Establishment of RCPA national guidelines for selective reporting of antimicrobials: processes, challenges and measuring the impact.

OBJECTIVES: In 2016, The Royal College of Pathologists of Australasia (RCPA) initiated the formation of a working group comprising medical microbiologists to establish guidelines to assist Australian laboratories to implement selective and cascade reporting of antimicrobials-the first guidelines of this type in the world. METHODS: A 2017 audit of antimicrobial reporting in Australian and New Zealand laboratories identified significant opportunities for improvement and standardization of selective reporting. RESULTS: The first draft of the RCPA Selective Reporting Guidelines was circulated to all RCPA Microbiology fellows for feedback in August 2018 and the first version was published in February 2019. Subsequently, version two of the guidelines has recently been published in Australia, and New Zealand adapted these guidelines for formulation of their own national guidelines to accommodate local needs. CONCLUSIONS: Here we describe the processes, acceptance and challenges associated with the establishment of these guidelines and measurement of their impact.

The outcome of patients with severe and severe-complicated Clostridium difficile infection treated with tigecycline combination therapy: a retrospective observational study.

BACKGROUND: Tigecycline is a third-line therapy for severe Clostridium difficile infection (CDI) in Australasian guidelines. Differences in strain types make it difficult to extrapolate international tigecycline efficacy data with combination or monotherapy to Australian practice, where experience is limited. AIM: To evaluate the efficacy and adverse effects associated with tigecycline combination therapy for severe and severe-complicated CDI in an Australian healthcare setting. METHODS: This was a retrospective observational study at a metropolitan university-affiliated hospital. All patients between February 2013 and October 2016 treated with adjunctive intravenous tigecycline for >48 h for severe or severe-complicated CDI were included. Tigecycline was given in addition to oral vancomycin ± intravenous metronidazole. The primary outcome was all-cause mortality at 30 days from start of tigecycline combination therapy. Secondary outcomes included clinical cure, colectomy, adverse events and recurrence rates. RESULTS: Thirteen patients with median age of 61 years had severe (n = 9) or severe-complicated (n = 4) CDI at tigecycline commencement. In 92% of patients, tigecycline started within 48 h after in-hospital CDI treatment, for median duration of 9 days. All-cause mortality at 30 days was 8% with no mortality in severe CDI and 25% (1/4) in patients with severe-complicated fulminant CDI, comparing favourably with historical rates of 9-38% and 30-80% in similar respective groups. Clinical cure was achieved in 77% of cases. There were no colectomies and one attributable tigecycline adverse reaction. CONCLUSIONS: Tigecycline appears safe and effective as a part of combination therapy in severe CDI, and may be given earlier and for shorter durations than in current guidelines.

The impact of a multidisciplinary antimicrobial stewardship team on the timeliness of antimicrobial therapy in patients with positive blood cultures: a randomized controlled trial.

BACKGROUND: Antimicrobial stewardship teams play an important role in assisting with the optimization of antimicrobial use in acute care settings. We aimed to determine whether a rapid review by a multidisciplinary antimicrobial stewardship team would improve the timeliness of optimal antimicrobial therapy for patients with positive blood cultures. METHODS: This prospective randomized controlled trial was undertaken in two Australian hospitals. Patients received either standard care (a clinical microbiologist, registrar or laboratory scientist communicating the positive blood culture by phone to the treating doctor) or intervention (standard care plus rapid review by a multidisciplinary antimicrobial stewardship team). Outcomes included time to appropriate and/or active antimicrobial therapy and in-hospital mortality. The trial was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12614000258651). RESULTS: A total of 160 patients were enrolled in this study: 81 in the standard care arm and 79 in the intervention arm. Patients in the intervention arm were commenced earlier on active (HR 8.02, 95% CI: 2.15-29.91) and appropriate antimicrobials (HR 1.95, 95% CI: 1.13-3.38), with a higher proportion of patients allocated to the intervention arm receiving active therapy at 48 h (96% versus 82%) and appropriate therapy at 72 h (70% versus 54%). The majority of patients where the blood culture was a contaminant were not started on antimicrobial therapy, and there were no significant differences in time to cessation of antimicrobial therapy. CONCLUSIONS: Antimicrobial stewardship team review of patients with pathogenic positive blood cultures improved the time to both active and appropriate antimicrobial therapy.

State-wide genomic epidemiology investigations of COVID-19 in healthcare workers in 2020 Victoria, Australia: Qualitative thematic analysis to provide insights for future pandemic preparedness.

Background: COVID-19 has affected many healthcare workers (HCWs) globally. We performed state-wide SARS-CoV-2 genomic epidemiological investigations to identify HCW transmission dynamics and provide recommendations to optimise healthcare system preparedness for future outbreaks. Methods: Genome sequencing was attempted on all COVID-19 cases in Victoria, Australia. We combined genomic and epidemiologic data to investigate the source of HCW infections across multiple healthcare facilities (HCFs) in the state. Phylogenetic analysis and fine-scale hierarchical clustering were performed for the entire dataset including community and healthcare cases. Facilities provided standardised epidemiological data and putative transmission links. Findings: Between March-October 2020, approximately 1,240 HCW COVID-19 infection cases were identified; 765 are included here, requested for hospital investigations. Genomic sequencing was successful for 612 (80%) cases. Thirty-six investigations were undertaken across 12 HCFs. Genomic analysis revealed that multiple introductions of COVID-19 into facilities (31/36) were more common than single introductions (5/36). Major contributors to HCW acquisitions included mobility of staff and patients between wards and facilities, and characteristics and behaviours of patients that generated numerous secondary infections. Key limitations at the HCF level were identified. Interpretation: Genomic epidemiological analyses enhanced understanding of HCW infections, revealing unsuspected clusters and transmission networks. Combined analysis of all HCWs and patients in a HCF should be conducted, supported by high rates of sequencing coverage for all cases in the population. Established systems for integrated genomic epidemiological investigations in healthcare settings will improve HCW safety in future pandemics. Funding: The Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.

Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure.

OBJECTIVES: The aim of this study was to establish the relationship between reduced vancomycin and daptomycin susceptibility among Australasian vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA) isolates from patients never exposed to daptomycin. METHODS: Forty-seven stored clinical isolates of hVISA/VISA collected before November 2008 from around Australia and New Zealand were selected. Daptomycin and vancomycin MIC testing was performed using broth microdilution (BMD) and Etest methods. Daptomycin population analysis was performed on a subset of isolates. RESULTS: The percentage of daptomycin non-susceptible isolates was 0% for vancomycin-susceptible S. aureus (VSSA) (Etest and BMD), for hVISA it was 26% by Etest and 15% by BMD, and for VISA 62% by Etest and 38% by BMD. Population analysis profile testing demonstrated daptomycin heteroresistance among the hVISA and VISA strains tested. CONCLUSIONS: This is the highest rate of daptomycin non-susceptibility reported among hVISA isolates to date. Clinicians should exhibit caution when using daptomycin in situations where serious hVISA or VISA infection is a possibility.

Multiplex RT-PCR provides improved diagnosis of skin and nail dermatophyte infections compared to microscopy and culture: a laboratory study and review of the literature.

Dermatophytes are the most common cause of superficial mycosis, estimated to affect 20% to 25% of the general population. We assessed the performance of a novel real-time polymerase chain reaction (RT-PCR) multiplex assay for diagnosis of dermatophytosis. To evaluate sensitivity and specificity, 10 known bacteria and 10 known fungi commonly found on skin, as well as 105 samples with culture confirmed dermatophytosis were tested using Dermatophyte and Fungi assay (AusDiagnostics, Sydney, Australia), a novel multiplex assay for diagnosis of dermatophytosis in skin and nail. This was followed by prospective evaluation of 195 clinical samples for dermatophytosis by both conventional methods and RT-PCR. RT-PCR showed almost two-fold higher sensitivity and high specificity in the diagnosis of skin and nail dermatophytosis compared to traditional microscopy and culture. In addition, RT-PCR demonstrated markedly reduced turnaround time from 4 to 6 weeks to 4 to 6 hours and ability for high throughput.

A Survey on Knowledge Gaps in Assessment and Management of Severe Drug Hypersensitivity Reactions: Multicenter Cross-Sectional Study of Australian Health Care Providers.

Severe drug hypersensitivity reactions (DHRs) are often encountered by health care professionals (HCPs). We evaluated knowledge of doctors and pharmacists in the assessment and management of severe DHRs using a structured questionnaire. A cross-sectional study was conducted in 4 metropolitan hospital networks in Melbourne, Australia. A 13-question, scenario-based multiple-choice questionnaire to assess specific knowledge domains in drug hypersensitivity syndrome recognition, causality attribution, cross-reactivity patterns, appropriate diagnostic tests, and therapy was administered to HCPs of various vocation and specialty groups. Data were analyzed according to profession, self-reported experience, and preparedness in managing severe DHRs. Two hundred thirty-eight participants (45.0% senior doctors, 24.4% junior doctors, and 30.7% pharmacists) across a range of subspecialties achieved an overall median score of 7 (IQR, 5-8)-overall 55.6% correct responses to all questions-with senior doctors outperforming junior doctors and pharmacists (P < .001). The best performance by all participants was in DHR syndrome recognition (60.9%), and the poorest was in diagnostics/therapy (52.0%). HCP group and experience level were significantly associated with better performance in the knowledge domains of cross-reactivity and diagnostics/therapy (P = .003 and < .001, respectively), but not in the domains of syndrome recognition and causality attribution (P > .05). Levels of self-reported preparedness in DHR management were not associated with performance rates in any of the knowledge domains. This study demonstrated significant knowledge gaps in the recognition and management of severe drug hypersensitivity reactions. Targeted multidisciplinary education of staff caring for these patients is needed to improve knowledge gaps.

Medical device data systems and FDA regulation. Should medical device data systems require FDA clearance?

It is widely understood why medical devices need to be regulated by the FDA and other governing bodies. However medical software does not typically require the same level of regulation. Currently the FDA is investigating whether one type of medical software, Medical Device Data Systems (MDDS), should require FDA clearance because of the potential risk they impose when interconnected with medical devices. Hospitals are looking to implement MDDS because the technology allows nursing staff to spend more time on direct patient care and reduces charting errors. This article will explore the FDA's proposal and will review the possible risks and provide a rationale for why MDDS should be regulated by the FDA and why MDDS vendors should have the right level of quality and risk management procedures in place to ensure that they are developing and bringing to market the safest products possible.

The location of Australian Buruli ulcer lesions-Implications for unravelling disease transmission.

BACKGROUND: Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on the human body. METHODS: Using notification data and clinical records review, we conducted a retrospective observational study of patients diagnosed with BU in Victoria from 1998-2015. We created electronic density maps of lesion locations using spatial analysis software and compared lesion distribution by age, gender, presence of multiple lesions and month of infection. FINDINGS: We examined 579 patients with 649 lesions; 32 (5.5%) patients had multiple lesions. Lesions were predominantly located on lower (70.0%) and upper (27.1%) limbs, and showed a non-random distribution with strong predilection for the ankles, elbows and calves. When stratified by gender, upper limb lesions were more common (OR 1·97, 95% CI 1·38-2·82, p<0·001) while lower limb lesions were less common in men than in women (OR 0·48, 95% CI 0·34-0·68, p<0·001). Patients aged ≥ 65 years (OR 3·13, 95% CI 1·52-6·43, p = 0·001) and those with a lesion on the ankle (OR 2·49, 95% CI 1·14-5·43, p = 0·02) were more likely to have multiple lesions. Most infections (71.3%) were likely acquired in the warmer 6 months of the year. INTERPRETATION: Comparison with published work in Cameroon, Africa, showed similar lesion distribution and suggests the mode of M. ulcerans transmission may be the same across the globe. Our findings also aid clinical diagnosis and provide quantitative background information for further research investigating disease transmission.

Immunogenicity and safety of Advax™, a novel polysaccharide adjuvant based on delta inulin, when formulated with hepatitis B surface antigen: a randomized controlled Phase 1 study.

There is a need for additional safe and effective human vaccine adjuvants. Advax™ is a novel adjuvant produced from semi-crystalline particles of delta inulin. In animal studies Advax enhanced humoral and cellular immunity to hepatitis B surface antigen (HBsAg) without inducing local or systemic reactogenicity. This first-in-man Phase 1 clinical trial tested the safety and tolerability of three intramuscular doses of HBsAg formulated with Advax in a group of healthy adult subjects. Advax was well tolerated with injection site pain scores not significantly different to subjects receiving HBsAg alone and no adverse events were reported in subjects that received Advax. Seroprotection and HBsAb geometric mean titers (GMT) after three immunizations were higher in the Advax 5mg (seroprotection 5/6, 83.3%, GMT 40.7, 95% CI 11.9-139.1) and 10mg (seroprotection 4/5, 80%, GMT 51.6, 95% CI 10.0-266.2) groups versus HBsAg alone (seroprotection 1/5, 20%, GMT 4.1, 95% CI 1.3-12.8). Similarly the proportion of subjects with positive CD4 T-cell responses to HBsAg was higher in the Advax 5mg (4/6, 67%) and Advax 10mg (4/5, 80%) groups versus HBsAg alone (1/5, 20%). These results confirm the safety, tolerability and immunogenicity of Advax adjuvant observed in preclinical studies. Advax may represent a suitable replacement for alum adjuvants in prophylactic human vaccines subject to confirmation of current results in larger studies. Australia and New Zealand Clinical Trial Registry: ACTRN12607000598482.

Evaluation of the Xpert™ MRSA/SA Blood Culture assay for the detection of Staphylococcus aureus including strains with reduced vancomycin susceptibility from blood culture specimens.

The Xpert MRSA/SA Blood Culture (BC) assay (Cepheid, Sunnyvale, CA) was prospectively compared to culture and found to have excellent specificity for both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in BC specimens with a sensitivity of 75% (3/4) and 100% (17/17), respectively. Among 28 heterogeneous vancomycin-intermediate S. aureus (hVISA)/VISA spiked BCs, the assay correctly identified 84.6% VISA and 80% hVISA isolates as MRSA.

Mutagenesis of the dengue virus type 2 NS3 proteinase and the production of growth-restricted virus.

The N-terminal one-third of the NS3 protein of Dengue virus type 2 (DEN-2) complexes with co-factor NS2B to form an active serine proteinase which cleaves the viral polyprotein. To identify sites within NS3 that may interact with NS2B, seven regions within the NS3 proteinase outside the conserved flavivirus enzyme motifs were mutated by alanine replacement. Five sites contained clusters of charged residues and were hydrophilic. Two sites were hydrophobic and highly conserved among flaviviruses. The effects of five mutations on NS2B/3 processing were examined using a COS cell expression system. Four retained significant proteinase activity. Three of these mutations and two more were introduced into genomic-length cDNA and tested for their effects on virus replication. The five mutant viruses showed reduced plaque size and two of the five showed significantly reduced titres. All seven mutations were mapped on the X-ray crystal structure of the DEN-2 NS3 proteinase: three were located at the N terminus and two at the C terminus of the NS2B-binding cleft. Two mutations were at the C terminus of the proteinase domain and one was solvent-exposed. The study demonstrated that charged-to-alanine mutagenesis in the viral proteinase can be used to produce growth-restricted flaviviruses that may be useful in the production of attenuated vaccine strains.