Resistance in Gram-negative bacteria has been increasing, particularly over the last 6 years. This is mainly due to the spread of strains producing extended-spectrum β-lactamases (ESBLs) such as CTX-M enzymes or AmpC β-lactamases. Many of the isolates producing these enzymes are also resistant to trimethoprim, quinolones and aminoglycosides, often due to plasmid co-expression of other resistance mechanisms. CTX-M-producing Escherichia coli often occurs in the community and as E. coli is one of the commonest organisms causing urinary tract infections (UTIs) the choice of agents to treat these infections is diminishing. Novel combinations of antibiotics are being used in the community and broad-spectrum agents such as carbapenems are being used increasingly as empirical treatment for severe infections. Of particular concern therefore are reports in the UK of organisms that produce carbapenemases. As resistance is becoming more widespread, prudent use of antimicrobials is imperative and, as asymptomatic bacteriuria is typically benign in the elderly, antibiotics should not be prescribed without clinical signs of UTI. The use of antibiotics as suppressive therapy or long-term prophylaxis may no longer be defensible.

I find it continually amazing that society as a whole does not recognize the consequences of rising antimicrobial resistance as the threat it most certainly is. This is not for a lack of sustained activity by those who share these concerns. Far from it. Since 1997 there have been a plethora of enquiries, reports and recommendations—many from important bodies in both Europe and North America, yet little meaningful action has materialized. Some might consider this to be rather negative and an overstatement, yet can they point out a concrete outcome to all this activity?

Objectives: Appropriate use of and access to antimicrobials are key priorities of global strategies to combat antimicrobial resistance (AMR). The WHO recently classified key antibiotics into three categories (AWaRe) to improve access (Access), monitor important antibiotics (Watch) and preserve effectiveness of ‘last resort’ antibiotics (Reserve). This classification was assessed for antibiotic stewardship and quality improvement in English hospitals. Methods: Using an expert elicitation exercise, antibiotics used in England but not included in the WHO AWaRe index were added to an appropriate category following a workshop consensus exercise with national experts. The methodology was tested using national antibiotic prescribing data and presented by primary and secondary care. Results: In 2016, 46/108 antibiotics included within the WHO AWaRe index were routinely used in England and an additional 25 antibiotics also commonly used in England were not included in the WHO AWaRe index. WHO AWaRe-excluded and -included antibiotics were reviewed and reclassified according to the England-adapted AWaRE index with the justification by experts for each addition or alteration. Applying the England-adapted AWaRe index, Access antibiotics accounted for the majority (60.9%) of prescribing, followed by Watch (37.9%) and Reserve (0.8%); 0.4% of antibiotics remained unclassified. There was unexplained 2-fold variation in prescribing between hospitals within each AWaRe category, highlighting the potential for quality improvement. Conclusions: We have adapted the WHO AWaRe index to create a specific index for England. The AWaRe index provides high-level understanding of antibiotic prescribing. Subsequent to this process the England AWaRe index is now embedded into national antibiotic stewardship policy and incentivized quality improvement schemes.

The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost–benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from ‘push’ to ‘pull’ and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, ‘from cradle to grave’, must be established.

1 The γ‐aminobutyric acid (GABA)_A/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. Binding of [¹¹C]‐flumazenil to this complex in vivo is reduced in hippocampal sclerosis (HS). It has been uncertain whether reduced cBZR binding is entirely due to neuronal loss in HS. 2 The objective of this study was to characterize abnormalities of the cBZR in HS with a correlative autoradiographic and quantitative neuropathological study. 3 Saturation autoradiographic studies were performed with [^†H]‐flumazenil to investigate relationships between neuronal density and receptor availability (B_max) and affinity (K_d) in HS. Hippocampal tissue was obtained at surgery from 8 patients with intractable temporal lobe epilepsy (TLE) due to HS and autopsies of 6 neurologically normal controls. Neuronal densities were obtained by means of a 3‐D counting method. 4 B_max values for [^†H]‐flumazenil binding in the subiculum, CA1, CA2, CA3, hilus and dentate gyrus were all found to be significantly reduced in HS compared with controls and significant increases in affinity were observed in the subiculum, hilus and dentate gyrus. In HS, cBZR density in the CA1 region was significantly reduced (P<0.05) to a greater extent than could be attributable to neurone loss. In other regions, B_max was reduced in parallel with neuronal density. 5 In HS, there is a loss of cBZR in CA1 over and above loss of neurones. This finding and increases in affinity for flumazenil in subiculum, hilus and dentate gyrus imply a functional abnormality of the GABA_A/cBZR complex that may have a role in the pathophysiology of epileptogenicity in HS. British Journal of Pharmacology (1997) 122, 358–364; doi:10.1038/sj.bjp.0701365