A tale of 2 digital hospitals: A qualitative study of antimicrobial stewardship teams.

AIMS: We aim to examine and understand the work processes of antimicrobial stewardship (AMS) teams across 2 hospitals that use the same digital intervention, and to identify the barriers and enablers to effective AMS in each setting. METHODS: Employing a contextual inquiry approach informed by the Systems Engineering Initiative for Patient Safety (SEIPS) model, observations and semistructured interviews were conducted with AMS team members (n = 15) in 2 Australian hospitals. Qualitative data analysis was conducted, mapping themes to the SEIPS framework. RESULTS: Both hospitals utilized similar systems, however, they displayed variations in AMS processes, particularly in postprescription review, interdepartmental AMS meetings and the utilization of digital tools. An antimicrobial dashboard was available at both hospitals but was utilized more at the hospital where the AMS team members were involved in the dashboard's development, and there were user champions. At the hospital where the dashboard was utilized less, participants were unaware of key features, and interoperability issues were observed. Establishing strong relationships between the AMS team and prescribers emerged as key to effective AMS at both hospitals. However, organizational and cultural differences were found, with 1 hospital reporting insufficient support from executive leadership, increased prescriber autonomy and resource constraints. CONCLUSION: Organizational and cultural elements, such as executive support, resource allocation and interdepartmental relationships, played a crucial role in achieving AMS goals. System interoperability and user champions further promoted the adoption of digital tools, potentially improving AMS outcomes through increased user engagement and acceptance.

Idiopathic granulomatous mastitis: case series and clinical review.

Idiopathic granulomatous mastitis is a chronic inflammatory breast disorder that typically affects young, parous women, often following lactation. Patients present with tender, erythematous breast lesions with histological evidence of non-caseating granulomata and an inflammatory cell infiltrate. An immune-mediated pathophysiology is hypothesised and an association with lipophilic Corynebacterium species is observed. Initial diagnosis is often delayed due to lack of awareness of the condition and management of refractory disease can be challenging. We present an extensive case series of patients collaboratively managed by subspecialty physicians and surgeons at a single centre in Sydney, Australia. The accompanying review expands on features of this condition and supports the utility of a multidisciplinary approach.

Antimicrobial stewardship audit and feedback rounds: the impact of electronic systems and moving beyond the restricted antibiotic list.

BACKGROUND: Current methods of antimicrobial usage surveillance have limited efficacy in changing practice due to delayed reporting to clinicians and the inability to stratify by medical specialty. This study was undertaken in a tertiary teaching hospital with a well established antimicrobial stewardship (AMS) programme and electronic medicines management (eMM) system in Sydney, Australia. AIMS: To describe and analyse the implementation of a novel AMS audit and feedback method, in the context of an eMM system. METHODS: The AMS team conducted the audit weekly, and the study design was a prospective, observational study. All acute, adult inpatients were included in this intervention. All active systemic antimicrobial prescriptions on the day of the rounds were included. RESULTS: The prevalence of patients on antimicrobial therapy was 37%. The median time taken per round was 44 min for eMM compared to 58 min for paper. All key performance indicators improved over the study period. Appropriateness compared to guidelines increased from 55% to 71%, and documentation of an indication increased from 75% to 98%. There were 1413 recommendations made, with the most common being to cease an antimicrobial agent. The recommendation uptake rate was 47% at 24 h post-round. CONCLUSIONS: AMS rounds are an effective tool for auditing and providing feedback on antimicrobial use and should include all antimicrobials rather than solely 'restricted' agents. These rounds had a high uptake rate, improvements in the appropriateness of antimicrobial use, and a planned duration or review date. A benefit of eMM was improvement in the documentation of indication for antimicrobial agents, and reduced time taken to audit.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation.

OBJECTIVE: BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. APPROACH AND RESULTS: Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 µM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (µm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. CONCLUSIONS: BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190.

Healthcare-acquired infections: prevention strategies.

Healthcare-acquired infections (HAI) impact on patient care and have cost implications for the Australian healthcare system. The management of HAI is exacerbated by rising rates of antimicrobial resistance (AMR). Health-care workers and a contaminated hospital environment are increasingly implicated in the transmission and persistence of multi-resistant organisms (MRO), as well as other pathogens, such as Clostridium difficile. This has resulted in a timely focus on a range of HAI prevention actions. Core components include antimicrobial stewardship, to reduce overuse and ensure evidence-based antimicrobial use; infection prevention strategies, to control MRO - particularly methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE) and, more recently, multi-resistant Gram-negative bacteria; enhanced institutional investment in hand hygiene; hospital cleaning and disinfection; and the development of prescribing guidelines and standards of care. AMR surveillance and comparisons of prescribing are useful feedback activities once effectively communicated to end users. Successful implementation of these strategies requires cultural shifts at local hospital level and, to tackle the serious threat posed by AMR, greater co-ordination at a national level. HAI prevention needs to be multi-modal, requires broad healthcare collaboration, and the strong support and accountability of all medical staff.

Genomic Epidemiology of Clostridium botulinum Isolates from Temporally Related Cases of Infant Botulism in New South Wales, Australia.

Infant botulism is a potentially life-threatening paralytic disease that can be associated with prolonged morbidity if not rapidly diagnosed and treated. Four infants were diagnosed and treated for infant botulism in NSW, Australia, between May 2011 and August 2013. Despite the temporal relationship between the cases, there was no close geographical clustering or other epidemiological links. Clostridium botulinum isolates, three of which produced botulism neurotoxin serotype A (BoNT/A) and one BoNT serotype B (BoNT/B), were characterized using whole-genome sequencing (WGS). In silico multilocus sequence typing (MLST) found that two of the BoNT/A-producing isolates shared an identical novel sequence type, ST84. The other two isolates were single-locus variants of this sequence type (ST85 and ST86). All BoNT/A-producing isolates contained the same chromosomally integrated BoNT/A2 neurotoxin gene cluster. The BoNT/B-producing isolate carried a single plasmid-borne bont/B gene cluster, encoding BoNT subtype B6. Single nucleotide polymorphism (SNP)-based typing results corresponded well with MLST; however, the extra resolution provided by the whole-genome SNP comparisons showed that the isolates differed from each other by >3,500 SNPs. WGS analyses indicated that the four infant botulism cases were caused by genomically distinct strains of C. botulinum that were unlikely to have originated from a common environmental source. The isolates did, however, cluster together, compared with international isolates, suggesting that C. botulinum from environmental reservoirs throughout NSW have descended from a common ancestor. Analyses showed that the high resolution of WGS provided important phylogenetic information that would not be captured by standard seven-loci MLST.

Yeast identification algorithm based on use of the Vitek MS system selectively supplemented with ribosomal DNA sequencing: proposal of a reference assay for invasive fungal surveillance programs in China.

Sequence analysis of the internal transcribed spacer (ITS) region was employed as the gold standard method for yeast identification in the China Hospital Invasive Fungal Surveillance Net (CHIF-NET). It has subsequently been found that matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is potentially a more practical approach for this purpose. In the present study, the performance of the Vitek MS v2.0 system for the identification of yeast isolates collected from patients with invasive fungal infections in the 2011 CHIF-NET was evaluated. A total of 1,243 isolates representing 31 yeast species were analyzed, and the identification results by the Vitek MS v2.0 system were compared to those obtained by ITS sequence analysis. By the Vitek MS v2.0 system, 96.7% (n = 1,202) of the isolates were correctly assigned to the species level and 0.2% (n = 2) of the isolates were identified to the genus level, while 2.4% (n = 30) and 0.7% (n = 9) of the isolates were unidentified and misidentified, respectively. After retesting of the unidentified and misidentified strains, 97.3% (n = 1,209) of the isolates were correctly identified to the species level. Based on these results, a testing algorithm that combines the use of the Vitek MS system with selected supplementary ribosomal DNA (rDNA) sequencing was developed and validated for yeast identification purposes. By employing this algorithm, 99.7% (1,240/1,243) of the study isolates were accurately identified with the exception of two isolates of Candida fermentati and one isolate of Cryptococcus gattii. In conclusion, the proposed identification algorithm could be practically implemented in strategic programs of fungal infection surveillance.

A tale of two studies: is peripheral eosinophilia associated with Dientamoeba fragilis detection in adult stool samples?

The protozoan parasite Dientamoeba fragilis is a frequently isolated stool organism and postulated cause of gastrointestinal symptoms. Peripheral blood eosinophilia has been described. This is the first study amongst the Australasian adult population to assess the relationship between organism detection and eosinophilia. A case-control study took place over 7 years at a single Sydney laboratory site, evaluating patients with D. fragilis identified on stool using real-time PCR with a recent full blood count, to control groups with Giardia spp. and sequential negatives with neither organism. A nested study compared those with microscopic evidence of D. fragilis as a marker of disease burden, to molecular diagnosis alone. Sixty-four D. fragilis, 30 Giardia spp., and 94 sequential controls were enrolled. Only 60.1% of samples were preserved in sodium acetate-acetic acid formalin (SAF) fixative, indication mostly not documented. The major co-organism detected amongst all participants was Blastocystis sp., particularly in the D. fragilis cohort (37.2%). The most common pathogen amongst sequential controls was Campylobacter spp. (7.4%). Patients with D. fragilis were more likely (12.5%) to have a clinically significant eosinophilia (>0.5×109/L) compared to those with Giardia spp. (3.3%) or sequential controls (4.3%) (p=0.03). A significant difference was also noted in the overall median eosinophil count of those with D. fragilis versus all controls (0.2 vs 0.1×109/L, p=0.01); however, this was within the reference interval (where up to >0.5×109/L is accepted in healthy individuals within a typical population). No eosinophil difference was found between those with molecular versus additional microscopic detection of D. fragilis (0.1 vs 0.1×109/L). These results support an association between the identification of clinically significant peripheral blood eosinophilia and D. fragilis presence, which may impact the diagnostic approach to the patient with unexplained eosinophilia. Further prospective trials may help assess any significance further and the implication of co-carriage with other enteric organisms. The importance of clinical indication and need for appropriate fixative media in diagnostic parasitology are also highlighted.

Dientamoeba fragilis: a family cluster of disease associated with marked peripheral eosinophilia.

Dientamoeba fragilis has emerged as an important and underrecognized cause of gastrointestinal illness. We report a familial cluster of D. fragilis associated with marked peripheral eosinophilia and gastrointestinal symptoms. Dientamoeba fragilis infection should be considered in the setting of unexplained eosinophilia. If confirmed, screening of household members should be considered.

Gauge against the machine: revisiting quality for multi-targeted serology platforms.

Diagnosis of infections of public health significance, such as leptospirosis, often present challenges for laboratories. To counter common challenges and ensure quality driven health responses, rigorous validation and verification processes are required. Despite such rigor, however, can one be certain laboratory reports are truly reflective of infection, given the risk of rare, but potentially very significant quality oversights? Here we present a real-world scenario where diagnosis of leptospirosis cases was compromised over a 6-year period despite quality measures suggesting a well performing serological assay. A subsequent investigation revealed this was attributed to the programming of an automated microtitration plate analyser, evading detection by both quality control and external quality assurance processes. The quality oversight provides insight into potential limitations in quality processes in multi-targeted serological platforms.

Antimicrobial Stewardship (AMS) During COVID-19: Eyes and Ears on the AMS Team.

Antimicrobial stewardship (AMS) programs in hospitals comprise coordinated strategies to optimise antimicrobial use. The COVID-19 pandemic had a significant impact on the healthcare system, including AMS. This study aimed to understand the work processes of AMS teams during COVID-19 hospital restrictions and the role technology played in supporting AMS. Observations and interviews were conducted with AMS teams at two hospitals in Sydney, Australia. Participants reported an increase in antimicrobial use, a loss of resources for AMS activities, and reduced in-person interactions. Meetings were performed through videoconferencing, which resulted in greater access to information but led to poorer communication and impacted interdisciplinary relationships. As COVID-19 restrictions recede, AMS program changes should be evaluated to understand the most effective strategies to facilitate evidence-based AMS practices.

Haemophilus influenzae blood-stream infection and third-generation cephalosporin susceptibility testing: a comparative case study using EUCAST and CLSI guidelines.

Introduction: In this comparative case study, we discuss clinically relevant discrepancies of antimicrobial susceptibility testing (AST) interpretation for ceftriaxone against a non-typable, beta-lactamase negative, ampicillin-resistant (BLNAR) Haemophilus influenzae isolated from a blood culture. Case report: A 74-year-old man presented with a 3 day illness characterized by shortness of breath and dry cough, and was noted to be febrile and hypoxic on admission. A blood culture bottle flagged positive with Gram-negative coccobacilli, later identified as Haemophilus influenzae with the patient commenced on ceftriaxone. The isolate was beta-lactamase negative and antibiotic susceptibility testing (AST) using disc diffusion revealed the isolate resistant to ceftriaxone and ampicillin by EUCAST methodology, with the patient subsequently changed to amoxicillin/clavulanate. Further AST using the CLSI methodology in parallel demonstrated discrepant results between the two susceptibility methods. The patient recovered without complications. Conclusion: This discrepancy could lead to inconsistent reporting of susceptibilities between laboratories, and consequently antibiotic prescribing, especially for invasive isolates. As more laboratories adopt EUCAST methodologies for AST interpretation in Australia and globally, it is important for clinicians to consider the clinical implications of these methodological discrepancies.

LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring.

BACKGROUND: Linezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). METHODS: Patients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. RESULTS: Linezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21-0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. CONCLUSIONS: This study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.

Imported malaria in the Northern Territory, Australia--428 consecutive cases.

Malaria is a notifiable disease in Australia with an average of 600 notifications per year in returned travellers or newly arrived refugees, migrants and visitors. Although endemic disease has been eliminated from the tropical north of Australia, the region remains malaria receptive due to the presence of efficient mosquito vectors. This study analyses enhanced surveillance data collected by the Centre for Disease Control on all cases of malaria notified in the Northern Territory from 1 January 2000 to 31 December 2010. There were 428 malaria episodes notified that occurred in 391 individuals with a median age of 26 years. Of these, 71.4% were male, 40.5% were Australian nationals and 38.0% were prescribed chemoprophylaxis. Primary infection consisted of 196 (51.3%) cases of Plasmodium falciparum, 165 (43.2%) P. vivax, 2 (0.5%) P. ovale, 1 (0.3%) P. malariae and 18 were mixed infections. There were 46 episodes of relapsed infection. Residents of non-malarious countries were most likely to have acquired primary infection in East Timor (40.6%), Papua New Guinea (27.8%), Indonesia (18.7%) and Africa (6.4%). Primary infection was diagnosed after a median 19 days (interquartile range (IQR) 7-69) after arrival in Australia for cases of P. vivax compared with 4 days for P. falciparum (IQR 2-11). Screening protocols led to the diagnosis of 27.2% of cases. Eighty-seven per cent of patients were admitted to hospital at the time of their malaria diagnosis with median duration of 3 days (IQR 2-4) and one patient died. Resettlement of people from endemic countries, as well as military and civilian activities, influences the prevailing notification rates and Plasmodium species type.

Wound infection caused by Neisseria zoodegmatis, a zoonotic pathogen: a case report.

The isolation of Neisseria zoodegmatis from a 63-year-old female presenting to the emergency department following a cat bite injury to her right hand is described in this report. N. zoodegmatis , also known as Centers for Disease Control (CDC) group EF-4b, is considered to be a zoonotic pathogen, and is usually associated with dog or cat bites. Despite the potential of this organism to cause serious soft tissue infections, it can be overlooked in routine clinical laboratories due to its slow growth characteristics and when the history of animal bite is not provided to the laboratory. This case highlights the importance of appropriate clinical history provision to the microbiology laboratory to help provide important information about potential pathogens and allow microbiologists to optimize culture and identification methods. The introduction of tools such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) into clinical laboratories allows identification and the interpretation of results to be performed within a few minutes of isolation on proper culture media, as opposed to traditional methods, whose slowness may be problematic, as shown in this case report.

Retrospective study of an as required dosing regimen of intravitreal bevacizumab in neovascular age-related macular degeneration in an Australian population.

PURPOSE: To investigate the efficacy of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) using an as required dosing regimen. METHODS: A retrospective study of 210 patients (231 eyes) with choroidal neovascularization resulting from neovasacular AMD. Patients were treated with 1.25 mg intravitreal bevacizumab at a vitreoretinal practice in Adelaide, South Australia. Patients were followed up at 2-4 weeks and then at 1-month intervals; repeat injections were offered in the event of recurrence. Recurrence was defined as either a decrease of best-corrected visual acuity or an increase in macular oedema, subretinal fluid or intraretinal fluid on optical coherence tomography, after complete or partial resolution in previous follow-up visits. Patient data were collected for 12 months of follow up or until the patient's treatment was changed to ranibizumab. RESULTS: Significant improvement in visual acuity and central retinal thickness was demonstrated at 1 month with an improvement of vision from logMAR equivalent 0.76 to 0.68 (P < 0.001) and a decrease of central retinal thickness from 306 µm to 244 µm (P < 0.001). This overall improvement was continued throughout the 12-month follow-up period; however, follow up was poor with 12-month data available for only a small number of patients (7.8%). Ocular and systemic side-effects were rare at 3.5% and 0.4%, respectively. CONCLUSION: Eyes with neovascular AMD treated with intravitreal bevacizumab for up to 12 months had significant functional and anatomical improvement. Further studies need to confirm the long-term safety and efficacy of this treatment.