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Multidrug-resistant Staphylococcus and vancomycin-resistant Enterococcus (VRE) are important human pathogens that are resistant to most clinical antibiotics. Treatment options are limited and often require the use of 'last-line' antimicrobials such as linezolid, daptomycin, and in the case of Staphylococcus, also vancomycin. The emergence of resistance to these last-line antimicrobial agents is therefore of considerable clinical concern. This mini-review provides an overview of resistance to last-line antimicrobial agents in Staphylococcus and VRE, with a particular focus on how genomics has provided critical insights into the emergence of resistant clones, the molecular mechanisms of resistance, and the importance of mobile genetic elements in the global spread of resistance to linezolid.© Copyright © 2021 Turner, Lee, Gorrie, Howden and Carter.

Objectives: To conduct a pilot study implementing combined genomic and epidemiologic surveillance for hospital-acquired multidrug-resistant organisms (MDROs) to predict transmission between patients and to estimate the local burden of MDRO transmission. Design(s): Pilot prospective multicenter surveillance study. Setting(s): The study was conducted in 8 university hospitals (2,800 beds total) in Melbourne, Australia (population 4.8 million), including 4 acute-care, 1 specialist cancer care, and 3 subacute-care hospitals. Method(s): All clinical and screening isolates from hospital inpatients (April 24 to June 18, 2017) were collected for 6 MDROs: VanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp), and carbapenem-resistant Pseudomonas aeruginosa (CRPa) and Acinetobacter baumannii (CRAb). Isolates were analyzed and reported as routine by hospital laboratories, underwent whole-genome sequencing at the central laboratory, and were analyzed using open-source bioinformatic tools. MDRO burden and transmission were assessed using combined genomic and epidemiologic data. Result(s): In total, 408 isolates were collected from 358 patients; 47.5% were screening isolates. ESBL-Ec was most common (52.5%), then MRSA (21.6%), vanA VRE (15.7%), and ESBL-Kp (7.6%). Most MDROs (88.3%) were isolated from patients with recent healthcare exposure. Combining genomics and epidemiology identified that at least 27.1% of MDROs were likely acquired in a hospital; most of these transmission events would not have been detected without genomics. The highest proportion of transmission occurred with vanA VRE (88.4% of patients). Conclusion(s): Genomic and epidemiologic data from multiple institutions can feasibly be combined prospectively, providing substantial insights into the burden and distribution of MDROs, including in-hospital transmission. This analysis enables infection control teams to target interventions more effectively. Copyright © 2020 by The Society

BACKGROUND: Multi-resistant organisms (MROs) pose a critical threat to public health. Population-based programs for control of MROs such as Carbapenemase-producing Enterobacterales (CPE) have emerged and evaluation is needed. We assess the feasibility and impact of a state-wide CPE surveillance and response program deployed in December 2015 across Victoria, Australia (population 6.5 million). METHOD(S): A prospective multi-modal intervention including active screening, carrier isolation, centralised case investigation and comparative pathogen genomics was implemented. We analyze trend in CPE incidence and clinical presentation, risk factors and local transmission over the program's first three years (January 2016 to December 2018). RESULT(S): CPE case ascertainment increased over the study period to 1.42 cases/100,000 population, linked to increased screening without a concomitant rise in active clinical infections (0.45-0.60 infections/100,000 population, p=0.640). KPC-2 infection decreased from 0.29 infections/100,000 population prior to intervention to 0.03 infections/100,000 population in 2018 (p=0.003). Comprehensive case investigation identified putative overseas community acquisition. Median time between isolate referral and initial genomic and epidemiological assessment for local transmission was 11 days (IQR 9-14). Prospective surveillance identified numerous small transmission networks (median 2, range 1-19 cases), predominantly IMP and KPC, with median pairwise distance of 8 (IQR 4-13) single nucleotide polymorphisms; low diversity between clusters of the same sequence type suggested genomic cluster definitions alone are insufficient for targeted response. CONCLUSION(S): We demonstrate the value of centralised CPE control programs to increase case ascertainment, resolve risk factors and identify putative local transmission through prospective genomic and epidemiological surveillance; methodologies are transferable to low-prevalence settings and MROs globa