Coagulase-negative staphylococci (CoNS) are important bloodstream pathogens that are typically resistant to multiple antibiotics. Despite the concern about increasing resistance, there have been no recent studies describing the national prevalence of CoNS pathogens. We used national resistance data over a period of 13 years (1999 to 2012) from The Surveillance Network (TSN) to determine the prevalence of and assess the trends in resistance for Staphylococcus epidermidis, the most common CoNS pathogen, and all other CoNS pathogens. Over the course of the study period, S. epidermidis resistance to ciprofloxacin and clindamycin increased steadily from 58.3% to 68.4% and from 43.4% to 48.5%, respectively. Resistance to levofloxacin increased rapidly from 57.1% in 1999 to a high of 78.6% in 2005, followed by a decrease to 68.1% in 2012. Multidrug resistance for CoNS followed a similar pattern, and this rise and small decline in resistance were found to be strongly correlated with levofloxacin prescribing patterns. The resistance patterns were similar for the aggregate of CoNS pathogens. The results from our study demonstrate that the antibiotic resistance in CoNS pathogens has increased significantly over the past 13 years. These results are important, as CoNS can serve as sentinels for monitoring resistance, and they play a role as reservoirs of resistance genes that can be transmitted to other pathogens. The link between the levofloxacin prescription rate and resistance levels suggests a critical role for reducing the inappropriate use of fluoroquinolones and other broad-spectrum antibiotics in health care settings and in the community to help curb the reservoir of resistance in these colonizing pathogens.

Globally, excess deaths during 2020-21 outnumbered documented COVID-19 deaths by 9.5 million, primarily driven by deaths in low- and middle-income countries (LMICs) with limited vital surveillance. Here we unravel the contributions of probable COVID-19 deaths from other changes in mortality related to pandemic control measures using medically-certified death registrations from Madurai, India-an urban center with well-functioning vital surveillance. Between March, 2020 and July, 2021, all-cause deaths in Madurai exceeded expected levels by 30% (95% confidence interval: 27-33%). Although driven by deaths attributed to cardiovascular or cerebrovascular conditions, diabetes, senility, and other uncategorized causes, increases in these attributions were restricted to medically-unsupervised deaths, and aligned with surges in confirmed or attributed COVID-19 mortality, likely reflecting mortality among unconfirmed COVID-19 cases. Implementation of lockdown measures was associated with a 7% (0-13%) reduction in all-cause mortality, driven by reductions in deaths attributed to injuries, infectious diseases and maternal conditions, and cirrhosis and other liver conditions, respectively, but offset by a doubling in cancer deaths. Our findings help to account for gaps between documented COVID-19 mortality and excess all-cause mortality during the pandemic in an LMIC setting.

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.

Haemophilus influenzae type b (Hib) affects 337,000 Indian children every year. A vaccine against Hib was introduced in 2011 as part of the pentavalent vaccine and scaled up nationwide. This study investigated the associations between Hib vaccination and child anthropometry, cognition, and schooling outcomes in India. We used longitudinal survey data and employed propensity score matching to control for observed systematic differences between children who reported receipt or nonreceipt of Hib vaccine before age 6 years (n = 1824). Z-scores of height-for-age (HAZ) and BMI-for-age (BMIZ), percentage scores of English, mathematics, reading, and Peabody Picture Vocabulary tests, and attained schooling grade of children were examined. Hib-vaccinated children had 0.25 higher HAZ, scored 4.09 percentage points (pp) higher on the English test and 4.78 pp higher on the mathematics test, and attained 0.16 more schooling grades than Hib-unvaccinated children at age 11-12 years. At age 14-15 years, they had 0.18 higher HAZ, scored 3.63 pp higher on the reading test and 3.22 pp higher on the mathematics test, and attained 0.15 more schooling grades than Hib-unvaccinated children. The findings indicate potential long-term health, cognitive, and schooling benefits of the Hib vaccine, subject to the effect of unobserved confounding factors.

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

SARS-CoV-2 has spread substantially within India over multiple waves of the ongoing COVID-19 pandemic. However, the risk factors and disease burden associated with COVID-19 in India remain poorly understood. We aimed to assess predictors of infection and mortality within an active surveillance study, and to probe the completeness of case and mortality surveillance.

Methods

In this prospective, active surveillance study, we used data collected under expanded programmatic surveillance testing for SARS-CoV-2 in the district of Madurai, Tamil Nadu, India (population of 3 266 000 individuals). Prospective testing via RT-PCR was done in individuals with fever or acute respiratory symptoms as well as returning travellers, frontline workers, contacts of laboratory-confirmed COVID-19 cases, residents of containment zones, patients undergoing medical procedures, and other risk groups. Standardised data collection on symptoms and chronic comorbid conditions was done as part of routine intake. Additionally, seroprevalence of anti-SARS-CoV-2 immunoglobulin G was assessed via a cross-sectional survey recruiting adults across 38 clusters within Madurai District from Oct 19, 2020, to Nov 5, 2020. We estimated adjusted odds ratios (aORs) for positive RT-PCR results comparing individuals by age, sex, comorbid conditions, and aspects of clinical presentation. We estimated case-fatality ratios (CFRs) over the 30-day period following RT-PCR testing stratified by the same variables, and adjusted hazard ratios (aHRs) for death associated with age, sex, and comorbidity. We estimated infection-fatality ratios (IFRs) on the basis of age-specific seroprevalence.

Results

Between May 20, 2020, and Oct 31, 2020, 13·5 diagnostic tests were done per 100 inhabitants within Madurai, as compared to 7·9 tests per 100 inhabitants throughout India. From a total of 440 253 RT-PCR tests, 15 781 (3·6%) SARS-CoV-2 infections were identified, with 8720 (5·4%) of 160 273 being positive among individuals with symptoms, and 7061 (2·5%) of 279 980 being positive among individuals without symptoms, at the time of presentation. Estimated aORs for symptomatic RT-PCR-confirmed infection increased continuously by a factor of 4·3 from ages 0-4 years to 80 years or older. By contrast, risk of asymptomatic RT-PCR-confirmed infection did not differ across ages 0-44 years, and thereafter increased by a factor of 1·6 between ages 45-49 years and 80 years or older. Seroprevalence was 40·1% (95% CI 35·8-44·6) at age 15 years or older by the end of the study period, indicating that RT-PCR clinical testing and surveillance testing identified only 1·4% (1·3-1·6%) of all infections in this age group. Among RT-PCR-confirmed cases, older age, male sex, and history of cancer, diabetes, other endocrine disorders, hypertension, other chronic circulatory disorders, respiratory disorders, and chronic kidney disease were each associated with elevated risk of mortality. The CFR among RT-PCR-confirmed cases was 2·4% (2·2-2·6); after age standardisation. At age 15 years or older, the IFR based on reported deaths was 0·043% (0·039-0·049), with reported deaths being only 11·0% (8·2-14·5) of the expected count.

Interpretation

In a large-scale SARS-CoV-2 surveillance programme in Madurai, India, we identified equal risk of asymptomatic infection among children, teenagers, and working-age adults, and increasing risk of infection and death associated with older age and comorbidities. Establishing whether surveillance practices or differences in infection severity account for gaps between observed and expected mortality is of crucial importance to establishing the burden of COVID-19 in India.

Funding

The Bill & Melinda Gates Foundation, the National Science Foundation, and the National Institute of General Medical Sciences.

Translation

For the Hindi translation of the abstract see Supplementary Materials section.

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.

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics^1-4. However, the effects of vaccination on antibiotic consumption remain poorly understood-especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest⁵. Here we show that vaccines that have recently been implemented in the World Health Organization's Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4-43.4%) and 11.4% (4.0-18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens^6,7. Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance⁸.

Background

Despite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs), but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases.

Methods and findings

We developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination. Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 6% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis.

Conclusions

A K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase.

Diarrhea is a leading cause of antibiotic consumption among children in low- and middle-income countries. While vaccines may prevent diarrhea infections for which children often receive antibiotics, the contribution of individual enteropathogens to antibiotic use is minimally understood. We used data from the Global Enteric Multicenter Study (GEMS) to estimate pathogen-specific incidence of antibiotic-treated diarrhea among children under five years old residing in six countries of sub-Saharan Africa and South Asia before rotavirus vaccine implementation. GEMS was an age-stratified, individually-matched case-control study. Stool specimens were obtained from children presenting to sentinel health clinics with newly-onset, acute diarrhea (including moderate-to-severe and less-severe diarrhea) as well as matched community controls without diarrhea. We used data from conventional and quantitative molecular diagnostic assays applied to stool specimens to estimate the proportion of antibiotic-treated diarrhea cases attributable to each pathogen. Antibiotics were administered or prescribed to 9,606 of 12,109 moderate-to-severe cases and 1,844 of 3,174 less-severe cases. Across all sites, incidence rates of clinically-attended, antibiotic-treated diarrhea were 12.2 (95% confidence interval: 9.0-17.8), 10.2 (7.4-13.9) and 1.9 (1.3-3.0) episodes per 100 child-years at risk at ages 6 weeks to 11 months, 12-23 months, and 24-59 months, respectively. Based on the recommendation for antibiotic treatment to be reserved for cases with dysentery, we estimated a ratio of 12.6 (8.6-20.8) inappropriately-treated diarrhea cases for each appropriately-treated case. Rotavirus, adenovirus serotypes 40/41, Shigella, sapovirus, Shiga toxin-producing Escherichia coli, and Cryptosporidium were the leading antibiotic-treated diarrhea etiologies. Rotavirus caused 29.2% (24.5-35.2%) of antibiotic-treated cases, including the largest share in both the first and second years of life. Shigella caused 14.9% (11.4-18.9%) of antibiotic-treated cases, and was the leading etiology at ages 24-59 months. Our findings should inform the prioritization of vaccines with the greatest potential to reduce antibiotic exposure among children.