The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences aff ect everybody in the world. Similarities with climate change are evident. Many eff orts have been made to describe the many diff erent facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to eff ective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha) 1 . In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type (WT) Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD). B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems compared to B.1.1.7, associated with B.1.617.2 spike in a predominantly cleaved state compared to B.1.1.7. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralising antibody as compared to WT spike. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx-1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era. India's first wave of SARS-CoV-2 infections in mid-2020 was relatively mild and was controlled by a nationwide lockdown. Since easing of restrictions, India has seen expansion in cases of COVID-19 since March

exploration of doctors' antibiotic use practices and possible interventions will be helpful in carrying out interventions to promote appropriate use of antibiotics in the community.

Inappropriate antibiotic dispensing and use owing to commercial interests and lack of knowledge about the rational use of antibiotics and antibiotic resistance were the main findings of this in-depth qualitative study. Community pharmacists were willing to participate in educational programme aimed at improving use of antibiotics. Such programmes should be initiated within a multidisciplinary framework including doctors, pharmacists, social scientists, government agencies and non-profit organizations.

Purpose Critically ill coronavirus disease 2019 (COVID-19) patients need hospitalization which increases their risk of acquiring secondary bacterial and fungal infections. The practice of empiric antimicrobial prescription, due to limited diagnostic capabilities of many hospitals, has the potential to escalate an already worrisome antimicrobial resistance (AMR) situation in India. This study reports the prevalence and profiles of secondary infections (SIs) and clinical outcomes in hospitalized COVID-19 patients in India. Patients and Methods A retrospective study of secondary infections in patients admitted in intensive care units (ICUs) and wards of ten hospitals of the Indian Council of Medical Research (ICMR) AMR surveillance network, between June and August 2020, was undertaken. The demographic data, time of infection after admission, microbiological and antimicrobial resistance data of secondary infections, and clinical outcome data of the admitted COVID-19 patients were collated. Results Out of 17,534 admitted patients, 3.6% of patients developed secondary bacterial or fungal infections. The mortality among patients who developed secondary infections was 56.7% against an overall mortality of 10.6% in total admitted COVID-19 patients. Gram-negative bacteria were isolated from 78% of patients. Klebsiella pneumoniae (29%) was the predominant pathogen, followed by Acinetobacter baumannii (21%). Thirty-five percent of patients reported polymicrobial infections, including fungal infections. High levels of carbapenem resistance was seen in A. baumannii (92.6%) followed by K. pneumoniae (72.8%). Conclusion Predominance of Gram-negative pathogens in COVID-19 patients coupled with high rates of resistance to higher generation antimicrobials is an alarming finding. A high rate of mortality in patients with secondary infections warrants extra caution to improve the infection control practices and practice of antimicrobial stewardship interventions not only to save patient lives but also prevent selection of drug-resistant infections, to which the current situation is very conducive.

The B.1.617 variant emerged in the Indian state of Maharashtra in late 2020 and has spread throughout India and to at least 40 countries. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. Here we delineate the phylogenetics of B.1.617 and spike mutation frequencies, in the context of others bearing L452R. The defining mutations in B.1.617.1 spike are L452R and E484Q in the RBD that interacts with ACE2 and is the target of neutralising antibodies. All B.1.617 viruses have the P681R mutation in the polybasic cleavage site region in spike. We report that B.1.617.1 spike bearing L452R, E484Q and P681R mediates entry into cells with slightly reduced efficiency compared to Wuhan-1. This spike confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies that is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. Furthermore we show that the P681R mutation significantly augments syncytium formation upon the B.1.617.1 spike protein, potentially contributing to increased pathogenesis observed in hamsters and infection growth rates observed in humans.

Objectives: To describe antimicrobial susceptibility among bacterial isolates associated with hospital infections collected from 266 centres in Asia/Pacific Rim (n 5 1947), North America (n 5 24 283), Latin America (n 5 1957) and Europe (n 5 8796).Methods: Isolates were collected from blood, respiratory tract, urine, skin, wound, body fluids and other defined sources between January 2004 and August 2006. Only one isolate per patient was accepted. In vitro MICs for the isolates were determined according to the CLSI (formerly NCCLS) guidelines.Results: Key organisms collected were Acinetobacter baumannii (n 5 2902), Enterobacter spp. (n 5 5731), Escherichia coli (n 5 6504), Klebsiella pneumoniae (n 5 4916), Pseudomonas aeruginosa (n 5 5128), Serratia marcescens (n 5 2313), Enterococcus faecalis (n 5 2701), Enterococcus faecium (n 5 1035) and Staphylococcus aureus (n 5 5753). Rates of methicillin resistance among S. aureus and of vancomycin resistance among enterococci were highest in North America (2016/3809, 52.9% and 571/2544, 22.4%, respectively) and lowest in Europe (337/1340, 25.1% and 36/916, 3.9%, respectively). Tigecycline was the only antimicrobial to maintain activity against all Gram-positive isolates (MIC 90 values of 0.25 mg/L). Overall, tigecycline and imipenem were the most active (>93% susceptibility in all regions) antimicrobials against the Gram-negative species, except for A. baumannii and P. aeruginosa. Piperacillin/tazobactam and amikacin were the most active against P. aeruginosa. Extended-spectrum b-lactamase producers among K. pneumoniae occurred most frequently in Latin America (124/282, 44.0%).Conclusions: Tigecycline is a novel broad-spectrum antimicrobial that is active against the common organisms associated with infections.

The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and has spread throughout India, displacing the B.1.1.7 (Alpha) variant and other pre-existing lineages. Mathematical modelling indicates that the growth advantage is most likely explained by a combination of increased transmissibility and immune evasion. Indeed in vitro, the delta variant is less sensitive to neutralising antibodies in sera from recovered individuals, with higher replication efficiency as compared to the Alpha variant. In an analysis of vaccine breakthrough in over 100 healthcare workers across three centres in India, the Delta variant not only dominates vaccine-breakthrough infections with higher respiratory viral loads compared to non-delta infections (Ct value of 16.5 versus 19), but also generates greater transmission between HCW as compared to B.1.1.7 or B.1.617.1 (p=0.02). In vitro, the Delta variant shows 8 fold approximately reduced sensitivity to vaccine-elicited antibodies compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against the SARS-CoV-2 Delta variant were significantly lower in participants vaccinated with ChadOx-1 as compared to BNT162b2 (GMT 3372 versus 654, p<0001). These combined epidemiological and in vitro data indicate that the dominance of the Delta variant in India has been most likely driven by a combination of evasion of neutralising antibodies in previously infected individuals and increased virus infectivity. Whilst severe disease in fully vaccinated HCW was rare, breakthrough transmission clusters in hospitals associated with the Delta variant are concerning and indicate that infection control measures need continue in the post-vaccination era.