40 years of veterinary papers in JAC – what have we learnt?

This review, for the occasion of the 40th anniversary of the Journal of Antimicrobial Chemotherapy (JAC), gives an overview of the manuscripts related to veterinary bacteriology published in the journal in the past 40 years with a focus on ‘One Health’ aspects. From 1975 to 2000 the number of manuscripts related to veterinary medicine was limited, but thereafter, the number steadily increased. Most manuscripts published were related to food-producing animals, but companion animals and minor species were also covered. Subjects included antimicrobial usage in animals and the consequences for human medicine, new resistance genes and mechanisms, the prevalence and epidemiology of antimicrobial resistance, and the emergence of resistant bacteria in animals with zoonotic potential such as livestock-associated MRSA (LA-MRSA), methicillin-resistant Staphylococcus pseudintermedius (MRSP) and ESBL-producing Enterobacteriaceae. These manuscripts have added to our knowledge on the risks of transmission of resistant bacteria from animals to humans and the importance of the prudent use of antimicrobial agents in veterinary medicine

Identification of a Type IV-A CRISPR-Cas System Located Exclusively on IncHI1B/IncFIB Plasmids in Enterobacteriaceae

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are diverse immune systems found in many prokaryotic genomes that target invading foreign DNA such as bacteriophages and plasmids. There are multiple types of CRISPR with arguably the most enigmatic being Type IV. During an investigation of CRISPR carriage in clinical, multi-drug resistant, Klebsiella pneumoniae, a Type IV-A3 CRISPR-Cas system was detected on plasmids from two K. pneumoniae isolates from Egypt (isolated in 2002–2003) and a single K. pneumoniae isolate from the United Kingdom (isolated in 2017). Sequence analysis of all other genomes available in GenBank revealed that this CRISPR-Cas system was present on 28 other plasmids from various Enterobacteriaceae hosts and was never found on a bacterial chromosome. This system is exclusively located on IncHI1B/IncFIB plasmids and is associated with multiple putative transposable elements. Expression of the cas loci was confirmed in the available clinical isolates by RT-PCR. In all cases, the CRISPR-Cas system has a single CRISPR array (CRISPR1) upstream of the cas loci which has several, conserved, spacers which, amongst things, match regions within conjugal transfer genes of IncFIIK/IncFIB(K) plasmids. Our results reveal a Type IV-A3 CRISPR-Cas system exclusively located on IncHI1B/IncFIB plasmids in Enterobacteriaceae that is likely to be able to target IncFIIK/IncFIB(K) plasmids presumably facilitating intracellular, inter-plasmid competition

Rapid and Point-of-Care Testing in Respiratory Tract Infections: An Antibiotic Guardian?

This is a narrative review on the potential of rapid and point-of-care microbiological testing in pneumonia patients, focusing particularly on hospital-acquired and ventilator-associated pneumonia, which have substantial mortality and diverse microbiology. This work is written from a United Kingdom perspective, but much of it is generalizable internationally. In a world where antimicrobial resistance is a major international threat, the use of rapid molecular diagnostics has great potential to improve both the management of pneumonia patients and the stewardship of antibiotics. Rapid tests potentially can distinguish patients with bacterial versus viral infection and can swiftly identify bacterial pathogens and their resistances. We seek to answer the question: "Can such tests be used as an antibiotic guardian?"Their availability at the bedside rather than in the laboratory should best ensure that results are swiftly used to optimize patient management but will raise new challenges, not the least with respect to maintaining quality control and microbiology/infection control input. A further challenge lies in assessing the degree of trust that treating clinicians will place in these molecular diagnostic tests, particularly when early de-escalation of antibiotic therapy is indicated

Review of health economic models exploring and evaluating treatment and management of hospital-acquired pneumonia and ventilator-associated pneumonia

BACKGROUND: Hospital-acquired pneumonia (HAP) is pneumonia that occurs ≥48 h after hospital admission; it is the most common hospital-acquired infection contributing to death. Ventilator-associated pneumonia (VAP) arises ≥48-72 h after intubation. Opinions differ on whether VAP is a subset of HAP; the same pathogens predominate in both. Compared with VAP-free controls, patients developing VAP are twice as likely to die and have significantly longer stays in intensive care units. Guidelines recommend that microbiological cultures should guide antibiotic treatment, but these lack sensitivity and take 48-72 h to process, meaning that initial therapy must be empiric, generally with broad-spectrum agents. Given increasing pressure to improve both antibiotic stewardship and patient outcomes, the National Institute for Health and Care Excellence and the Infectious Diseases Society of America recommend research into rapid molecular diagnostic tests to identify causative organisms and their antibiotic resistances. Ideally, these would supersede culture, being quicker and more sensitive. In the UK, the INHALE research programme, funded by the National Institute for Health Research, is exploring rapid molecular diagnostics to inform treatment of HAP/VAP and, given resource implications, incorporates a health economic component. AIM: To identify previous economic modelling of HAP/VAP costs to inform this component. METHODS: Literature review of HAP/VAP studies with economic modelling identified from three databases. FINDINGS: Twenty studies were identified. Only one study specifically evaluated strategies to improve diagnosis; the remaining 19 studies omitted this important aspect. CONCLUSION: HAP/VAP modelling would be improved by better awareness of long-term outcomes and treatment complexity. To the authors' knowledge, no similar literature reviews of economic modelling for HAP/VAP have been published

The Unyvero P55 ‘sample-in, answer-out’ pneumonia assay: A performance evaluation

Background: O’Neill’s recent Review on Antimicrobial Resistance expressed the view that by 2020 high-income countries should make it mandatory to support antimicrobial prescribing with rapid diagnostic evidence whenever possible. Methods: Routine microbiology diagnosis of 95 respiratory specimens from patients with severe infection were compared with those generated by the Unyvero P55 test, which detects 20 pathogens and 19 antimicrobial resistance markers. Supplementary molecular testing for antimicrobial resistance genes, comprehensive culture methodology and 16S rRNA sequencing were performed. Results: Unyvero P55 produced 85 valid results, 67% of which were concordant with those from the routine laboratory. Unyvero P55 identified more potential pathogens per specimen than routine culture (1.34 vs. 0.47 per specimen). Independent verification using 16S rRNA sequencing and culture (n = 10) corroborated 58% of additional detections compared to routine microbiology. Overall the average sensitivity for organism detection by Unyvero P55 was 88.8% and specificity was 94.9%. While Unyvero P55 detected more antimicrobial resistance markers than routine culture, some instances of phenotypic resistance were missed. Conclusions: The Unyvero P55 is a rapid pathogen detection test for lower respiratory specimens, which identifies a larger number of pathogens than routine microbiology. The clinical significance of these additional organisms is yet to be determined. Further studies are required to determine the effect of the test in practise on antimicrobial prescribing and patient outcomes

'Sample-in, answer-out'? Evaluation and comprehensive analysis of the Unyvero P50 pneumonia assay

This study aimed to evaluate the performance of the Unyvero P50 pneumonia assay, the first ‘sample-in, answer-out’ system for rapid identification of pathogens and antibiotic resistance markers directly from clinical specimens. Overall, Unyvero P50 displayed very good sensitivity (>95%); however, specificity was low (33%) mainly because 40% of the specimens were reported as normal flora. Specifically, one or more pathogens were identified in 28 of them. From a detailed analysis of 42 specimens selected at random, 76% of the additionally reported pathogens were confirmed present in primary specimens. Detection of selected resistance markers was compared to routine phenotypic susceptibility testing, supplemented with Checkpoints microarray system, PCR and sequencing. Concordance was mixed, primarily due to issues with panel’s choice of markers and detection of some intrinsic beta-lactamases. Finally, we offer a critical analysis of the assay’s microbial panel and resistance markers and provide suggestions for improvement

Phenotypic and genotypic distribution of ESBL, AmpC β-lactamase and carbapenemase-producing Enterobacteriaceae in community-acquired and hospital-acquired urinary tract infections in Sri Lanka

Objectives: Although Sri Lanka belongs to a region with a high prevalence of extended-spectrum β-lactamase (ESBL), AmpC β-lactamase and carbapenemase-producing Enterobacteriaceae, data regarding antimicrobial resistance (AMR) is limited. We studied the prevalence and diversity of β-lactamases produced by Enterobacteriaceae urinary pathogens from two hospitals in the Western Province of Sri Lanka. Methods: ESBL, AmpC β-lactamase and carbapenemase production was detected by phenotypic testing followed by genotyping. Results: The species responsible for urinary tract infections (UTI) were Escherichia coli (69%), Klebsiella pneumoniae (16%) and Enterobacter sp (6%). The prevalence of ESBL (50%), AmpC β-lactamase (19%) and carbapenemase (11%) phenotypes was high, and greater in hospital-acquired (HA-UTI) (75%) than in community-acquired UTI (CA-UTI) (42%). Identification of CA-UTI caused by carbapenemase-producing Enterobacteriaceae (5%) is alarming. Only one ESBL gene, blaCTX- M-15, was detected. AmpC β-lactamase genes found in E. coli and K. pneumoniae were blaCMY-2, blaCMY-42 and blaDHA-1, while Enterobacter sp. carried blaACT-1. Carbapenemase genes were blaNDM-1, blaNDM-4, blaOXA-181 and blaOXA-232, while blaKPC, blaIMP and blaVIM were absent. Co-occurrence of multiple bla genes, with some isolates harbouring six different bla genes, was common. Carbapenem-resistant isolates without carbapenemase genes displayed mutations in the outer membrane porin genes, ompF of E. coli and ompK36 of K. pneumoniae. Factors associated with UTI with β-lactamase-producing Enterobacteriaceae were age ≥50 years, previous hospitalization, presence of an indwelling urinary catheter, history of diabetes mellitus or other chronic illness and recurrent urinary tract infections. Conclusion: This study adds to the currently scarce data on AMR in Sri Lanka

Understanding decisions about antibiotic prescribing in ICU: an application of the Necessity Concerns Framework

Background: Antibiotics are extensively prescribed in intensive care units (ICUs), yet little is known about how antibiotic-related decisions are made in this setting. We explored how beliefs, perceptions and contextual factors influenced ICU clinicians’ antibiotic prescribing. / Methods: We conducted 4 focus groups and 34 semistructured interviews with clinicians involved in antibiotic prescribing in four English ICUs. Focus groups explored factors influencing prescribing, whereas interviews examined decision-making processes using two clinical vignettes. Data were analysed using thematic analysis, applying the Necessity Concerns Framework. / Results: Clinicians’ antibiotic decisions were influenced by their judgement of the necessity for prescribing/not prescribing, relative to their concerns about potential adverse consequences. Antibiotic necessity perceptions were strongly influenced by beliefs that antibiotics would protect patients from deterioration and themselves from the ethical and legal consequences of undertreatment. Clinicians also reported concerns about prescribing antibiotics. These generally centred on antimicrobial resistance; however, protecting the individual patient was prioritised over these societal concerns. Few participants identified antibiotic toxicity concerns as a key influencer. Clinical uncertainty often complicated balancing antibiotic necessity against concerns. Decisions to start or continue antibiotics often represented ‘erring on the side of caution’ as a protective response in uncertainty. This approach was reinforced by previous experiences of negative consequences (‘being burnt’) which motivated prescribing ‘just in case’ of an infection. Prescribing decisions were also context-dependent, exemplified by a lower perceived threshold to prescribe antibiotics out-of-hours, input from external team members and local prescribing norms. / Conclusion: Efforts to improve antibiotic stewardship should consider clinicians’ desire to protect with a prescription. Rapid molecular microbiology, with appropriate communication, may diminish clinicians’ fears of not prescribing or of using narrower-spectrum antibiotics