Understanding the Sequelae of Invasive Meningococcal Disease in the United States.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition that can result in reduced life expectancy and a broad spectrum of sequelae, many of which may be lifelong and devastating for those who survive the acute disease period. In the United States of America (USA), vaccination is available against the five meningococcal serogroups (A, B, C, W, and Y), but meningococcal vaccination rates among healthy USA adolescents and individuals at high risk because of medical conditions are low, rendering them vulnerable to IMD and its sequelae. Despite the severity of the disease, the clinical impact and rates of IMD sequelae in the USA are poorly understood, as USA-specific data are limited, and the methodology of existing research is heterogenous. This commentary presents clinical experts' perspectives on IMD sequelae based on the available published evidence and direct clinical experience. Among sequelae previously identified in a global systematic literature review, 16 conditions were considered as related to IMD by the present authors. These sequelae include short- and long-term physical, neurological, and emotional consequences that impose a substantial humanistic burden on survivors and their caregivers and result in considerable healthcare and societal costs. This commentary highlights existing knowledge gaps concerning IMD sequelae, including the unclear relationship between IMD and mental health disorders, the contribution of sequelae to the disease burden, prevalence of late-onset sequelae among survivors, and timing of the development of sequelae in different age groups. Addressing these knowledge gaps can inform decisions regarding clinical management in the post-acute period and help quantify the impact of prevention through meningococcal vaccination.

Invasive meningococcal disease is uncommon but life-threatening. Those who survive may have lasting conditions, also known as sequelae, that negatively impact their health. In this commentary, expert physicians used previous publications to identify 16 sequelae of invasive meningococcal disease, many of which, including loss of limbs, blindness, and intellectual disabilities, can severely affect the lives of survivors and their caregivers. It is important to better understand how sequelae affect patients and the cost of living with these conditions for the healthcare system and society. This information would help policymakers make decisions on preventing invasive meningococcal disease with vaccination and managing its sequelae.

Bacteriocin production facilitates nosocomial emergence of vancomycin-resistant Enterococcus faecium.

Vancomycin-resistant Enterococcus faecium (VREfm) is a prevalent healthcare-acquired pathogen. Gastrointestinal colonization can lead to difficult-to-treat bloodstream infections with high mortality rates. Prior studies have investigated VREfm population structure within healthcare centers. However, little is known about how and why hospital-adapted VREfm populations change over time. We sequenced 710 healthcare-associated VREfm clinical isolates from 2017-2022 from a large tertiary care center as part of the Enhanced Detection System for Healthcare-Associated Transmission (EDS-HAT) program. Although the VREfm population in our center was polyclonal, 46% of isolates formed genetically related clusters, suggesting a high transmission rate. We compared our collection to 15,631 publicly available VREfm genomes spanning 20 years. Our findings describe a drastic shift in lineage replacement within nosocomial VREfm populations at both the local and global level. Functional and genomic analysis revealed, antimicrobial peptide, bacteriocin T8 may be a driving feature of strain emergence and persistence in the hospital setting.

Evolution of extended-spectrum ß-lactamase-producing ST131 Escherichia coli at a single hospital over 15 years.

Escherichia coli multi-locus sequence type ST131 is a globally distributed pandemic lineage that causes multidrug-resistant extra-intestinal infections. ST131 E. coli frequently produce extended-spectrum ß-lactamases (ESBLs), which confer resistance to many ß-lactam antibiotics and make infections difficult to treat. We sequenced the genomes of 154 ESBL-producing E. coli clinical isolates belonging to the ST131 lineage from patients at the University of Pittsburgh Medical Center (UPMC) between 2004 and 2018. Isolates belonged to the well described ST131 clades A (8%), B (3%), and C (89%). Time-dated phylogenetic analysis estimated that the most recent common ancestor (MRCA) for all clade C isolates emerged around 1989, consistent with previous studies. We identified multiple genes potentially under selection in clade C, including the cell wall assembly gene ftsI, the LPS biosynthesis gene arnC, and the yersiniabactin uptake receptor fyuA. Diverse ESBL-encoding genes belonging to the blaCTX-M, blaSHV, and blaTEM families were identified; these genes were found at varying numbers of loci and in variable numbers of copies across isolates. Analysis of ESBL flanking regions revealed diverse mobile elements that varied by ESBL type. Overall, our findings show that ST131 subclade C dominated among patients and uncover possible signals of ongoing adaptation within this ST131 lineage.

Impact of discontinuation of contact precautions on surveillance- and whole genome sequencing-defined methicillin-resistant Staphylococcus aureus healthcare-associated infections.

Objective: Prior studies evaluating the impact of discontinuation of contact precautions (DcCP) on methicillin-resistant Staphylococcus aureus (MRSA) outcomes have characterized all healthcare-associated infections (HAIs) rather than those likely preventable by contact precautions. We aimed to analyze the impact of DcCP on the rate of MRSA HAI including transmission events identified through whole genome sequencing (WGS) surveillance. Design: Quasi experimental interrupted time series. Setting: Acute care medical center. Participants: Inpatients. Methods: The effect of DcCP (use of gowns and gloves) for encounters among patients with MRSA carriage was evaluated using time series analysis of MRSA HAI rates from January 2019 through December 2022, compared to WGS-defined attributable transmission events before and after DcCP in December 2020. Results: The MRSA HAI rate was 4.22/10,000 patient days before and 2.98/10,000 patient days after DcCP (incidence rate ratio [IRR] 0.71 [95% confidence interval 0.56-0.89]) with a significant immediate decrease (P = .001). There were 7 WGS-defined attributable transmission events before and 11 events after DcCP (incident rate ratio 0.90 [95% confidence interval 0.30-2.55]). Conclusions: DcCP did not result in an increase in MRSA HAI or, in WGS-defined attributable transmission events. Comprehensive analyses of the effect of transmission prevention measures should include outcomes specifically measuring transmission-associated HAI.

Changes in the cost-effectiveness of pneumococcal vaccination and of programs to increase its uptake in U.S. older adults.

BACKGROUND: Multiple factors, such as less complex U.S. adult pneumococcal recommendations that could increase vaccination rates, childhood pneumococcal vaccination indirect effects that decrease adult vaccination impact, and increased vaccine hesitancy (particularly in underserved minorities), could diminish the cost-effectiveness of programs to increase pneumococcal vaccination in older adults. Prior analyses supported the economic favorability of these programs. METHODS: A Markov model compared no vaccination and current recommendations (either 20-valent pneumococcal conjugate vaccine [PCV20] alone or 15-valent pneumococcal conjugate vaccine plus the 23-valent pneumococcal polysaccharide vaccine [PCV15/PPSV23]) without or with programs to increase vaccine uptake in Black and non-Black 65-year-old cohorts. Pre-pandemic population- and serotype-specific pneumococcal disease risk and illness/vaccine costs came from U.S. DATABASES: Program costs were $2.19 per vaccine-eligible person and increased absolute vaccination likelihood by 7.5%. Delphi panel estimates and trial data informed vaccine effectiveness values. Analyses took a healthcare perspective, discounting at 3%/year over a lifetime time horizon. RESULTS: Uptake programs decreased pneumococcal disease overall. In Black cohorts, PCV20 without program cost $216,805 per quality-adjusted life year (QALY) gained compared with no vaccination; incremental cost-effectiveness was $245,546/QALY for PCV20 with program and $425,264/QALY for PCV15/PPSV23 with program. In non-Black cohorts, all strategies cost >$200,000/QALY gained. When considering the potential indirect effects from childhood vaccination, all strategies became less economically attractive. Increased vaccination with less complex strategies had negligible effects. In probabilistic sensitivity analyses, current recommendations with or without programs were unlikely to be favored at thresholds <$200,000/QALY gained. CONCLUSION: Current U.S. pneumococcal vaccination recommendations for older adults were unlikely to be economically reasonable with or without programs to increase vaccine uptake. Alternatives to current pneumococcal vaccines that include pneumococcal serotypes associated with adult disease should be considered.

Genomic sequencing surveillance of patients colonized with vancomycin-resistant Enterococcus (VRE) improves detection of hospital-associated transmission.

Background: Vancomycin-resistant enterococcal (VRE) infections pose significant challenges in healthcare. Transmission dynamics of VRE are complex, often involving patient colonization and subsequent transmission through various healthcare-associated vectors. We utilized a whole genome sequencing (WGS) surveillance program at our institution to better understand the contribution of clinical and colonizing isolates to VRE transmission. Methods: We performed whole genome sequencing on 352 VRE clinical isolates collected over 34 months and 891 rectal screening isolates collected over a 9-month nested period, and used single nucleotide polymorphisms to assess relatedness. We then performed a geo-temporal transmission analysis considering both clinical and rectal screening isolates compared with clinical isolates alone, and calculated 30-day outcomes of patients. Results: VRE rectal carriage constituted 87.3% of VRE acquisition, with an average monthly acquisition rate of 7.6 per 1000 patient days. We identified 185 genetically related clusters containing 2-42 isolates and encompassing 69.6% of all isolates in the dataset. The inclusion of rectal swab isolates increased the detection of clinical isolate clusters (from 53% to 67%, P<0.01). Geo-temporal analysis identified hotspot locations of VRE transmission. Patients with clinical VRE isolates that were closely related to previously sampled rectal swab isolates experienced 30-day ICU admission (17.5%), hospital readmission (9.2%), and death (13.3%). Conclusions: Our findings describe the high burden of VRE transmission at our hospital and shed light on the importance of using WGS surveillance of both clinical and rectal screening isolates to better understand the transmission of this pathogen. This study highlights the potential utility of incorporating WGS surveillance of VRE into routine hospital practice for improving infection prevention and patient safety.

Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease among children in the United States between 2010 and 2019: An indirect cohort study.

BACKGROUND: A U.S. case-control study (2010-2014) demonstrated vaccine effectiveness (VE) for ≥ 1 dose of the thirteen-valent pneumococcal conjugate vaccine (PCV13) against vaccine-type (VT) invasive pneumococcal disease (IPD) at 86 %; however, it lacked statistical power to examine VE by number of doses and against individual serotypes. METHODS: We used the indirect cohort method to estimate PCV13 VE against VT-IPD among children aged < 5 years in the United States from May 1, 2010 through December 31, 2019 using cases from CDC's Active Bacterial Core surveillance, including cases enrolled in a matched case-control study (2010-2014). Cases and controls were defined as individuals with VT-IPD and non-PCV13-type-IPD (NVT-IPD), respectively. We estimated absolute VE using the adjusted odds ratio of prior PCV13 receipt (1-aOR x 100 %). RESULTS: Among 1,161 IPD cases, 223 (19.2 %) were VT cases and 938 (80.8 %) were NVT controls. Of those, 108 cases (48.4 %; 108/223) and 600 controls (64.0 %; 600/938) had received > 3 PCV13 doses; 23 cases (17.6 %) and 15 controls (2.4 %) had received no PCV doses. VE ≥ 3 PCV13 doses against VT-IPD was 90.2 % (95 % Confidence Interval75.4-96.1 %), respectively. Among the most commonly circulating VT-IPD serotypes, VE of ≥ 3 PCV13 doses was 86.8 % (73.7-93.3 %), 50.2 % (28.4-80.5 %), and 93.8 % (69.8-98.8 %) against serotypes 19A, 3, and 19F, respectively. CONCLUSIONS: At least three doses of PCV13 continue to be effective in preventing VT-IPD among children aged < 5 years in the US. PCV13 was protective against serotypes 19A and 19F IPD; protection against serotype 3 IPD did not reach statistical significance.

Genomic diversity and antimicrobial susceptibility of invasive Neisseria meningitidis in South Africa, 2016-2021.

BACKGROUND: Invasive meningococcal isolates in South Africa have in previous years (<2008) been characterized by serogroup B, C, W and Y lineages over time, with penicillin intermediate resistance (peni) at 6%. We describe the population structure and genomic markers of peni among invasive meningococcal isolates in South Africa, 2016-2021. METHODS: Meningococcal isolates were collected through national, laboratory-based invasive meningococcal disease (IMD) surveillance. Phenotypic antimicrobial susceptibility testing and whole-genome sequencing were performed, and the mechanism of reduced penicillin susceptibility was assessed in silico. RESULTS: Of 585 IMD cases reported during the study period, culture and PCR-based capsular group was determined for 477/585 (82%); and 241/477 (51%) were sequenced. Predominant serogroups included NmB (210/477; 44%), NmW (116/477; 24%), NmY (96/477; 20%) and NmC (48/477; 10%). Predominant clonal complexes (CC) were CC41/44 in NmB (27/113; 24%), CC11 in NmW (46/56; 82%), CC167 in NmY (23/44; 53%), and CC865 in NmC (9/24; 38%). Peni was detected in 16% (42/262) of isolates, and was due to the presence of a penA mosaic, with the majority harboring penA7, penA9 or penA14. CONCLUSION: IMD lineages circulating in South Africa were consistent with those circulating prior to 2008, however peni was higher than previously reported, and occurred in a variety of lineages.

Cost-effectiveness of an in-development adult-formulated 21-valent pneumococcal conjugate vaccine in US adults aged 50 years or older.

Indirect effects of childhood pneumococcal conjugate vaccines (PCV) have diminished the cost-effectiveness of current adult vaccine recommendations. An in-development adult-formulated 21-valent pneumococcal conjugate vaccine (PCV21) may play a critical role in reducing pneumococcal illness by targeting a larger number of serotypes responsible for adult pneumococcal infections. This study assesses the cost-effectiveness of PCV21 in US adults aged 50 years or older compared with currently recommended pneumococcal vaccines, from both the societal and healthcare perspectives. A Markov model evaluated the lifetime cost-effectiveness of PCV21 (given at age 50 years only, at ages 50/65 years, and risk-based at ages < 65 years plus age-based at age 65 years) compared to no vaccination and to currently recommended pneumococcal vaccines given either as currently recommended or routinely at ages 50/65 years. The analysis was conducted in hypothetical Black and non-Black cohorts aged 50 years or older, with and without considering childhood pneumococcal vaccination indirect effects. Model parameters were based on US data. Parameter uncertainty was assessed using 1-way and probabilistic sensitivity analyses. From the societal perspective, PCV21 at ages 50/65 years compared to PCV21 at age 50 years cost $7,410 per quality adjusted life year (QALY) gained in Black cohort analyses and $85,696/QALY gained in the non-Black cohort; PCV21 at ages 50/65 years had the most favorable public health outcomes. From the healthcare perspective, compared to no vaccination, PCV21 at age 50 years cost $46,213/QALY gained in the Black cohort and $86,629/QALY in non-Blacks. All other strategies were dominated in both cohorts and from both perspectives. When considering childhood pneumococcal vaccination indirect effects, costs of PCV21 at ages 50/65 years remained less than $140,000/QALY gained from the societal perspective in both populations. PCV21 is potentially cost-effective compared to currently approved pneumococcal vaccines in adults aged 50 years or older from both the societal and healthcare perspectives.

Pneumococcal Vaccination Strategies in 50-Year-Olds to Decrease Racial Disparities: A US Societal Perspective Cost-Effectiveness Analysis.

OBJECTIVES: This study assesses the impact of expanding pneumococcal vaccination to all 50-year-olds to decrease racial disparities by estimating from the societal perspective, the cost-effectiveness of 20-valent pneumococcal conjugate vaccine (PCV20) and 15-valent conjugate vaccine followed by 23-valent polysaccharide vaccine (PCV15/PPSV23) for 50-year-olds. METHODS: A Markov model compared the cost-effectiveness of PCV20 or PCV15/PPSV23 in all general population 50- and 65-years-olds compared with current US recommendations and with no vaccination in US Black and non-Black cohorts. US data informed model parameters. Pneumococcal disease societal costs were estimated using direct and indirect costs of acute illness and of pneumococcal-related long-term disability and mortality. Hypothetical 50-year-old cohorts were followed over their lifetimes with costs and effectiveness discounted 3% per year. Deterministic and probabilistic sensitivity analyses assessed model uncertainty. RESULTS: In Black cohorts, PCV20 for all at ages 50 and 65 was the least costly strategy and had greater effectiveness than no vaccination and current recommendation strategies, whereas PCV15/PPSV23 at 50 and 65 cost more than $1 million per quality-adjusted life year (QALY) gained compared with PCV20 at 50 and 65. In non-Black cohorts, PCV20 at 50 and 65 cost $62 083/QALY and PCV15/PPSV23 at 50 and 65 cost more than $1 million/QALY with current recommendations, again being more costly and less effective. In probabilistic sensitivity analyses, PCV20 at 50 and 65 was favored in 85.7% (Black) and 61.8% (non-Black) of model iterations at a $100 000/QALY gained willingness-to-pay threshold. CONCLUSIONS: When considering the societal costs of pneumococcal disease, PCV20 at ages 50 and 65 years in the general US population is a potentially economically viable strategy, particularly in Black cohorts.

Real-time genomic epidemiologic investigation of a multispecies plasmid-associated hospital outbreak of NDM-5-producing Enterobacterales infections.

OBJECTIVES: New Delhi metallo-ß-lactamase (NDM) is an emergent mechanism of carbapenem resistance associated with high mortality and limited treatment options. Because the blaNDM resistance gene is often carried on plasmids, traditional infection prevention and control (IP&C) surveillance methods and reactive whole genome sequencing (WGS) may not detect plasmid transfer in multispecies outbreaks. METHODS: Initial outbreak detection of NDM-producing Enterobacterales identified at an acute care hospital occurred via traditional IP&C methods and was supplemented by real-time WGS surveillance performed weekly. To resolve NDM-encoding plasmids, we performed long-read sequencing and constructed hybrid assemblies. WGS data for suspected outbreaks was shared with the IP&C team for assessment and intervention. RESULTS: We observed a multispecies outbreak of NDM-5-producing Enterobacterales isolated from 15 patients between February 2021 and February 2023. The 19 clinical and surveillance isolates sequenced included 7 bacterial species encoding the same NDM-5 plasmid. WGS surveillance and epidemiologic investigation characterized 10 horizontal plasmid transfer events and 6 bacterial transmission events between patients in varying hospital units. CONCLUSIONS: Our investigation revealed a complex, multispecies outbreak of NDM involving multiple plasmid transfer and bacterial transmission events. We highlight the utility of combining traditional IP&C and prospective genomic methods in identifying and containing plasmid-associated outbreaks.

Incidence and transmission associated with respiratory viruses in an acute care facility: An observational study.

We estimated the extent of respiratory virus transmission over three pre-COVID-19 seasons. Of 16,273 assays, 22.9% (3,726) detected ≥1 respiratory virus. The frequency of putatively hospital-acquired infection ranged from 6.9% (influenza A/B) to 24.7% (adenovirus). The 176 clusters were most commonly associated with rhinovirus/enterovirus (70) and influenza A/B (62).

Meningococcal Disease in Persons With HIV Reported Through Active Surveillance in the United States, 2009-2019.

Persons with HIV (PWH) are at increased risk for bacterial infections, and previous publications document an increased risk for invasive meningococcal disease (IMD) in particular. This analysis provides evidence that PWH face a 6-fold increase in risk for IMD based on Active Bacterial Core surveillance data collected during 2009-2019.

Two Artificial Tears Outbreak-Associated Cases of Extensively Drug-Resistant Pseudomonas aeruginosa Detected Through Whole Genome Sequencing-Based Surveillance.

We describe 2 cases of extensively drug-resistant Pseudomonas aeruginosa infection caused by a strain of public health concern, as it was recently associated with a nationwide outbreak of contaminated artificial tears. Both cases were detected through database review of genomes in the Enhanced Detection System for Hospital-Associated Transmission (EDS-HAT), a routine genome sequencing-based surveillance program. We generated a high-quality reference genome for the outbreak strain from an isolate from our center and examined the mobile elements encoding blaVIM-80 and bla-GES-9 carbapenemases. We used publicly available Pseudomonas aeruginosa genomes to explore the genetic relatedness and antimicrobial resistance genes of the outbreak strain.

Societal Cost of Racial Pneumococcal Disease Disparities in US Adults Aged 50 Years or Older.

OBJECTIVE: This study aimed to estimate the societal cost of racial disparities in pneumococcal disease among US adults aged ≥  50 years. METHODS: In a model-based analysis, societal costs of invasive pneumococcal disease (IPD) and hospitalized nonbacteremic pneumococcal pneumonia (NBP) were estimated using (1) direct medical costs plus indirect costs of acute illness; (2) indirect costs of pneumococcal mortality; and (3) direct and indirect costs of related disability. Disparities costs were calculated as differences in average per-person pneumococcal disease cost between Black and non-Black adults aged ≥  50 years multiplied by the Black population aged ≥  50 years. Costs were in 2019 US dollars (US$), with future costs discounted at 3% per year. RESULTS: Total direct and indirect costs per IPD case were US$186,791 in Black populations and US$182,689 in non-Black populations; total hospitalized NBP costs per case were US$100,632 (Black) and US$96,781 (non-Black). The difference in population per-person total pneumococcal disease costs between Black and non-Black adults was US$47.85. Combined societal costs of disparities for IPD and hospitalized NBP totaled US$673.2 million for Black adults aged ≥  50 years. Disease and disability risks, life expectancy, and case-fatality rates were influential in one-way sensitivity analyses, but the lowest cost across all analyses was US$194 million. The 95% probability range of racial disparity costs were US$227.2-US$1156.9 million in a probabilistic sensitivity analysis. CONCLUSIONS: US societal cost of racial pneumococcal disease disparities in persons aged ≥ 50 years is substantial. Successful pneumococcal vaccination policy and programmatic interventions to mitigate these disparities could decrease costs and improve health.

The utility of whole-genome sequencing to inform epidemiologic investigations of SARS-CoV-2 clusters in acute-care hospitals.

OBJECTIVE: To evaluate the utility of selective reactive whole-genome sequencing (WGS) in aiding healthcare-associated cluster investigations. DESIGN: Mixed-methods quality-improvement study. SETTING: Thes study was conducted across 8 acute-care facilities in an integrated health system. METHODS: We analyzed healthcare-associated coronavirus disease 2019 (COVID-19) clusters between May 2020 and July 2022 for which facility infection prevention and control (IPC) teams selectively requested reactive WGS to aid the epidemiologic investigation. WGS was performed with real-time results provided to IPC teams, including genetic relatedness of sequenced isolates. We conducted structured interviews with IPC teams on the informativeness of WGS for transmission investigation and prevention. RESULTS: In total, 8 IPC teams requested WGS to aid the investigation of 17 COVID-19 clusters comprising 226 cases and 116 (51%) sequenced isolates. Of these, 16 (94%) clusters had at least 1 WGS-defined transmission event. IPC teams hypothesized transmission pathways in 14 (82%) of 17 clusters and used data visualizations to characterize these pathways in 11 clusters (65%). The teams reported that in 15 clusters (88%), WGS identified a transmission pathway; the WGS-defined pathway was not one that was predicted by epidemiologic investigation in 7 clusters (41%). WGS changed the understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in 8 clusters (47%) and altered infection prevention interventions in 8 clusters (47%). CONCLUSIONS: Selectively utilizing reactive WGS helped identify cryptic SARS-CoV-2 transmission pathways and frequently changed the understanding and response to SARS-CoV-2 outbreaks. Until WGS is widely adopted, a selective reactive WGS approach may be highly impactful in response to healthcare-associated cluster investigations.

Genomic Epidemiologic Investigation of a Multispecies Hospital Outbreak of NDM-5-Producing Enterobacterales Infections.

Background: New Delhi metallo-ß-lactamase (NDM) represents an emergent mechanism of carbapenem resistance associated with high mortality and limited antimicrobial treatment options. Because the blaNDM resistance gene is often carried on plasmids, traditional infection prevention and control (IP&C) surveillance methods like speciation, antimicrobial resistance testing, and reactive whole genome sequencing (WGS) may not detect plasmid transfer in multispecies outbreaks. Methods: Initial outbreak detection of NDM-producing Enterobacterales identified at an acute care hospital occurred via traditional IP&C methods and was supplemented by real-time WGS surveillance, which was performed weekly using the Illumina platform. To resolve NDM-encoding plasmids, we performed long-read Oxford Nanopore sequencing and constructed hybrid assemblies using Illumina and Nanopore sequencing data. Reports of relatedness between NDM-producing organisms and reactive WGS for suspected outbreaks were shared with the IP&C team for assessment and intervention. Findings: We observed a multispecies outbreak of NDM-5-producing Enterobacterales isolated from 15 patients between February 2021 and February 2023. The 19 clinical and surveillance isolates sequenced included seven bacterial species and each encoded the same NDM-5 plasmid, which showed high homology to NDM plasmids previously observed in Asia. WGS surveillance and epidemiologic investigation characterized ten horizontal plasmid transfer events and six bacterial transmission events between patients housed in varying hospital units. Transmission prevention focused on enhanced observation and adherence to basic infection prevention measures. Interpretation: Our investigation revealed a complex, multispecies outbreak of NDM that involved multiple plasmid transfer and bacterial transmission events, increasing the complexity of outbreak identification and transmission prevention. Our investigation highlights the utility of combining traditional IP&C and prospective genomic methods in identifying and containing plasmid-associated outbreaks. Funding: This work was funded in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (R01AI127472) (R21AI1783691).