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ANNUAL 2016Joining Forces to Fight Antimicrobial ResistanceA

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At Sandoz, we discover new ways to improve and extend people’s lives. We pioneer novel approaches to help people around the world access high-quality medicine. This is how we contribute to improving society’s ability to support growing healthcare needs. Increasingly challenging in this context is the advance of antimicrobial resistance (AMR). Last year’s edition of the Sandoz Annual already touched on the subject. This year, because of the urgency of the matter, we decided to dedicate the whole publication to AMR.

At Sandoz and as a key part of the Novartis group, Anti-Infectives is leading the way when it comes to AMR. Our leadership position gives us the opportunity to remind people not only about the importance of antibiotics, but also about using them responsibly. Therefore, we strongly support stewardship practices promoting the rational and appropriate use of antibiotics. In order to tackle the root causes of AMR, Sandoz is committed to working with other stakeholders. We are determined not only to ensure stable manufacturing and secure supply of antibiotics, but also to understand the mechanisms underlying the occurrence of AMR as well as to research and develop novel antibiotics that cure the most prevalent nosocomial and opportunistic infections. The adoption of novel formulations and incremental innovations is also an essential part of our work. Therefore, the Novartis Group supports the “Innovative Medicines Initiative” of the EU, which invests 344 million euros into antimicrobial resistance measures and activities.

This Annual informs you about the multifactorial challenge presented by resistance. From page 6 onwards, we give you a broad understanding about the subject – the problem of antibiotic overuse, the arduous development of new components and the environmental issues involved. What surprising role a surface modeled on sharkskin can play in the fight against superbugs you will discover on page 22. Furthermore, we present to you key initiatives from around the world, new developments in diagnostics that shorten the time needed to diagnose, and we invite you along to snow-covered Davos in the Swiss mountains, where over 80 organizations joined forces and signed a declaration against AMR.

I hope you enjoy our Annual and have a stimulating read.

With best regards,

Michael KocherGlobal Head Commercial OperationsAnti-Infectives & API

OUR COMMITMENT TO THE FUTURE OF ANTIBIOTICS

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Joining Forces

Bacteria are developing rising immunity against antibiotics.

New solutions are needed to maintain the silver bullet against infections.

Ships, sharks and staphylococcus

Bionics at its best: a bacteria-shedding surface

modeled on sharkskin has been created.

CONTENTS

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LEGA L I N FOR M ATIONPublisher: Sandoz GmbH, Biochemiestraße 10, A-6250 Kundl / Tirol (Publication Manager: Markus Schardt) · Corporate Publishing: Egger & Lerch, A-1030 Vienna, www.egger-lerch.at (Editor: Greta Lun. Graphics and layout: Elisabeth Ockermüller, Sabine Peter) · Photography: Sandoz GmbH, getty images (pp. 1, 4, 6, 14, 15, 19, 51, 52), Shutterstock (pp. 4, 5, 22, 25, 29, 30, 41, 42, 45), iStock (pp. 5, 39, 48), SharkletTM Technologies (p. 25), Universitätsklinikum Heidelberg (p. 47) · Translation: CLS Communication AG · Printing: Samson Druck, A-5581 St. Margarethen

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A contract against superbugs

Over 80 organizations signed a declaration in Davos to take joint

action on tackling resistance.

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AMR in figures

What the statistics say about the status quo regarding antibiotics,

resistance and the development of new antimicrobial drugs.

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Taking the initiative against AMR

The fight against resistance must

be waged on a broad front.

Five major initiatives have risen to

the challenge.

Redefining diagnostics

New test methods and technologies

promise to drastically cut the time

needed to establish a diagnosis.

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JOINING FORCESThere is increasing evidence that

antibiotics are becoming less

effective, with bacteria developing

growing immunity against them.

Scientists and pharma companies

are working on new solutions to the

challenge in order to maintain the

ultimate remedy against infections.

Methicillin-resistant Staphylococcus aureus (MRSA): these bacteria are commonly also known as hospital superbugs, since that is where they are most often transmitted.

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The figures are already alarming: every year in the USA and EU alone, some 50,000 people die due to multi-drug-resistant bacteria – and these are the less affected regions. Worldwide, there are 700,000 deaths as a result of antimicrobial resistance (AMR) every year. But the prognosis is far more serious: experts believe that this figure will rise to 10 million by 2050, if nothing is done.

PREC IOUS COMPOUN DS

“All the scientific communities are crying out, including the World Health Organization (WHO), the Infectious Diseases Society of America (IDSA) and the European Commission. We are finding horror stories of the impend-ing post-antibiotic era everywhere,” says Michael Borek, Therapeutic Area Head at Sandoz in Kundl, explaining the magnitude of the issue. Antibiotic resistance is one of the three most serious threats to human health according to the WHO. Margaret Chan, Director General of the WHO, describes the post-antibiotic era as “in effect, an end to modern medicine as we know it.”

“It’s not just a matter of patients in hospital becoming in-fected with resistant bacteria that nothing works against anymore as a complication,” explains antibiotic specialist Michael Borek. “Without antibiotics, standard medical treatments – in oncology, transplant medicine or surgery,

for example – would no longer work. Patients would die from internal infections. Problems are arising for which we are out of ammunition.”

TH E GOOD, TH E BAD, AN D TH E UGLY

Bacteria are the world’s oldest inhabitants. Many people associate them with serious epidemics – but in reality, only 1% of bacteria cause diseases. Many single-cell organisms are actually vital for humans. They aid our digestion and metabolism. The human gut is home to some 10 to 100 billion bacteria; by way of comparison, our entire body only comprises one billion cells. Four hundred different species of bacteria populate our gut. They provide us with vitamin K and produce important acids and bacteriocins, which inhibit the growth of dangerous species of bacteria, thereby protecting us.

Humans have had an effective resource against the bad bacteria or pathogens since the discovery of penicillin. Antibiotics have already saved millions of lives. They are real miracle drugs, which are able to completely cure patients of fatal diseases. But it did not take long for the bacteria to mutate and establish defense mechanisms against the medications. “Antibacterial resistance has been around since the development of antibiotics. It is a part of evolution. But the problem has gotten worse over

Time between drug approval and initial resistance

OxazolidinonesStreptograminsResistance against

penicillin emerged four years before the antibiotic was approved

KetolidesCyclical lipopeptides

GlycylcyclinesPleuromutilins

CarbapenemsFluoroquinolones

CephalosporinsLincosamides

GlycopeptidesMacrolides

PolymyxinsTetracyclines

AmphenicolsAminoglycosides

Sulfonamides

1940 1950 1960 1970 1980 1990 2000 2010

HOW QUIC KLY RES IS TANC E DE VE LOPS

To date, researchers have discovered 18 important antibiotic groups. Each group fights bacteria in its own way. Pharmaceutical companies have developed countless products from these substances.

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the last 25 years,” says Don Ganem. As Global Head of Infectious Diseases Research & VP, he heads up the research unit of the Novartis Institutes in Emeryville near San Francisco, which focuses on the development of new antibiotics.

Don Ganem has first-hand knowledge of the problem. He was Professor of Microbiology at the University of California for 30 years, where he ran an infection research laboratory. “We saw a lot of patients who had a complicated procedure, for example to insert a pros-thetic hip, and then developed an infection with MRSA. And it was heartbreaking!” he says. That meant a further operation to remove the newly-implanted prosthesis, six weeks of bed rest, and treatment with strong antibiotics, followed by further hospitalization and another hip replacement operation. “That is quite a price to pay for a resistant infection. This is the kind of thing I would see practically every time I was on service,” according to Don Ganem.

Infections with pan-resistant bacteria, that is pathogens against which standard antibiotics are powerless, are common in hospitals and present a serious risk to human health because there are very few reserve antibiotics available that can be used against these superbugs. In

some cases, these emergency medications have severe side effects. And the first resistant bacteria that we have no weapon against have already emerged.

Escherichia coli, commonly known as E. coli, lives in our intestinal flora and produces essential vitamins. However, there are also numerous pathogenic strains that cause infectious diseases. One new resistant form is carbapenem-resistant Enterobacteriaceae, or CRE. “These are extremely dangerous because they are resistant to practically every antibiotic that we have,” explains researcher Don Ganem. The only antibiotics to reliably treat CRE are poly myxins. They were developed in the 1960s and are rarely used as they cause organ damage. Between 20% and 25% of patients treated with these drugs suffer permanent damage to their kidneys. If CRE enters the bloodstream, the mortality rate is 50%. “The good news is, the next generation of antibiotics that can treat CRE is being devel-oped. One has already been licensed and we will begin clinical trials soon on another,” says Ganem.

BAC TE RIA F IGHT ING BAC K

When the EHEC epidemic was rife in Europe in 2011, more than 3,800 people went to their doctor with stomach cramps and bloody diarrhea. Hundreds were in intensive care and 53 patients died. Microbiologists

“The good news is, the next generation of antibiotics is being developed.” Don Ganem, Novartis

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HOW ANTIB IOT ICS WORK

Antibiotics can fight against bacteria in two ways. They either destroy the bacteria’s cell walls or membranes, or they interfere with the reproductive ability of the bacteria, for example by preventing their genetic blueprint, DNA, from being copied.

Cell wall

Cell membrane

Transcription

Protein synthesis

DNA RNA

quickly realized that the pathogen type, enterohemor-rhagic Escherichia coli, was a particularly aggressive in-testinal bacterium which was resistant to many antibiotics as it is ESBL-producing. ESBL or extended spectrum beta-lactamases are enzymes which bacteria can use to simply neutralize various antibiotics such as penicillin and cephalosporin. They act as tools that break up the antibiotic molecule, thereby incapacitating it.

EHEC is also problematic because it is a Gram-negative bacterium and therefore a tough case for researchers. While all bacterial strains develop resistance at some point, unlike Gram-positive pathogens, Gram-negative bacteria have two membranes. “It is very difficult to get drugs into Gram-negative bacteria,” explains Don Ga-nem. “They are really armor plated to get rid of potential drugs – the outer membrane is very impermeable to small molecules.” They also have efflux pumps, which kick out the few medications that make it through the membrane.

AN OVE RUS E OF ANTIB IOT ICS

It has long been proven that the development of resis-tance is clearly linked to overconsumption. Michael Borek explains the principle: “When the addition of an antibiotic to a population of bacteria creates selection pressure, those strains that are resistant to it are selected.” Significant blame for the development and spread of resistance lies with humans themselves. Because doctors prescribe antibiotics too readily, and often preventively. Because patients often ask for them and put pressure on doctors. Because antibiotics are frequently used in inten-sive livestock farming. And because the environment is contaminated with them in less developed countries. Every antibiotic becomes ineffective at some point as a result.

Explaining to doctors, medical staff, pharmacists and patients how to use antibiotics is therefore a vital strategy because many antibiotics are prescribed unnecessarily: according to studies, this amounts to around one-third of or approximately 47 million prescriptions in the USA. Global use in human medicine rose by an alarming 40% between 2000 and 2010. Yet most diseases in the upper body, such as respiratory tract infections, are viral. Anti-biotics target bacteria and cannot do anything to combat viruses. However, many doctors prefer to prescribe an antibiotic straight away as a precautionary measure on the basis that “even if it does nothing, it won’t hurt.”

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Bacterial invasion An antibiotic is administered.

The bacteria die or are unable to reproduce.

IDE AL SC E NARIO WITH ANTIB IOT ICS AS A TRE ATME NT

Bacteria become immune to antibiotics as

a result of natural mutations in their DNA. They become resistant.

An antibiotic is administered.

Resistant bacteria survive, while

non-resistant bacteria die off.

The surviving resistant bacteria reproduce.

The resistant bacteria are able to transfer

the genetic information in their DNA to other

bacteria, which also become resistant.

RES IS TANC E

How bacteria become immune to antibiotics

12 Raising awareness of only using valuable medications where they are actually needed is just as important as ex-plaining how to use them correctly – stopping treatment too soon also promotes the development of resistance.

In hospitals, hygiene is the vital factor in ensuring bacte-ria spread less extensively. In addition to the strict rules on hand-washing, sterilizing equipment, etc. that have already been implemented, there have been detailed programs on “antibiotic stewardship” since the 1990s. Under such programs, a package of measures is intro-duced to ensure that medications are administered sensi-bly. The choice of API, dosage and treatment duration are optimized to minimize the selection pressure on the bacteria population. This also benefits the patients as the treatment is adjusted individually to them and their dis-ease. One antibiotic stewardship strategy is diversifica-tion, or the use of different APIs – this also seems to be producing results. In Europe, there is a clear North-South divide when it comes to antibiotic resistance. Distribution, or what type of molecule is used, also plays a role here. “Scandinavians use both fewer and different, older products such as narrow-spectrum penicillin – which is also an important factor,” comments Michael Borek.

However, all of these approaches are still not standards: while health organizations provided detailed guidelines on antibiotic stewardship, to date they are nothing more than recommendations. Some countries do have national

guidelines, which are observed to varying degrees. In practice, the use of antibiotics is also impacted by cultural factors. “In Nordic countries, doctors largely comply with the guidelines, more so than in Southern Europe where doctors see these as an attack on their freedom of choice,” explains Michael Borek.

INC RE DIBLE IN DIA

Timothy Walsh from the University of Cardiff is known worldwide for the discovery of the resistance gene New Delhi NDM-1, which he detected in India and which is spreading faster internationally than any other resistant form. “We could track resistance going from one country to another. It was a new type of resistance, multidrug resistance,” says Walsh, who published a sensational paper on this in the journal The Lancet in 2012. “In two days of being published we had over four million internet hits.”

India produces around 40% of the antibiotics adminis-tered globally. Poor controls mean that there is tremen-dous environmental contamination.

Even travel promotes the spread of AMR. More than 300 million people visit regions with low hygiene stan dards every year, and the majority of them return home with resistant pathogens. This enables bacteria to swap their optimized genetic material with one another. University Hospital Helsinki examined 430 Finnish

“Scandinavians use both fewer and different, older products such as narrow-spectrum penicillin – which is also an important factor.”Michael Borek, Sandoz

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Antibiotic resistance genes

Plasmid

Effl ux pump

Antibiotic-splitting enzyme

Bacterial cell

Antibiotic

Antibiotic

Antibiotic

Antibiotic-altering enzyme

RESISTANCE MECHANISMS

They cause the antibiotic to mutate, which inhibits its activity.

They produce an enzyme that splitsthe antibiotic, thus inactivating it.

An effl ux pump in the membrane expels the antibiotic.

Antibiotic resistance genes on the plasmid use various techniques to protect themselves against antibiotics:

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E. coli intestinal bacteria are among the most frequent causes of infectious diseases. They account for 80% of all urinary tract infections and diarrheal diseases. The thread-like pili are typical of Gram-negative bacteria, which are particularly difficult to treat.

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In healthy individuals, Clostridium difficile is a harmless intestinal bacterium. The mutated variant of the pathogen, which develops primarily as a result of the all-too-ready administration of antibiotics, can cause life-threatening infections.

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How serious is the problem of an-timicrobial resistance (AMR) and how can it be tackled? Antibiotics are the backbone of healthcare. But bacteria are becoming more and more resistant. Sandoz has a very broad portfolio of antibiotics – and we endeavour to develop new components. Still, there is evidence that antibiotics are losing effectiveness faster than they are being replaced by new innovative drugs. It is important to recognize that AMR is a multifactorial problem. It requires not just one industry or stakeholder – we need to work to-gether. If we are to have any impact, we need to follow three broad strate-gies: first of all, to discover and de-velop novel antibiotics. Secondly, to rapidly and globally implement anti-biotic stewardship programs. And last but definitely not least, to drive the adoption of responsible manu-facturing practices with proper environmental control – this is one of the key topics.

What are the main difficulties?R&D efforts can take years and re-quire significant financial investment. Given the epidemic proportions we are already seeing with AMR, there

is an urgent need for quicker solu-tions. Stewardship programs repre-sent one such “quick fix.” These medical guidelines and practices en-courage better and more responsible use of antibiotics, by encouraging re-duced prescribing, smarter use of dif-ferent classes, reintroduction of older antibiotics and the development of novel diagnostics to differentiate be-tween bacterial and viral infections.

What about new drugs? Novel antibiotics take time to develop, manufacturers are able to generate new formulations much more quickly. These novel formulations such as pediatric dosage forms can help decrease non-adherence to therapy, which is also a cause of AMR. How-ever, current procurement trends and pricing for antibiotics do not incentiv-ize manufacturers to invest in novel formulations. Shaping antibiotic pro-curement to support the sustainability of the antibiotics industry has the potential to bring back investment into this area.

What would you expect from non-pharmaceutical groups? We see very different guidelines about the use of antibiotics from

“SANDOZ IS CONTRIBUTING ON MANY FRONTS”Rex Clements is Global Head of Anti - Infectives and API

at Sandoz, one of the leading manufacturers of antibiotics

in the world. He talks about the fight against infections and

his personal motivation in the Sandoz mission to provide

high-quality, affordable medicines globally.

governments around the world – including the EU where different states follow different approaches. There is a need to develop a very clear and unified guideline on the responsible use of antibiotics and provide incentives of good practices. Governments could also launch a consumer-directed campaign on key topics such as infection control through personal hygiene, differen-tiation between viral and bacterial infections, adherence to antibiotic regimens, and so on.

How is Sandoz contributing to the fight against AMR?We are contributing on many fronts. We are one of the biggest manufac-turers of antibiotics and the last remaining fully integrated producer of penicillin in the western world. Actually, the first oral antibiotic in the world was developed here at Sandoz by the scientists Ernst Brandl and Hans Margreiter in 1951. So, since the beginning of the antibiotic era, we have been driven by innovation in order to supply patients around the world with effective drugs. In ad-dition to supply, we work a lot with Novartis on new and novel ap-proaches for antibiotics. The think-

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infection. A high percentage of kids in Africa get heart failure – from a condition that is curable by very common antibiotics. If you think about it, it is such a different world we live in. The access to an effective and affordable medication really makes the difference between life and death for so many kids around the world. That’s my motivation for this. If we are able to stop losing the effects of antibiotics, we will keep a lot of our capab i l ity in modern healthcare.

tourists before and after their trips: 70% returning from India, 50% returning from Southeast Asia and 33% returning from the Middle East brought back multidrug-resistant bacteria. These can cause severe infections even years later.

A PAR ADOXIC AL BUS IN ESS

The world urgently needs new antibiotics, but pharma companies are developing fewer and fewer. One reason is that antibiotics are not profitable: in 1990, 18 of the 50 largest pharma companies were carrying out re-search in the area of antibiotics; today, there are only six. “Many big companies have gotten out of the game – that’s a shame,” says Don Ganem. “Right now it is the case that cancer drugs are much more profitable, be-cause companies can command premium prices and the barrier to registration of a new cancer drug is much lower.” To ensure that antibiotics remain effective, they should be used as infrequently as possible. However, the market is based on the principles of increasing sales and maximizing revenues. The business model that allows money to be made from a product that is sold as little as possible has yet to be devised.

Antibiotic development is extremely time and cost inten-sive; many research approaches are proving to be unsuitable: only 1.5% to 3.5% of researched substances make it to the regulatory approval stage. “Antibiotics are life-saving drugs that are taken only a few times in a

“Since the beginning of the antibiotic era, we have been driven by innovation in order to supply patients around the world with effective drugs.”Rex Clements, Sandoz

tank of Novartis is committed to understanding mechanisms of occur-rence of AMR in order to identify new targets against the most impor-tant nosocomial infections. Novartis also supports the “Innovative Medi-cines Initiative” of the EU, which is investing 344 million euros into anti-microbial resistance measures and activities. Sandoz, alongside more than 30 organizations, signed a joint declaration at the World Economic Forum in 2016 calling on govern-ments and our industry to work to-gether to take comprehensive action against drug -resistant infections. We need to recognize that there are a lot of initiatives going on, like supply chain controls.

What is your motivation in the fight against AMR?I have a four-year-old little boy. A few months ago he contracted a throat infection and I walked straight to the pharmacy in Munich with the prescription, then gave my boy the antibiotic. The next day he felt much better and seven days later he was great. Then I went to a rheumatic heart disease conference in Addis Ababa. Rheumatic heart disease is caused by an untreated throat

18 person’s life for perhaps two weeks. By contrast, devel-opment is time-consuming, expensive and associated with certain limitations that cause both the companies and the regulatory authorities to have to grit their teeth,” says Michael Borek, summarizing the problem. Experts agree that incentives are urgently needed to bring more players into the game – both policy and economic experts are needed here.

Bringing new APIs onto the market therefore remains the biggest challenge in the battle against AMR. “It is hard to discover compounds that will kill bacteria and have an acceptable level of toxicity to the host,” admits Don Ganem. “Mostly, what we have been doing is modifying existing classes of antibiotics. But with each generation it becomes harder and harder to pull a new rabbit out of that hat.” Innovative approaches are needed, but many come to nothing. More than 70 years ago, the use of phages – viruses that kill bacteria – was tested, but with little success. “Each virus strain is narrowly specific for a narrow group of organisms. There is a tremendous diversity of strains out there – that requires a huge collection of phages to cover them all. And bugs become resistant to phages – usually it takes a single mutation,” says Ganem.

One other possibility is reviving old, forgotten APIs. Ursula Theuretzbacher, principal and founder of the Center for Anti-Infective Agents (CEFAIA) in Vienna,

Austria, advocates the return to older antibiotics. Some of the APIs discovered in the 1950s, 1960s and 1970s were only used for a short time as new, better tolerated medications emerged. Today, they could expand treat-ment options, thereby reducing the appearance of resist-ance. However, reauthorization is a difficult undertaking as the products are no longer available, the patents have often expired and the clinical studies carried out at the time do not meet current standards.

DE VE LOP, L IMIT, D IAGNOS E

Antibiotic resistance is a global problem with which we can only come to grips through cooperation. Don Ganem summarizes the three major fields of action in the battle against AMR as follows: “One is the development of new antibiotics, one is the stewardship movement to limit the overuse of antibiotics. The third is trying to change diagnostic practices.” Right now, a great deal of hope is being placed in the development of rapid tests. If doctors are able to determine the cause of a disease in their practice within a short time, targeted prescription is pos-sible – which would avoid much use of antibiotics from the outset. Don Ganem is certain: “In the next years, we will see progress here.”

“It is hard to discover compounds that will kill bacteria and have an acceptable level of toxicity to the host.” Don Ganem, Novartis

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Stenotrophomonas maltophilia is a Gram-negative bacterium which is resistant to many antibiotics and can cause infections that are difficult to treat – particularly in patients with a weakened immune system.

AMR IN FIGURES

2 mnPEOPLE IN TH E USA ARE IN FEC TE D WITH

ANTIB IOT IC - RES IS TANT MIC ROBES E VE RY YE AR .

23,000DIE AS A RESULT. 1

1.5%–3.5%OF C AN DIDATE - AC T IVE SUBS TANC ES ARE APPROVE D BEC AUS E

OF TH E COMPLE X DRUG DE VE LOPME NT PROC ESS AN D I TS SAFE T Y

AN D QUALIT Y REQUIREME NTS 2

12 YEARS

PHAS E I

33% SUCC ESS R ATE

PHAS E I I

59.3% SUCC ESS R ATE

PHAS E I I I

75. 7% SUCC ESS R ATE

DRUG APPROVAL PROC E DURE

79. 7% SUCC ESS R ATE

RES E ARC H AN D

PREC L IN IC AL PHAS E

17.3% SUCC ESS R ATE

Number of antibiotics in the pipeline that are effective against most of the resistant bacteria that pose a serious threat to human health: 3 Estimated time to possible market launch, in years: 10 to 15 Estimated costs for suffi cient promotion of antibiotic development in the next 10 years, in billions of dollars: 16 to 37 Number of antibiotics that account for >88% of prescriptions today: 19 Of which recently developed: 0 2

TES TS FOR DRUG APPROVAL TAKE AT LE AS T

EUROPE

390,000AS IA

4,730,000

OC E AN IA

22,000AFRIC A

4,150,000L AT IN A ME RIC A

392,000

NORTH A ME RIC A

317,000

DE ATHS AT TR IBUTABLE TO A MR E VE RY YE AR , BY 2050 3

number of deaths

TOTAL COS TS OF RES E ARC H AN D DE VE LOPME NT FOR

TH E 10 B IGGES T PHARM AC EUT IC AL COMPAN IES: 2

USD 65.8 BNTOTAL A MOUNT S PE NT BY TH E EU AN D TH E US NAT IONAL

INS T ITUTES OF H E ALTH TOGE TH E R TO PROMOTE RES E ARC H INTO

ANTIB IOT ICS AGAINS T MULT IRES IS TANT BAC TE RIA : 2

USD 0.4 BN

8. 2 m i l l i on

A MR IN 2050

10 mnDE ATHS AT TR IBUTABLE TO A MR

E VE RY YE AR COMPARE D TO OTH E R

M A JOR C AUS ES OF DE ATH 4

A MR

C ANC E R

D IABE TES

D IARRHOE AL D IS E AS E

ROAD TR AFF IC ACC IDE NTS

C HOLE R A

ME AS LES

TE TANUS

1. 5 m i l l i on

1. 4 m i l l i on

1. 2 m i l l i on

120,0 0 0

130,0 0 0

60,0 0 0

Sources:1 Centers for Disease Control and Prevention:

www.cdc.gov/drugresistance/about.html2 Securing New Drugs For Future Generations:

The Pipeline of Antibiotics, Review on Antimicrobial Resistance, 2015: bit.ly/sandoz_annual201601

3 Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations, Review on Antimicrobial Resistance 2014: bit.ly/sandoz_annual201602

4 Tackling Drug-resistant Infections Globally: Final Report and Recommendations, Review on Antimicrobial Resistance, 2016: bit.ly/sandoz_annual201603

A MR NOW

700,000

SHIPS, SHARKS AND STAPHYLOCOCCUS Have you ever touched a shark? Far from feeling slippery,

it is unexpectedly rough. Its skin is covered in grooved scales

that greatly reduce flow resistance. Based on this model,

a synthetic surface has been created that sheds bacteria and

has a wide range of applications in medicine.

24It all started in Hawaii in 2002. Anthony Brennan, Professor of Materials Science and Engineering at the University of Florida, visited the Pearl Harbor naval base. The US Navy had asked him to solve a widespread problem in shipping. Ships’ hulls become covered with barnacles and algae. This reduces the ships’ speed and maneuverability and can even damage them. In the past, a chemical cudgel was used: highly toxic paints were applied which kept the unwelcome visitors at bay. However, they also contaminated fish and the ocean floor with heavy metals. These toxic agents are now banned. Brennan gazed out to sea and noticed a submarine making for the harbor with all sorts of marine deposits clinging to it. It reminded him of a whale, and he began to wonder why barnacles cling to whales but not to sharks. “Sharks swim faster,” a colleague suggested. But Brennan was not satisfied with this answer. He believed there must be something special about the texture of the shark’s skin.

THOUSAN DS OF T IN Y TE E TH

One month later, Professor Brennan was able to confirm his suspicions in the lab. The University of Florida has an extensive research program to study sharks. It was therefore easy for Brennan to get his hands on a sample of sharkskin. Under the electron microscope, he observed what makes sharkskin so special: it is covered in thousands of tiny teeth with small microscopic grooves. This has two key advantages for sharks: the texture

reduces frictional resistance, making sharks fast swimmers. At the same time, bothersome algae and barnacles are unable to gain a purchase, so that sharks are not plagued by them.

But Anthony Brennan made his truly pioneering discovery five years later. The structure of sharkskin also prevents bacteria from adhering to it. Microbes are simply unable to stick to the nano-scale surface irregularities. The materials scientist had gained an important insight, with the potential to solve one of the most urgent questions in modern medicine.

S HARK IS BE T TE R THAN COPPE R

The value of an idea lies in its realization. However, production proved daunting. How can a surface with a microscopic texture – with grooves that measure less than one-tenth of the diameter of a human hair – be manufactured on an industrial scale? Brennan searched for dynamic business partners and was able to set up the company Sharklet Technologies in 2007. This was followed by a period of intensive investment and research, during which innovative industrial companies were consulted for their expertise. Ultimately, their efforts were crowned with success. The artificial sharkskin was manufactured, patented and extensively tested. The results are impressive: the surface inspired by nature scored better in tests in terms of its antibacterial performance than conventional coatings, for example

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Under the microscope, sharkskin is scaly and covered in grooves. Based on this model, Sharklet has developed an artificial surface.

In 1976, only

5% of staphylococcal infections were resistant. Today that figure is more than

50% 80%fewer bacteria settle on copper plates than on smooth surfaces.

94–99%fewer bacteria settle on the artificial sharkskin.

Staphylococci on a test plate: the right side with an antimicrobial coating showed significantly less bacterial contamination in the test.

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AIRC R AF T

Special adhesive riblet films enhance aerodynamic behavior so that the aircraft flies faster and consumes less fuel.

S H IPS

Ships’ hulls used to be coated with toxic substances, which are now banned. The structure of sharkskin kills two birds with one stone: it reduces flow resistance for greater maneuverability, and prevents bothersome barnacles and algae from clinging to it.

WIN D TURB IN E ROTORS

The surface structure also helps in generating green energy. The rotors rotate faster and generate more electric power.

SWIMSUITS

Sleek as a shark: the special surface structure can also be used on wetsuits, making them more ergonomic. The British sporting goods manufacturer Speedo, for example, has developed a full wetsuit for competitive swimmers based on research into streamlined sharkskin.

SM ARTPHON ES

The average user looks at his or her cell phone every twelve minutes and picks it up around 80 times a day. Sharklet has developed a case with a sharkskin surface for smartphones to keep it as free of bacteria as possible.

SURFAC E F I L MS

Sharklet films can be used in hospitals or in busy areas to cover tables, doors and other objects that come into contact with numerous hands. It is an innovative and cost-effective method for avoiding bacteria and infections.

BAN DAGES

Even textiles can be produced with the properties of sharkskin. Fewer bacteria collect in the bandages, which accelerates the healing process.

ME DIC AL TUBES

Catheters and intubation tubes are often colonized by bacteria. The surface of the tube can be covered with the typical sharkskin texture to prevent infections.

The structure of sharkskin reduces flow

resistance and has an antibacterial

effect. These properties result in many

potential applications:

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copper-based bactericidal surfaces. 94% to 99% fewer dangerous hospital microbes settled on the sharkskin structure than on smooth surfaces. The copper alloys achieved a score of “only” 80%.

S HARKS KIN ON DOOR HAN DLES

Bacteria are lazy. They seek out the path of least resis-tance, and they find the uneven surface of sharkskin unwelcoming. It is an inhospitable place for microbes. The texture is extremely detailed. The grooves are only around three micrometers long and two micrometers wide. They are invisible to the naked eye and cannot be sensed with the fingertips. But they are precisely the right size to discourage microbes. To settle on such a surface, microbes have to expend a great deal of energy. They therefore prefer to seek out a better place, or they die.

The surface developed by Sharklet keeps many species of bacteria at bay, including methicillin-resistant staphy-lococci, the antibiotic-resistant germs so dreaded in hospitals. Hospital hygiene is crucial, as many different pathogens have to be combated every day. Many practical applications exist in this setting for the innova-tive, bacteria-inhibiting surface. Anything that frequently comes into contact with numerous hands, such as door handles, waiting room chairs and telephones, can be

Flow resistance is increased by deposits of algae by up to

20% and by barnacle

60% This reduces speed, increases fuel consumption by up to

40%and costs the US Navy one billion dollars a year in additional fuel and cleaning costs.

28

covered with a textured film. Medical materials such as bandages and tubes can also be produced with the texture of sharkskin. This helps prevent wound and inter-nal infections, which translates into more rapid healing.

T IN Y GROOVES, HUGE E FFEC T

The most important thing about the discovery is that the structure alone is responsible for fending off bacteria without any chemical treatment whatsoever. As an example, consider a central venous catheter (CVC), which is inserted into the upper body of severely ill patients to supply them with medications and nutrient solutions. If a thin plastic tube is inserted into the venous system, bacteria can adhere to it and find their way into the body, where they multiply. CVCs are responsible for around 90% of all cases of catheter-associated blood infection, known as catheter sepsis. It is one of the most common complications associated with the use of central venous catheters and is often fatal, causing around 28,000 deaths a year in the USA. A common antimicrobial practice has been to impregnate or coat the tubes with drugs. However, if antibiotics are used, there is a risk of resistance developing. The prophylactic use of antibiotics in particular reduces their efficacy.

Thanks to the artificial sharkskin, those methods are now a thing of the past. The tube itself has a finely grooved texture that makes it difficult for bacteria to collect on it. The use of this new product alone could save many lives.

Medical science needs restructuring to meet the challenges it faces, but who would have thought that this was meant so literally. The artificial sharkskin raises hopes in the fight against antibiotic resistance. And it shows once again that nature has already come up with comprehensive solutions. It is just a matter of discovering them. What has worked for sharks for 400 million years can make shipping more efficient and can be a blessing for the pharmaceutical sector.

The structure alone is responsible for fending off bacteria without any chemical treatment whatsoever.

29

TH E GEC KO E FFEC T

Aristotle himself marveled at the slip-resistant feet of lizards that appear to defy gravity. Their astonishing adhesive ability is achieved by millions of fine hairs on the lizards’ toes. Each hair tip splits into more than a thousand ends. This makes it possible to exploit the weak attractive forces between molecules, known as van-der-Waals forces. The structure of the gecko’s foot improves the gripping power of car tires and industrial grippers. And it promises to further the development of dry adhesives.

TH E LOTUS E FFEC T

The lotus effect was discovered by the German botanist Wilhelm Barthlott in the mid-1970s. The lotus plant grows in muddy bodies of water, but its leaves are always immaculately clean thanks to their water-repelling surface. Examination under the microscope reveals wart-like elevations covered in tiny wax crystals. Water droplets roll off, forming typical water beads. Many products with beading properties are now available on the market, for example roof tiles, paints and window-cleaning agents.

VE LC RO

While walking with his dog in 1951, Swiss engineer George de Mestral observed the principle of the hook-and-loop fastener by examining the burr of the goose grass plant. He immediately filed a patent under the name Velcro. The burrs are spread by sticking to animals, and so this is a means of dissemination for the plant. The burr’s structure consists of bristles with minute hooks at the end. Today, this textbook example of bionics can be found on numerous objects, for example shoes, clothing, cable ties and support bandages.

NATURE AS A MODEL

Many product innovations that have proved to be a boon to mankind have

been inspired by flora and fauna. These examples from bionics, the interface

between biology and mechanics, all started with the observation of nature and

translated evolutionary solutions into user-friendly products.

30

31

TAKING THE INITIATIVE AGAINST AMR

Whether preventing infections, raising awareness about the cautious

use of antibiotics or supporting research and development, the fight

against antibiotic-resistant microbes must be waged on a broad front.

Many initiatives are already committed to tackling the

problems – covering many different aspects.

PROJEC TS AN D IN IT IAT IVES AROUN D TH E WORLD

Raising awareness, promoting research,

improving data quality: the EU has been implementing measures against AMR for 15 years

and can point to small initial successes.

PAGE

36

European Union against resistance

Five goals in fi ve years: the National

Action Plan of the US government defi nes

key objectives – almost doubling the budget for the pre-vention and control

of resistance.

The American way of fi ghting AMR

PAGE

34

Using antibiotics responsibly:

a multilingual initiative in

Latin American is raising awareness among patients,

pharmacists and HCPs.

PAGE

38

Better Care, More Health for Latin America

A global approach to health: antibiotic resistance is in the crosshairs of the most powerful

industrial nations on earth with a view to developing common

standards.

PAGE

40

What is AMR to the G7?

A united front against resistance: the Global Action Plan of the World Health Organiza-tion (WHO) has

called for unity and sets out a uniform

guideline.

PAGE

32

WHO calls for joint action

32

“Without harmonized and immediate action on a global scale, the world is heading towards a post-antibiotic era in which common infections could once again kill.” With these somber words, Margaret Chan, Director-General of the WHO, described the urgent need to take action in her foreword to the Global Action Plan on AMR. The response of individual healthcare providers and pharmaceutical manufacturers will not be enough. What is needed is a globally coordinated and well thought-out campaign. The WHO’s Global Action Plan is a fi rst step in this direction. The plan presents an integral approach to the problem based on fi ve objectives.

M AN Y S TAKE HOLDE RS , ON E H E ALTH

The WHO underscores the need for an effective “One Health” approach to tackling the problem jointly with research institutes, agricultural industry representatives, politicians, the pharmaceutical industry, healthcare professionals and patients. “An all-out effort is needed,” says Chan. In this context, the Global Action Plan calls for continued cooperation with organizations such as the

WHO CALLS FOR JOINT ACTION The Global Action Plan on AMR was announced at the 68th World

Health Assembly in May 2015 as an overarching guideline in the global

fight against AMR (antimicrobial resistance). Since then, the World

Health Organization (WHO) has also issued a monitoring standard for

uniform data collection and has called for the cooperation of various

members and organizations.

Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE). But other relevant stakeholders and WHO departments, such as those studying malaria, HIV and tuberculosis, should be more closely involved in fi nding a solution.

BRINGING ORDE R TO TH E DATA

The WHO is appealing to its member states to proclaim their support for the Global Action Plan by 2017, and in particular to develop and implement regional plans. Improving the general body of data is a key concern. In order to interlink the country-specifi c initiatives, the WHO has therefore developed a global data platform to assist local policymakers and researchers. Under its catchy acronym GLASS, the Global AMR Surveillance System will establish an overarching frame of reference to which national databases will gradually be linked. From test protocols through data classifi cation to institutional control structures, the GLASS manual contains some 40 pages that set out how AMR data

33

TH E E IGHT MOS T DANGE ROUS

RES IS TANC E - DE VE LOPING BAC TE RIA

ACCORDING TO TH E WHO:

• Escherichia coli (E. coli)• Klebsiella pneumoniae • Acinetobacter spp. • Staphylococcus aureus • Streptococcus pneumoniae • Salmonella spp. • Shigella spp. • Neisseria gonorrhoeae

should be collected and organized. The aim is to create a reliable, ordered body of data on the basis of which sound decisions for the future can be made.

TOGE TH E R WE KNOW MORE

All countries and organizations are invited to join GLASS and thus to contribute to the establishment of a global information network. In return, the WHO will provide assistance in analyzing fi ndings and will publish periodic reports on the AMR situation. A WHO-developed data-management software package is also provided for processing microbiological and clinical data.

ANTIBIOTIC RESISTANCE

Only use antibiotics when prescribed by a certified health professional

1

2

3

4

5

Never use left over antibiotics

Never share antibiotics with others

Prevent infections by regularly washing your hands, avoiding contact with sick people and keeping your vaccinations up to date

Antibiotic resistance happens when bacteria change and become resistant to the antibiotics used to treat the infections they cause.

#AntibioticResistancewww.who.int/drugresistance

WHAT YOU CAN DO

Always take the full prescription, even if you feel better

ANTIBIOTIC RESISTANCE

1

2

3

4

5

Improve surveillance of antibiotic- resistant infections

Ensure you have a robust national action plan to tackle antibiotic resistance

Strengthen infection prevention and control measures

Make information on the impact of antibiotic resistance available

Regulate and promote the appropriate use of quality medicines

Antibiotic resistance happens when bacteria change and become resistant to the antibiotics used to treat the infections they cause.

#AntibioticResistance www.who.int/drugresistance

WHAT POLICY MAKERS CAN DO

Prevent infections by ensuring your hands, instruments and environment are clean

1

2

3

4

5

Antibiotic resistance happens when bacteria change and become resistant to the antibiotics used to treat the infections they cause.

#AntibioticResistancewww.who.int/drugresistance

ANTIBIOTIC RESISTANCE WHAT HEALTH WORKERS CAN DO

Keep your patients’ vaccinations up to date

If you think a patient might need antibiotics, where possible, test to confirm and find out which one

Only prescribe and dispense antibiotics when they are truly needed

Prescribe and dispense the right antibiotic at the right dose for the right duration

ü....................

ü....................

ü....................

ü....................

ü....................

F IVE OBJEC T IVES OF TH E

GLOBAL AC T ION PL AN:

1 2 3 4 5

Improve awareness of the problem

Collect information and strengthen research

Reduce the incidence of infection through hygiene and prevention measures

Optimize the use of antibiotics in human and animal health

Promote economically sustainable measures to develop new medicines

34

Every year, fi ve out of six Americans are given a pre-scription for antibiotics – some 262 million prescriptions in total. Many of them are unnecessary. Studies have shown that 95% of healthcare professionals in the USA sometimes prescribe antibiotics even if they are uncer-tain whether they will work. Another aspect lies in the agricultural sector, where antibiotics are added to ani-mal feed – a widespread practice in the USA. Antibiotic-resistant pathogens are responsible for an estimated two million infections a year in the USA. The US govern-ment’s National Action Plan aims to reduce the overpre-scription of antibiotics and also calls for other measures.

GIVE ME F IVE

The topic has also reached the desks of top decision-makers in the USA and is high on their agenda. In early 2015, President Barack Obama announced the Nation-al Action Plan for Combating Antibiotic-Resistant Bacte-ria. Scheduled to run until 2020, it defi nes fi ve major goals (see information box). The White House has also put its money where its mouth is: it has earmarked 1.2 billion dollars for the prevention and control of

THE AMERICAN WAY OF FIGHTING AMR A far-reaching action plan against antimicrobial

resistance (AMR) has been launched in the USA. Five

ambitious goals are to be reached in just five years.

35

resistance, almost doubling the previous budget.The plan is also intended to act as an economic incentive. The government’s long-term commitment to combating AMR sends a message to pharmaceutical companies and research institutes that new antibiotics are a future market that is worth investing in. Moreover, some of the allocated money will be used directly to develop new drugs.

B IG DATA

Data collection plays a key role. When are antibiotics prescribed and for what? How do superbugs spread? A sophisticated system is to be established by 2020. The collected data will help detect the emergence of resistant bacteria and report the findings in real time to hospitals and physicians. Because microbes know no national borders, the White House is counting on international cooperation. These, too, are ways to contain the spread of resistance, because they allow preventive action to be taken early.

TH E F IVE GOALS OF TH E

NAT IONAL AC T ION PL AN:

Slow the emergence of resistant bacteria and prevent the spread of resistant infections

Strengthen national One-Health surveillance efforts to combat resistance

Advance the development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria

Accelerate basic and applied research and development for new antibiotics, other therapeutics and vaccines

Improve international collaboration and capacities for antibiotic resistance prevention, surveillance, control and antibiotic research and development

36

The European Centre for Disease Prevention and Control (ECDC) estimates that around 25,000 patients a year in Europe die as the result of infection caused by multi-resistant pathogens such as MRSA, but the number of unreported cases could be much higher. The fi gures are alarming even in the EU, where hygiene standards are upheld. This has galvanized the European Commission, which has already been implementing measures against antibiotic resistance for 15 years and has issued a comprehensive action plan.

TH E M AGN IF IC E NT S E VE N

Since 2011, the fi ve-year Action Plan against the Rising Threats from Antimicrobial Resistance has combined the initiatives of the EU. Seven fi elds of activity are defi ned, and in each area there are practical actions, totaling twelve in number (see box). Among other things, the European Commission is relying on raising public awareness, promoting research and encouraging international cooperation, and new EU laws to curb the use of antibiotics in livestock. Being aware of the status quo is fundamental to all projects. One aim is to improve the quality of resistance data by harmonizing monitoring systems across Europe. Only then will it be possible to draw comparisons between member states and to better evaluate how resistant microbes spread and whether the measures are having an effect.

EUROPEAN UNION AGAINST RESISTANCE The EU is combating antibiotic resistance on a broad front with ambitious

measures and can point to initial, though small, successes.

A GL IMME R OF HOPE

Despite all these efforts, the most recent fi gures from the European Centre for Disease Prevention and Control (ECDC) make sobering reading. The report issued in November 2015 shows that resistance of most bacteria is still on the rise. But there are glimmers of hope. For the fi rst time, antibiotic consumption in fi ve EU countries has decreased signifi cantly: in Denmark, Luxembourg, Slovenia, Spain and Sweden. A study has shown that the public is increasingly aware that antibiotics are powerless against viruses and that their use in most respiratory infections therefore makes no sense. One factor was the observance in many countries of European Antibiotic Awareness Day on November 18, to encourage physicians and patients to use antibiotics prudently. The media campaigns appear to be bearing fruit.

37

1. APPROPRIATE US E OF ANTIMIC ROBIALS

Action 1: Strengthen the promotion of the appropriate use of antimicrobials in human medicine

Action 2: Strengthen the regulatory framework on veterinary medicines and on medicated feed

Action 3: Introduce recommendations for prudent use in veterinary medicine

2. PRE VE NT MIC ROBIAL IN FEC T IONS

AN D TH E IR S PRE AD

Action 4: Strengthen infection prevention and control in healthcare settings

Action 5: Adoption of a proposal for an EU Animal Health Law

3. DE VE LOP N E W E FFEC T IVE ANTIMIC ROBIALS

OR ALTE RNATIVES FOR TRE ATME NT

Action 6: To promote, in a staged approach, unprecedented collaborative research and development efforts to bring new antibiotics to patients

Action 7: Promote efforts to analyze the need for new antibiotics in veterinary medicine

4 . JO IN ING FORC ES WITH INTE RNATIONAL

PARTN E RS TO CONTAIN TH E R IS KS OF A MR

Action 8: Develop and/or strengthen multilateral and bilateral commitments for the prevention and control of AMR in all sectors

5. MON ITORING AN D SURVE I LL ANC E

Action 9: Strengthen surveillance systems for AMR and antimicrobial consumption in human medicine

Action 10: Strengthen surveillance systems for AMR and antimicrobial consumption in veterinary medicine

6 . ADDIT IONAL RES E ARC H AN D IN NOVATION

Action 11: Reinforce and coordinate research efforts

7. COMMUN IC AT ION, E DUC ATION AN D

TR AIN ING

Action 12: Communication, education and training: Survey and comparative effectiveness research

Seven main areas, twelve actions:

The action plan of the European Commission

38

AMR is a huge problem. What is the situation in Latin America?AMR is a bigger problem than in northern countries in Europe or the USA because there is signifi cant misuse of antibiotics throughout Latin America. Patients use antibiotics for a virus, not in the correct dosage or not for the correct period of time. And healthcare systems are less advanced here. Patients rely com-pletely on the pharmacist. But in most of the cases, they are not trained well enough to give the right antibiotic. You can walk into a pharmacy and buy antibiotics with-out a prescription. So it is not just having to educate the patients, but also the pharmacists.

BETTER CARE, MORE HEALTH FOR LATIN AMERICASandoz developed “Better Care, More Health”, a multi - language

campaign for Latin America to create awareness on the responsible

use of antibiotics. Emilio Fernandez, Head of Business Franchise

Anti - Infectives, is based in Miami and manages the business of the

whole region, from Mexico to Chile with more than 700 employees.

So you started a campaign to promote the responsible use of antibiotics.About two years ago, we saw the need to tackle this problem. We did some market research and found out that mothers are the ones that go to pharmacies and buy antibiotics – for their kids, their husbands or them-selves. So, our target audience were women aged 18 to 50. The idea was to launch the campaign during wintertime, when people take antibiotics the most.

What are the main objectives of the campaign?The main objective is to drive aware-ness. The second objective is to say:

there is a brand out there that you can reach without being so expensive. The campaign followed a two-way approach to educate internally and externally. One of the touch points was our sales force, which emphasize the quality of Sandoz in antibiotics.

What concrete actions were taken?The list is long. It is a combination of different actions for different stake-holders in different channels. And eve-rything was done in three languages.On the traditional side, we had bro-chures, folders for the counter of the pharmacy, posters in pharmacies, at the doctor’s offi ce or even in the hall of the hospitals. We had a video on the website – in Brazil they showed

39

it on pharmacy TV. On the digital side, there is e-mail marketing, the website, and e-learning. As a con-sumer or patient, you could learn about the responsible use of anti-biotics on the website and take a mini quiz – and you would get a certificate. Internally, the e-learning for the sales force was more techni-cal and product-based.

Is the initiative making a difference?People did learn a lot about the responsible use of antibiotics. Not only were the sales reps proud to go and communicate this to their customers, namely pharmacists and doctors, but the customers also ap-preciated that they could give some-thing to their patients. We received encouraging feedback from all of them. They actually requested more material to share with their patients. On the patient side, the engagement level on the website was quite high.When the campaign was launched in Mexico, I had the pleasure to talk to doctors as we were handing them some of the materials. The response was very good. AMR is a hot topic, doctors are happy to hear that the industry is taking care of overuse and raising consciousness.

What were the challenges you encountered?At first, the challenge was internal resistance because it might seem contradictory to push for a responsible use of antibiotics in a commercial organization.

The campaign in Latin America primarily targets mothers, because it is they who obtain antibiotics for

themselves and their family.

This makes some commercial people think that you are diminishing sales. But we look at the long term, and the value for the patient. We had to spend some time with legal compliance for them to under-stand what we were trying to do. But we were turning the challenge into an opportunity. We feel very proud that we won four awards for this campaign. We got second place for “Eye for Pharma” in Latin America. And we actually won first place for our responsibility to the patient for an integrated campaign.

What are the future goals of “Better Care, More Health”?The second wave of the campaign started in July this year in Brazil. We will continue encouraging the responsible use of antibiotics using paid media and earned media. Our goal is to create more traffic on our website and keep promoting our materials to increase people’s awareness on this topic.

What is your personal motivation in the fight against AMR?I think it is our responsibility, and mine, to assure that the new generations will be healthy. By fight-ing the resistance of antibiotics, I make sure that in the future, when-ever our children and grandchildren have an infection, their treatment will be effective. Antibiotics are life-saving resources, and in order to maintain their effectiveness, the community should make responsible use of them.

40

An alarming report went around the world precisely when the most infl uential heads of state were assembled at the G7 summit in Japan in May 2016. A 49-year-old American woman had contracted an infection with a pan-resistant superbug, a variant of the bacterium Escherichia coli, against which even the otherwise effective stand-by antibiotic proved ineffective. She had not traveled recently; she had contracted the pathogen in the USA. The news was covered by all the media, which warned of a “return to the pre-antibiotic era”.

FE WE R ME DIC IN ES , MORE RES E ARC H

The state and government heads of the USA, the United Kingdom, Canada, Japan, France, Italy and Germany all agreed that antibiotic resistance poses “a signifi cant threat to public health”. On the day of the bad news from the USA, David Cameron, at that time British Prime Minister, appeared before the press at the Summit venue in Ise-Shima: “In too many cases antibiotics have stopped working. That means people are dying of simple infections that should not mean a death sentence.” Cameron promised to halve the quantity of antibiotics prescribed in the UK by 2020, because their excessive use is a factor contributing to the development of resistance. Furthermore, he promised to work together with international partners to set up a system which rewards companies that introduce new antibiotics to the

WHAT IS AMR TO THE G7?The danger of antibiotic resistance is a topic that has long

concerned the most powerful nations in the world. It figured

prominently on the agenda of the two most recent G7 summits.

marketplace. The British are also putting their money where their mouth is. “The UK has put in place £265 million to track the spread of resistance in developing countries, and £50 million into a global fund for antimicrobial resistance research and development,” Cameron said.

WITH UN ITE D FORC ES

As early as 2015, German Chancellor Angela Merkel placed the topic of resistance on the agenda when she hosted the G7 summit in the German Schloss Elmau. In the declaration entitled Joint Efforts to Combat Antimicrobial Resistance, the seven industrialized nations defi ned the key areas of commitment. They endorsed the WHO Glob-al Action Plan (see also page 32). In addition, investments are to be made into R&D to encourage the development of new medicines and diagnostic aids. The declaration also contained a pledge to promote basic research, epidemiological research, and research into the preven-tion and treatment of infections as well as the develop-ment of alternative therapies, vaccines and rapid tests. The G7’s undertaking follows the One Health strategy advocated by the WHO, which takes into account the health of humans and animals as well as agriculture and the environment, as the proper use of antibiotics in ani-mals is also called for as a matter of urgency. “We need common standards,” German Chancellor Merkel said.

41

A GLOBAL PROBLEM

After the summit, the G7 health ministers met for consultation in Berlin in October 2015. This meeting also culminated in a joint declaration. “More than ever before, we have to think about health globally, because diseases do not stop at borders,” German Minister of Health Hermann Gröhe said. “Only through joint international efforts will we be able to protect people effectively against multiresistant microbes and cross-border epidemics.”

. . . AN D AC T ION!

The feedback from NGOs after the summit in Japan was split. The fact that the G7 governments want to invest in research into new antimicrobials and tackle AMR with national action plans based on the WHO recommenda-tions was received positively. However, the declaration does not contain concrete objectives, for example specific measures to reduce the use of antibiotics in animal husbandry. Overall, the resolutions are thought to be too hesitant. So far, the many regional and national initiatives in the seven industrialized nations have had an important impact. However, seeing the big picture and creating international standards for tackling AMR remains a challenge. Explanations alone will not be sufficient to manage the emergence of resistance. Actions must now follow.

“We have to think about health globally, as diseases don’t stop at borders.”Hermann Gröhe, German Minister of Health

The G7 nations have agreed to increase investment in research.

The future of diagnostics: new test

methods and technologies promise

to drastically cut the time needed

to establish a diagnosis. We

present several of the new tests

and take you to Heidelberg, where

a high-tech laboratory line has

been opened.

43REDEFINING DIAGNOSTICSFast, reliable diagnosis is a key factor in the fight against

antibiotic resistance. It ensures that antibiotics are only used

where they are actually needed. In our interview, Gabriel

Morelli, Head of Commercial Strategy, Anti - Infectives at

Sandoz International, explains which new test methods are

particularly promising.

Dr. Morelli, how important is a fast diagnosis?Developing rapid and inexpensive diagnostic tools has become essential to winning the fight against AMR and improve healthcare. However, despite what most people believe, distinguishing between a virus and a bacterial infection is still challenging from a technical point of view with no perfect tool available today.

What are the common tests in use?The usual approach is to go the empirical route. Only if the infection persists and becomes dangerous is a diagnostic test performed and the optimal treatment

becomes delayed. The most relevant methods used today include the Maldi-Tof, which helps with the identification of colonies, providing results from minutes to hours as opposed to overnight, and sequencing, which provides an accurate identification of organisms and methods for direct specimen testing. For example, if you were to employ rapid diagnostics for blood stream infection, you would typically use FISH probes, Maldi-Tof, Rapid MRSA testing, Verigene and film arrays, among others. For urinary tract infections (UTI), the methods used today include gram stain, dipsticks for nitrates and white blood cells, and instruments that can enumerate microbes in broth rapidly.

4 4

Which of the new tests do you find promising?A new very promising test developed for urinary tract infection is the BacterioScan 216R. It consists of a forward laser scattering combined with optical density highlighting when sensitivity is outside predefined margins, presenting bacteria growth imaging. About 94% sensitivity with 78% specificity could be achieved after only 90 minutes of incubation, which makes it potentially the best rapid test in the market today. However, the majority of tests still need to go through clinical trials and become approved. Most start-ups developing these tests are focusing on diagnostics that are cheap, quick, accurate and easy to use.

How fast do doctors and patients know the reason for the sickness by using the new diagnostic tools?It really varies by test, but today it is possible to get fairly accurate results between 2 to 4 hours, allowing the patient to stay while the sample is analyzed. In the future, we should be able to go to the doctor and in 5 minutes understand if the infection is bacterial or viral, what type of bacteria is causing the infection, if the bacteria is resistant to specific antibiotics, and which drugs could be effective in removing the infection.

Are there also disadvantages?All methods are very different and there is no “one fits all”. All of them have different strengths and weaknesses. The key barriers that still need to be overcome are that some of the tests are too expensive, the devices required too bulky to keep at hand and some of them require specialist skills to properly manage them. And of course, accuracy and reliability is also key. Those diagnostic tools are mostly used in reference hospitals. They need a sizeable critical mass of patients to justify the investment required for their use.

What development of diagnostics do you foresee?We are starting to think about them as a great compan-ion to new antibiotics to address patients and doctor needs. A critical issue these days, also highlighted in the media every week, is the misuse of antibiotics. We will surely see great diagnostic tools in the coming years assuming the right incentives and commercial models are put into place to stimulate innovation.

M ALDI - TOF: TH E L AS E R TES T

Maldi-Tof refers to a specific form of mass spectrometry. The abbreviation stands for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The bacteria must be in a pure culture. A pinhead-sized quantity is dissolved in a matrix, which is applied to a carrier and ionized by laser bombardment in a mass spectrometer. The method separates the proteins contained in the bacteria. The overall pattern that emerges is, so to speak, the fingerprint of the bacterium. Advantages of the Maldi-Tof method are that it lowers costs (though the mass spectrometer itself is relatively expensive to purchase) and delivers results comparatively quickly. Once the bacterium has been isolated, no further incubation is required.

PC T: TH E PROTE IN TES T

The blood test measures the plasma concentration of the acute-phase protein procalcitonin (PCT). In healthy individuals, the value is below 0.05 ng/mL. In the presence of viral infections, it increases by a factor of 10 to 100; in bacterial infections by a factor of 1,000 to 100,000. Because the test quickly indicates whether an infection is viral or bacterial, it is also suitable for primary care practices. However, the PCT method is not available as a quick test. The samples have to be sent to a laboratory, and the result is available within two hours.

DUKE: TH E GE N E TES T

A new blood test from Duke University in Durham, North Carolina, analyzes the activation patterns of specific genes. Analysis of the genome can reveal whether the immune system is currently fighting off a viral or bacterial infection. The test promises better reliability than the usual PCT method. However, work still needs to be done on the timing, as it currently takes up to twelve hours to get a result. Scientists are refining the test so that a diagnosis can be made more quickly and more cost-efficiently in the future. The study was only carried out in patients with respiratory infections. The method may not be suitable for other pathologies.

C RP: TH E QUIC K TES T

A tiny finger prick, and that’s it. A few drops of blood are sufficient for testing whether an antibiotic is needed. The indicator is C-reactive protein, or CRP for short. If the patient has a bacterial infection, the protein concentration in the blood increases. The quick test indicates within ten minutes whether the cause is viral or bacterial. However, there are drawbacks: The blood CRP value does not rise until after 12 to 24 hours and then remains elevated for three to seven days. The test is therefore not useful outside this time window. The CRP test is also relatively expensive and is therefore rarely used.

Under scrutiny: What can the different tests do?

IMMUNOXPE RT: TH E TR IPLE TES T

Researchers from Haifa analyzed 600 immune-system-related proteins and for the first time discovered markers for viral infections. The test is designed to detect three indicators simultaneously. An especially specific marker is the TRAIL concentration in the blood, which stands for TNF-related apoptosis-inducing ligand. In viral infections, the concentration is greatly elevated, whereas in bacterial infections it is decreased. The test also measures the values of CRP and interferon-γ-induced protein 10 (IP-10). Clinical studies have demonstrated sensitivity and specificity values of over 90%, which exceed the reliability of previously available tests. Because the proteins from the immune system circulate throughout the body, the test can also diagnose infections that are not directly accessible, such as pulmonary infections. A point-of-care device is in the development phase.

BAC TE RIOSC AN:

TH E URIN E TES T

BacterioScan 216R is a simple, compact and inexpensive quick test for the diagnosis of urinary infections. It distinguishes between bacterial and non-bacterial infections and between gram-positive and gram-negative bacteria. A diagnosis is available within one-and-a-half to three hours, making it suitable for medical practices.

46

For Stefan Zimmermann, Head of the Bacteriology Division at Heidelberg University Hospital, the hundreds of small Petri dishes being carried along on the conveyor belt are somewhat reminiscent of a sushi restaurant. The new, fully automatic line has been in operation in the Department of Infectious Diseases since the beginning of 2016. All swabs as well as blood, urine and stool samples from the hospital are transported here via pneumatic tubes. Six other hospitals in the region also use the diagnostic facility in which microbes are cultivated and analyzed.

QUIC KE R D IAGNOS IS

“Every week, we’re confronted with pan-resistant microbes against which all the usual antibiotics are powerless,” says Stefan Zimmermann, explaining the extent of the problem. “In those cases we have to resort to stand-by antibiotics that either have more side effects or are much more expensive. The sooner we know the cause of a disorder, the sooner we’re able to begin the right treatment.” Whereas it takes 48 hours or longer to analyze results in conventional laboratory situations, the new diagnostics system achieves significantly shorter times thanks to the faster process and the maintenance of ideal conditions. “Here, we can obtain a result in around 24 to 26 hours,” says Zimmermann.

MIC ROBES ON TH E CONVE YOR BE LT

As soon as a sample has been taken, the physician or a medical assistant enters the information into the system, receives a label with a barcode, attaches the label to the container and sends it via the pneumatic tube system with a total length of 35 kilometers. It reaches the laboratory in a matter of minutes. By scanning the barcode, the system not only reads the patient’s data but also determines the ideal nutrient medium for the sample. A robotic gripper arm picks up the tube and pipettes the precise required volume of the sample onto the Petri dish on the conveyor belt. The way the sample is distributed on the dish is important for enabling colonies of the microbes to grow. The better this is done, the easier it will be to identify them subsequently. “The streaking system uses a special magnetic ball to distribute the substance on the nutrient medium. It creates a four-meter-long streak line – in a small dish just nine centimeters in diameter,” Zimmermann explains. Even with years of experience, a human could never match that.

MULT ICULTURES IN A PE TR I D IS H

Some bacteria grow better in a carbon dioxide atmos-phere, while others prefer ambient air. The Heidelberg laboratory has a total of four incubators, each of which can hold 1200 plates. The system knows from

RUNNING PETRIA fully automated laboratory line for patient screening and

microbiological diagnostics has been opened at Heidelberg

University Hospital. Quicker, more efficient cultivation of

microbes and high-resolution imaging technology shorten

the time needed to obtain results, and until the appropriate

antibiotic can be prescribed.

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scanning the barcode what it has to do. It carries each bacterial culture to the incubator that provides the ideal environment for its growth. Thanks to the automated process, the Petri dishes are conveyed to the incubation chamber within a minute, and cultivation can begin with-out delay. In conventional laboratories, a lab worker does all of this manually. It can take up to an hour to process all the samples from a stand. Then the inoculated plates have to be incubated, during which the door of the incubator is opened around 10 to 15 times a day, resulting in the loss of CO

2 and heat. “In our automated system, the plates on the conveyor belt enter the incuba-tor through a small slot. Consequently, the temperature and CO2 level remain constant. This means that the microbes grow faster,” Zimmermann says, explaining the advantages of the conveyor belt method.

DIGITAL PL ATE RE ADING

The plate-reading process in Heidelberg is also digital. High-resolution cameras photograph the plates after a specified number of hours. A lab worker can examine the pathogen cultures on a computer screen and zoom in on the images. “It surprised us how well the imaging works. We see more than if we had the physical sample in front of us,” Zimmermann says with enthusiasm. That has big advantages for the lab workers. They are no

longer exposed to the smell of bacteria, and the risk of contracting an infection is greatly reduced.

PRE - SORT ING, PLE AS E

Many diagnostic tests are carried out preventively. Around 90 percent of samples tested for MRSA or resis-tant gut pathogens are negative. A pilot project for im-proved imaging is underway that starts here and aims to speed up diagnostics still further. “If the system automati-cally flags the negative findings, the lab worker has more time to devote to the positive samples. Negative findings are actually extremely important, as they help reduce the use of precious antibiotics,” bacteriologist Zimmermann explains. “My colleagues often comment that they wait for the results before starting targeted treatment. That’s possible if a diagnosis can be made within 16 hours. But trying to console the patient for three days? The patient would rather go to another physician.”

The next step will be for the system to flag positive samples that need further analysis as well and convey them automatically to a mass spectrometer. Zimmermann believes that this will simplify work in the department enormously. “Because of increased screening, the number of samples has almost doubled in the past ten years. We’re very grateful for the system.”

To Stefan Zimmermann (right), the size of the laboratory line – eight meters long and six meters wide – is still impressive. Two rooms had to be joined to create space for the system. The high-tech automated lab line can streak 250 plates per hour. Because the lab is only manned for 12 hours, a maximum of 3,000 plates a day can be cultivated. Twice that number of plates would be possible if the lab ran around the clock.

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A CONTRACT AGAINST SUPERBUGS Presenting a united front against antibiotic-

resistant microbes: Over 80 organizations in the

pharmaceutical, biotechnology and diagnostics

industries signed a declaration in Davos. The wintry

Swiss mountains saw the emergence, for the first

time, of a joint battle plan for tackling one of the

greatest challenges facing modern medicine.

At the World Economic Forum in Davos, Switzerland, Sandoz, among other companies and associations, signed a groundbreaking declaration against resistance.

49Topics that move the world: Everyone who is anyone in politics, economics and science gathered at the annual meeting of the World Economic Forum to exchange information. The meeting of these luminaries took place in Davos from January 20 to 23, 2016. Around 2,500 participants from around the world met against a snow-covered Swiss backdrop, including US Vice President Joe Biden, Facebook COO Sheryl Sandberg, French Prime Minister Manuel Valls, Queen Máxima of the Netherlands and activist and lead singer of the Irish band U2, Bono. The topics covered the digital economy, extremism, equal opportunities and fossil fuels, to name but a few.

AS A M AT TE R OF PR INC IPLE

The issue of the growing resistance of bacteria to antibi-otics was also on the agenda. More than 80 companies signed the Declaration by the Pharmaceutical, Biotech-nology and Diagnostics Industries on Combating Anti-microbial Resistance. Thus, leading players from industry stood alongside politicians in committing themselves to step up efforts in the fight against antibiotic resistance. For the first time, they set out joint principles. The declara-tion defines how governments and industrial companies should work together to invest sustainably in new products to deal with the growing resistance problem.

“Antimicrobial resistance is beyond the capacity of any organization or country to manage or mitigate alone”, explained Margaret Chan, the Director-General of the

World Health Organization (WHO). “WHO and its Member States have called for the development of new antimicrobial medicines and affordable access to them, in line with the global action plan on antimicrobial resistance. This Declaration affirms that the challenges of AMR can be addressed only through collaboration and global collective action.”

A JOINT PL AN OF AC T ION

Altogether, 85 companies and nine industrial associa-tions from 18 countries signed the declaration, including Sandoz. Sandoz is one of the biggest manufacturers of generics and ranks among the top three producers of antibiotics. “This declaration sits at the heart of who we are. Antimicrobial resistance is one of the most pressing challenges facing global healthcare today. We fully sup-port the goals of the Davos declaration,” Rex Clements, Head of Anti-Infectives at Sandoz said, pointing out the urgent need to combine forces.

The declaration calls for the responsible use of existing antibiotics. Improved diagnostics are also crucial in order to quickly determine whether an infection is bacte-rial or viral. The signatory organizations will undertake to administer antibiotics only to those patients who need them and to raise the awareness of physicians and other healthcare professionals in this respect. Infections will be avoided by further promoting improved hygiene, vaccinations and other preventive measures to reduce the need for the use of medications. Based on the “one

„This declaration sits at the heart of who we are. We fully support the goals of the Davos declaration.“Rex Clements, Sandoz

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health approach”, contamination of the environment with antibiotics, for example as a result of the drug treatment of livestock, will be curbed.

R&D ON TR IAL

The 80-plus signatories to the declaration agreed to invest in research and development with the aim of generating innovative drugs, vaccines, alternative technologies and new diagnostic methods. The industry will also cooperate with public research centers to achieve this. Companies in the pharmaceutical industry as well as private and public research institutes have invested billions in the development of new antibiotics. Yet not a single drug against gram-negative infections has been approved in the past four decades.

BRE AKING TH E RULES OF ECONOMY

Antibiotics are valuable, and this is reflected in their prices in developed countries. Economic models are also required to better regulate the antibiotics market and create incentives for companies engaged in research and development. New remuneration approaches should decouple prices from sales volumes so that it is not always more profitable to sell more and more antibiotics. Moreover, bonus systems for physicians, veterinary surgeons and pharmacists that encourage the large-scale prescription of antibiotics should be prohibited. This practice is one of the main reasons why these precious medicines are losing their efficacy. Instead, methods are needed that encourage research, for example the payment of a lump-sum market entry reward for the approval of a new medicine. This would help reduce the financial risk for developers.

GLOBAL COORDINATION, LOC AL AC T ION

These measures must be globally coordinated, imple-mented at the local level and adapted to circumstances. The signatories are therefore appealing to governments to lend their support to the cause with laws, guidelines and awareness-enhancing campaigns and to ensure that antibiotics are only administered if they are actually needed.

At the same time, the signatories are encouraging global access to current and future antibiotics for everyone who needs them, irrespective of their income. This is to be accomplished as part of the WHO Global Action Plan. The declaration will be updated every two years to take account of international developments. The first step was taken in Davos. Many others will follow.

TH E TH RE E COMMITME NTS

OF TH E DEC L AR AT ION:

1. Encourage better and more appropriate use of new and existing antibiotics both by patients and physicians

2. Increase investment in R&D in new antibiotics, diagnostics, vaccines and other alternative treatments

3. Improve access to high-quality antibiotics for all

„The challenges of AMR can be addressed only through collaboration and global collective action.“Margaret Chan, WHO

For further information please contact sandoz.antiinfectives@sandoz.com

www.sandoz.com

Sandoz GmbH September 2016

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