited to trials and specialist centers. Although their use is limited by availability, ultrasound and guided aspiration is the investigation of choice in suspected empyema. It is safer, more sensitive, provides more information, and, in the case of guided-drainage, is more likely to be effective. Finally, there is a growing body of literature that supports very early involvement of thoracic surgeons in empyema management. An emerging question for the future is whether some or indeed all patients with empyema should now bypass medical thoracostomy and proceed directly to video-assisted thoracoscopic surgery for both acute and chronic empyemas. SUMMARY A summary of the most recent opinions and results in thoracic empyema management is outlined. Treatment of empyema can be summarized as appropriate antibiotic therapy combined with medical or surgical pleural space drainage, management of any underlying factors, with further surgery indicated for chronic disease.

Summary An HIV-infected man receiving antiretroviral therapy—who also had lupus-like vasculitis and membranous glomerulonephritis (treated with prednisolone and azathioprine), beta-thalassaemia minor trait and post-radiotherapy functional asplenia (mimicking sickle cell disease-induced hyposplenism)—developed focal soft issue and bone infection caused by Salmonella enteritidis at the site of previous mycobacterial infection.

A 29-year-old man was admitted with fevers, cough, left-sided chest pain and lethargy for 1 week. He had a cardiac transplant 10 years prior and was on immunosuppressive drugs. He was found to have a pulmonary lesion and went on to develop a lung abscess. Propionibacterium acnes was identified on matrix-assisted laser desorption ionisation mass spectrometry-time of flight and 16s rRNA gene sequencing after drainage. He was curatively treated with co-trimoxazole and co-amoxiclav. He divulged a longstanding history of seborrhoeic dermatitis with frequent flares leading to large volumes of squames collecting on his bed sheets. We hypothesise this was a possible route of entry: inhalation of the Propionibacterium. This case highlights how a common commensal bacterium, P. acnes, was able to cause pathology in an immunosuppressed patient. This is the only case of a patient with transplantation developing a P. acnes pulmonary infection and the only case of P. acnes causing these clinical features to be reported in the literature.