Efficacy of rifampicin combination therapy for the treatment of enterococcal infections assessed in vivo using a Galleria mellonella infection model.

Enterococci are a leading cause of healthcare-associated infection worldwide and display increasing levels of resistance to many of the commonly used antimicrobials, making treatment of their infections challenging. Combinations of antibiotics are occasionally employed to treat serious infections, allowing for the possibility of synergistic killing. The aim of this study was to evaluate the effects of different antibacterial combinations against enterococcal isolates using an in vitro approach and an in vivo Galleria mellonella infection model. Five Enterococcus faecalis and three Enterococcus faecium strains were screened by paired combinations of rifampicin, tigecycline, linezolid or vancomycin using the chequerboard dilution method. Antibacterial combinations that displayed synergy were selected for in vivo testing using a G. mellonella larvae infection model. Rifampicin was an effective antibacterial enhancer when used in combination with tigecycline or vancomycin, with minimum inhibitory concentrations (MICs) of each individual antibiotic being reduced by between two and four doubling dilutions, generating fractional inhibitory concentration index (FICI) values between 0.31 and 0.5. Synergy observed with the chequerboard screening assays was subsequently observed in vivo using the G. mellonella model, with combination treatment demonstrating superior protection of larvae post-infection in comparison with antibiotic monotherapy. In particular, rifampicin in combination with tigecycline or vancomycin significantly enhanced larvae survival. Addition of rifampicin to anti-enterococcal treatment regimens warrants further investigation and may prove useful in the treatment of enterococcal infections whilst prolonging the clinically useful life of currently active antibiotics

Pasteurella multocida Endocarditis with Septic Arthritis: Case Report and Review of the Literature

Background: There is a paucity of evidence regarding optimal management of Pasteurella spp. endocarditis. The authors report the first case of Pasteurella spp. endocarditis with septic arthritis and review the literature. Case Description: A 79-year-old patient with significant comorbidities, including prosthetic aortic valve, was admitted with left knee swelling, fever, and confusion, having been scratched by a cat 2-weeks prior. At presentation, there was a metallic click, a Grade 3 pan-systolic murmur and Grade 1 flow murmur audible on auscultation. Blood and synovial fluid cultures both isolated Pasteurella multocida, identified by matrix-assisted laser desorption ionisation–time of flight, which was sensitive to penicillin according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST); minimum inhibitory concentration: 0.094). The patient underwent joint washout and received intravenous piperacillin/tazobactam for 3 days before switching to benzylpenicillin once sensitivities were known. Due to continued pyrexia, a transthoracic echocardiogram was obtained, which revealed a small mobile mass on a thickened mitral valve suspicious for a vegetation. On review by the Infective Endocarditis team, conservative management was deemed best, given the presence of comorbidities. Despite requiring further joint washout due to persistent knee pain, the patient was successfully treated with 8 weeks of antibiotic therapy (24 days of benzylpenicillin monotherapy, 2 weeks of benzylpenicillin and ciprofloxacin, and 15 days ciprofloxacin monotherapy). Discussion: Previous literature reviews report a higher mortality of Pasteurella spp. endocarditis when managed without cardiac surgery, thus recommending surgery in all cases. The authors found these to have confounding factors, including inadequate duration of antimicrobials, aortic root abscess, and rapid progression to death. The authors’ case of Pasteurella spp. endocarditis, complicated by septic arthritis, showed successful therapy without cardiac surgery

Bacteraemia during transurethral resection of the prostate: what are the risk factors and is it more common than we think?

The aim of this work was to investigate the microbial causes, incidence, duration, risk factors and clinical implications of bacteraemia occurring during transurethral resection of the prostate (TURP) surgery to better inform prophylaxis strategies. An ethically approved, prospective, cohort study of patients undergoing TURP was conducted. Clinical information and follow-up details were collected using standardized data collection sheets. Blood was obtained for culture at 6 different time points peri-procedure. Standard of care antibiotic prophylaxis was given prior to surgery. Bacteriuria was assessed in a pre-procedure urine sample. Histopathology from all prostate chips was assessed for inflammation and malignancy. 73 patients were consented and 276 blood samples obtained. No patients developed symptomatic bacteraemia during the procedure, 17 patients developed asymptomatic bacteraemia (23.2%). Enterococcus faecalis and Pseudomonas aeruginosa were the most common organisms cultured. 10 minutes after the start of the TURP, the odds ratio (OR) of developing bacteraemia was 5.38 (CI 0.97-29.87 p=0.05), and 20 minutes after the start of the procedure, the OR was 6.46 (CI 1.12-37.24, p=0.03), compared to before the procedure. We also found an association between the development of intra-operative bacteraemia and recent antibiotic use (OR 4.34, CI 1.14-16.62, p=0.032), the presence of a urinary catheter (OR 4.92, CI 1.13-21.51, p=0.034) and a malignant histology (OR 4.90, CI 1.30-18.46, p=0.019). There was no statistical relationship between pre-operative urine culture results and blood culture results. This study shows that asymptomatic bacteraemia is commonly caused by TURP and occurs in spite of antibiotic prophylaxis. Our findings challenge the commonly held view that urine is the primary source of bacteraemia in TURP-associated sepsis and raise the possibility of occult prostatic infection as a cause of bacteraemia. More work will be needed to determine the significance of transient bacteraemia in relation to more serious complications like infective endocarditis and malignancy

A Systematic Review of the Effect of Therapeutic Drug Monitoring on Patient Health Outcomes during Treatment with Carbapenems

Adjusting dosing regimens based on measurements of carbapenem levels may improve carbapenem exposure in patients. This systematic review aims to describe the effect carbapenem therapeutic drug monitoring (TDM) has on health outcomes, including the emergence of antimicrobial resistance (AMR). Four databases were searched for studies that reported health outcomes following adjustment to dosing regimens, according to measurements of carbapenem concentration. Bias in the studies was assessed with risk of bias analysis tools. Study characteristics and outcomes were tabulated and a narrative synthesis was performed. In total, 2 randomised controlled trials (RCTs), 17 non-randomised studies, and 19 clinical case studies were included. Significant variation in TDM practice was seen; consequently, a meta-analysis was unsuitable. Few studies assessed impacts on AMR. No significant improvement on health outcomes and no detrimental effects of carbapenem TDM were observed. Five cohort studies showed significant associations between achieving target concentrations and clinical success, including suppression of resistance. Studies in this review showed no obvious improvement in clinical outcomes when TDM is implemented. Optimisation and standardisation of carbapenem TDM practice are needed to improve intervention success and enable study synthesis. Further suitably powered studies of standardised TDM are required to assess the impact of TMD on clinical outcomes and AMR

‘Warning: allergic to penicillin’: association between penicillin allergy status in 2.3 million NHS general practice electronic health records, antibiotic prescribing and health outcomes

Background The prevalence of reported penicillin allergy (PenA) and the impact these records have on health outcomes in the UK general population are unknown. Without such data, justifying and planning enhanced allergy services is challenging. Objectives To determine: (i) prevalence of PenA records; (ii) patient characteristics associated with PenA records; and (iii) impact of PenA records on antibiotic prescribing/health outcomes in primary care. Methods We carried out cross-sectional/retrospective cohort studies using patient-level data from electronic health records. Cohort study: exact matching across confounders identified as affecting PenA records. Setting: English NHS general practices between 1 April 2013 and 31 March 2014. Participants: 2.3 million adult patients. Outcome measures: prevalence of PenA, antibiotic prescribing, mortality, MRSA infection/colonization and Clostridioides difficile infection. Results PenA prevalence was 5.9% (IQR = 3.8%–8.2%). PenA records were more common in older people, females and those with a comorbidity, and were affected by GP practice. Antibiotic prescribing varied significantly: penicillins were prescribed less frequently in those with a PenA record [relative risk (RR)  = 0.15], and macrolides (RR = 4.03), tetracyclines (RR = 1.91) nitrofurantoin (RR = 1.09), trimethoprim (RR = 1.04), cephalosporins (RR = 2.05), quinolones (RR = 2.10), clindamycin (RR = 5.47) and total number of prescriptions were increased in patients with a PenA record. Risk of re-prescription of a new antibiotic class within 28 days (RR = 1.32), MRSA infection/colonization (RR = 1.90) and death during the year subsequent to 1 April 2013 (RR = 1.08) increased in those with PenA records. Conclusions PenA records are common in the general population and associated with increased/altered antibiotic prescribing and worse health outcomes. We estimate that incorrect PenA records affect 2.7 million people in England. Establishing true PenA status (e.g. oral challenge testing) would allow more people to be prescribed first-line antibiotics, potentially improving health outcomes

Penicillin allergy de-labelling ahead of elective surgery: feasibility and barriers

Background: Around 10–15% of the in-patient population carry unsubstantiated ‘penicillin allergy’ labels, the majority incorrect when tested. These labels are associated with harm from use of broad-spectrum non-penicillin antibiotics. Current testing guidelines incorporate both skin and challenge tests; this is prohibitively expensive and time-consuming to deliver on a large scale. We aimed to establish the feasibility of a rapid access de-labelling pathway for surgical patients, using direct oral challenge. Methods: ‘Penicillin allergic’ patients, recruited from a surgical pre-assessment clinic, were risk-stratified using a screening questionnaire. Patients at low risk of true, immunoglobulin E (IgE)-mediated allergy were offered direct oral challenge using incremental amoxicillin to a total dose of 500 mg. A 3-day course was completed at home. De-labelled patients were followed up to determine antibiotic use in surgery, and attitudes towards de-labelling were explored. Results: Of 219 patients screened, 74 were eligible for inclusion and offered testing. We subsequently tested 56 patients; 55 were de-labelled. None had a serious reaction to the supervised challenge, or thereafter. On follow-up, 17 of 19 patients received appropriate antimicrobial prophylaxis during surgery. Only three of 33 de-labelled patients would have been happy for the label to be removed without prior specialist testing. Conclusion: Rapid access de-labelling, using direct oral challenge in appropriately risk-stratified patients, can be incorporated into the existing surgical care pathway. This provides immediate and potential long-term benefit for patients. Interest in testing is high among patients, and clinicians appear to follow clinic recommendations. Patients are unlikely to accept removal of their allergy label on the basis of history alone

Development and randomized controlled trial of an animated film aimed at reducing behaviours for acquiring antibiotics

Background Antimicrobial resistance (AMR) is a global health crisis but reducing antibiotic use can help. Some antibiotic use is driven by patient demand. Objectives To develop an intervention to discourage antibiotic-seeking behaviour in adults. Methods Literature reviewed to identify behaviours for acquiring antibiotics among adults in the community. Behaviour change wheel approach was used to select the target behaviour and behaviour change techniques. An intervention in the form of a short animated film was developed and its potential impact evaluated in a randomized, controlled, online questionnaire study. Results Asking a general medical/dental practitioner for antibiotics was identified as the target behaviour. A short stop-motion animated film was chosen to deliver several behaviour-change techniques. Education and persuasion were delivered around information about the normal microbial flora, its importance for health, the negative effect of antibiotics, and about AMR. 417 UK-based individuals completed the questionnaire; median age 34.5 years, 71% female, 91% white ethnicity. 3.8% of participants viewing the test film intended to ask for antibiotics compared with 7.9% viewing the control film. Test film viewers had significantly higher knowledge scores. At 6 week follow up, knowledge scores remained significantly different, while most attitude and intention scores were not different. Conclusions Some patients continue to ask for antibiotics. The film increased knowledge and reduced intentions to ask for antibiotics. At 6 weeks, knowledge gains remained but intentions not to ask for antibiotics had waned. Evaluation in the clinical environment, probably at the point of care, is needed to see if antibiotic prescribing can be impacted

Production of Giant Unilamellar Vesicles and Encapsulation of Nematic Lyotropic Liquid Crystals

We describe a modified microfluidic method for making Giant Unilamellar Vesicles (GUVs)viawater/octanol-lipid/water double emulsion droplets. At a high enough lipid concentration we show that thede-wetting of the octanol from these droplets occurs spontaneously (off-chip) without the need to useshear to aid the de-wetting process. The resultant mixture of octanol droplets and GUVs can beseparated by making use of the buoyancy of the octanol. A simpler microfluidic device and pumpsystem can be employed and, because of the higher flow-rates and much higher rate of formation ofthe double emulsion droplets (B1500 s 1compared to up toB75 s 1), it is easier to make largernumbers of GUVs and larger volumes of solution. Because of the potential for using GUVs thatincorporate lyotropic nematic liquid crystals in biosensors we have used this method to make GUVs thatincorporate the nematic phases of sunset yellow and disodium chromoglycate. However, the phasebehaviour of these lyotropic liquid crystals is quite sensitive to concentration and we found that there isan unexpected spread in the concentration of the contents of the GUVs obtained

Textures of Nematic Liquid Crystal Cylindric-Section Droplets Confined by Chemically Patterned Surfaces

The director fields adopted by nematic liquid crystals (LCs) that are confined by the surface to form long, thin droplets are investigated using polarising optical microscopy. Samples are produced by de-wetting of the LC on a surface patterned with alternating high-surface energy and low-surface energy stripes of 10–30 μm width. The droplets obtained are expected to adopt a profile which is that of a longitudinal section of a cylinder and, as this suggests, the director fields observed are variants in the case where the LC is constrained in a cylindrical capillary or fibre. Hence, when there is normal anchoring at the air interface, the textures observed are related to the well-known escaped radial texture (for the nematic LC mixture E7) or plane polar texture (for the LC mixture MLC6609). More surprising is the observation that the nematic LC mixture MLC7023, which is anchored in a planar or tilted manner at the air interface, also gives what appears to be an escaped radial director field. As an exploration of the possibility of using these systems in creating sensors, the effects of adding a chiral dopant and of adding water to the substrates are also investigated

Diagnosis of Aortic Graft Infection: A Case Definition by the Management of Aortic Graft Infection Collaboration (MAGIC)

OBJECTIVE/BACKGROUND: The management of aortic graft infection (AGI) is highly complex and in the absence of a universally accepted case definition and evidence-based guidelines, clinical approaches and outcomes vary widely. The objective was to define precise criteria for diagnosing AGI. METHODS: A process of expert review and consensus, involving formal collaboration between vascular surgeons, infection specialists, and radiologists from several English National Health Service hospital Trusts with large vascular services (Management of Aortic Graft Infection Collaboration [MAGIC]), produced the definition. RESULTS: Diagnostic criteria from three categories were classified as major or minor. It is proposed that AGI should be suspected if a single major criterion or two or more minor criteria from different categories are present. AGI is diagnosed if there is one major plus any criterion (major or minor) from another category. (i) Clinical/surgical major criteria comprise intraoperative identification of pus around a graft and situations where direct communication between the prosthesis and a nonsterile site exists, including fistulae, exposed grafts in open wounds, and deployment of an endovascular stent-graft into an infected field (e.g., mycotic aneurysm); minor criteria are localized AGI features or fever ≥38°C, where AGI is the most likely cause. (ii) Radiological major criteria comprise increasing perigraft gas volume on serial computed tomography (CT) imaging or perigraft gas or fluid (≥7 weeks and ≥3 months, respectively) postimplantation; minor criteria include other CT features or evidence from alternative imaging techniques. (iii) Laboratory major criteria comprise isolation of microorganisms from percutaneous aspirates of perigraft fluid, explanted grafts, and other intraoperative specimens; minor criteria are positive blood cultures or elevated inflammatory indices with no alternative source. CONCLUSION: This AGI definition potentially offers a practical and consistent diagnostic standard, essential for comparing clinical management strategies, trial design, and developing evidence-based guidelines. It requires validation that is planned in a multicenter, clinical service database supported by the Vascular Society of Great Britain & Ireland