Primary, allied health, selected specialists, and mental health service utilisation by home care recipients in Australia before and after accessing the care, 2017-2019.

OBJECTIVES: To examine changes in primary, allied health, selected specialists, and mental health service utilisation by older people in the year before and after accessing home care package (HCP) services. METHODS: A retrospective cohort study using the Registry of Senior Australians Historical National Cohort (≥ 65 years old), including individuals accessing HCP services between 2017 and 2019 (N = 109,558), was conducted. The utilisation of general practice (GP) attendances, health assessments, chronic disease management plans, allied health services, geriatric, pain, palliative, and mental health services, subsidised by the Australian Government Medicare Benefits Schedule, was assessed in the 12 months before and after HCP access, stratified by HCP level (1-2 vs. 3-4, i.e., lower vs. higher care needs). Relative changes in service utilisation 12 months before and after HCP access were estimated using adjusted risk ratios (aRR) from Generalised Estimating Equation Poisson models. RESULTS: Utilisation of health assessments (7-10.2%), chronic disease management plans (19.7-28.2%), and geriatric, pain, palliative, and mental health services (all ≤ 2.5%) remained low, before and after HCP access. Compared to 12 months prior to HCP access, 12 months after, GP after-hours attendances increased (HCP 1-2 from 6.95 to 7.5%, aRR = 1.07, 95% CI 1.03-1.11; HCP 3-4 from 7.76 to 9.32%, aRR = 1.20, 95%CI 1.13-1.28) and allied health services decreased (HCP 1-2 from 34.8 to 30.7%, aRR = 0.88, 95%CI 0.87-0.90; HCP levels 3-4 from 30.5 to 24.3%, aRR = 0.80, 95%CI 0.77-0.82). CONCLUSIONS: Most MBS subsidised preventive, management and specialist services are underutilised by older people, both before and after HCP access and small changes are observed after they access HCP.

Primary health care service utilisation before and after entry into long-term care in Australia.

OBJECTIVES: To examine utilisation of primary health care services (subsidised by the Australian Government, Medicare Benefits Schedule, MBS) before and after entry into long-term care (LTC) in Australia. METHODS: A retrospective cohort study of older people (aged ≥65 years) who entered LTC in Australia between 2012 and 2016 using the Historical Cohort of the Registry of Senior Australians. MBS-subsidised general attendances (general practitioner (GP), medical and nurse practitioners), health assessment and management plans, allied health, mental health services and selected specialist attendances accessed in 91-day periods 12 months before and after LTC entry were examined. Adjusted relative changes in utilisation 0-3 months before and after LTC entry were estimated using risk ratios (RR) calculated using Generalised Estimating Equation Poisson models. RESULTS: 235,217 residents were included in the study with a median age of 84 years (interquartile range 79-89) and 61.1% female. In the first 3 months following LTC entry, GP / medical practitioner attendances increased from 86.6% to 95.6% (aRR 1.10 95%CI 1.10-1.11), GP / medical practitioner urgent after hours (from 12.3% to 21.1%; aRR 1.72, 95%CI 1.70-1.74) and after-hours attendances (from 18.5% to 33.8%; aRR 1.83, 95%CI 1.81-1.84) increased almost two-fold. Pain, palliative and geriatric specialist medicine attendances were low in the 3 months prior (<3%) and decreased further following LTC admission. CONCLUSION: There is an opportunity to improve the utilisation of primary health care services following LTC entry to ensure that residents' increasingly complex care needs are adequately met.

Preventing empirical antibiotic treatment failure in migrant populations: screening by infection risk, not ethnic background.

Multidrug-resistant organisms (MDROs) are a major international health threat. In many low and middle-income countries poorly regulated antibiotic use, limited surveillance, and inadequate sanitation give rise to high rates of antibiotic resistance. A resulting reliance on last-line antibiotic options further contributes to the emergence of MDROs. The potential for these pathogens to spread across international borders is a matter of considerable concern. However, this problem is commonly framed as primarily a threat to the health security of countries where resistance is not yet endemic. In fact, it is little acknowledged that those at greatest risk from antibiotic treatment failure are individuals who move from regions of high MDRO prevalence to settings where standard empirical treatment options remain largely effective. In this perspective, we highlight the poor treatment outcomes for disseminated bacterial infections in individuals who have moved from settings in which MDROs are common to those where MDROs are currently less common. We discuss MDRO screening strategies that could avoid stigmatizing vulnerable populations by focusing on future risk of disseminated infection, rather than past risk of acquisition. In practical terms, this means screening individuals before childbirth, immunosuppressive treatments, major surgery, or other events associated with disseminated infection risk, rather than prioritizing screening for individuals from regions with high carriage rates. We argue that such measures would reduce antibiotic treatment failure and improve outcomes while protecting migrant populations from the divisive consequences of targeted screening programs.

Primary, allied health, geriatric, pain and palliative healthcare service utilisation by aged care residents, 2012-2017.

OBJECTIVES: To examine the incidence and trends in primary care, allied health, geriatric, pain and palliative care service use by permanent residential aged care (PRAC) residents and the older Australian population. METHODS: Repeated cross-sectional analyses on PRAC residents (N = 318,484) and the older (≥65 years) Australian population (N ~ 3.5 million). Outcomes were Medicare Benefits Schedule (MBS) subsidised primary care, allied health, geriatric, pain and palliative services between 2012-13 and 2016-17. GEE Poisson models estimated incidence rates and incidence rate ratios (IRR). RESULTS: In 2016-17, PRAC residents had a median of 13 (interquartile range [IQR] 5-19) regular general medical practitioner (GP) attendances, 3 (IQR 1-6) after-hours attendances and 5% saw a geriatrician. Highlights of utilisation changes from 2012-13 to 2016-17 include the following: GP attendances increased by 5%/year (IRR = 1.05, 95% confidence interval [CI] 1.05-1.05) for residents compared to 1%/year (IRR = 1.01, 95%CI 1.01-1.01) for the general population. GP after-hours attendances increased by 15%/year (IRR = 1.15, 95%CI 1.14-1.15) for residents and 9%/year (IRR = 1.08, 95%CI 1.07-1.20) for the general population. GP management plans increased by 12%/year (IRR = 1.12, 95%CI 1.11-1.12) for residents and 10%/year (IRR = 1.10, 95%CI 1.09-1.11) for the general population. Geriatrician consultations increased by 28%/year (IRR = 1.28, 95%CI 1.27-1.29) for residents compared to 14%/year (IRR = 1.14, 95%CI 1.14-1.15) in the general population. CONCLUSIONS: The utilisation of most examined services increased in both cohorts over time. Preventive and management care, by primary care and allied health care providers, was low and likely influences the utilisation of other attendances. PRAC residents' access to pain, palliative and geriatric medicine services is low and may not address the residents' needs.

Quality and safety in residential aged care: an evaluation of a national quality indicator programme.

BACKGROUND: In Australia, 243 000 individuals live in approximately 2700 residential aged care facilities yearly. In 2019, a National Aged Care Mandatory Quality Indicator programme (QI programme) was implemented to monitor the quality and safety of care in facilities. AIM: To examine the validity of the QI programme indicators using explicit measure review criteria. METHODS: The QI programme manual and reports were reviewed. A modified American College of Physicians Measure Review Criteria was employed to examine the QI programme's eight indicators. Five authors rated each indicator on importance, appropriateness, clinical evidence, specifications and feasibility using a nine-point scale. A median score of 1-3 was considered to not meet criteria, 4-6 to meet some criteria and 7-9 to meet criteria. RESULTS: All indicators, except polypharmacy, met criteria (median scores = 7-9) for importance, appropriateness and clinical evidence. Polypharmacy met some criteria for importance (median = 6, range 2-8), appropriateness (median = 5, range 2-8) and clinical evidence (median = 6, range 3-8). Pressure injury, physical restraints, significant unplanned weight loss, consecutive unplanned weight loss, falls and polypharmacy indicators met some criteria for specifications validity (all median scores = 5) and feasibility and applicability (median scores = 4 to 6). Antipsychotic use and falls resulting in major injury met some criteria for specifications (median = 6-7, range 4-8) and met criteria for feasibility and applicability (median = 7, range 4-8). CONCLUSIONS: Australia's National QI programme is a major stride towards a culture of quality promotion, improvement and transparency. Measures' specifications, feasibility and applicability could be improved to ensure the programme delivers on its intended purposes.

An eye to the future: Acute and long-term neuro-ophthalmological and neurological complications of COVID-19.

COVID-19 has had a significant impact on the global population and has produced compelling evidence of non-pulmonary organ dysfunction, including the nervous system. It is vital that specialists in ophthalmology and neurology are informed of the potential complications of COVID-19 and gain a deeper understanding of how COVID-19 can cause diseases of the nervous system. In this review we detail four possible mechanisms by which COVID-19 infection may result in neurological or neuro-ophthalmological complications: (1) Toxic and metabolic effects of severe pulmonary COVID-19 disease on the neural axis including hypoxia and the systemic hyper-inflammatory state, (2) endothelial dysfunction, (3) dysimmune responses directed again the neuroaxis, and (4) direct neuro-invasion and injury by the virus itself. We explore the pathological evidence for each of these and how they may link to neuro-ophthalmological disorders. Finally, we explore the evidence for long-term neurological and neuro-ophthalmological complications of COVID-19, with a focus on neurodegeneration.

Conventional myelosuppressive chemotherapy for non-haematological malignancy disrupts the intestinal microbiome.

BACKGROUND: The gut microbiota influences many aspects of host physiology, including immune regulation, and is predictive of outcomes in cancer patients. However, whether conventional myelosuppressive chemotherapy affects the gut microbiota in humans with non-haematological malignancy, independent of antibiotic exposure, is unknown. METHODS: Faecal samples from 19 participants with non-haematological malignancy, who were receiving conventional chemotherapy regimens but not antibiotics, were examined prior to chemotherapy, 7-12 days after chemotherapy, and at the end of the first cycle of treatment. Gut microbiota diversity and composition was determined by 16S rRNA gene amplicon sequencing. RESULTS: Compared to pre-chemotherapy samples, samples collected 7-12 days following chemotherapy exhibited increased richness (mean 120 observed species ± SD 38 vs 134 ± 40; p = 0.007) and diversity (Shannon diversity: mean 6.4 ± 0.43 vs 6.6 ± 0.41; p = 0.02). Composition was significantly altered, with a significant decrease in the relative abundance of gram-positive bacteria in the phylum Firmicutes (pre-chemotherapy median relative abundance [IQR] 0.78 [0.11] vs 0.75 [0.11]; p = 0.003), and an increase in the relative abundance of gram-negative bacteria (Bacteroidetes: median [IQR] 0.16 [0.13] vs 0.21 [0.13]; p = 0.01 and Proteobacteria: 0.015 [0.018] vs 0.03 [0.03]; p = 0.02). Differences in microbiota characteristics from baseline were no longer significant at the end of the chemotherapy cycle. CONCLUSIONS: Conventional chemotherapy results in significant changes in gut microbiota characteristics during the period of predicted myelosuppression post-chemotherapy. Further study is indicated to link microbiome changes during chemotherapy to clinical outcomes.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota.

Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota. Germ-free or antibiotic-treated mice have significantly reduced colitis, CRS, and liver damage following IAA treatment compared with conventional mice or germ-free mice recolonized via fecal microbiota transplant. MyD88 signaling is required for IAA-induced CRS and for anti-CD137-induced, but not anti-CD40-induced, liver damage. Importantly, antibiotic treatment does not impair IAA anti-tumor efficacy, alone or in combination with anti-PD1. Our results suggest that microbiota-targeted therapies could overcome the toxicity induced by IAAs without impairing their anti-tumor activity.

Utilisation of general practice health assessments around an aged care assessment is associated with lower mortality risk in older Australians.

OBJECTIVE: (i) to describe the general practitioner utilisation of health assessments, management plans, coordination of team care arrangements and medication review item numbers within 6 months of an aged care eligibility assessment for home care packages (HCP) and (ii) investigate the impact of health assessments on the risk of mortality and entry into permanent residential aged care (PRAC) of individuals accessing HCP. DESIGN AND SETTING: retrospective cohort study utilising data from the Registry of Senior Australians (ROSA) was conducted. SUBJECTS: 75,172 individuals aged ≥75 years who received HCP between 2011 and 2015. OUTCOME MEASURE: for objective 1: the use of comprehensive assessments (Medicare Benefits Schedule (MBS) items 705 or 707), management plans (MBS 721), coordination of team care arrangements (MBS 723), and medication reviews (MBS 900). For objective 2: time to death and entry into PRAC. RESULTS: of the 75,172 individuals, 28.2% (95% confidence interval (CI): 27.8-8.5%) had comprehensive assessments, 36.7% (95% CI: 36.3-37.0%) had management plans, 33.0% (95% CI: 32.7-33.3%) received coordination of team care arrangements and 5.4% (95% CI: 5.2-5.5%) had medication reviews. Individuals with a comprehensive assessment had a 5% lower risk of mortality (adjusted hazard ratio (aHR), 95% CI = 0.95, 0.92-0.98) but 5% higher risk of transition to PRAC (adjusted subdistribution HRs, 95% CI = 1.05, 1.02-1.08) compared to those who did not have these services. CONCLUSION: the utilisation of health assessments was associated with a lower risk of mortality. There is an opportunity for increased use of item numbers in frailer individuals.

The cystic fibrosis gut as a potential source of multidrug resistant pathogens.

BACKGROUND: The emergence of multidrug resistant (MDR) pathogens represents a profound threat to global health. Individuals with CF have amongst the highest cumulative antibiotic exposure of any patient group, including to critically-important last-line agents. While there is little evidence that antibiotic resistance in airway pathogens results in worse clinical outcomes for CF patients, the potential emergence of MDR pathogens in non-respiratory systems, as a consequence of CF care, represents a potential health threat to the wider population, including family and carers. METHODS: Stool from 19 adults with CF and 16 healthy adult controls was subjected to metagenomic sequencing, to assess faecal resistome, and culture-based analysis. Resistant isolates were identified phenotypically, and genetic determinants of resistance characterised by whole genome sequencing. RESULTS: CF and control faecal resistomes differed significantly (P = 0.0003). The proportion of reads that mapped to mobile genetic elements was significantly higher in CF (P = 0.014) and the composition was significantly different (P = 0.0001). Notably, CF patients displayed higher carriage of plasmid-mediated aminoglycoside-modifying genes ant(6)-Ib, aac(6')-Ip, and aph(3')-IIIa (P < 0.01). Culture-based analysis supported higher aminoglycoside resistance, with a higher proportion of aminoglycoside-resistant, Gram-negative bacteria (P < 0.0001). Isolated extended spectrum beta lactamase (ESBL)-positive Escherichia coli from CF stool exhibited phenotypic resistance to tobramycin and gentamicin. Genomic analysis showed co-localisation of both aminoglycoside resistance and ESBL genes, consistent with MDR emergence through horizontal gene transfer. CONCLUSIONS: The carriage of potentially transmissible resistance within the adult CF gut microbiome is considerably greater than in healthy individuals and could contribute to the emergence and dissemination of MDR pathogens.

General practitioner conduct of clinical services representing comprehensive geriatric assessment is associated with lower risk of mortality in older Australians receiving home care packages.

OBJECTIVES: The purpose of this paper is to investigate the utilisation of general practice Medicare Benefit Schedule (MBS) services aligned to Comprehensive Geriatric Assessment (CGA) within 6 months of an aged care eligibility assessment and its effects on mortality and transition to permanent residential aged care (PRAC). DESIGN: Retrospective cohort study from the Historical Cohort of the Registry of Senior Australians. SETTING: Community. PARTICIPANTS: In total, 69,171 Individuals (aged 75+) receiving home care packages (HCPs) between 2011 and 2015. OUTCOME MEASURES: Mortality and transition to PRAC. RESULTS: The claims for a management plan with team care arrangement (TCA) within 3 months of the health assessment (i.e. CGA) was present in 5% and associated with 14% lower mortality (adjusted hazard ratio [aHR], 95%CI = 0.86, 0.80-0.93) compared to no claims, lower than that seen with partial CGA which was either health assessment claims only 7.0% (aHR, 95%CI = 0.93, 0.89-0.97) or management plan coupled with TCA claims only 9.0% (aHR, 95%CI = 0.91, 0.89-0.97). This pattern was seen in those frailer but not in those where the frailty index score was <0.21. Claims for management plans coupled with TCAs alone were associated with a 10% lower transition to PRAC (asHR, 95%CI = 0.90, 0.85-0.96) in those with FI score < 0.21 while this estimate was not significant in individuals with FI score ≥ 0.21. CONCLUSION: It appears the conduct of a combination of interventions considered to be components of the CGA by GPs was associated with a lower risk of mortality that no claims or partial conduct of CGA.

Intestinal microbiology shapes population health impacts of diet and lifestyle risk exposures in Torres Strait Islander communities.

Poor diet and lifestyle exposures are implicated in substantial global increases in non-communicable disease burden in low-income, remote, and Indigenous communities. This observational study investigated the contribution of the fecal microbiome to influence host physiology in two Indigenous communities in the Torres Strait Islands: Mer, a remote island where a traditional diet predominates, and Waiben a more accessible island with greater access to takeaway food and alcohol. Counterintuitively, disease markers were more pronounced in Mer residents. However, island-specific differences in disease risk were explained, in part, by microbiome traits. The absence of Alistipes onderdonkii, for example, significantly (p=0.014) moderated island-specific patterns of systolic blood pressure in multivariate-adjusted models. We also report mediatory relationships between traits of the fecal metagenome, disease markers, and risk exposures. Understanding how intestinal microbiome traits influence response to disease risk exposures is critical for the development of strategies that mitigate the growing burden of cardiometabolic disease in these communities.

Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterised by reduced airway clearance, microbial accumulation, inflammation, and lung function decline. Certain bacterial species may contribute disproportionately to worsening lung disease. However, the relative importance of these microorganisms compared to the absolute abundance of all bacteria is uncertain. We aimed to identify the characteristics of lower airway microbiology that best reflect CF airway inflammation and disease in children. METHODS: Analysis was performed on bronchoalveolar lavage (BAL) fluid from 78 participants of the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial, aged 4.5-5.5 years. Universal bacterial quantitative PCR (qPCR), species-specific qPCR, and 16S rRNA gene sequencing were performed on DNA extracts to determine total bacterial load, species-specific load and taxa relative abundance. Quantification of pre-specified pathogens was performed by culture-based methods. Bacteriological data were related to neutrophil counts, interleukin-8, lung function, and two computed-tomography based measures, CF-CT (as the primary measure) and PRAGMA. RESULTS: Of all bacteriological measures assessed, total bacterial load determined by qPCR correlated most strongly with structural disease (CF-CT total score, rs=0.30, P=0.0095). Specifically, total bacterial load correlated with bronchiectasis, airway wall thickening, mucus plugging and parenchymal disease sub-scores. In contrast, culture-based quantification, microbiota-derived measures, and pathogen-specific qPCR-based quantification were weakly associated with total CF-CT. Regression analyses supported correlation findings, with total bacterial load explaining the greatest variance in total CF-CT (R2=0.097, P=0.0061). Correlations with PRAGMA score were comparable to CF-CT total score. CONCLUSIONS: Within the ACFBAL trial, culture-independent quantification of total bacteria provided the most clinically-informative bacteriological measure in 5-year-old CF patients.

Improving Risk-Benefit in Faecal Transplantation through Microbiome Screening.

Faecal microbiota transplantation (FMT) has been shown to be effective in the treatment of a growing number of conditions, and its clinical use continues to rise. However, recent cases of antibiotic-resistant pathogen transmission through FMT, resulting in at least one case of fatal sepsis, highlight the need to reevaluate current donor screening practices. Commensal gut microbes profoundly influence infection risk but are not routinely assessed in donor stool. Extending the assessment of donor material beyond pathogen populations to include the composition and structure of the wider faecal microbiota has the potential to reduce infectious complications in FMT recipients.

Opportunistic bacteria confer the ability to ferment prebiotic starch in the adult cystic fibrosis gut.

Chronic disruption of the intestinal microbiota in adult cystic fibrosis (CF) patients is associated with local and systemic inflammation, and has been linked to the risk of serious comorbidities. Supplementation with high amylose maize starch (HAMS) might provide clinical benefit by promoting commensal bacteria and the biosynthesis of immunomodulatory metabolites. However, whether the disrupted CF gut microbiota has the capacity to utilise these substrates is not known. We combined metagenomic sequencing, in vitro fermentation, amplicon sequencing, and metabolomics to define the characteristics of the faecal microbiota in adult CF patients and assess HAMS fermentation capacity. Compared to healthy controls, the faecal metagenome of adult CF patients had reduced bacterial diversity and prevalence of commensal fermentative clades. In vitro fermentation models seeded with CF faecal slurries exhibited reduced acetate levels compared to healthy control reactions, but comparable levels of butyrate and propionate. While the commensal genus Faecalibacterium was strongly associated with short chain fatty acid (SCFA) production by healthy microbiota, it was displaced in this role by Clostridium sensu stricto 1 in the microbiota of CF patients. A subset of CF reactions exhibited enterococcal overgrowth, resulting in lactate accumulation and reduced SCFA biosynthesis. The addition of healthy microbiota to CF faecal slurries failed to displace predominant CF taxa, or substantially influence metabolite biosynthesis. Despite significant microbiota disruption, the adult CF gut microbiota retains the capacity to exploit HAMS. Our findings highlight the potential for taxa associated with the altered CF gut microbiotato mediate prebiotic effects in microbial systems subject to ongoing perturbation, irrespective of the depletion of common commensal clades.

Measuring research impact: a large cancer research funding programme in Australia.

BACKGROUND: Measuring research impact is of critical interest to philanthropic and government funding agencies interested in ensuring that the research they fund is both scientifically excellent and has meaningful impact into health and other outcomes. The Beat Cancer Project (BCP) is a AUD $34 m cancer research funding scheme that commenced in 2011. It was initiated by an Australian charity (Cancer Council SA), and supported by the South Australian Government and the state's major universities. METHODS: This study applied Buxton and Hanney's Payback Framework to assess research impact generated from the BCP after 3 years of funding. Data sources were an audit of peer-reviewed publications from January 2011 to September 2014 from Web of Knowledge and a self-report survey of investigators awarded BCP research funding during its first 3 years of implementation (2011-2013). Of the 104 surveys, 92 (88%) were completed. RESULTS: The BCP performed well across all five categories of the Payback Framework. In terms of knowledge production, 1257 peer-reviewed publications were generated and the mean impact factor of publishing journals increased annually. There were many benefits to future research with 21 respondents (23%) reporting career advancement, and 110 higher degrees obtained or expected (including 84 PhDs). Overall, 52% of funded projects generated tools for future research. The funded research attracted substantial further income yielding a very high rate of leverage. For every AUD $1 that the cancer charity invested, the BCP gained an additional AUD $6.06. Five projects (5%) had informed policy and 5 (5%) informed product development, with an additional 31 (34%) and 35 (38%) projects, respectively, anticipating doing so. In terms of health and sector and broader economic benefits, 8 (9%) projects had influenced practice or behaviour of health staff and 32 (34%) would reportedly to do so in the future. CONCLUSIONS: Research impact was a priority of charity and government funders and led to a deliberate funding strategy. Emphasising research impact while maintaining rigorous, competitive processes can achieve the joint objectives of excellence in research, yielding good research impact and a high rate of leverage for philanthropic and public investment, as indicated by these early results.

Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.

Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae (P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae (P = 0.024) and Actinomyces odontolyticus (P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. (P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm(A), erm(B), erm(C), erm(F), mef(A/E), and msrA macrolide resistance genes. However, the abundance of erm(B) and mef(A/E) gene copies within carriers who had received erythromycin increased significantly (P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance.IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.

Not Just Antibiotics: Is Cancer Chemotherapy Driving Antimicrobial Resistance?

The global spread of antibiotic-resistant pathogens threatens to increase the mortality of cancer patients significantly. We propose that chemotherapy contributes to the emergence of antibiotic-resistant bacteria within the gut and, in combination with antibiotics, drives pathogen overgrowth and translocation into the bloodstream. In our model, these processes are mediated by the effects of chemotherapy on bacterial mutagenesis and horizontal gene transfer, the disruption of commensal gut microbiology, and alterations to host physiology. Clinically, this model manifests as a cycle of recurrent sepsis, with each episode involving ever more resistant organisms and requiring increasingly broad-spectrum antimicrobial therapy. Therapies that restore the gut microbiota following chemotherapy or antibiotics could provide a means to break this cycle of infection and treatment failure.

FUT2 genotype influences lung function, exacerbation frequency and airway microbiota in non-CF bronchiectasis.

OBJECTIVE: To assess whether FUT2 (secretor) genotype affects disease severity and airway infection in patients with non-cystic fibrosis bronchiectasis. PARTICIPANTS: Induced sputum samples were obtained from 112 adult patients with high-resolution CT scan-proven bronchiectasis and at least two exacerbations in the previous year, as part of an unrelated randomised control trial. OUTCOME MEASURES: Presence of null FUT2 polymorphisms were determined by gene sequencing and verified by endobronchial biopsy histochemical staining. Outcome measures were FEV1% predicted, exacerbation frequency, and bacterial, fungal and viral components of the microbiota (measured by culture independent approaches). RESULTS: Patients were grouped by FUT2 loss-of-function genotype; categorised as non-secretors (n=27, sese), heterozygous secretors (n=54, Sese) or homozygous secretors (n=31, SeSe). FEV1% was significantly lower in SeSe patients compared with sese patients (mean 61.6 (SD 20.0) vs 74.5 (18.0); p=0.023). Exacerbation frequency was significantly higher in SeSe (mean count 5.77) compared with sese (4.07; p=0.004) and Sese (4.63; p=0.026) genotypes. The time until first exacerbation was significantly shorter in SeSe compared with Sese (HR=0.571 (95% CI 0.343 to 0.950); p=0.031), with a similar trend for sese patients (HR=0.577 (0.311 to 1.07); p=0.081). sese had a significantly reduced frequency of Pseudomonas aeruginosa-dominated airway infection (8.7%) compared with Sese (31%; p=0.042) and SeSe (36%; p=0.035). In contrast, fungal, viral and non-dominant bacterial components of the microbiome were not significantly different between FUT2 genotypes. CONCLUSIONS: FUT2 genotype in patients with non-cystic fibrosis bronchiectasis was significantly associated with disease outcomes, with homozygous secretors exhibiting lower lung function, higher exacerbation number and a higher frequency of P. aeruginosa-dominated infection. TRIAL REGISTRATION NUMBER: ACTRN12609000578202 (anzctr.org.au); Pre-results.

Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.