•Resistance to critically important antimicrobials registered in human medicine such as carbapenems was not detected.•Frequency of resistance was classified as low for FQN and moderate for 3GC among ...clinical E. coli from dogs.•Frequency of resistance was classified as low for both FQN and 3GC among clinical E. coli from cats.•Chronic disease and prior antimicrobial use were the main risk factors for the isolation of MDR E. coli from UTI.
Multidrug-resistant (MDR) Escherichia coli have become a major public health concern to both humans and animal health. While the frequency of antimicrobial resistance (AMR) in clinical E. coli is monitored regularly in human medicine, current frequency of AMR in companion animals remains unknown in Australia. In this study we conducted antimicrobial susceptibility testing (AST) and where possible, determined potential risk factors for MDR infection among 883 clinical Escherichia coli isolated from dogs (n=514), cats (n=341) and horses (n=28). AST was undertaken for 15 antimicrobial agents according to the Clinical Laboratory Standards Institute (CLSI) guidelines and interpreted using epidemiological cut-off values (ECOFFs) as well as CLSI veterinary and human clinical breakpoints. The AST revealed complete absence of resistance to carbapenems while resistance to amikacin was observed at a low level in isolates from dogs (1.6%) and cats (1.5%) compared to horses (10.7%). Among dog isolates, resistance to fluoroquinolones ranged from 9.1%–9.3% whereas among cat isolates, it ranged from 3.2%–5%. Among dog isolates, the proportion showing a 3rd generation cephalosporin (3GC) non-wild type phenotype was significantly higher (P<0.05) in skin and soft tissue infection (SSTI, n=122) isolates (17.2%–20.5%) compared to urinary tract infection (UTI, n=392) isolates (9.9%–10.2%). The frequency of multidrug resistance was 18.1%, 11.7% and 42.9% in dog, cat and horse isolates, respectively. Risk factor analysis revealed that MDR E. coli isolated from UTI were positively associated with chronicity of infection and previous antimicrobial treatment. Dogs and cats with chronic UTI that had been previously treated with antimicrobials were eight times and six times more likely to be infected with MDR E. coli compared to dogs and cats with non-chronic UTI, and no history of antimicrobial treatment, respectively. This study revealed that pre-existing disease condition and prior antimicrobial use were the major risks associated with UTI with MDR E. coli in companion animals.
Carbapenem-resistant Enterobacteriaceae (CRE) are a pressing public health issue due to limited therapeutic options to treat such infections. CREs have been predominantly isolated from humans and ...environmental samples and they are rarely reported among companion animals. In this study we report on the isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from a companion animal. Carbapenemase-producing S. enterica Typhimurium carrying bla
was identified from a systemically unwell (index) cat and three additional cats at an animal shelter. All isolates were identical and belonged to ST19. Genome sequencing revealed the acquisition of a multidrug-resistant IncHI2 plasmid (pIMP4-SEM1) that encoded resistance to nine antimicrobial classes including carbapenems and carried the bla
-qacG-aacA4-catB3 cassette array. The plasmid also encoded resistance to arsenic (MIC-150 mM). Comparative analysis revealed that the plasmid pIMP4-SEM1 showed greatest similarity to two bla
carrying IncHI2 plasmids from Enterobacter spp. isolated from humans in China. This is the first report of CRE carrying a bla
gene causing a clinical infection in a companion animal, with presumed nosocomial spread. This study illustrates the broader community risk entailed in escalating CRE transmission within a zoonotic species such as Salmonella, and in a cycle that encompasses humans, animals and the environment.
Methicillin-resistant coagulase-positive staphylococci (CoPS) have become increasingly recognised as opportunistic pathogens that limit therapeutic options in companion animals. The frequency of ...methicillin resistance amongst clinical isolates on an Australia-wide level is unknown. This study determined antimicrobial susceptibility patterns for CoPS isolated from clinical infections in companion animals (dogs, cats and horses) as part of the first nation-wide survey on antimicrobial resistance in animal pathogens in Australia for a one-year period (January 2013 to January 2014). Clinical Staphylococcus spp. isolates (n = 888) obtained from 22 veterinary diagnostic laboratories were identified by MALDI-TOF mass spectrometry and subjected to antimicrobial susceptibility testing for 16 antimicrobials, representing 12 antimicrobial classes. Potential risk factors associated with methicillin resistance in Staphylococcus pseudintermedius isolates from dogs were analysed based on demographic factors and clinical history, including gender, age, previous antimicrobial treatment, chronic and/or recurrent diseases and site of infections. The most commonly identified CoPS were S. pseudintermedius (70.8%; dogs n = 616, cats n = 13) and S. aureus (13.2%, horses n = 53, dogs n = 47 and cats n = 17). Overall, the frequency of methicillin resistance among S. pseudintermedius (MRSP) and S. aureus (MRSA) was 11.8% and 12.8%, respectively. MRSP isolates were strongly associated with resistance to fluoroquinolones (OR 287; 95%CI 91.2-1144.8) and clindamycin (OR 105.2, 95%CI 48.5-231.9). MRSA isolates from dogs and cats were also more likely to be resistant to fluoroquinolones (OR 5.4, 95%CI 0.6-252.1), whereas MRSA from horses were more likely to be resistant to rifampicin. In multivariate analysis, MRSP-positive status was significantly associated with particular infection sites, including surgical (OR 8.8; 95%CI 3.74-20.7), and skin and soft tissue (OR 3.9; 95%CI 1.97-7.51). S. pseudintermedius isolated from dogs with surgical site infections were three times more likely to be methicillin-resistant if cases had received prior antimicrobial treatment. Whilst the survey results indicate the proportion of CoPS obtained from Australian companion animals that are methicillin-resistant is currently moderate, the identified risk factors suggest that it could rapidly increase without adequate biosecurity and infection control procedures in veterinary practice.
Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS ...malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C-C chemokine receptor type 2 (CCR2
) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2
HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8
T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2
HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.
The World Health Organisation has defined "highest priority critically important antimicrobials" (CIAs) as those requiring the greatest control during food production. Evidence demonstrating that ...restricted antimicrobial usage prevents the emergence of resistance to CIA's amongst pathogenic and commensal organisms on a production system-wide scale would strengthen international efforts to control antimicrobial resistance (AMR). Therefore, in a designed survey of all major chicken-meat producers in Australia, we investigated the phenotypic AMR of E. coli (n = 206) and Salmonella (n = 53) from caecal samples of chickens at slaughter (n = 200). A large proportion of E. coli isolates (63.1%) were susceptible to all tested antimicrobials. With regards to CIA resistance, only two E.coli isolates demonstrated resistance to fluoroquinolones, attributed to mutations in the quinolone resistance-determining regions of gyrA. Antimicrobial resistance was observed for trimethoprim/sulfamethoxazole (8.7%), streptomycin (9.7%), ampicillin (14.1%), tetracycline (19.4%) and cefoxitin (0.5%). All Salmonella isolates were susceptible to ceftiofur, chloramphenicol, ciprofloxacin, colistin, florfenicol, gentamicin and tetracycline. A low frequency of Salmonella isolates exhibited resistance to streptomycin (1.9%), ampicillin (3.8%), and cefoxitin (11.3%). AMR was only observed among Salmonella Sofia serovars. None of the Salmonella isolates exhibited a multi-class-resistant phenotype. Whole genome sequencing did not identify any known resistance mechanisms for the Salmonella isolates demonstrating resistance to cefoxitin. The results provide strong evidence that resistance to highest priority CIA's is absent in commensal E. coli and Salmonella isolated from Australian meat chickens, and demonstrates low levels of resistance to compounds with less critical ratings such as cefoxitin, trimethoprim/sulfamethoxazole, and tetracycline. Apart from regulated exclusion of CIAs from most aspects of livestock production, vaccination against key bacterial pathogens and stringent biosecurity are likely to have contributed to the favorable AMR status of the Australian chicken meat industry. Nevertheless, industry and government need to proactively monitor AMR and antimicrobial stewardship practices to ensure the long-term protection of both animal and human health.
In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate/severe TII ...develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts.
Data was acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep learning models and other computer vision techniques.
High B cell densities were associated with protection from ESRD. In contrast, CD8, γδ and other CD4-CD8- T cells, were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with T follicular helper cells while CD4- T cells formed small neighborhoods in the tubulointerstitium whose frequency predicted progression to ESRD.
These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease.
These studies were funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083) and Alliance for Lupus Research, NIH S10-OD025081, S10-RR021039, and P30-CA14599 awards.
An influential model of the neural mechanisms of creative thought suggests that creativity is manifested in the joint contributions of the Default Mode Network (DMN; a set of regions in the medial ...PFC, lateral and medial parietal cortex, and the medial temporal lobes) and the executive networks within the dorsolateral PFC. Several empirical reports have offered support for this model by showing that complex interactions between these brain systems account for individual differences in creative performance. The present study examined whether the engagement of these regions in idea generation is modulated by one’s eminence in a creativity-related field. Twenty (n = 20) healthy eminent creators from diverse fields of expertise and a ‘smart’ comparison group of sixteen (n = 16) age- and education-matched non-eminent thinkers were administered a creative generation task (an adaptation of the Alternative Uses Task) and a control perceptual task, while undergoing functional magnetic resonance imaging (fMRI). The participants’ verbal responses were recorded through a noise-canceling microphone and were later coded for fluency and accuracy. Behavioral and fMRI analyses revealed commonalities between groups, but also distinct patterns of activation in default mode and executive brain regions between the eminent and the non-eminent participants during creative thinking. We interpret these findings in the context of the well-documented contributions of these regions in the generation of creative ideas as modulated, in this study, by participants’ creative eminence.
•We examined neural differences in creative thinking between eminent and non-eminent thinkers.•Eminent creators from diverse fields were compared to a ‘smart’ control group.•Eminence was determined based on Creative Achievement Questionnaire scores.•There were no behavioral differences observed in creativity performance.•Eminent creators engaged more temporoparietal and less occipital and prefrontal areas than controls during creativity.
Controlling the use of the most critically important antimicrobials (CIAs) in food animals has been identified as one of the key measures required to curb the transmission of antimicrobial resistant ...bacteria from animals to humans. Expanding the evidence demonstrating the effectiveness of restricting CIA usage for preventing the emergence of resistance to key drugs amongst commensal organisms in animal production would do much to strengthen international efforts to control antimicrobial resistance (AMR). As Australia has strict controls on antimicrobial use in layer hens, and internationally comparatively low levels of poultry disease due to strict national biosecurity measures, we investigated whether these circumstances have resulted in curtailing development of critical forms of AMR. The work comprised a cross-sectional national survey of 62 commercial layer farms with each assessed for AMR in Escherichia coli isolates recovered from faeces. Minimum inhibitory concentration analysis using a panel of 13 antimicrobials was performed on 296 isolates, with those exhibiting phenotypic resistance to fluoroquinolones (a CIA) or multi-class drug resistance (MCR) subjected to whole genome sequencing. Overall, 53.0% of isolates were susceptible to all antimicrobials tested, and all isolates were susceptible to cefoxitin, ceftiofur, ceftriaxone, chloramphenicol and colistin. Resistance was observed for amoxicillin-clavulanate (9.1%), ampicillin (16.2%), ciprofloxacin (2.7%), florfenicol (2.4%), gentamicin (1.0%), streptomycin (4.7%), tetracycline (37.8%) and trimethoprim/sulfamethoxazole (9.5%). MCR was observed in 21 isolates (7.0%), with two isolates exhibiting resistance to four antimicrobial classes. Whole genome sequencing revealed that ciprofloxacin-resistant (fluoroquinolone) isolates were devoid of both known chromosomal mutations in the quinolone resistance determinant regions and plasmid-mediated quinolone resistance genes (qnr)-other than in one isolate (ST155) which carried the qnrS gene. Two MCR E. coli isolates with ciprofloxacin-resistance were found to be carrying known resistance genes including aadA1, dfrA1, strA, strB, sul1, sul2, tet(A), blaTEM-1B, qnrS1 and tet(A). Overall, this study found that E. coli from layer hens in Australia have low rates of AMR, likely due to strict control on antimicrobial usage achieved by the sum of regulation and voluntary measures.
This study investigated the ecology, epidemiology and plasmid characteristics of extended-spectrum cephalosporin (ESC)-resistant E. coli in healthy pigs over a period of 4 years (2013-2016) following ...the withdrawal of ESCs. High carriage rates of ESC-resistant E. coli were demonstrated in 2013 (86.6%) and 2014 (83.3%), compared to 2015 (22%) and 2016 (8.5%). ESC resistance identified among E. coli isolates was attributed to the carriage of an IncI1 ST-3 plasmid (pCTXM1-MU2) encoding bla
. Genomic characterisation of selected E. coli isolates (n = 61) identified plasmid movement into multiple commensal E. coli (n = 22 STs). Major STs included ST10, ST5440, ST453, ST2514 and ST23. A subset of the isolates belong to the atypical enteropathogenic E. coli (aEPEC) pathotype that harboured multiple LEE pathogenic islands. pCTXM1-MU2 was similar (99% nt identity) to IncI1-ST3 plasmids reported from Europe, encoded resistance to aminoglycosides, sulphonamides and trimethoprim, and carried colicin Ib. pCTXM1-MU2 appears to be highly stable and readily transferable. This study demonstrates that ESC resistance may persist for a protracted period following removal of direct selection pressure, resulting in the emergence of ESC-resistance in both commensal E. coli and aEPEC isolates of potential significance to human and animal health.
•No MRSA was detected among bovine mastitis-associated Staphylococcus aureus isolates in Australia.•Over all low levels of antimicrobial resistance was detected. Resistance to only penicillin (12.4%) ...and erythromycin (0.5%) was identified among bovine mastitis-associated S. aureus isolates in Australia.•Most bovine mastitis-associated S. aureus belong to clonal complexes 97, 705, and 1.•Comparative genomic analysis revealed that Australian bovine S. aureus isolates clustering together according to their ST separately from human isolates.•S. aureus ST352 phylogeny provided evidence for geographical clustering of Australian strains into a distinct grouping separate from international bovine isolates.•Australian S. aureus isolates have limited genetic diversity and are genetically distinct from human and international bovine S. aureus isolates.
The aim of this study was to investigate antimicrobial resistance and population structure of bovine mastitis-associated Staphylococcus aureus isolates, and compare them to human isolates obtained from Western Australian hospitals and overseas strains to determine relatedness to human isolates from a zoonotic or reverse zoonotic aspect. Antimicrobial susceptibility testing was performed on 202 S. aureus isolates of which 166 isolates underwent whole genome sequencing. Only resistance to penicillin (12.4%) and erythromycin (0.5%) was identified and of note, no resistance was demonstrated to oxacillin. Genomic characterisation identified 14 multilocus sequence types (STs), with most isolates belonging to clonal complexes 97, 705, and 1. Four distinct clades based on virulence gene composition were identified. The four clades were predominantly ST based, consisting of ST352, ST97, ST81/ST1, and ST705. Core genome comparison of the bovine and human S. aureus isolates demonstrated defined clustering by ST, with the Australian bovine S. aureus isolates clustering together according to their ST separately from human isolates. In addition, a bovine specific cluster comprising Australian ST151 and ST705 isolates, and ST151 isolates from Irish dairy cattle was clearly delineated. Examination of a detailed ST352 phylogeny provided evidence for geographical clustering of Australian strains into a distinct grouping separate from international strains. This study has identified Australian S. aureus isolates have limited genetic diversity and are genetically distinct from human and international bovine S. aureus isolates. Current first line therapies for bovine mastitis in Australian dairy cattle remain appropriate.
PDF
