Search

Background: The increase in SARS-CoV-2 infections in December 2021 was driven primarily by the Omicron variant, which largely displaced the Delta over a three-week span. Outcomes from infection with Omicron remain uncertain. We evaluated whether clinical outcomes and viral loads differed between Delta and Omicron infections during the period when both variants were co-circulating., Methods: In this retrospective observational cohort study, remnant clinical specimens, positive for SARS-CoV-2 after standard of care testing at the Johns Hopkins Microbiology Laboratory, between the last week of November and the end of December 2021, were used for whole viral genome sequencing. Cycle threshold values (Ct) for viral RNA, the presence of infectious virus, and levels of respiratory IgG were measured, and clinical outcomes were obtained. Differences in each measure were compared between variants stratified by vaccination status., Findings: The Omicron variant displaced Delta during the study period and constituted 95% of the circulating lineages by the end of December 2021. Patients with Omicron infections (N = 1,119) were more likely to be vaccinated compared to patients with Delta (N = 908), but were less likely to be admitted (0.33 CI 0.21-0.52), require ICU level care (0.38 CI 0.17-0.87), or succumb to infection (0.26 CI 0.06-1.02) regardless of vaccination status. There was no statistically significant difference in Ct values based on the lineage regardless of the vaccination status. Recovery of infectious virus in cell culture was reduced in boosted patients compared to fully vaccinated without a booster and unvaccinated when infected with the Delta lineage. However, in patients with Omicron infections, recovery of infectious virus was not affected by vaccination., Interpretation: Compared to Delta, Omicron was more likely to cause breakthrough infections of vaccinated individuals, yet admissions were less frequent. Admitted patients might develop severe disease comparable to Delta. Efforts for reducing Omicron transmission are required as, though the admission risk might be lower, the increased numbers of infections cause large numbers of hospitalizations., Funding: NIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N2772201400007C, Johns Hopkins University, Maryland department of health, Centers for Disease Control and Prevention contract 75D30121C11061, and The Modeling Infectious Diseases in Healthcare Network (MInD) under awards U01CK000589., Competing Interests: Declaration of interests We declare no relevant competing interests, (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Injuries disproportionately impact low- and middle-income countries like Malawi. The Lancet Commission on Global Surgery's indicators include the population proportion accessing laparotomy and open fracture care, key trauma interventions, within two hours. The "Golden Hour" for receiving facility-based resuscitation also guides injury care system strengthening. Firstly, we estimated the proportion of the local population able to reach primary, secondary and tertiary facility care within two and one hours using Geographic Information System (GIS) analysis. Secondly, we compared community household-reported with GIS-estimated travel time., Methods: Using information from a Health and Demographic Surveillance Site (Karonga, Malawi) on road network, facility location, and local staff-estimated travel speeds, we used a GIS-generated friction surface to calculate the shortest travel time from all households to each facility serving the population. We surveyed community households who reported travel time to their preferred, closest, government secondary and tertiary facilities. For recently injured community members, time to reach facility care was recorded. To assess the relationship between community household-reported travel time and GIS-estimated travel time, we used linear regression to generate a proportionality constant. To assess associations and agreement between injured patient-reported and GIS-estimated travel time, we used Kendall rank and Cohen's kappa tests., Results: Using GIS, we estimated 79.1% of households could reach any secondary facility, 20.5% the government secondary facility, and 0% the government tertiary facility, within two hours. Only 28.2% could reach any secondary facility within one hour, 0% for the government secondary facility. Community household-reported travel time exceeded GIS-estimated travel time. The proportionality constant was 1.25 (95%CI 1.21-1.30) for the closest facility, 1.28 (95%CI 1.23-1.34) for the preferred facility, 1.45 (95%CI 1.33-1.58) for the government secondary facility, and 2.12 (95%CI 1.84-2.41) for tertiary care. Comparing injured patient-reported with GIS-estimated travel time, the correlation coefficient was 0.25 (SE 0.047) and Cohen's kappa was 0.15 (95%CI 0.078-0.23), suggesting poor agreement., Discussion: Most households couldn't reach government secondary care within recognised thresholds indicating poor temporal access. Since GIS-estimated travel time was shorter than community-reported travel time, the true proportion may be lower still. GIS derived estimates of population emergency care access in similar contexts should be interpreted accordingly., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To evaluate the role of procalcitonin (PCT) results in antibiotic decisions for COVID-19 patients at hospital presentation., Design, Setting, and Participants: Multicenter retrospective observational study of patients ≥18 years hospitalized due to COVID-19 at the Johns Hopkins Health system. Patients who were transferred from another facility with >24 hours stay and patients who died within 48 hours of hospitalization were excluded., Methods: Elevated PCT values were determined based on each hospital's definition. Antibiotic therapy and PCT results were evaluated for patients with no evidence of bacterial community-acquired pneumonia (bCAP) and patients with confirmed, probable, or possible bCAP. The added value of PCT testing to clinical criteria in detecting bCAP was evaluated using receiving operating curve characteristics (ROC)., Results: Of 962 patients, 611 (64%) received a PCT test. ROC curves for clinical criteria and clinical criteria plus PCT test were similar (at 0.5 ng/mL and 0.25 ng/mL). By bCAP group, median initial PCT values were 0.58 ng/mL (interquartile range [IQR], 0.24-1.14), 0.23 ng/mL (IQR, 0.1-0.63), and 0.15 ng/mL (IQR, 0.09-0.35) for proven/probable, possible, and no bCAP groups, respectively. Among patients without bCAP, an elevated PCT level was associated with 1.8 additional days of CAP therapy (95% CI, 1.01-2.75; P < .01) compared to patients with a negative PCT result after adjusting for potential confounders. Duration of CAP therapy was similar between patients without a PCT test ordered and a low PCT level for no bCAP and possible bCAP groups., Conclusions: PCT results may be abnormal in COVID-19 patients without bCAP and may result in receipt of unnecessary antibiotics.

Background: Multidrug resistance and fluoroquinolone non-susceptibility (FQNS) are major concerns for the epidemiology and treatment of typhoid fever. The 2018 prequalification of the first typhoid conjugate vaccine (TCV) by WHO provides an opportunity to limit the transmission and burden of antimicrobial-resistant typhoid fever., Methods: We combined output from mathematical models of typhoid transmission with estimates of antimicrobial resistance from meta-analyses to predict the burden of antimicrobial-resistant typhoid fever across 73 lower-income countries eligible for support from Gavi, the Vaccine Alliance. We considered FQNS and multidrug resistance separately. The effect of vaccination was predicted on the basis of forecasts of vaccine coverage. We explored how the potential effect of vaccination on the prevalence of antimicrobial resistance varied depending on key model parameters., Findings: The introduction of routine immunisation with TCV at age 9 months with a catch-up campaign up to age 15 years was predicted to avert 46-74% of all typhoid fever cases in 73 countries eligible for Gavi support. Vaccination was predicted to reduce the relative prevalence of antimicrobial-resistant typhoid fever by 16% (95% prediction interval [PI] 0-49). TCV introduction with a catch-up campaign was predicted to avert 42·5 million (95% PI 24·8-62·8 million) cases and 506 000 (95% PI 187 000-1·9 million) deaths caused by FQNS typhoid fever, and 21·2 million (95% PI 16·4-26·5 million) cases and 342 000 (95% PI 135 000-1·5 million) deaths from multidrug-resistant typhoid fever over 10 years following introduction., Interpretation: Our results indicate the benefits of prioritising TCV introduction for countries with a high avertable burden of antimicrobial-resistant typhoid fever., Funding: The Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests RB is now employed by Merck Sharp & Dohme. AJP has received grants from National Institute for Health Research, the Bill & Melinda Gates Foundation, Wellcome Trust, and Astra Zeneca outside of the submitted work; chairs the UK Department of Health's Joint Committee on Vaccination and Immunisation; and is a member of WHO's Strategic Advisory Group of Experts. VEP has received reimbursement from Merck and Pfizer for travel expenses to Scientific Input Engagements unrelated to the subject of this Article; and is a member of the WHO's Immunization and Vaccine-related Implementation Research Advisory Committee. The views expressed in this manuscript are those of the authors and do not necessarily reflect the views of the Joint Committee on Vaccination and Immunisation, Department of Health, or WHO. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

India is among the top three countries in the world both in COVID-19 case and death counts. With the pandemic far from over, timely, transparent, and accessible reporting of COVID-19 data continues to be critical for India's pandemic efforts. We systematically analyze the quality of reporting of COVID-19 data in over one hundred government platforms (web and mobile) from India. Our analyses reveal a lack of granular data in the reporting of COVID-19 surveillance, vaccination, and vacant bed availability. As of 5 June 2021, age and gender distribution are available for less than 22% of cases and deaths, and comorbidity distribution is available for less than 30% of deaths. Amid rising concerns of undercounting cases and deaths in India, our results highlight a patchy reporting of granular data even among the reported cases and deaths. Furthermore, total vaccination stratified by healthcare workers, frontline workers, and age brackets is reported by only 14 out of India's 36 subnationals (states and union territories). There is no reporting of adverse events following immunization by vaccine and event type. By showing what, where, and how much data is missing, we highlight the need for a more responsible and transparent reporting of granular COVID-19 data in India., Competing Interests: The authors declare that there are no competing interests., (Copyright: © 2022 Vasudevan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Large-scale SARS-CoV-2 molecular testing coupled with whole genome sequencing in the diagnostic laboratories is instrumental for real-time genomic surveillance. The extensive genomic, laboratory, and clinical data provide a valuable resource for understanding cases of reinfection versus prolonged RNA shedding and protracted infections. In this study, data from a total of 22,292 clinical specimens, positive by SARS-CoV-2 molecular diagnosis at Johns Hopkins clinical virology laboratory between March 11 th 2020 to September 23 rd 2021, were used to identify patients with two or more positive results. A total of 3,650 samples collected from 1,529 patients who had between 2 and 20 positive results were identified in a time frame that extended up to 403 days from the first positive. Cycle threshold values (Ct) were available for 1,622 samples, the median of which was over 30 by 11 days after the first positive. Extended recovery of infectious virus on cell culture was notable for up to 70 days after the first positive in immunocompromised patients. Whole genome sequencing data generated as a part of our SARS-CoV-2 genomic surveillance was available for 1,027 samples from patients that had multiple positive tests. Positive samples collected more than 10 days after initial positive with high quality sequences (coverage >90% and mean depth >100), were more likely to be from unvaccinated, or immunosuppressed patients. Reinfections with viral variants of concern were found in 3 patients more than 130 days from prior infections with a different viral clade. In 75 patients that had 2 or more high quality sequences, the acquisition of more substitutions or deletions was associated with lack of vaccination and longer time between the recovered viruses. Our study highlights the value of integrating genomic, laboratory, and clinical data for understanding the biology of SARS-CoV-2 as well as for setting a precedent for future epidemics and pandemics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morris, Luo, Sachithanandham, Li, Schwartz, Gaston, Gniazdowski, Giraldo-Castillo, Amadi, Norton, Wright, Klein, Pekosz and Mostafa.)

Universal coverage of routine childhood vaccines remains a challenge in many low- and middle-income countries (LMICs). In India, vaccination campaigns have increased full immunization coverage among 12-23 month old children from an estimated 62% in 2015-2016 to 76% in 2019-2020. Long-term improvements in coverage will likely require systemic changes to both the supply and demand sides of immunization programs. However, the effect of health system inputs on child vaccination outcomes remains poorly quantified in India. We examined the association between the quality of public health facilities and child vaccination outcomes in rural India using data from the nationally representative Integrated Child Health and Immunization Survey (2015-2016) which covered 1,346 public primary health sub-centers and 44,571 households. We constructed two indices of sub-center quality using multiple correspondence analysis: one related to the general health infrastructure quality and the other measuring vaccine service delivery. Using probit regression, we analyzed the relationship between vaccination outcomes in children under 2 years of age and sub-center quality, controlling for household socioeconomic characteristics. Additionally, we conducted Fairlie decomposition analysis by wealth group - bottom wealth quintile relative to the top four wealth quintiles- to examine factors contributing to gaps in immunization between rich and poor households. Infrastructure quality index was positively associated with completion of seven vaccination outcomes: full immunization, DPT-1 (first dose of diphtheria, pertussis, and tetanus), DPT-2, DPT-3, Bacillus Calmette-Guérin (BCG), hepatitis B (birth dose), and on-time vaccination (OTV). Vaccine service delivery index was positively associated with completion of measles vaccination. The distribution of infrastructure quality contributed to increased gaps in full immunization and OTV between rich and poor households, while greater proximity to vaccination site for poorer households reduced these gaps. Improved quality of health facilities, particularly facilities used by low-income households, may improve vaccination outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: India has been severely affected by the ongoing COVID-19 pandemic. However, due to shortcomings in disease surveillance, the burden of mortality associated with COVID-19 remains poorly understood. We aimed to assess changes in mortality during the pandemic in Chennai, Tamil Nadu, using data on all-cause mortality within the district., Methods: For this observational study, we analysed comprehensive death registrations in Chennai, from Jan 1, 2016, to June 30, 2021. We estimated expected mortality without the effects of the COVID-19 pandemic by fitting models to observed mortality time series during the pre-pandemic period, with stratification by age and sex. Additionally, we considered three periods of interest: the first 4 weeks of India's first lockdown (March 24 to April 20, 2020), the 4-month period including the first wave of the pandemic in Chennai (May 1 to Aug 31, 2020), and the 4-month period including the second wave of the pandemic in Chennai (March 1 to June 30, 2021). We computed the difference between observed and expected mortality from March 1, 2020, to June 30, 2021, and compared pandemic-associated mortality across socioeconomically distinct communities (measured with use of 2011 census of India data) with regression analyses., Findings: Between March 1, 2020, and June 30, 2021, 87 870 deaths were registered in areas of Chennai district represented by the 2011 census, exceeding expected deaths by 25 990 (95% uncertainty interval 25 640-26 360) or 5·18 (5·11-5·25) excess deaths per 1000 people. Stratified by age, excess deaths numbered 21·02 (20·54-21·49) excess deaths per 1000 people for individuals aged 60-69 years, 39·74 (38·73-40·69) for those aged 70-79 years, and 96·90 (93·35-100·16) for those aged 80 years or older. Neighbourhoods with lower socioeconomic status had 0·7% to 2·8% increases in pandemic-associated mortality per 1 SD increase in each measure of community disadvantage, due largely to a disproportionate increase in mortality within these neighbourhoods during the second wave. Conversely, differences in excess mortality across communities were not clearly associated with socioeconomic status measures during the first wave. For each increase by 1 SD in measures of community disadvantage, neighbourhoods had 3·6% to 8·6% lower pandemic-associated mortality during the first 4 weeks of India's country-wide lockdown, before widespread SARS-CoV-2 circulation was underway in Chennai. The greatest reductions in mortality during this early lockdown period were observed among men aged 20-29 years, with 58% (54-62) fewer deaths than expected from pre-pandemic trends., Interpretation: Mortality in Chennai increased substantially but heterogeneously during the COVID-19 pandemic, with the greatest burden concentrated in disadvantaged communities. Reported COVID-19 deaths greatly underestimated pandemic-associated mortality., Funding: National Institute of General Medical Sciences, Bill & Melinda Gates Foundation, National Science Foundation., Translation: For the Hindi translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

This paper assesses the economic value of genetically engineered (GE) Anopheles gambiae mosquitoes as a malaria control strategy. We use an epidemiological-economic model of malaria transmission to evaluate this technology for a range of village-level transmission settings. In each setting, we evaluate public health outcomes following introduction of GE mosquitoes relative to a "status quo" baseline scenario. We also assess results both in contrast to-and in combination with-a Mass Drug Administration (MDA) strategy. We find that-in low transmission settings-the present value (PV) public health benefits of GE mosquito release are substantial, both relative to status quo dynamics and MDA. In contrast, in high transmission settings, the release of GE mosquitoes may increase steady-state infection rates. Our results indicate that there are substantial policy complementarities when GE mosquito release is combined with local MDA-the combined control strategy can lead to local eradication., (© 2021 Wiley-VCH GmbH.)

SignificanceStrategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens, and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria. In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 mo of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.

Background: The rising prevalence of multi-drug resistant organisms (MDROs), such as Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE), and Carbapenem-resistant Enterobacteriaceae (CRE), is an increasing concern in healthcare settings., Materials and Methods: Leveraging data from electronic healthcare records and a unique MDRO universal screening program, we developed a data-driven modeling framework to predict MRSA, VRE, and CRE colonization upon intensive care unit (ICU) admission, and identified the associated socio-demographic and clinical factors using logistic regression (LR), random forest (RF), and XGBoost algorithms. We performed threshold optimization for converting predicted probabilities into binary predictions and identified the cut-off maximizing the sum of sensitivity and specificity., Results: Four thousand six hundred seventy ICU admissions (3,958 patients) were examined. MDRO colonization rate was 17.59% (13.03% VRE, 1.45% CRE, and 7.47% MRSA). Our study achieved the following sensitivity and specificity values with the best performing models, respectively: 80% and 66% for VRE with LR, 73% and 77% for CRE with XGBoost, 76% and 59% for MRSA with RF, and 82% and 83% for MDRO (i.e., VRE or CRE or MRSA) with RF. Further, we identified several predictors of MDRO colonization, including long-term care facility stay, current diagnosis of skin/subcutaneous tissue or infectious/parasitic disease, and recent isolation precaution procedures before ICU admission., Conclusion: Our data-driven modeling framework can be used as a clinical decision support tool for timely predictions, characterization and identification of high-risk patients, and selective and timely use of infection control measures in ICUs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Çaǧlayan, Barnes, Pineles, Harris and Klein.)

Background: Next-generation sequencing has considerably increased the number of genomes available in the public domain. However, efforts to use these genomes for surveillance of antimicrobial resistance have thus far been limited and geographically heterogeneous. We inferred global resistance trends in Escherichia coli in food animals using genomes from public databases., Methods: We retrieved 7632 E. coli genomes from public databases (NCBI, PATRIC and EnteroBase) and screened for antimicrobial resistance genes (ARGs) using ResFinder. Selection bias towards resistance, virulence or specific strains was accounted for by screening BioProject descriptions. Temporal trends for MDR, resistance to antimicrobial classes and ARG prevalence were inferred using generalized linear models for all genomes, including those not subjected to selection bias., Results: MDR increased by 1.6 times between 1980 and 2018, as genomes carried, on average, ARGs conferring resistance to 2.65 antimicrobials in swine, 2.22 in poultry and 1.58 in bovines. Highest resistance levels were observed for tetracyclines (42.2%-69.1%), penicillins (19.4%-47.5%) and streptomycin (28.6%-56.6%). Resistance trends were consistent after accounting for selection bias, although lower mean absolute resistance estimates were associated with genomes not subjected to selection bias (difference of 3.16%±3.58% across years, hosts and antimicrobial classes). We observed an increase in extended-spectrum cephalosporin ARG blaCMY-2 and a progressive substitution of tetB by tetA. Estimates of resistance prevalence inferred from genomes in the public domain were in good agreement with reports from systematic phenotypic surveillance., Conclusions: Our analysis illustrates the potential of using the growing volume of genomes in public databases to track AMR trends globally., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Assessing the effectiveness of antibiotics and communicating the problem of resistance are essential when devising antimicrobial stewardship programs (ASPs) in hospital settings. The Drug Resistance Index (DRI) is a useful tool that combines antibiotic consumption and bacterial resistance into a single measure. In this study, we used the DRI to assess the impact of introducing a new antibiotic restriction form on antibiotic effectiveness for the treatment of Gram-negative infections in the intensive care unit (ICU)., Methods: This was an observational study to assess and evaluate the antibiotic susceptibility of Gram-negative bacteria and antibiotic prescribing rates for the antibiotics indicated for Gram-negative bacteria following the introduction of a new antibiotic restriction form. The study was conducted from 2015 to 2017 at King Abdulaziz Medical City, a tertiary care facility in Jeddah, Saudi Arabia. Changes in antibiotic effectiveness before and after the introduction of the form were evaluated by calculating the DRI for four of the most common Gram-negative pathogens and eight commonly used antibiotic classes., Results: The overall DRI for the adult ICU was higher (59.45) in comparison to the hospital-wide DRI (47.96). A higher DRI was evident for carbapenems and antipseudomonal penicillins + beta-lactamase inhibitors. Acinetobacter baumannii had the highest DRI followed by Klebsiella pneumoniae in both the adult ICU and hospital-wide. After the implementation of antibiotic restriction in the adult ICU, the DRI for carbapenems was significantly lower in the post-intervention phase (from 31.61 to 26.05) (p = 0.031)., Conclusion: The DRI is a useful tool for tracking the effectiveness of antibiotics over time. The results of our study are significant in the way that it highlights the importance of having an effective antibiotic stewardship program in healthcare settings and regular feedback of antibiotic consumption data to the stakeholders to keep the antibiotic prescriptions in check, thereby ensuring their sustained effectiveness., Competing Interests: Professor Essack is the chairperson of the Global Respiratory Infection Partnership (GRIP) sponsored by an unrestricted educational grant from Reckitt and Benckiser (Pty) Limited, UK. We declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022, Yaseen et al.)

Competing Interests: RL reports grants from the Bill & Melinda Gates Foundation, outside the area of work commented on here.

India's Universal Immunization Programme (UIP) is among the largest routine childhood vaccination programmes in the world. However, only an estimated 65% of Indian children under the age 2 years were fully vaccinated in 2019. We estimated the cost of raising childhood vaccination coverage to a minimum of 90% in each district in India. We obtained vaccine price data from India's comprehensive multi-year strategic plan for immunization. Cost of vaccine delivery by district was derived from a 2018 field study in 24 districts. We used propensity score matching methods to match the remaining Indian districts with these 24, based on indicators from the National Family Health Survey (2015-16). We assumed the same unit cost of vaccine delivery in matched pair districts and estimated the total and incremental cost of providing routine vaccines to 90% of the current cohort of children in each district. The estimated national cost of providing basic vaccinations-one dose each of Bacillus Calmette-Guerin (BCG) and measles vaccines, and three doses each of oral polio (OPV) and diphtheria, pertussis and tetanus vaccines-was $784.91 million (2020 US$). Considering all childhood vaccines included in UIP during 2018-22 (one dose each of BCG, hepatitis B and measles-rubella; four doses of OPV; two doses of inactivated polio; and three doses each of rotavirus, pneumococcal and pentavalent vaccines), the estimated national cost of vaccines and delivery to 90% of target children in each district was $1.73 billion. The 2018 UIP budget for vaccinating children, pregnant women and adults was $1.17 billion (2020 US$). In comparison, $1.73 billion would be needed to vaccinate 90% of children in all Indian districts with the recommended schedule of routine childhood vaccines. Additional costs for infrastructural investments and communication activities, not incorporated in this study, may also be necessary., (© The Author(s) 2021. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

In the early stages of a pandemic, non-pharmaceutical interventions (NPIs) that encourage physical distancing and reduce contact can decrease and delay disease transmission. Although NPIs have been implemented globally during the COVID-19 pandemic, their intensity and timing have varied widely. This paper analyzed the country-level determinants and effects of NPIs during the early stages of the pandemic (January 1st to April 29th, 2020). We examined countries that had implemented NPIs within 30 or 45 days since first case detection, as well as countries in which 30 or 45 days had passed since first case detection. The health and socioeconomic factors associated with delay in implementation of three NPIs-national school closure, national lockdown, and global travel ban-were analyzed using fractional logit and probit models, and beta regression models. The probability of implementation of national school closure, national lockdown, and strict national lockdown by a country was analyzed using a probit model. The effects of these three interventions on mobility changes were analyzed with propensity score matching methods using Google's social mobility reports. Countries with larger populations and better health preparedness measures had greater delays in implementation. Countries with greater population density, higher income, more democratic political systems, and later arrival of first cases were more likely to implement NPIs within 30 or 45 days of first case detection. Implementation of lockdowns significantly reduced physical mobility. Mobility was further reduced when lockdowns were enforced with curfews or fines, or when they were more strictly defined. National school closures did not significantly change mobility., (© 2021. The Author(s).)

Background: The increase in SARS-CoV-2 infections in December 2021 in the United States was driven primarily by the Omicron variant which largely displaced the Delta over a three week span. Outcomes from infection with the Omicron remain uncertain. We evaluate whether clinical outcomes and viral loads differ between Delta and Omicron infections during the period when both variants were co-circulating., Methods: Remnant clinical specimens from patients that tested positive for SARS-CoV-2 after standard of care testing between the last week of November and the end of December 2021were used for whole viral genome sequencing. Cycle threshold values (Ct) for viral RNA, the presence of infectious virus, and levels of respiratory IgG were measured, and clinical outcomes were obtained. Differences in each measure were compared between variants stratified by vaccination status., Results: The Omicron variant displaced the Delta during the study period and constituted 95% of the circulating lineages by the end of December 2021. Patients with Omicron infections (N= 1121) were more likely to be vaccinated compared to patients with Delta (N = 910), but were less likely to be admitted, require ICU level care, or succumb to infection regardless of vaccination status. There was no significant difference in Ct values based on the lineage regardless of the vaccination status. Recovery of infectious virus in cell culture was reduced in boosted patients compared to fully vaccinated without a booster and unvaccinated when infected with the Delta lineage. However, in patients with Omicron infections, recovery of infectious virus was not affected by vaccination., Conclusions: Omicron infections of vaccinated individuals are expected, yet admissions are less frequent. Admitted patients might develop severe disease comparable to Delta. Efforts for reducing the Omicron transmission are required as even though the admission risk is lower, the numbers of infections continue to be high., Research in Context Evidence Before This Study: The unprecedented increase in COVID-19 cases in the month of December 2021, associated with the displacement of the Delta variant with the Omicron, triggered a lot of concerns. An understanding of the disease severity associated with infections with Omicron is essential as well as the virological determinants that contributed to its widespread predominance. We searched PubMed for articles published up to January 23, 2022, using the search terms ("Omicron") AND ("Disease severity") as well as ("Omicron") AND ("Viral load") And/ or ("Cell culture"). Our search yielded 3 main studies that directly assessed the omicron's clinical severity in South Africa, its infectious viral load compared to Delta, and the dynamics of viral RNA shedding. In South Africa, compared to Delta, Omicron infected patients showed a significant reduction in severe disease. In this study, Omicron and non-Omicron variants were characterized based on S gene target failure using the TaqPath COVID-19 PCR (Thermo Fisher Scientific). In the study from Switzerland that assessed the infectious viral load in Omicron versus Delta, the authors analyzed only 18 Omicron samples that were all from vaccinated individuals to show that compared to Delta, Omicron had equivalent infectious viral titers. The third study that assessed the Omicron viral dynamics showed that the peak viral RNA in Omicron infections is lower than Delta. No published studies assessed the clinical discrepancies of Omicron and Delta infected patients from the US, nor comprehensively assessed, by viral load and cell culture studies, the characteristics of both variants stratified by vaccination status., Added Value of This Study: To the best of our knowledge, this is the only study to date to compare the clinical characteristics and outcomes after infection with the Omicron variant compared to Delta in the US using variants characterized by whole genome sequencing and a selective time frame when both variant co-circulated. It is also the first study to stratify the analysis based on the vaccination status and to compare fully vaccinated patients who didn't receive a booster vaccination to patients who received a booster vaccination. In addition, we provide a unique viral RNA and infectious virus load analyses to compare Delta and Omicron samples from unvaccinated, fully vaccinated, and patients with booster vaccination., Implications of All the Available Evidence: Omicron associated with a significant increase in infections in fully and booster vaccinated individuals but with less admissions and ICU level care. Admitted patients showed similar requirements for supplemental oxygen and ICU level care when compared to Delta admitted patients. Viral loads were similar in samples from Omicron and Delta infected patients regardless of the vaccination status. The recovery of infectious virus on cell culture was reduced in samples from patients infected with Delta who received a booster dose, but this was not the case with Omicron. The recovery of infectious virus was equivalent in Omicron infected unvaccinated, fully vaccinated, and samples from patients who received booster vaccination., Funding: NIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N2772201400007C, Johns Hopkins University, Maryland department of health, Centers for Disease Control and Prevention contract 75D30121C11061.

Standard treatment guidelines (STGs) are an important tool for ensuring high quality clinical care and prudent antimicrobial use (AMU) and stewardship (AMS). In 2018, African Union (AU) member state representatives recognized the lack of STGs as a barrier to AMS at national and facility levels. Previous research reported that only 17 of 55 (31%) member states had STGs that provided disease- or pathogen-specific antimicrobial treatment recommendations, excluding those that covered only treatment of HIV, malaria, and tuberculosis). The Africa Centres for Disease Control and Prevention convened expert panels to develop first edition antibiotic treatment guidelines for priority infectious diseases and clinical syndromes for pediatric and adult patient populations in Africa. The purpose of the guidelines is to provide healthcare workers with treatment guidance by harmonising existing national STGs, filling gaps where existing STGs are not available, and serving as a model for future guidelines. Two expert panels of 28 total clinicians, pharmacists, and other relevant stakeholders from 14 AU member states representing each continental region convened to develop consensus treatment recommendations for select priority bacterial infections and clinical syndromes. In developing recommendations, the panels considered treatment recommendations from existing STGs, drug availability, clinical experience, and available antimicrobial resistance data. The guidelines underwent an external review process where clinical stakeholders who did not serve on either panel were invited to submit feedback prior to their publication. The guidelines provide empiric antibiotic therapy guidelines - including drug selection, route of administration, formulation, dosage, and therapy duration - and principles of stewardship for 28 bacterial infections or clinical syndromes. The first edition guidelines for the treatment of common infectious diseases and clinical syndromes in Africa aims to improve clinical treatment and antimicrobial stewardship and will serve as a template for future regional guidelines., Competing Interests: Conflict of interest: The authors declare no conflicts of interest., (©Copyright: the Author(s).)

Background: Multiple factors affect incident infection rates (IIR) for Pseudomonas aeruginosa (PA) and methicillin resistant Staphylococcus aureus (MRSA) at CF care centers. We assessed changes in IIR across CF centers temporally associated with the 2013 Infection/Prevention & Control guidelines controlling for center-specific factors., Methods: Using the CF Foundation Patient Registry we defined and measured changes in IIR between 2010-2012 and 2014-2016. Data were compared to non-CF rates of MRSA and resistant PA in geographically similar regions. Characteristics of each CF center (n centers: Adult 54 in 2010 to 82 in 2016. Pediatric ∼106) and their respective population were evaluated for associations with IIR and with changes in IIR between the study periods., Results: Across the years 35613 patients were included. Incident-infection rates for PA (mean 19.2±0.04% Pediatric, 21.2±0.07% Adult centers) were higher than for MRSA (mean 9.4±0.03% Pediatric, 7.8±0.03% Adult). The IIR decreased for MRSA (-1.54±0.54%, p<0.001) and PA (-4.77±0.63%, p<0.001) at Pediatric but only for PA (-3.20±1.31, p=0.02) at Adult centers. Except for Adult CF, MRSA rates (CF and non-CF) were highest in the South. In 2014-2016, private insurance and a higher proportion of LatinX patients at a center were associated with lower MRSA IIR while larger center size, higher proportion of LatinX, and lower mean center-wide lung function were associated with higher PA IIR. Higher IIR in 2010-2012, were predictive of a more pronounced decrease in IIR in 2014-2016 for MRSA and PA (p<0.001). Different factors indicative of lower social status (smoking, insurance, education) in 2010-2012 predicted decreases in MRSA or PA IIR., Conclusion: Comparisons of IIR across U.S. CF centers should consider location, ethnic background and socio-economic variables of a center's population., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To identify and compare antimicrobial treatment guidelines from African Union (AU) Member States., Methods: We reviewed national government agency and public health institutes' websites and communicated with country or regional focal points to identify existing treatment guidelines from AU Member States. We included guidelines if they contained disease-, syndrome- or pathogen-specific treatment recommendations and if those recommendations included antimicrobial name or class, dosage and therapy duration. The scope of the review was limited to infections and clinical syndromes that often have a bacterial cause. We assessed treatment guidelines for alignment with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. We compared treatment recommendations for various common bacterial infections or clinical syndromes described across national guidelines and those described in three World Health Organization guidelines., Findings: We identified 31 treatment guidelines from 20 of the 55 (36%) AU Member States; several countries had more than one treatment guideline that met our inclusion criteria. Fifteen (48%) guidelines from 10 countries have been published or updated since 2015. Methods used to develop the guidelines were not well described. No guidelines were developed according to the GRADE approach. Antimicrobial selection, dosage and duration of recommended therapies varied widely across guidelines for all infections and syndromes., Conclusion: AU Member States lack antimicrobial treatment guidelines that meet internationally accepted methods and that draw from local evidence about disease burden and antimicrobial susceptibility., ((c) 2022 The authors; licensee World Health Organization.)

Objective: To reduce inappropriate antibiotic prescribing for acute respiratory infections (ARIs) by employing peer comparison with behavioral feedback in the emergency department (ED)., Design: A controlled before-and-after study., Setting: The study was conducted in 5 adult EDs at teaching and community hospitals in a health system., Patients: Adults presenting to the ED with a respiratory condition diagnosis code. Hospitalized patients and those with a diagnosis code for a non-respiratory condition for which antibiotics are or may be warranted were excluded., Interventions: After a baseline period from January 2016 to March 2018, 3 EDs implemented a feedback intervention with peer comparison between April 2018 and December 2019 for attending physicians. Also, 2 EDs in the health system served as controls. Using interrupted time series analysis, the inappropriate ARI prescribing rate was calculated as the proportion of antibiotic-inappropriate ARI encounters with a prescription. Prescribing rates were also evaluated for all ARIs. Attending physicians at intervention sites received biannual e-mails with their inappropriate prescribing rate and had access to a dashboard that was updated daily showing their performance relative to their peers., Results: Among 28,544 ARI encounters, the inappropriate prescribing rate remained stable at the control EDs between the 2 periods (23.0% and 23.8%). At the intervention sites, the inappropriate prescribing rate decreased significantly from 22.0% to 15.2%. Between periods, the overall ARI prescribing rate was 38.1% and 40.6% in the control group and 35.9% and 30.6% in the intervention group., Conclusions: Behavioral feedback with peer comparison can be implemented effectively in the ED to reduce inappropriate prescribing for ARIs., (© The Author(s) 2021.)

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Data from the National Inpatient Sample demonstrate that methicillin-resistant Staphylococcus aureus (MRSA)-related septicemia hospitalizations increased from 1.67 (95% CI, 1.63-1.72) to 1.94 (95% CI, 1.88-2.00; P trend  < .001) discharges per 1000 hospitalizations between 2016 and 2019. Regionally, the trends were similar. Rates of MSSA-related septicemia and pneumonia hospitalizations also increased significantly over this time period., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The number of bacterial genomes deposited each year in public databases is growing exponentially. However, efforts to use these genomes to track trends in antimicrobial resistance (AMR) have been limited thus far. We used 22,102 genomes from public databases to track AMR trends in nontyphoidal Salmonella in food animals in the United States. In 2018, genomes deposited in public databases carried genes conferring resistance, on average, to 2.08 antimicrobial classes in poultry, 1.74 in bovines, and 1.28 in swine. This represents a decline in AMR of over 70% compared to the levels in 2000 in bovines and swine, and an increase of 13% for poultry. Trends in resistance inferred from genomic data showed good agreement with U.S. phenotypic surveillance data (weighted mean absolute difference ± standard deviation, 5.86% ± 8.11%). In 2018, resistance to 3rd-generation cephalosporins in bovines, swine, and poultry decreased to 9.97% on average, whereas in quinolones and 4th-generation cephalosporins, resistance increased to 12.53% and 3.87%, respectively. This was concomitant with a decrease of bla CMY-2 but an increase in bla CTX-M-65 and gyrA D87Y (encoding a change of D to Y at position 87). Core genome single-nucleotide polymorphism (SNP) phylogenies show that resistance to these antimicrobial classes was predominantly associated with Salmonella enterica serovar Infantis and, to a lesser extent, S. enterica serovar Typhimurium and its monophasic variant I 4,[5],12:i:-, whereas quinolone resistance was also associated with S. enterica serovar Dublin. Between 2000 and 2018, trends in serovar prevalence showed a composition shift where S. Next-generation sequencing has led to an exponential increase in the number of genomes deposited in public repositories. This growing volume of information presents opportunities to track the prevalence of genes conferring antimicrobial resistance (AMR), a growing threat to the health of humans and animals. Using 22,102 public genomes, we estimated that the prevalence of multidrug resistance (MDR) in the United States decreased in nontyphoidal Salmonella isolates recovered from bovines and swine between 2000 and 2018, whereas it increased in poultry. These trends are consistent with those detected by national surveillance systems that monitor resistance using phenotypic testing. However, using genomes, we identified that genes conferring resistance to critically important antimicrobials were associated with specific MDR serovars that could be the focus for future interventions. Our analysis illustrates the growing potential of public repositories to monitor AMR trends and shows that similar efforts could soon be carried out in other regions where genomic surveillance is increasing.S. Infantis increased. Our findings illustrate the growing potential of using genomes in public databases to track AMR in regions where sequencing capacities are currently expanding. IMPORTANCE Next-generation sequencing has led to an exponential increase in the number of genomes deposited in public repositories. This growing volume of information presents opportunities to track the prevalence of genes conferring antimicrobial resistance (AMR), a growing threat to the health of humans and animals. Using 22,102 public genomes, we estimated that the prevalence of multidrug resistance (MDR) in the United States decreased in nontyphoidal Salmonella isolates recovered from bovines and swine between 2000 and 2018, whereas it increased in poultry. These trends are consistent with those detected by national surveillance systems that monitor resistance using phenotypic testing. However, using genomes, we identified that genes conferring resistance to critically important antimicrobials were associated with specific MDR serovars that could be the focus for future interventions. Our analysis illustrates the growing potential of public repositories to monitor AMR trends and shows that similar efforts could soon be carried out in other regions where genomic surveillance is increasing.

Artificial intelligence (AI) refers to the performance of tasks by machines ordinarily associated with human intelligence. Machine learning (ML) is a subtype of AI; it refers to the ability of computers to draw conclusions (ie, learn) from data without being directly programmed. ML builds from traditional statistical methods and has drawn significant interest in healthcare epidemiology due to its potential for improving disease prediction and patient care. This review provides an overview of ML in healthcare epidemiology and practical examples of ML tools used to support healthcare decision making at 4 stages of hospital-based care: triage, diagnosis, treatment, and discharge. Examples include model-building efforts to assist emergency department triage, predicting time before septic shock onset, detecting community-acquired pneumonia, and classifying COVID-19 disposition risk level. Increasing availability and quality of electronic health record (EHR) data as well as computing power provides opportunities for ML to increase patient safety, improve the efficiency of clinical management, and reduce healthcare costs., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2021.)

Antibiotic use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients during the COVID-19 pandemic has exceeded the incidence of bacterial coinfections and secondary infections, suggesting inappropriate and excessive prescribing. Even in settings with established antimicrobial stewardship (AMS) programmes, there were weaknesses exposed regarding appropriate antibiotic use in the context of the pandemic. Moreover, antimicrobial resistance (AMR) surveillance and AMS have been deprioritised with diversion of health system resources to the pandemic response. This experience highlights deficiencies in AMR containment and mitigation strategies that require urgent attention from clinical and scientific communities. These include the need to implement diagnostic stewardship to assess the global incidence of coinfections and secondary infections in COVID-19 patients, including those by multidrug-resistant pathogens, to identify patients most likely to benefit from antibiotic treatment and identify when antibiotics can be safely withheld, de-escalated or discontinued. Long-term global surveillance of clinical and societal antibiotic use and resistance trends is required to prepare for subsequent changes in AMR epidemiology, while ensuring uninterrupted supply chains and preventing drug shortages and stock outs. These interventions present implementation challenges in resource-constrained settings, making a case for implementation research on AMR. Knowledge and support for these practices will come from internationally coordinated, targeted research on AMR, supporting the preparation for future challenges from emerging AMR in the context of the current COVID-19 pandemic or future pandemics., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Only an estimated 62% of Indian children under the age of 2 years are fully immunized. We examined the association between India's Mission Indradhanush (MI)-a periodic intensification of the routine immunization program-which was implemented in phases across districts between March 2015 and July 2017, and routine vaccination coverage and timeliness among children. We used data from a 2015 to 2016 national survey of children (n = 29,532) and employed difference-in-difference regressions to examine binary indicators of receipt of 11 vaccines and whether vaccines were received at recommended ages. The full immunization rate was 27% higher among children under 2 years old residing in MI phase 1 and 2 districts (intervention group) as compared with those residing elsewhere (control group). The rate of receiving all vaccines at recommended ages was 8% higher in the intervention group. Receiving doses of oral polio vaccine (OPV) birth dose, OPV dose 1 (OPV1), OPV2, OPV3, bacillus Calmette-Guérin, and hepatitis B birth dose vaccines were 9%, 9%, 11%, 16%, 5%, and 19% higher in the intervention group than the control group, respectively. More research is required on the cost-effectiveness of investing in MI-type programs as compared with routine immunization., (© 2021 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

India has one of the highest rates of antimicrobial resistance (AMR) worldwide. Despite being prescription drugs, antibiotics are commonly available over-the-counter (OTC) at retail pharmacies. We aimed to gain insight into the OTC sale of antibiotics at retail pharmacies and to elucidate its underlying drivers. We conducted face-to-face, in-depth interviews using convenience sampling with 22 pharmacists and 14 informal dispensers from 36 retail pharmacies across two Indian states (Haryana and Telangana). Thematic analysis revealed that antibiotics were often dispensed OTC for conditions e.g., fever, cough and cold, and acute diarrhea, which are typically viral and self-limiting. Both Access and Watch groups of antibiotics were dispensed for 1-2 days. Respondents had poor knowledge regarding AMR and shifted the blame for OTC practices for antibiotics onto the government, prescribers, informal providers, cross practice by alternative medicine practitioners, and consumer demand. Pharmacists suggested the main drivers for underlying OTC dispensing were commercial interests, poor access to public healthcare, economic and time constraints among consumers, lack of stringent regulations, and scanty inspections. Therefore, a comprehensive strategy which is well aligned with activities under the National Action Plan-AMR, including stewardship efforts targeting pharmacists and evidence-based targeted awareness campaigns for all stakeholders, is required to curb the inappropriate use of antibiotics.

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was a concern over possible increase in antibiotic use due to coinfections among COVID-19 patients in the community. Here, we evaluate the changes in nationwide use of broad-spectrum antibiotics during the COVID-19 epidemic in South Korea., Methods: We obtained national reimbursement data on the prescription of antibiotics, including penicillin with β-lactamase inhibitors, cephalosporins, fluoroquinolones, and macrolides. We examined the number of antibiotic prescriptions compared with the previous 3 years in the same period from August to July. To quantify the impact of the COVID-19 epidemic on antibiotic use, we developed a regression model adjusting for changes of viral acute respiratory tract infections (ARTIs), which are an important factor driving antibiotic use., Results: During the COVID-19 epidemic in South Korea, the broad-spectrum antibiotic use dropped by 15%-55% compared to the previous 3 years. Overall reduction in antibiotic use adjusting for ARTIs was estimated to be 14%-30%, with a larger impact in children., Conclusions: Our study found that broad-spectrum antibiotic use was substantially reduced during the COVID-19 epidemic in South Korea. This reduction can be in part due to reduced ARTIs as a result of stringent public health interventions including social distancing measures., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Pneumococcal diseases are a leading cause of morbidity and mortality among children globally, and the burden of these diseases might be worsened by antimicrobial resistance. To understand the effect of pneumococcal conjugate vaccine (PCV) deployment on antimicrobial resistance in pneumococci, we assessed the susceptibility of paediatric pneumococcal isolates to various antimicrobial drugs before and after PCV implementation., Methods: We did a systematic review of studies reporting antimicrobial susceptibility profiles of paediatric pneumococcal isolates between 2000 and 2020 using PubMed and the Antimicrobial Testing Leadership and Surveillance database (ATLAS; Pfizer). Population-based studies of invasive pneumococcal disease or nasopharyngeal colonisation were eligible for inclusion. As primary outcome measures, we extracted the proportions of isolates that were non-susceptible or resistant to penicillin, macrolides, sulfamethoxazole-trimethoprim, third-generation cephalosporins, and tetracycline from each study. Where available, we also extracted data on pneumococcal serotypes. We estimated changes in the proportion of isolates with reduced susceptibility or resistance to each antibiotic class using random-effects meta-regression models, adjusting for study-level and region-level heterogeneity, as well as secular trends, invasive or colonising isolate source, and countries' per-capita gross domestic product., Findings: From 4910 studies screened for inclusion, we extracted data from 559 studies on 312 783 paediatric isolates. Susceptibility of isolates varied substantially across regions both before and after implementation of any PCV product. On average across all regions, we estimated significant absolute reductions in the proportions of pneumococci showing non-susceptibility to penicillin (11·5%, 95% CI 8·6-14·4), sulfamethoxazole-trimethoprim (9·7%, 4·3-15·2), and third-generation cephalosporins (7·5%, 3·1-11·9), over the 10 years after implementation of any PCV product, and absolute reductions in the proportions of pneumococci resistant to penicillin (7·3%, 5·3-9·4), sulfamethoxazole-trimethoprim (16·0%, 11·0-21·2), third-generation cephalosporins (4·5%, 0·3-8·7), macrolides (3·6%, 0·7-6·6) and tetracycline (2·0%, 0·3-3·7). We did not find evidence of changes in the proportion of isolates non-susceptible to macrolides or tetracycline after PCV implementation. Observed changes in penicillin non-susceptibility were driven, in part, by replacement of vaccine-targeted serotypes with non-vaccine serotypes that were less likely to be non-susceptible., Interpretation: Implementation of PCVs has reduced the proportion of circulating pneumococci resistant to first-line antibiotic treatments for pneumonia. This effect merits consideration in assessments of vaccine impact and investments in coverage improvements., Funding: Bill & Melinda Gates Foundation., Competing Interests: JAL has received grants and consulting fees from Pfizer and Merck Sharp & Dohme; and consulting fees from VaxCyte and Kaiser Permanente, unrelated to the submitted work. All other authors declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: The emerging SARS-CoV-2 variant of concern (VOC) B.1.6.17.2 (Delta) quickly displaced the B.1.1.7 (Alpha) and is associated with increases in COVID-19 cases nationally. The Delta variant has been associated with greater transmissibility and higher viral RNA loads in both unvaccinated and fully vaccinated individuals. Data is lacking regarding the infectious virus load in Delta infected individuals and how that compares to individuals infected with other SARS-CoV-2 lineages., Methods: Whole genome sequencing of 2,785 clinical isolates was used to characterize the prevalence of SARS-CoV-2 lineages circulating in the National Capital Region between January and July 2021. Clinical chart reviews were performed for the Delta, Alpha, and B.1.2 (a control predominant lineage prior to both VOCs) variants to evaluate disease severity and outcome and Cycle threshold values (Cts) were compared. The presence of infectious virus was determined using Vero-TMPRSS2 cells and anti-SARS-CoV-2 IgG levels were determined from upper respiratory specimen. An analysis of infection in unvaccinated and fully vaccinated populations was performed., Results: The Delta variant displaced the Alpha variant to constitute 88.2% of the circulating lineages in the National Capital Region by July, 2021. The Delta variant associated with increased breakthrough infections in fully vaccinated individuals that were mostly symptomatic when compared to the Alpha breakthrough infections, though it is important to note there was a significantly longer period of time between vaccination and infection with Delta infections. The recovery of infectious virus on cell culture was significantly higher with the Delta variant compared to Alpha in both vaccinated and unvaccinated groups. The impact of vaccination on reducing the recovery of infectious virus from clinical samples was only observed with Alpha variant infections but was strongly associated with low localized SARS-CoV-2 IgG for both variants. A comparison of Ct values showed a significant decrease in the Delta compared to Alpha with no significant differences between unvaccinated and vaccinated groups., Conclusions: Our data indicate that the Delta variant is associated with increased infectious virus loads when compared to the Alpha variant and decreased upper respiratory antiviral IgG levels. Measures to reduce transmission in addition to increasing vaccinations rates have to be implemented to reduce Delta variant spread., Funding: NIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N2772201400007C, Johns Hopkins University, Maryland department of health, Centers for Disease Control and Prevention contract 75D30121C11061.

Objectives: Hospital observation is a key disposition option from the emergency department (ED) and encompasses up to one third of patients requiring post-ED care. Observation has been associated with higher incidence of catastrophic financial costs and has downstream effects on post-discharge clinical services. Yet little is known about the non-clinical determinants of observation assignment. We sought to evaluate the impact of patient-level demographic factors on observation designation among Maryland patients., Methods: We conducted a retrospective analysis of all ED encounters in Maryland between July 2012 and January 2017 for four priority diagnoses (heart failure, chronic obstructive pulmonary disease [COPD], pneumonia, and acute chest pain) using multilevel logistic models allowing for heterogeneity of the effects across hospitals. The primary exposure was self-reported race and ethnicity. The primary outcome was the initial status assignment from the ED: hospital observation versus inpatient admission., Results: Across 46 Maryland hospitals, 259,788 patient encounters resulted in a disposition of inpatient admission (65%) or observation designation (35%). Black (adjusted odds ratio [aOR]: 1.19; 95% confidence interval [CI]: 1.16-1.23) and Hispanic (aOR: 1.11; 95% CI: 1.01-1.21) patients were significantly more likely to be placed in observation than white, non-Hispanic patients. These differences were consistent across the majority of acute-care hospitals in Maryland (27/46)., Conclusion: Black and Hispanic patients in Maryland are more likely to be treated under the observation designation than white, non-Hispanic patients independent of clinical presentation. Race agnostic, time-based status assignments may be key in eliminating these disparities., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The rise of antimicrobial resistance (AMR) in animals is being fuelled by the widespread use of veterinary antimicrobials. China is the largest global consumer of veterinary antimicrobials, and improving AMR surveillance strategies in this region could help prioritize intervention and preserve antimicrobial efficacy. Here we mapped AMR rates in pigs, chickens and cattle in China using 446 surveys of event-based surveillance between 2000 and 2019 for foodborne bacteria, in combination with geospatial models to identify locations where conducting new surveys could have the highest benefits. Using maps of uncertainty, we show that eastern China currently has the highest AMR rates, and southwestern and northeastern China would benefit the most from additional surveillance efforts. Instead of distributing new surveys evenly across administrative divisions, using geographically targeted surveillance could reduce AMR prediction uncertainty by two-fold. In a context of competing disease control priorities, our findings present a feasible option for optimizing surveillance efforts-and slowing the spread of AMR., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Antimicrobial resistance (AMR) is a growing threat to the health of humans and animals that requires global actions. In high-income countries, surveillance systems helped inform policies to curb AMR in animals. In low- and middle-income countries (LMICs), demand for meat is rising, and developing policies against AMR is urgent. However, surveillance of AMR is at best nascent, and the current evidence base to inform policymakers is geographically heterogeneous. We present resistancebank.org, an online platform that centralizes information on AMR in animals from 1,285 surveys from LMICs. Surveys were conducted between 2000 and 2019 and include 22,403 resistance rates for pathogens isolated from chickens, cattle, sheep, and pigs. The platform is built as a shiny application that provides access to individual surveys, country-level reports, and maps of AMR at 10 × 10 kilometers resolution. The platform is accessed via any internet browser and enables users to upload surveys to strengthen a global database. resistancebank.org aims to be a focal point for sharing AMR data in LMICs and to help international funders prioritize their actions., (© 2021. The Author(s).)

The study objective assessed the energy demand and economic cost of two hospital-based COVID-19 infection control interventions: negative pressure (NP) treatment rooms and xenon pulsed ultraviolet (XP-UV) equipment. After projecting COVID-19 hospitalizations, a Hospital Energy Model and Infection De-escalation Models quantified increases in energy demand and reductions in infections. The NP intervention was applied to 11, 22, and 44 rooms for small, medium, and large hospitals, while the XP-UV equipment was used eight, nine, and ten hours a day. For small, medium, and large hospitals, the annum kWh for NP rooms were 116,700 kWh, 332,530 kWh, 795,675 kWh, which correspond to annum energy costs of $11,845 ($1,077/room), $33,752 ($1,534/room), and $80,761 ($1,836/room). For XP-UV, the annum-kilowatt-hours (and costs) were 438 ($45), 493 ($50), and 548 ($56) for small, medium, and large hospitals. While energy efficiencies may be expected for the large hospital, the hospital contained more energy-intensive use rooms (ICUs) which resulted in higher operational and energy costs. XP-UV had a greater reduction in secondary COVID-19 infections in large and medium hospitals. NP rooms had a greater reduction in secondary SARS-CoV-2 transmission in small hospitals. Early implementation of interventions can result in realized cost savings through reduced hospital-acquired infections., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V.)

Global health and global economies are predicted to be severely affected by antimicrobial resistance (AMR). The three organizations World Health Organization/World Organisation for Animal Health/Food and Agriculture Organization (WHO/OIE/FAO) are working in their domains to prevent any future AMR crisis. Antimicrobial use (AMU), especially in food animals, is contributing to the development and dissemination of AMR bacteria and genes. AMU monitoring is a strategic objective of the global and national action plans on AMR. However, the AMU reporting metrics at different levels are not harmonized yet, posing difficulties in comparisons among AMU data from different sources. A tripartite WHO/OIE/FAO collaboration is urgently required to develop and implement a globally accepted AMU metric system to ensure reliable comparisons among various data sets., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Global Challenges published by Wiley‐VCH GmbH.)

Background: Antimicrobial resistance (AMR) is one of the greatest global health challenges today, but burden assessment is hindered by uncertainty of AMR prevalence estimates. Geographical representation of AMR estimates typically pools data collected from several laboratories; however, these aggregations may introduce bias by not accounting for the heterogeneity of the population that each laboratory represents., Methods: We used AMR data from up to 381 laboratories in the United States from The Surveillance Network to evaluate methods for estimating uncertainty of AMR prevalence estimates. We constructed confidence intervals for the proportion of resistant isolates using (1) methods that account for the clustered structure of the data, and (2) standard methods that assume data independence. Using samples of the full dataset with increasing facility coverage levels, we examined how likely the estimated confidence intervals were to include the population mean., Results: Methods constructing 95% confidence intervals while accounting for possible within-cluster correlations (Survey and standard methods adjusted to employ cluster-robust errors), were more likely to include the sample mean than standard methods (Logit, Wilson score and Jeffreys interval) operating under the assumption of independence. While increased geographical coverage improved the probability of encompassing the mean for all methods, large samples still did not compensate for the bias introduced from the violation of the data independence assumption., Conclusion: General methods for estimating the confidence intervals of AMR rates that assume data are independent, are likely to produce biased results. When feasible, the clustered structure of the data and any possible intra-cluster variation should be accounted for when calculating confidence intervals around AMR estimates, in order to better capture the uncertainty of prevalence estimates.

Vaccines can reduce antibiotic use and, consequently, antimicrobial resistance by averting vaccine-preventable and secondary infections. We estimated the associations between private vaccine and antibiotic consumption across Indian states during 2009-2017 using monthly and annual consumption data from IQVIA and employed fixed-effects regression and the Arellano-Bond Generalized Method of Moments (GMM) model for panel data regression, which controlled for income and public sector vaccine use indicators obtained from other sources. In the annual data fixed-effects model, a 1% increase in private vaccine consumption per 1000 under-5 children was associated with a 0.22% increase in antibiotic consumption per 1000 people (P < 0.001). In the annual data GMM model, a 1% increase in private vaccine consumption per 1000 under-5 children was associated with a 0.2% increase in private antibiotic consumption (P < 0.001). In the monthly data GMM model, private vaccine consumption was negatively associated with antibiotic consumption when 32, 34, 35, and 44-47 months had elapsed after vaccine consumption, with a positive association with lags of fewer than 18 months. These results indicate vaccine-induced longer-term reductions in antibiotic use in India, similar to findings of studies from other low- and middle-income countries., (© 2021 New York Academy of Sciences.)

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

Background: COVID-19 vaccines have been approved and made available. While questions of vaccine allocation strategies have received significant attention, important questions remain regarding the potential impact of the vaccine given uncertainties regarding efficacy against transmission, availability, timing, and durability., Methods: We adapted a susceptible-exposed-infectious-recovered (SEIR) model to examine the potential impact on hospitalization and mortality assuming increasing rates of vaccine efficacy, coverage, and administration. We also evaluated the uncertainty of the vaccine to prevent infectiousness as well as the impact on outcomes based on the timing of distribution and the potential effects of waning immunity., Findings: Increased vaccine efficacy against disease reduces hospitalizations and deaths from COVID-19; however, the relative benefit of transmission blocking varied depending on the timing of vaccine distribution. Early in an outbreak, a vaccine that reduces transmission will be relatively more effective than one introduced later in the outbreak. In addition, earlier and accelerated implementation of a less effective vaccine is more impactful than later implementation of a more effective vaccine. These findings are magnified when considering the durability of the vaccine. Vaccination in the spring will be less impactful when immunity is less durable., Interpretation: Policy choices regarding non-pharmaceutical interventions, such as social distancing and face mask use, will need to remain in place longer if the vaccine is less effective at reducing transmission or distributed slower. In addition, the stage of the local outbreak greatly impacts the overall effectiveness of the vaccine in a region and should be considered when allocating vaccines., Funding: Centers for Disease Control and Prevention (CDC) MInD-Healthcare Program (U01CK000589, 1U01CK000536), James S. McDonnell Foundation 21st Century Science Initiative Collaborative Award in Understanding Dynamic and Multiscale Systems, National Science Foundation (CNS-2027908), National Science Foundation Expeditions (CCF1917819), C3.ai Digital Transformation Institute (AWD1006615), and Google, LLC., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Antimicrobial resistance (AMR) is a complex global health issue and will push twenty-four million people into extreme poverty by 2030, risking the sustainable development goals (SDGs) 2, 3, 6, 9, 12, and 17 if not addressed immediately. Humans, animals, and the environment are the reservoirs that contribute and allow AMR to propagate in interconnected ecosystems. The emergence of antibiotic-resistant bacteria and antibiotic-resistant genes in the water environment has become an important environmental health issue. One of the major influencers from environment sector is the pharmaceutical industry which is growing globally to meet the ever-increasing demand of antibiotics, especially in low- and middle-income countries. The pharmaceutical effluent has a mix of large concentrations of antibiotics and antibiotic resistance genes, and these sites act as hotspots for environmental contamination and the spread of AMR. Inadequate treatment of the effluent and its irresponsible disposal leads to unprecedented antibiotic contamination in the environment and their persistent presence in the environment significantly modulates the bacterial genomes' expression that is responsible for increase and spread of AMR. However, not much interventions are suggested in the National Action Plan developed on AMR by many countries. There are no regulations across the globe till date for the level of antibiotic residues in pharmaceutical effluent for the growing pharmaceutical industry. This review put together the work done showing several detrimental effects of the antimicrobial residues in the pharmaceutical effluent which leads to rise in development of AMR. The environment risk approach and need to have indicators to measure environment risk is a way forward for all countries engage in antibiotic manufacturing. Overall, efforts to address the problem are isolated and fragmented. Policymakers, regulators, manufacturers, researchers, civil society, and the community need to collaborate so that antibiotics are produced sustainably and continue to stay effective in treating bacterial infections.

Background: Multidisciplinary and multisectoral approaches such as One Health and related concepts (e.g., Planetary Health, EcoHealth) offer opportunities for synergistic expertise to address complex health threats. The connections between humans, animals, and the environment necessitate collaboration among sectors to comprehensively understand and reduce risks and consequences on health and wellbeing. One Health approaches are increasingly emphasized for national and international plans and strategies related to zoonotic diseases, food safety, antimicrobial resistance, and climate change, but to date, the possible applications in clinical practice and benefits impacting human health are largely missing., Methods: In 2018 the "Application of the One Health Approach to Global Health Centers" conference held at the Albert Einstein College of Medicine convened experts involved in One Health policy and practice. The conference examined issues relevant to One Health approaches, sharing examples of challenges and successes to guide application to medical school curricula and clinical practice for human health. This paper presents a synthesis of conference proceedings, framed around objectives identified from presentations and audience feedback., Findings and Recommendations: The following objectives provide opportunities for One Health involvement and benefits for medical schools and global health centers by: 1) Improving One Health resource sharing in global health and medical education; 2) Creating pathways for information flow in clinical medicine and global health practice; 3) Developing innovative partnerships for improved health sector outcomes; and 4) Informing and empowering health through public outreach. These objectives can leverage existing resources to deliver value to additional settings and stakeholders through resource efficiency, more holistic and effective service delivery, and greater ability to manage determinants of poor health status. We encourage medical and global health educators, practitioners, and students to explore entry points where One Health can add value to their work from local to global scale., Competing Interests: All authors also completed COI forms for their speaking and organizing roles in the conference that this paper developed from., (Copyright: © 2021 The Author(s).)

Objectives: As of 13 January 2021, there have been 3 113 963 confirmed cases of SARS-CoV-2 and 74 619 deaths across the African continent. Despite relatively lower numbers of cases initially, many African countries are now experiencing an exponential increase in case numbers. Estimates of the progression of disease and potential impact of different interventions are needed to inform policymaking decisions. Herein, we model the possible trajectory of SARS-CoV-2 in 52 African countries under different intervention scenarios., Design: We developed a compartmental model of SARS-CoV-2 transmission to estimate the COVID-19 case burden for all African countries while considering four scenarios: no intervention, moderate lockdown, hard lockdown and hard lockdown with continued restrictions once lockdown is lifted. We further analysed the potential impact of COVID-19 on vulnerable populations affected by HIV/AIDS and tuberculosis (TB)., Results: In the absence of an intervention, the most populous countries had the highest peaks in active projected number of infections with Nigeria having an estimated 645 081 severe infections. The scenario with a hard lockdown and continued post-lockdown interventions to reduce transmission was the most efficacious strategy for delaying the time to the peak and reducing the number of cases. In South Africa, projected peak severe infections increase from 162 977 to 2 03 261, when vulnerable populations with HIV/AIDS and TB are included in the analysis., Conclusion: The COVID-19 pandemic is rapidly spreading across the African continent. Estimates of the potential impact of interventions and burden of disease are essential for policymakers to make evidence-based decisions on the distribution of limited resources and to balance the economic costs of interventions with the potential for saving lives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Beta-lactam- and in particular carbapenem-resistant Enterobacteriaceae represent a major public health threat. Despite strong variation of resistance across geographical settings, there is limited understanding of the underlying drivers. To assess these drivers, we developed a transmission model of cephalosporin- and carbapenem-resistant Klebsiella pneumoniae. The model is parameterized using antibiotic consumption and demographic data from eleven European countries and fitted to the resistance rates for Klebsiella pneumoniae for these settings. The impact of potential drivers of resistance is then assessed in counterfactual analyses. Based on reported consumption data, the model could simultaneously fit the prevalence of extended-spectrum beta-lactamase-producing and carbapenem-resistant Klebsiella pneumoniae (ESBL and CRK) across eleven European countries over eleven years. The fit could explain the large between-country variability of resistance in terms of consumption patterns and fitted differences in hospital transmission rates. Based on this fit, a counterfactual analysis found that reducing nosocomial transmission and antibiotic consumption in the hospital had the strongest impact on ESBL and CRK prevalence. Antibiotic consumption in the community also affected ESBL prevalence but its relative impact was weaker than inpatient consumption. Finally, we used the model to estimate a moderate fitness cost of CRK and ESBL at the population level. This work highlights the disproportionate role of antibiotic consumption in the hospital and of nosocomial transmission for resistance in gram-negative bacteria at a European level. This indicates that infection control and antibiotic stewardship measures should play a major role in limiting resistance even at the national or regional level., Competing Interests: The authors have declared that no competing interests exist.

There have been notable advances in the development of vaccines against active tuberculosis (TB) disease for adults and adolescents. Using mathematical models, we seek to estimate the potential impact of a post-exposure TB vaccine, having 50% efficacy in reducing active disease, on global rifampicin-resistant (RR-) TB burden. In 30 countries that together accounted for 90% of global RR-TB incidence in 2018, a future TB vaccine could avert 10% (95% credible interval: 9.7-11%) of RR-TB cases and 7.3% (6.6-8.1%) of deaths over 2020-2035, with India, China, Indonesia, Pakistan, and the Russian Federation having the greatest contribution. This impact would increase to 14% (12-16%) and 31% (29-33%) respectively, when combined with improvements in RR-TB diagnosis and treatment relative to a scenario of no vaccine and no such improvements. A future TB vaccine could have important implications for the global control of RR-TB, especially if implemented alongside enhancements in management of drug resistance.

Background: The WHO Access, Watch, and Reserve (AWaRe) antibiotic classification framework aims to balance appropriate access to antibiotics and stewardship. We aimed to identify how patterns of antibiotic consumption in each of the AWaRe categories changed across countries over 15 years., Methods: Antibiotic consumption was classified into Access, Watch, and Reserve categories for 76 countries between 2000, and 2015, using quarterly national sample survey data obtained from IQVIA. We measured the proportion of antibiotic use in each category, and calculated the ratio of Access antibiotics to Watch antibiotics (access-to-watch index), for each country., Findings: Between 2000, and 2015, global per-capita consumption of Watch antibiotics increased by 90·9% (from 3·3 to 6·3 defined daily doses per 1000 inhabitants per day [DIDs]) compared with an increase of 26·2% (from 8·4 to 10·6 DIDs) in Access antibiotics. The increase in Watch antibiotic consumption was greater in low-income and middle-income countries (LMICs; 165·0%; from 2·0 to 5·3 DIDs) than in high-income countries (HICs; 27·9%; from 6·1 to 7·8 DIDs). The access-to-watch index decreased by 38·5% over the study period globally (from 2·6 to 1·6); 46·7% decrease in LMICs (from 3·0 to 1·6) and 16·7% decrease in HICs (from 1·8 to 1·5), and 37 (90%) of 41 LMICs had a decrease in their relative access-to-watch consumption. The proportion of countries in which Access antibiotics represented at least 60% of their total antibiotic consumption (the WHO national-level target) decreased from 50 (76%) of 66 countries in 2000, to 42 (55%) of 76 countries in 2015., Interpretation: Rapid increases in Watch antibiotic consumption, particularly in LMICs, reflect challenges in antibiotic stewardship. Without policy changes, the WHO national-level target of at least 60% of total antibiotic consumption being in the Access category by 2023, will be difficult to achieve. The AWaRe framework is an important measure of the effort to combat antimicrobial resistance and to ensure equal access to effective antibiotics between countries., Funding: US Centers for Disease Control and Prevention., (Copyright © 2020 Elsevier Ltd. All rights reserved.)