Mycobacterium immunogenum acquisition from hospital tap water: a genomic and epidemiologic analysis.

We identified 23 cases of Mycobacterium immunogenum respiratory acquisition linked to a colonized plumbing system at a new hospital addition. We conducted a genomic and epidemiologic investigation to assess for clonal acquisition of M. immunogenum from hospital water sources and improve understanding of genetic distances between M. immunogenum isolates. We performed whole-genome sequencing on 28 M. immunogenum isolates obtained from August 2013 to July 2021 from patients and water sources on four intensive care and intermediate units at an academic hospital. Study hospital isolates were recovered from 23 patients who experienced de novo respiratory isolation of M. immunogenum and from biofilms obtained from five tap water outlets. We also analyzed 10 M. immunogenum genomes from previously sequenced clinical (n = 7) and environmental (n = 3) external control isolates. The 38-isolate cohort clustered into three clades with pairwise single-nucleotide polymorphism (SNP) distances ranging from 0 to 106,697 SNPs. We identified two clusters of study hospital isolates in Clade 1 and one cluster in Clade 2 for which clinical and environmental isolates differed by fewer than 10 SNPs and had less than 0.5% accessory genome variation. A less restrictive combined threshold of 40 SNPs and 5% accessory genes reliably captured additional isolates that met clinical criteria for hospital acquisition, but 12 (4%) of 310 epidemiologically unrelated isolate pairs also met this threshold. Core and accessory genome analyses confirmed respiratory acquisition of multiple clones of M. immunogenum from hospital water sources to patients. When combined with epidemiologic investigation, genomic thresholds accurately distinguished hospital acquisition.

Impact of the COVID-19 pandemic on adult mental health-related admissions at a large university health system in North Carolina - one year into the pandemic.

OBJECTIVE: Pandemic-associated stress may have exacerbated preexisting mental health and substance use disorders (MH/SUD) and caused new MH/SUD diagnoses which would be expected to lead to an increase in visits to emergency departments and hospital admissions for these conditions. This study assessed whether the proportion of hospital and emergency department encounters for MH/SUD diagnoses increased during the first year of the COVID-19 pandemic in the United States. METHODS: We conducted a longitudinal (interrupted time series) analysis of 994,724 eligible encounters identified by electronic query between January 1, 2016 and March 31, 2021. Of these, 55,574 encounters involved MH/SUD diagnosis. The pre-pandemic period was defined as January 1, 2016 to March 31, 2020, and the pandemic period was defined as April 1, 2020 to March 31, 2021. All statistical analyses were performed with R. RESULTS: No significant trend in MH/SUD encounters at baseline (rate ratio 1.00, 95% CI 0.99-1.01, p = 0.75) was observed. However, the onset of the pandemic was temporally associated with a significant level increase in the proportion of MH/SUD encounters relative to overall encounters (rate ratio 1.14, 95% CI 1.06-1.21, p<0.001) with no change in the overall trend (rate ratio 0.99, 95% CI 0.90-1.10, p = 0.89). CONCLUSIONS: The significant pandemic-associated increase in the proportion of MH/SUD encounters relative to overall encounters was driven largely by sustained numbers of MH/ SUD encounters despite a decrease in total encounters. Increased support for mental health care is needed for these vulnerable patients during pandemics.

Disparities in Mpox Vaccination Among Priority Populations During the 2022 Outbreak.

Background: The 2022 mpox outbreak disproportionately affected men who have sex with men and persons living with HIV (PLWH). A 2-dose mpox vaccine series was deployed in mid-2022. Structural racism and insurance status may have affected equitable vaccination. Methods: We defined 3 cohorts: PLWH with at least 1 clinic visit between 1 July 2021 and 1 July 2022 (n = 2066), HIV preexposure prophylaxis (PrEP) recipients as of 1 January 2022 (n = 262), and all mpox-vaccinated patients in our health system between 1 July 2022 and 30 November 2022 (n = 807). We identified patients with prior diagnosed sexually transmitted infections (STIs) as having a positive test result for gonorrhea, chlamydia, or syphilis between 1 July 2021-1 July 2022. The primary outcome was receipt of at least 1 dose of mpox vaccine. Results: We identified 224 (10.8%) PLWH and 50 (19.0%) PrEP patients who received at least 1 dose of mpox vaccine. Among PLWH, White race (odds ratio [OR], 1.55; 95% CI, 1.11-2.16), private insurance (OR, 1.83; 95% CI, 1.01-3.34), prior STI (OR, 3.04; 95% CI, 2.16-4.27), prior COVID-19 vaccination (OR, 3.17; 95% CI, 1.93-5.20), and prior influenza vaccination (OR, 1.42; 95% CI, 1.30-1.96) independently predicted mpox vaccination. Within the PrEP cohort, prior COVID-19 vaccination and seasonal influenza vaccination predicted mpox vaccination. Uninsured patients were vaccinated later in the outbreak than patients with private insurance (median time to vaccination, 41 days in the privately insured group vs 83 days in the uninsured group; P < .0001). Conclusions: Race, insurance status, prior STI, and previous receipt of other vaccines influenced uptake of mpox vaccine. Addressing health disparities and vaccine acceptance will be essential in improving future outbreak response.

Concurrent Sexually Transmitted Infection Testing Among Patients Tested for Mpox at a Tertiary Healthcare System.

Coinfection with sexually transmitted infections (STIs) and mpox is common. We evaluated concurrent STI testing among Duke Health patients tested for mpox. We found that most patients tested for mpox were not comprehensively tested for STIs, despite concurrent STIs being diagnosed in 15% of patients when testing was performed.

Association of Neighborhood Deprivation With Healthcare Utilization Among Persons With Human Immunodeficiency Virus: A Latent Class Analysis.

Background: We previously identified 3 latent classes of healthcare utilization among people with human immunodeficiency virus (PWH): adherent, nonadherent, and sick. Although membership in the "nonadherent" group was associated with subsequent disengagement from human immunodeficiency virus (HIV) care, socioeconomic predictors of class membership remain unexplored. Methods: We validated our healthcare utilization-based latent class model of PWH receiving care at Duke University (Durham, North Carolina) using patient-level data from 2015 to 2018. SDI scores were assigned to cohort members based on residential addresses. Associations of patient-level covariates with class membership were estimated using multivariable logistic regression and movement between classes was estimated using latent transition analysis. Results: A total of 1443 unique patients (median age of 50 years, 28% female sex at birth, 57% Black) were included in the analysis. PWH in the most disadvantaged (highest) SDI decile were more likely to be in the "nonadherent" class than the remainder of the cohort (odds ratio [OR], 1.58 [95% confidence interval {CI}, .95-2.63]) and were significantly more likely to be in the "sick" class (OR, 2.65 [95% CI, 2.13-3.30]). PWH in the highest SDI decile were also more likely to transition into and less likely to transition out of the "sick" class. Conclusions: PWH who resided in neighborhoods with high levels of social deprivation were more likely to have latent class membership in suboptimal healthcare utilization groupings, and membership persisted over time. Risk stratification models based on healthcare utilization may be useful tools in the early identification of persons at risk for suboptimal HIV care engagement.

Use of Interferon-Gamma Release Assays in Children <2 Years Old.

While interferon-gamma release assays (IGRAs) are widely used for detecting tuberculosis (TB) infection, tuberculin skin tests (TSTs) remain preferred for children under the age of 2 years. The preference for TST stems from concern over IGRA sensitivity in young children. However, TSTs are susceptible to false-positive results following Bacille Calmette-Guérin (BCG) vaccination, which is common in infancy, and exposure to nontuberculous mycobacteria. We reviewed available data for IGRA performance in children under age 2 years. Across four cohorts of high-risk children under age 2 (mostly case contacts or those born in tuberculosis endemic regions), 0 of 575 untreated children with negative IGRA test results progressed to tuberculosis disease-including 0 of 70 who were TST positive but IGRA negative. While neither TSTs nor IGRAs are perfectly sensitive for the diagnosis of tuberculosis infection, IGRAs are an acceptable alternative to TST in children <2 years of age.

Examining Test Cutoffs to Optimize Diagnosis of Latent Tuberculosis Infection in People Born Outside the United States.

Rationale: Detection of latent tuberculosis infection (LTBI) in persons born in high tuberculosis (TB) incidence countries living in low TB incidence countries is key to TB elimination in low-incidence countries. Optimizing LTBI tests is critical to targeting treatment. Objectives: To compare the sensitivity and specificity of tuberculin skin test (TST) and two interferon-γ release assays at different cutoffs and of a single test versus dual testing. Methods: We examined a subset (N = 14,167) of a prospective cohort of people in the United States tested for LTBI. We included non-U.S.-born, human immunodeficiency virus-seronegative people ages 5 years and older with valid TST, QuantiFERON-TB Gold-in-Tube (QFT), and T-SPOT.TB (TSPOT) results. The sensitivity/specificity of different test cutoffs and test combinations, obtained from a Bayesian latent class model, were used to construct receiver operating characteristic (ROC) curves and assess the area under the curve (AUC) for each test. The sensitivity/specificity of dual testing was calculated. Results: The AUC of the TST ROC curve was 0.81 (95% credible interval (CrI), 0.78-0.86), with sensitivity/specificity at cutoffs of 5, 10, and 15 mm of 86.5%/61.6%, 81.7%/71.3%, and 55.6%/88.0%, respectively. The AUC of the QFT ROC curve was 0.89 (95% CrI, 0.86-0.93), with sensitivity/specificity at cutoffs of 0.35, 0.7, and 1.0 IU/mL of 77.7%/98.3%, 66.9%/99.1%, and 61.5%/99.4%. The AUC of the TSPOT ROC curve was 0.92 (95% CrI, 0.88-0.96) with sensitivity/specificity for five, six, seven, and eight spots of 79.2%/96.7%, 76.8%/97.7%, 74.0%/98.6%, and 71.8%/99.5%. Sensitivity/specificity of TST-QFT, TST-TSPOT, and QFT-TSPOT at standard cutoffs were 73.1%/99.4%, 64.8%/99.8%, and 65.3%/100%. Conclusion: Interferon-γ release assays have a better predictive ability than TST in people at high risk of LTBI.

Use of Statistical Process Control Methods for Early Detection of Healthcare Facility-Associated Nontuberculous Mycobacteria Outbreaks: A Single-Center Pilot Study.

BACKGROUND: Nontuberculous mycobacteria (NTM) are emerging pathogens increasingly implicated in healthcare facility-associated (HCFA) infections and outbreaks. We analyzed the performance of statistical process control (SPC) methods in detecting HCFA NTM outbreaks. METHODS: We retrospectively analyzed 3 NTM outbreaks that occurred from 2013 to 2016 at a tertiary care hospital. The outbreaks consisted of pulmonary Mycobacterium abscessus complex (MABC) acquisition, cardiac surgery-associated extrapulmonary MABC infection, and a bronchoscopy-associated pseudo-outbreak of Mycobacterium avium complex (MAC). We analyzed monthly case rates of unique patients who had positive respiratory cultures for MABC, non-respiratory cultures for MABC, and bronchoalveolar lavage cultures for MAC, respectively. For each outbreak, we used these rates to construct a pilot moving average (MA) SPC chart with a rolling baseline window. We also explored the performance of numerous alternative control charts, including exponentially weighted MA, Shewhart, and cumulative sum charts. RESULTS: The pilot MA chart detected each outbreak within 2 months of outbreak onset, preceding actual outbreak detection by an average of 6 months. Over a combined 117 months of pre-outbreak and post-outbreak surveillance, no false-positive SPC signals occurred (specificity, 100%). Prospective use of this chart for NTM surveillance could have prevented an estimated 108 cases of NTM. Six high-performing alternative charts detected all outbreaks during the month of onset, with specificities ranging from 85.7% to 94.9%. CONCLUSIONS: SPC methods have potential to substantially improve HCFA NTM surveillance, promoting early outbreak detection and prevention of NTM infections. Additional study is needed to determine the best application of SPC for prospective HCFA NTM surveillance in other settings.

Factors Associated With Receiving Longer Than Recommended Therapy Among Culture-Negative Pulmonary Tuberculosis Patients.

Background: US tuberculosis (TB) guidelines recommend treatment ≥6 months with a regimen composed of multiple effective anti-TB drugs. Since 2003, a 4-month regimen for a specific subset of TB patients has also been recommended. Methods: We used 2011-2018 US National Tuberculosis Surveillance System data to characterize factors associated with 4-month (111-140 days) therapy among adult patients who had completed treatment and were potentially eligible at that time for 4-month therapy (culture-negative pulmonary-only TB, absence of certain risk factors, and initial treatment that included pyrazinamide). We used modified Poisson regression with backward elimination of main effect variables to calculate adjusted relative risks (aRRs). Results: During 2011-2018, 63 393 adults completed TB treatment: 5560 (8.8%) were potentially eligible for 4-month therapy; of these, 5560 patients (79%) received >4-month therapy (median, 193 days or ∼6 months). Patients with cavitary disease were more likely to receive >4-month therapy (aRR, 1.10; 95% CI, 1.07-1.14) vs patients without cavitary disease. Patients more likely to receive 4-month therapy included patients treated by health departments vs private providers only (aRR, 0.94; 95% CI, 0.91-0.98), those in the South and West vs the Midwest, non-US-born persons (aRR, 0.95; 95% CI, 0.91-0.99) vs US-born persons, and aged 25-64 years vs 15-24 years. Conclusions: Most patients potentially eligible for 4-month therapy were treated with standard 6-month courses. Beyond clinical eligibility criteria, other patient- and program-related factors might be more critical determinants of treatment duration.

An ancestral mycobacterial effector promotes dissemination of infection.

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.

Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis.

BACKGROUND: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. METHODS: We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. RESULTS: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). CONCLUSIONS: The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.

Clinical Features and Treatment Outcomes of Pulmonary Mycobacterium avium-intracellulare Complex With and Without Coinfections.

Coinfections are more common in patients with cystic fibrosis and bronchiectasis. Infiltrates on imaging studies are seen more commonly in patients with coinfections, but coinfections did not affect treatment outcomes of pulmonary Mycobacterium avium complex.

A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis.

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.

COVID-19 Trials: Who Participates and Who Benefits?

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately afflicted vulnerable populations. Older adults, particularly residents of nursing facilities, represent a small percentage of the population but account for 40% of mortality from COVID-19 in the United States. Racial and ethnic minority individuals, particularly Black, Hispanic, and Indigenous Americans have experienced higher rates of infection and death than the White population. Although there has been an unprecedented explosion of clinical trials to examine potential therapies, participation by members of these vulnerable communities is crucial to obtaining data generalizable to those communities. METHODS: We undertook an open-label, factorial randomized clinical trial examining hydroxychloroquine and/or azithromycin for hospitalized patients. RESULTS: Of 53 screened patients, 11 (21%) were enrolled. Ten percent (3/31) of Black patients were enrolled, 33% (7/21) of White patients, and 50% (6/12) of Hispanic patients. Forty-seven percent (25/53) of patients declined participation despite eligibility; 58%(18/31) of Black patients declined participation. Forty percent (21/53) of screened patients were from a nursing facility and 10% (2/21) were enrolled. Enrolled patients had fewer comorbidities than nonenrolled patients: median modified Charlson comorbidity score 2.0 (interquartile range 0-2.5), versus 4.0 (interquartile range 2-6) for nonenrolled patients (P = 0.006). The limitations of the study were the low participation rate and the multiple treatment trials concurrently recruiting at our institution. CONCLUSIONS: The high rate of nonparticipation in our trial of nursing facility residents and Black people emphasizes the concern that clinical trials for therapeutics may not target key populations with high mortality rates.

Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Variability of interferon-γ release assays in people at high risk of tuberculosis infection or progression to tuberculosis disease living in the United States.

OBJECTIVES: Interferon-γ release assays, including T-SPOT.TB (TSPOT) and QuantiFERON Gold In-Tube (QFT), are important diagnostic tools for tuberculosis infection, but little work has been done to study the performance of these tests in populations prioritized for tuberculosis testing in the United States, especially those other than health care personnel. METHODS: Participants were enrolled as part of a large, prospective cohort of people at high risk of tuberculosis infection or progression to tuberculosis disease. All participants were administered a tuberculin skin test, TSPOT, and QFT test. A subset of participants had their QFT (n = 919) and TSPOT (n = 885) tests repeated when they returned to get their tuberculin skin test read 2 to 3 days later (repeat study). A total of 531 participants had a TSPOT performed twice on the same sample taken at the same time (split study). RESULTS: The QFT repeat test interpretations were discordant (one test positive and the other negative) for 6.4% of participants (59 of 919), and the TSPOT tests were discordant for 60 of 885 participants in the repeat study (6.8%) and 41 of 531 participants in the split study (7.7%). There was a high degree of variability in the quantitative test results for both QFT and TSPOT, and discordance was not associated with both test results being near the established cut-offs. Furthermore, the proportion of discordance was similar when comparing participants in both the TSPOT repeat and TSPOT split studies. DISCUSSION: Both QFT and TSPOT were 6% to 8% discordant. The results should be interpreted with caution, particularly when seeing a conversion or reversion in serial testing.

Consensus management recommendations for less common non-tuberculous mycobacterial pulmonary diseases.

The 2020 clinical practice guideline for the treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) by the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America; and the 2017 management guideline by the British Thoracic Society covered pulmonary diseases in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus. In order to provide evidence-based recommendations for the treatment of less common non-tuberculous mycobacterial (NTM) species in adult patients without cystic fibrosis or HIV infection, our expert panel group performed systematic literature searches to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Treatment recommendations were developed by a structured consensus process. The evidence from the scientific literature published in English for treatment recommendations for pulmonary diseases caused by other NTM species was of very low quality, with the exception of M malmoense, and based on the evaluation of case reports and case series. For M malmoense, results from two randomised controlled trials and three retrospective cohort studies provided a better evidence base for treatment recommendations, although the evidence was still of low quality.