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## University of Dundee

Skip to 0 minutes and 6 secondsMulti-resistance is a growing problem faced by clinicians and microbiologists, especially for gram-negative organisms. It's exemplified here for carbapenemase-producing Enterobactericeae, CPE-- refer to England's National Reference Laboratory. Across the top of the table are the organisms. Down the side of the table are the different drugs. It's a simple traffic light system. Red cells indicate a drug that's active against less than 50% of the organisms. Green indicates a drug active against at least 90% of the organisms. What we'd like to see, of course, is lots of green, but that's not the reality. Only colistin, a polymyxin with toxicity issues is active against, at least, 90% percent of all of these different types of carbapenem resistant organisms.

Skip to 1 minute and 12 secondsWe need new antibiotics to overcome such multi-resistance. There are no new antibiotics, and this is simply not true. There's a trickling antibiotic pipeline, but it urgently needs restitution.

Skip to 1 minute and 31 secondsIt's reviewed and monitored regularly by a number of organisations, including the Pew Charitable Trust, which produces quarterly updates of its status and all drugs therein. These are publicly available through the charity's website.

Skip to 1 minute and 52 secondsThis slide shows new antibiotics either recently approved by the FDA, in the United States, and awaiting approval in Europe or still in phase three development. The two recent US approvals of cephalosporin beta-lactamase inhibitor combinations. Ceftolozane tazobactam couples a new cephalosporin with a known beta-lacatmase inhibitor, whereas ceftazidime-avibactame is a known cephalosporin coupled with a new beta-lactamase inhibitor. Assessing whether or not these drugs actually overcome the resistance problems that we face and have potential to help is tricky. There are many ways to compare them. Once way, shown on the left of this slide, is simply to look at how many molecules have been fast-tracked by the FDA.

Skip to 2 minutes and 58 secondsAnd you can see that in all phases of development, we have a number of fast-tracked molecules. A formal rigorous criterion, however, is to consider that traffic light system that we've already discussed and to try and identify those that would be green, those that would, in addition to colistin, be active against, at least, 90% of these multi-resistant organisms with carbapenemases. And here, the histogram, for exactly the same set of molecules, looks far bleaker with only three potential green molecules, which may have activity against, at least, 90% of these most resistant gram-negative bacteria.

Skip to 3 minutes and 52 secondsSo quite simply, we don't have enough antibiotics in development to tackle the resistance issues that we face now. But, of course, you have to remember that the success of those that are in development is not guaranteed. A drug that's in phases one, two, or three may not be licenced or subsequently marketed. This lack of antibiotics with sufficient coverage to overcome the resistance problems we face has been highlighted by the World Health Organisation, in the US by President Barack Obama, and in the UK by Prime Minister David Cameron. The Prime Minister established a review on antimicrobial resistance in July 2014, which is chaired by Lord Jim O'Neill shown top right.

Skip to 4 minutes and 46 secondsThe first paper from the review team assessed the potential impact of antimicrobial resistance if left unchecked and concluded that by 2050 more than 10 million people across the globe could be dying per year as the result of an antimicrobial resistant infection. That's more than currently died because of cancer. They also estimated the economic cost cumulatively to be more than $100 trillion US. That's a vast sum beyond the conception of most people. Put simply, it equates to burning$15,000 US, 10,000 pounds for every man, woman, and child on the planet.

Skip to 5 minutes and 39 secondsThe review second paper identified five steps that could be taken now to start to make inroads into our battle against the growing AMR crisis. Firstly, they recommend setting up a global AMR innovation fund to ensure that more early stage ideas could actually attract funding. Secondly, they emphasised the importance of conserving the drugs we've got, which of course is a fundamental tenet of antimicrobial stewardship, the focus of this MOOC. Thirdly, they recognise the growing importance of new diagnostic technologies. We need to ensure that antibiotics are only prescribed when people have bacterial infections, and we need to get far more clever about deciding which drugs will be active against those infections and against those infecting organisms.

Skip to 6 minutes and 39 secondsWe need to recognise susceptibility faster and reduce the reliance on broad-spectrum empiric antibiotics. Fourthly, we need to retain a high calibre skill base, not least to ensure that within pharmaceutical industries we retain the corporate memory for drug discovery, development, licencing, and marketing. And we also need to change the way we survey drug resistance on a global scale, improving access to real time information by those that need it. The third paper from the review team is focused specifically on securing new antimicrobial drugs. And it highlights that in order to make research and development commercially sustainable, we need a more predictable market. We need to de-link profit from sales.

Skip to 7 minutes and 39 secondsAnd we need to replace this with a system potentially of lump-sum payments, where pharma is rewarded for developing, licencing, and marketing drugs that are subsequently found to be clinically successful. The innovation cycle for antibiotics has been highlighted through the innovation fund and would boost early-stage research and development, not just into new antibiotics, but also into those diagnostics for AMR that we're going to need. And we need also to reduce the barriers to drug development, lowering the costs, improving the efficiency of research, and lowering regulatory barriers.

Skip to 8 minutes and 28 secondsSo although, at first glance, it might seem that antibiotic stewardship and new drug development are actually at opposing corners, I do not think that they are mutually exclusive. It does, however, require attitude change. In the future, new antibiotics will have to be viewed differently. Prescribers will not be able to regard them as cure more replacements for the drugs they currently have. And equally, the pharmaceutical industry will not be able to regard new antibiotics as potential market blockbusters. Attitudes, behaviours, and expectations will have to be measured and changed on all sides. Not least, we need those new better, faster diagnostics.

Skip to 9 minutes and 22 secondsWe need to be able to give prescribers the confidence that an old drug is likely to work whenever an infection is caused by a susceptible organism, and we need to indicate those infections where the cause of organisms are resistant to our existing drugs and so where a new drug might be used appropriately.

# The discovery void

In this video Professor Neil Woodford describes the trickling antibiotic pipeline, new antibiotics and how these are assessed, five steps to be taken now and the new drug developments.