BP6 1amr

Priority Medicines for Europe and the World "A Public Health Approach to Innovation"
Update on 2004 Background Paper Written by Per Nordberg, Dominique L. Monnet, Otto Cars
Background Paper 6.1 Antimicrobial resistance
By Emma M. Lodato, Boston University and Warren Kaplan, PhD, JD, MPH, Boston University April 2013
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
Table of Contents
Acknowledgements ............................................................................................................................................ 3 Acronyms .............................................................................................................................................................. 4 1. 2. Introduction ................................................................................................................................................. 5 Why does the problem persist? ................................................................................................................ 6 2.1 2.2 2.3 3. New variants of resistance have continued to emerge .................................................................. 7 Transmission of antibiotic-resistant bacteria .................................................................................. 8 Antibiotic misuse continues to be a challenge ................................................................................ 9
Epidemiological trends ........................................................................................................................... 10 3.1 Increasing levels of Gram negative resistant bacteria in Europe ............................................... 10 3.1.1 Escherichia coli ............................................................................................................................. 11 3.1.2 Multidrug-resistant Klebsiella pneumoniae ............................................................................. 12 3.1.3 Carbapenem resistance in Pseudomonas aeruginosa ............................................................. 12 3.1.4 Staphylococcus aureus................................................................................................................. 13 3.1.5 Emerging carbapenemase-producing bacteria in Europe. ..................................................... 14 3.2 Antibiotic resistance in other regions ............................................................................................ 15 3.2.1 The Americas ................................................................................................................................ 15 3.2.2 Asia and the World ...................................................................................................................... 15
4. 5.
The disease and economic burdens of antibiotic resistance ............................................................ 16 What are the current policy initiatives regarding AMR control? .................................................... 17 5.1 5.2 5.3 5.4 European Union ................................................................................................................................ 17 World Health Organization ............................................................................................................ 19 World.................................................................................................................................................. 20 The Americas ..................................................................................................................................... 21
6.
Research into the past and present pharmaceutical interventions: what can be learnt? ............. 22 6.1 6.2 6.3 6.4 6.5 Antibiotic development ................................................................................................................... 22 Are incentives insufficient for the pharmaceutical industry? .................................................... 22 Public resources for basic and applied research ........................................................................... 23 What is in the current antibiotic pipeline? .................................................................................... 23 Optimization of antibiotic dosing regimens ................................................................................. 24
7. What are the gaps between current research and potential research issues which could make a difference? .......................................................................................................................................................... 25 7.1 7.2 7.3 Need for Rapid and inexpensive diagnostics ............................................................................... 25 Identifying the most urgent needs for new antibiotics................................................................ 25 New therapeutic approaches .......................................................................................................... 26
6.1-2

7.3.1 7.3.2 7.3.3 7.3.4 7.3.5 8. Alternatives to antimicrobials: Antivirulence medicines ....................................................... 26 Host-pathogen interactions ......................................................................................................... 27 Non-antibiotics ............................................................................................................................. 27 Use of Phage and Phage Therapy .............................................................................................. 27 Vaccines: Primary prevention of resistance .............................................................................. 28
Conclusion ................................................................................................................................................. 29
References........................................................................................................................................................... 30 Annexes ............................................................................................................................................................... 41 Annex 6.1.1: Examples of Global Activities and Publications Addressing Antimicrobial Resistance ...................................................................................................................................................................... 42 Annex 6.1.2: Correlation between Antibiotic Consumption and Resistance in Europe .................. 48 Annex 6.1.3: Correlation between Antibiotic Consumption and Resistance in the World ............. 49 Annex 6.1.4: Outpatient Antibiotic Consumption ................................................................................ 50 Annex 6.1.5: Examples of Campaigns Addressing the Issue of Antimicrobial Resistance ............. 52 Annex 6.1.6: Successful Campaigns for Prudent and Appropriate Antibiotic Use .......................... 56 Annex 6.1.7: Examples of Diagnostics for Containing Antimicrobial Resistance............................. 58 Annex 6.1.8: Antibiotic Resistant Streptococcus pneumonia trends in Europe, 2005 and 2010 ..... 65 Annex 6.1.9: Antibiotic Resistant Escherichia coli trends in Europe, 2005 and 2010 ....................... 67 Annex 6.1.10: Meticillin Resistant Staphylococcus aureus trends in Europe, 2005 and 2010 ......... 71 Annex 6.1.11: Antibiotic Resistant Enterococcus faecium trends in Europe, 2005 and 2010 .......... 74 Annex 6.1.12: Epidemiological Trends in the USA ............................................................................... 77 Annex 6.1.13: Epidemiological Trends in the World ............................................................................ 81 Annex 6.1.14: Examples of the Economic Impact of Antimicrobial Resistance ................................ 85 Annex 6.1.15: Activity Review of the European Commission on Antimicrobial Resistance .......... 90 Annex 6.1.16: Press Release of IMI's 223.7 Programme to Combat Antibiotic Resistance ............ 95 Annex 6.1.17: European Commission Funded FP7 Projects on Antimicrobial Resistance .............. 97 Annex 6.1.18: Activity Review of the WHO and Antimicrobial Resistance .................................... 102 Annex 6.1.19: Examples of Concerted Action Addressing Antimicrobial Resistance in Europe . 106 Annex 6.1.20: Examples of Public Private Partnerships Concerning Antimicrobial Resistance .. 109 Annex 6.1.21: FDA Approved New Molecular Entity Antibiotics, 2004 2012 ............................. 113 Annex 6.1.22: Incentives to Encourage Antimicrobial Research and Development ...................... 114 Annex 6.1.23: Antibiotic Development Pipeline, 2011 ....................................................................... 117 Annex 6.1.24: Bacterial Vaccines Licensed for Distribution in the USA, 2005 2012 .................... 121
Acknowledgements
We wish to thank all of those who have helped me to complete this update: Anita KorinsekPorta, Eric Georget, Drs. Louis Kazis, David Rosenbloom:, Dr. Sean Devlin
6.1-3
Acronyms
AMR CGD CDC CHMP EARS-NET-Net EC EARS-NET EEA EMA ESBL ESPID EPRUMA EU FDA GAIN GBS HAI IDSA IMI LOS MDR TB MRSA NDM 1 NIAID OSDD PDCO PDUFA PPP R&D ReAct TATFAR USA WHO Antimicrobial resistance Centre for Global Development US Centers for Disease Control and Prevention Committee for Medicinal Products for Human Use European Antimicrobial Resistance Surveillance System Network European Commission European Centre for Disease Prevention and Control European economic area European Medicines Agency Extended-spectrum beta-lactamase European Society for Paediatric Infectious Diseases European Platform for the Responsible Use of Medicines in Animals European Union US Food and Drug Agency Generating antibiotic incentives now Group B streptococcal septicemia Hospital acquired infection Infectious Diseases Society of America Innovative Medicines Initiative Length of stay Multidrug resistant tuberculosis Meticillin resistant Staphylococcus aureus New Delhi metallo-lactamase 1 National Institute of Allergy and Infectious Diseases Open source drug discovery Paediatric Committee Prescription Drug User Fee Act Public private partnerships Research and development Action on Antibiotic Resistance Transatlantic Taskforce on Antimicrobial Resistance United States of America World Health Organization
6.1-4
1.
Introduction
The increasing prevalence of antimicrobial1 resistance (AMR) coupled with the dry antimicrobial development pipeline threatens the success and continuation of clinical medicine as we know it. This threat decreases the ability to successfully treat numerous infectious diseases while simultaneously increasing health risks for vulnerable patients. Medical procedures, such as hip replacements, organ transplants, chemotherapy, hemodialysis and care for preterm infants may become too risky or impossible due to untreatable community-acquired (nosocomial) infections. Common infectious diseases may once again result in death.1 The increased public health threats caused the World Health Organization (WHO) to declare AMR to be one of the three greatest threats to human health as reported for World Health Day 2011.2 In 2004, when the Priority Medicines for Europe and the World report was published, AMR was given great attention.3 This review together with annexes identifies what has occurred since 2004 to address this continuing challenge.4,5,6,7,8,9 Overall, there have also been a number of success stories since 2004: Surveillance programmes have been initiated at local, national and international levels.10 Successful programmes have led to better interventions aimed at assessing AMR and ensuring more appropriate antibiotic prescribing. The adoption in November 2011 of the Communication from the Commission to the European Parliament and the Council on an Action Plan on Antimicrobial Resistance has significantly strengthened the combat against AMR. (See Section 5.1) There have been major improvements in the development of diagnostic tools. Inexpensive and readily available diagnostic tools are now available for a variety of infectious diseases. Some of these tools are able to distinguish between viral and bacterial infections, while others are able to distinguish between bacterial species (see Annex 6.1.7). Since 2004, various national and international organizations have responded to the issue of AMR through numerous meetings, task forces, workshops, and publications (see Annex 6.1.1). Several major publications addressing AMR and its public health threat are in print. One success in efforts to slow the development of AMR in Europe is the overall decline in the prevalence of meticillin-resistant Staphylococcus aureus (MRSA) in this region since 2005 (see Figure 6.1.4).
The term antimicrobial is intended to encompass microorganisms generally, which includes bacteria, viruses and protozoans and typically are unicellular. As most resistance issues deal with bacteria, we shall use antimicrobial and antibacterial inter changeably in this background paper but the reader should be aware of the distinctions. If we specifically mean one or the other, we shall note this.
1
6.1-5
2.
Why does the problem persist?
Table 6.1.1 has been developed from the CGD report The Race Against Drug Resistance.11 This table aims to summarize the complex interactions related to antimicrobial resistance. Explanations concerning the persistence of AMR include biological, societal, industrial and legislative factors. Each perspective, by itself, is not solely responsible for the persistence of AMR. In order to accurately address this concern, these different perspectives must be appropriately addressed in a holistic manner in order to effectively contain and address the persistence of resistance.
Table 6.1.1: Explaining antimicrobial resistance from different perspectives Biological Explanation (contributing factors) Selective pressure: Bacteria that are not killed by an antimicrobial continue to survive thereby becoming the prevailing type. This results in an imbalance of the ideal microflora at a community and individual level. Evolution: To ensure survival in the presence of antibiotics, bacteria develop genetic and biochemical mechanisms such as alterations within the existing genome and gene transfer within and between species. Transmission: The transmission of gene sequences encoding for resistance is highly efficacious due to the small number of successful clonal lineages that share genetics related in pathogenicity and antimicrobial resistance. Societal Explanation (contributing factors) Overuse: Capacious antibiotic use includes use based on the incorrect medical indications, administration route, dose and/or treatment duration. This then creates a selective pressure favoring resistant bacteria. Transmission: Factors such as poor hygiene, densely populated settings, international trade, travelling, ecosystem disturbances and the increase of the ageing and immunocompromised populations further promote the propagation of resistant microbes. Underuse: An inadequate or adulterated supply of the appropriate antimicrobials to treat an individual perpetuates AMR by creating a selective pressure to favor resistant bacteria. Hospitals: Antibiotics are often less expensive than AMR prevention strategies. This often results in many hospitals preferring to provide treatment rather than implement prevention mechanisms. Behaviors: Patients may demand antibiotics from their providers thereby resulting in inappropriate antibiotic use. Additionally, providers may feel pressured to engage in inappropriate antibiotic use thereby further discouraging prudent antibiotic use. Economic: Many healthcare systems are weak and underfunded. Coupled with the rising costs of healthcare services, pressure on providers to seek economical alternatives is created. Since antibiotics are often inexpensive, providers may feel pressured to distribute them as a hasty alternative. Weak surveillance is also an issue since many surveillance systems cannot be fully and appropriately developed due to lack of funds. Agriculture: More than half of all of the antibiotics consumed within the USA are utilized for agriculture. This overuse creates a selective pressure that favors bacteria that are resistant to antimicrobials. The capacious overuse affects the surrounding livestock, surrounding water and soil and public health. The contribution by this animal reservoir is not insignificant although nosocomial (i.e. hospital-derived) infections and human-to-
6.1-6

human transfer of bacteria occurs constantly and routinely (sharing meals, aerosolized dissemination of bacteria, and intimate physical contact). Industrial Explanation Diagnostic tools: Providers may not have the appropriate tools to properly distinguish between a viral and bacterial infection that would benefit from treatment and this may result in a misdiagnosis and inappropriate antimicrobial use. The development of diagnostic tools to distinguish between viral and bacterial infections is critical to appropriately treat the patient while reducing the misuse of antibiotics. Access to existing tools is also required as it is lacking in many low- and middle-income countries. Pharmaceutical industries: The R & D for antibiotics often lacks the financial incentives that many pharmaceutical companies seek. This results in a lack of innovative antimicrobial therapies against AMR. Further, antimicrobial residues from pharmaceutical industries and hospitals are contaminating water supplies in many parts of the world. Pipeline: Between 1930 and 1962, more than 20 new classes of antibiotics were developed. Between then and 2011, only two new classes of antibiotics have been marketed for human use. A dearth of new antibiotics results in inability to treat emerging resistance to existing antibiotics, but resistance is an inevitable process. Legislative Explanation* Registration: There have been several antibiotic registration difficulties. These difficulties may present additional costs, time and other resources that may discourage the company to continue the process. These registration difficulties may discourage other companies from entering the antibiotic development pipeline. Requirements: The FDA has implemented stricter requirements, such as decreased noninferiority margins. This results in increased costs and clinical trial time which further discourage the development of antibiotics. Legislation against over the counter (OTC) sale is absent or not enforced in many countries.
Source: Nugent R, Back E, Beith A. The race against drug resistance: Center for Global Development; 2010 Note: * Legislative action or inaction does not per se cause AMR. To the extent legislative barriers discourage innovation of antimicrobials, AMR may be exacerbated
2.1
New variants of resistance have continued to emerge
An important change in resistance prevalence rates has occurred with the shift from Grampositive to multi-resistant Gram-negative bacteria, for which treatment options are limited or entirely lacking. Particular attention has been drawn to a gene that codes for New Delhi metallo-lactamase 1 (NDM1) which makes Gram-negative enterobacteria resistant to last line antibiotics, such as carbapenems.12 (See Section 3.2.2.) Indeed, this illustrates the AMR problem as there has been a general increase in carbapenemase-producing enterobacteria in Europe and globally as a consequence largely of acquisition of carbapenemase genes. Other emerging problems during the last decade include multi-or extensively resistant tuberculosis, Neisseria (i.e. gonorrhoea-causing bacteria) resistant to the latest cephalosporins and Clostridium difficile causing severe colitis resistant to moxifloxacin. Advancements have, however, been made in understanding the complexities of the reversibility of resistance.13
6.1-7

Research has revealed that there is a low possibility, if at all, of reversing AMR once it has been established in both community and non-community settings.14, 15
2.2
Transmission of antibiotic-resistant bacteria
The exploding emergence of multi-resistance, particularly among Gram-negative bacteria, has drawn attention to the increasing importance of transmission of genetic elements coding for muti-resistance, and also for the potential of zoonotic (animal-based) transmission. New information about the transmissibility of AMR pathogens is exemplified by the resistome.16 The resistome is a collection of genes originally found in soil bacteria. It is thought to be responsible for the development of various resistance mechanisms that permit soil bacteria to survive in the presence of antibiotics that are found naturally within the environment.17 It is believed that the genes of the resistome may have the potential to be transferred to non-soil bacteria thereby exacerbating the issues of resistance. Although debatable, research suggests that some resistant bacteria have been more successful in perpetuating extensively and surviving because of the resistome.18 Misuse of antimicrobials outside of human medicine is a further exacerbating factor in AMR, particularly the emergence of AMR in animals and humans.19,20,21,22,23 Use of antimicrobials in agriculture can create an important source of antimicrobial resistant bacteria that can spread to humans through the food supply when the animals are eaten. This includes nontherapeutic use such as for growth promotion. It also includes use as prophylaxis to try to prevent infections developing in food animals and use as a therapeutic agent to treat sick animals. See previous section. Agriculture serves as a reservoir of transmission of AMR pathogens both to and from humans.24,25,26,27 Yet it continues remains difficult to correlate antibiotic resistance of foodborne pathogens, antibiotic uses on farms and clinical isolation of a resistant pathogen in humans. That is, the ecosystem interactions amongst humans and agriculture are dynamic so that increased incidence of illness in any given year may or may not parallel increased use of antibiotics potentially selecting for resistant bacteria. In 1976, it was proven that one could track resistant E. coli from chickens in an experimental farm plot to the human farmers in close proximity.28 Recently, it has been possible to trace the connections between two farmers in Denmark, each of whom suffered a MRSA infection, and animals on their farms, which lie 28 miles apart.29 More specifically, one farmer who kept two horses and two cows, was diagnosed with a MRSA blood infection. The other had a flock of 10 sheep and the farmer had a wound that had become infected with MRSA. When their cases came to light they were recognized as a new MRSA strain that has been reported in cattle and so Danish researchers went out to check the animals on both farms. One cow on one farm, and three sheep on the other farm were carrying the new strain. All bacterial samples from both farms and both humans were identical on several different assays and had the same resistance pattern, i.e., susceptible to antibiotics that were not betalactams (penicillins and cephalosporins). A whole-genome sequencing was then done (something impossible in 1976) and compared to see how closely all samples really were. The isolates from the farmer and the cow samples were all functionally identical (5 SNPs), and so were the isolates from the other farmer and the majority of the sheep. Across all samples there was a difference of 154 SNPs (single nucleotide polymorphisms single-letter 6.1-8

copying errors in the genetic code). Based on their relatedness, the samples made clusters that corresponded to the two farms: the first farmer and a cow, and the second farmer and the sheep. Thus, phylogenetic analysis revealed two distinct farm-specific clusters comprising isolates from the human case and their own livestock, whereas human and animal isolates from the same farm only differed by a small number of SNPs, which supports the likelihood of zoonotic transmission. Further analyses identified a number of genes and mutations that may be associated with host interaction and virulence and that that these specific mecC-MRSA CC130 isolates are rarely found in humans. The inference is that they were transmitted between animals and humans. However, the challenges of this kind of proof remain. This was not observed experimentally and the sample size was small. It is possible that whatever genetic diversity of the isolates that did exist on a given farm could represent a second introduction of MRSA into the flock, not one introduction followed by dissemination. If that happened, then a human-to-animal transmission might be as likely as a zoonotic one. The host range of species carrying mecC CC130 MRSA is worryingly large and includes not just cows and sheep, but horses, rabbits, cats, dogs, deer, seals, rats and wild birds. Research clearly has supported the hypothesis that modern society has enhanced the opportunity for resistant pathogens to perpetuate and thrive throughout the animal and human ecosystem.30,31 The implication of this observation is that as trade increases, the AMR threat will also increase and thus the need to develop new antimicrobial products.
2.3
Antibiotic misuse continues to be a challenge
Antibiotic misuse continues to exacerbate AMR issues. Decrease of unwarranted high prescription rates has been proven to be achievable with national activities in several European countries. The prevalence of resistance is still strongly related to consumption of antimicrobials.32,33 See Annex 6.1.3. Patterns of antibiotic consumption throughout different regions of the world have changed over time. See Annex 6.1.4. Furthermore, there are serious cultural and behavioral challenges. For instance, most antibiotics are prescribed by physicians with varying levels of interest and sophistication in thinking about how to use molecular and microbiological data to inform therapeutic choices.34 Strategies designed to modify physician antimicrobial-prescribing practices must therefore choose simplicity over complexity and must acknowledge their fundamental ignorance of many of the specifics of antibiotic-microorganism interactions. They must also acknowledge the critical nature of bacterial illnesses in hospitalized patients and the importance of delivering effective antimicrobial therapy early in the illness.35 In short, major challenges still remain with respect to promoting rational use of antimicrobials and measuring and monitoring use. Unfortunately, this use of antimicrobial agents includes agents defined by the WHO as being critically important for human medicine. The World Health Organization (WHO) has developed and applied criteria to rank antimicrobials according to their relative importance in human medicine. Clinicians, regulatory agencies, policy-makers and other stakeholders can use this ranking when developing risk management strategies for the use of antimicrobials in food production animals. The list has subsequently been re-examined and 6.1-9

updated during WHO-AGISAR expert meetings held in Copenhagen in 2009 (second revision) and in Oslo, Norway in 2011 (third revision).36 The highest priority critically important antimicrobials were identified in this WHO document based on these three criteria: 1. High absolute number of people affected by diseases for which the antimicrobial is the sole or one of few alternatives to treat serious human disease. 2. High frequency of use of the antimicrobial for any indication in human medicine, since usage may favour selection of resistance. 3. Greater degree of confidence that there are non-human sources that result in transmission of resistant bacteria (Campylobacter spp.), or their resistance genes, to humans (high for Salmonella spp., Escherichia coli and Enterococcus spp.). These highest priority antimicrobials are listed below: Fluoroquinolones: These are known to select for fluoroquinolone-resistant Salmonella spp. and E.coli in animals. At the same time, fluoroquinolones are one of few available therapies for serious Salmonella spp. and E.coli infections in humans. 3rd and 4th generation cephalosporins are known to select for cephalosporin-resistant Salmonella spp. and E. coli in animals. At the same time, 3rd and 4th generation cephalosporins are one of few available therapies for serious Salmonella and E. coli infections, particularly in children. Macrolides are known to select for macrolide-resistant Campylobacter spp. in animals, especially Campylobacter jejuni in poultry. At the same time, macrolides are one of few available therapies for serious campylobacter infections, particularly in children, in whom quinolones are not recommended for treatment. Glycopeptides are known to select for glycopeptides-resistant Enterococcus spp. in food animals (e.g., when avoparcin was used as a growth promoter, vancomycin resistant enterococcus (VRE) developed in food animals and were transmitted to people). At the same time, glycopeptides are one of the few available therapies for serious enterococcal infections.
3.
3.1
Epidemiological trends
Increasing levels of Gram-negative resistant bacteria in Europe
Surveillance programmes have been initiated on local, national and international levels.37,38,39 These programmes have demonstrated that the prevalence of AMR is increasing throughout the world resulting in the EARS-net placing AMR as one of the primary work areas.9 Successful programmes have led to better interventions aimed at assessing AMR and maximize antibiotic prescribing.40,41,42 Continuous and uniform surveillance is still needed to appropriately address the issue of resistance.43 However, an important issue is the increasing resistance to antibiotics in Gram-negative bacteria. Gram-negative bacteria cause infections including pneumonia, bloodstream infections, wound or surgical site infections, and meningitis in healthcare settings. The distinctive feature of Gram-negative bacteria is the presence of a double membrane surrounding each bacterial cell. Although all bacteria have an inner cell membrane, Gram-
6.1-10

negative bacteria have a unique outer membrane. This outer membrane excludes certain drugs and antibiotics from penetrating the cell, partially accounting for why Gram-negative bacteria are generally more resistant to antibiotics than are Gram-positive bacteria. Gramnegative bacteria have a great facility for exchanging genetic material (DNA) among strains of the same species and even among different species. Resistance is increasing in Europe for Gram-negative bacteria such as Escherichia coli or Klebsiella pneumonia collected from normally sterile sites, i.e. blood or cerebrospinal fluid.44 Also, there have been no novel mechanism agents for Gram-negative organisms for decades.
3.1.1 Escherichia coli

Predictions of a worrisome increasing trend of resistance to this Gram-negative and extremely common microbe have been confirmed in Europe. Increased prevalence trends over time reveal decreased fluoroquinolone susceptibility (i.e. increasing resistance) as shown in Figure 6.1.1. E. coli formerly susceptible to carbapenem and third generation cephalosporins strains exhibit similar trends. (See Annex 6.1.9). Figure 6.1.1: Percentage of invasive isolates of E. coli that are resistant to fluoroquinolones in participating countries, 2005 (upper) and 2011 (lower)
Source: EARS-NET interactive database. 2
6.1-11
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance 3.1.2 Multidrug-resistant Klebsiella pneumoniae
Predictions of a worrisome increasing trend of resistance to these Gram-negative bacteria have been confirmed in Europe. Increased prevalence trends over time reveal decreased multiple drug resistance increasing as shown in Figure 6.1.2.
Figure 6.1.2: Klebsiella pneumoniae isolates in participating countries in 2005 (left figure) and 2011 (right Figure) that are resistant to third-generation cephalosporins, fuoroquinolones and aminoglycosides.
Source: EARS-NET Net database.
3.1.3 Carbapenem resistance in Pseudomonas aeruginosa

Pseudomonas aeruginosa carries multiresistance plasmids less often than does Klebsiella pneumoniae, develops mutational resistance to cephalosporins less readily than Enterobacter species. What nevertheless makes P. aeruginosa uniquely problematic is a combination of the following: the species' inherent resistance to many drug classes; its ability to acquire resistance, via mutations, to all relevant treatments; its high and increasing rates of resistance locally; and its frequent role in serious infections. A few isolates of P. aeruginosa are resistant to all reliable antibiotics.45 As seen in Figure 6.1.3, the situation with regard to P. aeruginosa is mixed, with many (but not all) countries in Eastern Europe showing a decreasing trend in the fraction of all P. aeruginosa isolates that are resistant but an increasing trend in some southern European countries such as Italy and Portugal.
6.1-12

Figure 6.1.3: Proportion of carbapenems resistant (R) Pseudomonas aeruginosa isolates in participating countries 2005 2011
3.1.4 Staphylococcus aureus

The issue of increased resistance of the Gram-positive meticillin resistant Staphylococcus aureaus (MRSA) has been ameliorated somewhat (See Figure 6.1.4: France, Eastern European countries, United Kingdom, Scandinavia). Thus, there has been an overall decreased prevalence of MRSA within Europe although some European countries continue to exhibit a continued high prevalence of MRSA. See Figure 4 and Annex 6.1.10. Activities to improve compliance to infection control practices have probably decreased transmission in healthcare settings. Instead, community acquired MRSA is now reported to be the dominating problem. A particular problem has been the emergence of MRSA in livestock. See also above, Section 2.2. In 2005, decades after the discovery of the hospital acquired and community-acquired MRSA, a new MRSA type was isolated from pigs and pig farmers in the Netherlands and was named livestock-associated MRSA or LA-MRSA. Resistance to the antibiotics used in livestock farming such as tetracycline, trimethoprim, aminoglycosides, etc. was found in LAMRSA isolates. Further, LA-MRSA has been reported worldwide, and is known to colonize humans and livestock animals such as pigs, cattle and chickens.46
6.1-13

Figure 6.1.4: Proportion of meticillin resistant Staphylococcus aureus isolates in participating countries, 2005 and 2010 2005 2010
3.1.5 Emerging carbapenemase-producing bacteria in Europe.

Carbapenems have the broadest antibacterial spectrum compared to penicillins and cephalosporins. In addition, they are generally resistant to the typical bacterial enzyme, lactamase, which is one of the principal -lactam resistance mechanisms of bacteria, Carbapenemases are a group of clinically important enzymes that efficiently inactivate most beta-lactam-type antibiotics such as cephalosporins and penicillins. Resistance to carbapenems (via carbapenamase-production) has emerged and spread among the Enterobacteriaceae family of bacteria worldwide. Resistance is endemic in certain countries. risk factors include severity of illness, a history of hospitalisation or a stay in an intensive care unit, prior antimicrobial use and immunosuppression. Patient mobility has also recently been highlighted as a risk factor for the acquisition of carbapenamase activity and many reports by Member States discuss the introduction and spread of carbapenemases into healthcare settings as a result of patient transfer, mostly from endemic areas, across borders. EARS-net risk assessment. 2011.47 DNA encoding carbapenamases are easily introduced because they are highly transmissible, resulting in colonisation or infection of patients. Thus, dissemination of mobile genetic elements coding for resistance and of epidemic, multidrug-resistant strains has been the cause of many reported outbreaks. Infections with carbapenamase producing bacteria are a threat to patient safety due to their resistance to multiple antimicrobials, meaning that there are very few therapeutic options with which to treat infected patients. Furthermore, human infections are associated with poorer patient outcomes, increased morbidity, mortality and higher hospital costs. The risk for humans becomes greater since therapeutic options are limited because there are very few novel antimicrobial agents in the development pipeline.
6.1-14
3.2
Antibiotic resistance in other regions
3.2.1 The Americas

Resistance within the United States has not changed substantially with the exception of an increased concern about Gram-negative pathogens. Mortality and morbidity rates for MRSA are still high with more than 19 000 deaths and 90 000 infections per year.48,49 (Annex 6.1.12). Research has also revealed the USA exhibits seasonal patterns of AMR with antibiotic use as shown in Figure 6.1.5.50
Figure 6.1.5: Mean monthly seasonal variation for trimethoprim / sulfamethoxazole prescriptions and E. coli resistance to trimethoprim / sulfamethoxazole
Source: Sun L, Klein EY, Laxminarayan R. Seasonality and temporal correlation between community antibiotic use and resistance in the United States. Clinical Infectious Diseases: An Official Publication Of The Infectious Diseases Society of America. 2012.50
3.2.2 Asia and the World

High prevalence rates of numerous resistant bacterial pathogens are still commonly reported throughout Asia.12,51 In India, rates of antimicrobial resistance are very high. A high prevalence of extended-spectrum -lactamase (ESBL)producing bacteria is increasing the prevalence of resistance to carbapenems. More specifically, metallo-beta-lactamase-1 (NDM1) is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. NDM-1 was first detected in a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin in 2008. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States, Canada, and Japan. The most common bacteria that make this enzyme are Gram-negative such as Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transfer. The original organism was found to be resistant to all antimicrobial agents tested except colistin. Molecular examination of the isolate revealed that it contained a novel metallo-beta-
6.1-15

lactamase that readily hydrolyzed penicillins, cephalosporins, and carbapenems (with the exception of aztreonam).52 See also Annex 6.1.13.53
4.
The disease and economic burdens of antibiotic resistance
Infectious diseases are one of the leading causes of mortality, with an excess of 25 000 additional deaths per year in EU member states alone.54 Although surveillance systems have helped, estimating the disease burden of AMR remains a difficult challenge.9 This burden greatly increases the duration of hospital length of stay (LOS), complication risks and mortality risks.55,56,57 Recently, using data from the Burden of Resistance and Disease in European Nations project58 the European burden of disease associated with meticillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli blood stream infections was estimated, and expressed as excess number of deaths, excess number of days in hospital, and excess costs. 55 An estimated 5 503 excess deaths were associated with blood stream infections caused by meticillin-resistant S. aureus (with the United Kingdom and France predicted to experience the highest excess mortality), and 2 712 excess deaths with blood stream infections caused by third-generation cephalosporin-resistant E. coli (predicted to be the highest in Turkey and the United Kingdom). This study also found that blood stream infections caused by both meticillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli contributed respective excesses of 255 683 and 120 065 extra bed-days, accounting for an estimated extra cost of 62.0 million euros (92.8 million US dollars). Excess mortality associated with these infections caused by meticillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli is high, and the associated prolonged length of stays in hospital imposes a considerable burden on health care systems in Europe. The possible shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections is of some concern. Overall, the economic burden associated with AMR is considerable and there is more extensive data than in 2004.59 These costs are primarily due to the doubled increase in hospital LOS, additional discharge costs to facilities, extra medical care needed and productivity loss. Societal costs of infections (including productivity losses, extra length of stay, in-patient and out-patient costs) due to various resistant Gram-positive (mostly MRSA and vancomycin-resistant Enterococcus faecium) and Gram negative (third-generation cephalosporin-resistant E. coli and K. pneumoniae, and carbapenem-resistant P. aeruginosa) for the EU, Iceland and Norway in 2007 were estimated in excess of 1.5 billion per year.9 A more detailed summary of information is presented within Annex 6.1.14. Table 6.1.2 is a brief summary of the ranges of this burden.
6.1-16

Table 6.1.2: Summary of the economic burden of antimicrobial resistance Country USA60,61,62,63,64,65,66 Spain67,68,69 Europe9,70 Israel71,72 Additional Costs US$ 10 276 50 896/patient 1 205.75 5 614/patient 1.5 billion total (societal cost) US$ 30 093/patient Additional Hospital LOS 4.3 16 days/patient 2 29 days/patient 2.5 million days total 6 - 10 days/patient
5.
5.1
What are the current policy initiatives regarding AMR control?

European Union
Various national and international organizations such as the European Centre for Disease Control and Prevention (EARS-net), the European Medicines Agency (EMA), the European Commission (EC), the Centre for Global Development (CGD), the European Federation of Pharmaceutical Industries and Associations (EFPIA) (Annex 6.1.1).5 Much information on antibiotic use has been collected via international projects. For instance, ESAC-Net (formerly ESAC) is a Europe-wide network of national surveillance systems, providing European reference data on antimicrobial consumption both in the community and in the hospital sector. The collected data are used to provide timely information and feedback to EU countries on indicators of antimicrobial consumption. These indicators provide a basis for monitoring the progress of countries towards prudent use of antimicrobials.73 As another example, from 2009-2011, the European Centre for Disease Prevention and Control (EARS-NET) funded the HALT project (Healthcare Associated infections in LongTerm care facilities). The aim of this project was to develop and implement a protocol for surveillance of antimicrobial use and resistance in European long-term care facilities (i.e., nursing homes and the like) in order to establish baseline rates and identify priorities for improvement. A point prevalence survey was conducted across 25 European countries. An antimicrobial prevalence study will be repeated in mid-2013.74 The European Union (EU) has produced major publications addressing AMR and its public health threat include The Race Against Drug Resistance, Extending the Cure, Innovative Incentives for Effective Antibacterials, Recommendations for Future Collaboration between the USA and EU and The Bacterial Challenge: Time to React.5,6,7,8,9 These diverse efforts demonstrate the need for concerted action to address the current and future concerns of AMR. In brief overview, FP5-7 (1999-2012) has spent about 600 million for projects related to antimicrobial resistance. The priorities included: developing new strategies for prudent/rational antibiotics use in medicine and agriculture; understanding how antimicrobial resistance develops; testing new antimicrobial drugs and alternatives to antibiotics; developing diagnostic tests to determine whether and which antimicrobials to prescribe.
6.1-17

Since 2004, the issue of AMR has been the subject of many initiatives, both educational and scientific. The problem of AMR has been recognized both by the Council and the European Parliament. The Council adopted on 10th June 2008 Conclusions on AMR calling upon the EC in accordance with the "health in all policies" approach, to promote cooperation between the EC and Member States against AMR, and on 1 December 2009 the Council adopted conclusions on innovative incentives for effective antibiotics calling upon the Commission to develop a comprehensive action plan concerning incentives to develop new effective antibiotics including ways to secure their rational use. On 12th May 2011 the European Parliament (EP) adopted a non-legislative resolution on antibiotic resistance in which it stressed that AMR has become a huge issue in recent years. To cope with this growing problem and the consequent treatment failures, the EP called on the Commission to establish an EU-wide plan to combat AMR. The European Parliament subsequently issued a resolution on 27 October 2011 on the public health threat of antimicrobial resistance.75 On the same day, the EC presented a recommendation on a Joint Programming Initiative (JPI) entitled The Microbial Challenge - An Emerging Threat to Human Health.76 The EC encouraged Member States, amongst other things, to develop a common Strategic Research Agenda (SRA) establishing medium to long-term research needs and objectives in the area of antimicrobial resistance. The SRA should be further developed towards an implementation plan, establishing priorities and timelines and specifying the actions, instruments and resources required for its implementation. Similarly, in 2011, an Action plan against the rising threats from Antimicrobial Resistance was issued from the EC. The EC proposed to put in place a five-year Action Plan to fight against AMR based on 12 key actions.77 In particular the actions related to research activities promoting public-private collaborative research and development to bring new antibiotics to patients (Action 6) as well as the reinforcing and coordinating research efforts (Action 11) are already well advanced in their implementation. All these actions have strengthened the combat against AMR. As another example, European Antibiotic Awareness Day is an annual European public health initiative that takes place on 18 November to raise awareness about the threat to public health of antibiotic resistance and prudent antibiotic use.78 In addition, the EU has enacted numerous strategies and policies to deal with use outside human medicine.79 In 2006, the EU banned the feeding of antibiotics to livestock for growth promotion purposes.80 We note that the US Food and Drug Administration (FDA) is also promoting judicious use with three directives: the Veterinary Feed Directive, Guidance #209 and Guidance #213.81 The Innovative Medicines Initiative (IMI)82 has recently launched research calls for their new theme NewDrugs4BadBugs (ND4BB) which aims to bring new antibiotics by funding research in which small and medium-sized enterprises (SMEs) and academics work in close collaboration with large pharmaceutical companies in order to establish a vibrant antimicrobial drug discovery hub.
6.1-18

In February 2013, the IMI launched its first two projects under New Drugs for Bad Bugs. The new projects are Combacte (Combatting Bacterial Resistance in Europe) and Translocation (Molecular basis of the bacterial cell wall permeability). COMBACTE will last for seven years and will bring together about 20 partners from all over Europe. It is designed to generate innovative trials to facilitate the registration of new anti-bacterial agents, mainly through the creation of a network of experienced investigators. It will also design and validate tests to support the diagnosis of patients, identify the most suitable treatments and monitor the treatment response.83 TRANSLOCATION aims to increase the overall understanding of how to get antibiotics into multi-resistant Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae and how to stop the bacteria from ejecting the drug. In sharing the knowledge and data discovered, TRANSLOCATION will develop guidelines for designing and developing new drugs to tackle antibiotic resistance and create an information centre for pre-existing and ongoing antibacterial research data which will be used to establish best practices for future antibacterial drug discovery efforts.84 The EC currently funds numerous projects, under the FP-7 projects programme, to help develop the necessary tools needed to contain AMR (See Research and Innovation Initiatives to support AMR related research in the EU 85 and Annex 6.1.17. There are numerous national antibiotic stewardship campaigns, although mostly in high-income countries. (Annex 6.1.5). The European Technology Platform on Nanomedicine has also been established to create diagnostic tools to identify a disease at the earliest possible stage to encourage appropriate antibiotic use.86 Top Institute (TI) Pharma, a non profit organization in the Netherlands, has also provided support for projects concerning MRSA and MDR pathogens.87
5.2
World Health Organization
The WHO has been heavily involved with a range of national and global activities concerning AMR and has a long history of engagement in containing AMR. Some of the highlights are listed in Annex 6.1.18. AMR was chosen as the subject for the World Health Day 2011 under the theme No action today - no cure tomorrow.88 During this day, a six-point policy package was launched to reaffirm that a multifaceted approach is needed to deal with this complex issue. The points for action are to: 1. Commit to a comprehensive, financed national plan with accountability and civil society engagement (a master plan to combat antimicrobial resistance) 2. Strengthen surveillance and laboratory capacity 3. Ensure uninterrupted access to essential medicines of assured quality 4. Regulate and promote rational use of medicines, including in animal husbandry and ensure proper patient care. Reduce use of antimicrobials in food-producing animals 5. Enhance infection prevention and control 6. Foster innovations and research and development for new tools On 8 March, 2012, WHO launched a new book "The evolving threat of antimicrobial resistance - Options for action".89 It examines the experiences with interventions which address the growing threat of antimicrobial resistance, describes the lessons learnt along the way and highlights the gaps 6.1-19

still remaining. It draws attention to areas where knowledge is lacking and where urgent action is still needed. A specific objective is therefore to encourage policy-makers and the global community to commit to intensified action against AMR. In additional to these global actions several of the WHO regional offices have specific activities: WHO Euro has launched a strategic plan90 which has been adopted in the biennial work-plan of some 20 non-EU countries. A number of key strategic actions are proposed to mitigate, prevent and control antibiotic resistance. These include promoting national coordination to implement national strategic plans of action and develop regulatory functions and guidance; promoting the prudent use of antibiotics across many sectors; strengthening surveillance systems to monitor the use of antibiotics and resistant bacteria; and creating awareness of the prudent use of antibiotics and the fact that new antibiotic drugs are not coming onto the market soon.91,92 WHO-SEARO has released a regional resolution prevention and containment of antimicrobial resistance.93 Through resolutions passed by the World Health Assembly (WHA), WHO Member States have highlighted not only the public health threat of resistant organisms, but also the harm caused by misuse of antimicrobials by patients, prescribers and medicine dispensers. Activities following publication of the 2004 Report are encapsulated in the following WHA Resolutions: WHA58.27 Improving the containment of antimicrobial resistance, 25 May 2005 (see Appendix 1.1). WHA60.16 Progress in the rational use of medicines, 23 May 2007 (see Appendix 1.2). WHA62.15 Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis, 22 May 2009 (see Appendix 1.3).
5.3
World
Chinas activities concerning AMR are rather recent but are expanding.94,95 In 2004, China created its first AMR surveillance programme and national guidelines for appropriate antibiotic use.96,97 Israel has had success with a national campaign promoting prudent antibiotic use.98,99 Numerous other countries have also implemented stewardship campaigns and other control strategies.100 The recent Chennai Declaration for India is an outgrowth of a meeting of leaders from medical societies, federal and state governments, and representatives from the World Health Organization, that gathered in 2012 in Chennai, India. The Chennai Declaration proposes a plan to create a road map for tackling the challenge of antimicrobial resistance in India.101 Among many recommendations, the declaration calls for regulation of over-the-counter sales of antibiotics, monitoring of in-hospital antibiotic use, and development of a national antimicrobial resistance surveillance system. It also suggests roles for a variety of stakeholders, including the Ministry of Health and Family Welfare, the Medical Council of India (the statutory body regulating medical colleges), and the World Health Organization.
6.1-20
5.4
The Americas
The activities of the USA concerning AMR are extensive and have expanded. and the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) have reacted with numerous meetings, task forces, workshops and publications to address this issue. 9 The Transatlantic Taskforce was established between the EU and the USA as a transatlantic task force on urgent antimicrobial resistance issues focused on appropriate therapeutic use of antimicrobial medicines in the medical and veterinary communities, prevention of bother healthcare and community associated medicine-resistant infections and strategies for improving the pipeline of new antimicrobial medicines, which could be better addressed by intensified cooperation between us .9 The taskforces purpose is to identify issues related to AMR that would be better addressed through collaboration between the EU and the USA. The primary areas of focus of the TATFAR are the appropriate use of antimicrobial medicines in the medical setting and veterinary community, prevention of AMR infections both within the community and hospital settings and fostering the antimicrobial development pipeline. In 2011, the TATFAR published its first report Recommendations for Future Collaboration Between the USA and EU. An action plan released in March 2011 by the Interagency Task Force on Antimicrobial Resistance, co-chaired by the CDC, FDA, and NIH. The action items are organized into four focus areas: surveillance, prevention and control, research, and product development. In commemoration of World Health Day 2011, The Infectious Diseases Society of America (IDSA) released the official publication "Combating Antimicrobial Resistance: Policy Recommendations to Save Lives,"102 which summarizes IDSA recommendations about how to address antibiotic resistance. APUA is a strong supporter of IDSA's work to address the dry antibiotic pipeline and the crisis of antibiotic resistance. The IDSA has an advocacy campaign, the 10x'20 initiative,103 to address the dry antibiotic pipeline and call for 10 new antibiotics by 2020. 10 x '20 encourages the development of antibiotics and the improvement of diagnostic tests for priority resistant infections, as well as the creation of incentives that stimulate new antibacterial research and development. The IDSA has published a report entitled, Bad Bugs, No Drugs. 104 On April 13, 2012, the FDA issued a final guidance on the Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals,105 concluding that the unnecessary or inappropriate use of medically important antimicrobials in food animal production is not beneficial to public health. In agreement with APUA, FDA recommends that antibiotics be used with veterinary oversight. FDA does not consider use for growth promotion or improvement of feed efficiency to be judicious, but does consider antimicrobial use for treatment, control, and prevention of disease to be necessary for assuring the he alth of food-producing animals. Several actions by Congress have also occurred such as passing the Generating Antibiotic Incentives Now (GAIN) Act.106 This is an economic incentivization tool to encourage new antibiotic R&D. In South America there is also the South American Infectious Diseases Initiative to contain AMR.107 The Pan American Health Organization (PAHO) has conducted for many years a project on surveillance of AMR and has produced an annual report since 2004, although the last report appears to be in 2009.108
6.1-21
6. Research into the past and present pharmaceutical interventions: what can be learnt?
6.1 Antibiotic development
The number of new molecular entity FDA approved antibiotics continues to decrease. (Annex 6.1.21). Only 10 antibiotics that are New Molecular Entities have been approved by the FDA from 2004 to 2012 whereas 13 were approved between 1996 and 2003.
Figure 6.1.6: FDA Approved New Molecular Entity Antibiotics, 2004 2012
FDA Approved New Molecular Entity Antibiotics, 2004 - 2012

5 New Molecular Entity Antibiotics 4 3 2 1 0 2004 2005 2006 2007 2008 Year Source: CenterWatch. FDA approved drugs for immunology/infectious diseases. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.centerwatch.com/drug-information/fdaapprovals/drug-areas.aspx?AreaID=7109 2009 2010 2011 2012
6.2
Are incentives insufficient for the pharmaceutical industry?
The financial incentives for the pharmaceutical industry to bring a new antibiotic compound through the stages of medicine development appear to be insufficient. Linking profits from product sales is exactly the driver of increased sales of antimicrobials that should be discouraged.110,111 Of course, this poses a problem for the current R&D business models. Numerous incentives have been proposed that have attracted industry interest. (Annex 6.1.22.) Examples of these incentives include patent extensions, data exclusivity, market exclusivity, and a special market approval track.
6.1-22
6.3
Public resources for basic and applied research
Public funding for AMR research has greatly increased since 2004. (Annex 6.1.20). Publicprivate partnerships (PPPs) have shown to be attractive for both the private and public sectors.112 Public resources that are used to help stimulate the dry antibiotic development pipeline are commonly utilized within a PPP. Additionally, some private companies are providing funds to public organizations, such as universities, to also stimulate pipeline development.
6.4
What is in the current antibiotic pipeline?
The rather weak antibiotic pipeline discussed in the 2004 Report continues. As of early 2012, only 109 antibiotics are in the pipeline in which 70% are in the early stages of development. Only 31 potential candidates are in Phase 2 and nine candidates in Phase 3. Sixty - six companies are developing these 109 antibiotics in which only nine are large companies while the remaining 57 companies are small/medium enterprises.113 Of the 15 large pharmaceutical companies that previous had active antimicrobial programmes, only five remain. Reports reveal that only a few antimicrobials are in the company pipelines and only two candidates target Gram-negative resistant bacteria as shown in Figure 6.1.7.9,114,115 (Annex 6.1.23).
Figure 6.1.7: Antimicrobials in development as of 2011 Gramnegative versus Gram positive

16 14 Antibiotics in development 12 10 8 6 4 2 0 Gram - positive Gram - negative Source: Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? British Journal of Pharmacology. 2011; 163:184-94.116
Recently, there is renewed interest in research to find new effective antimicrobials, much of it being carried out by small biotechnology companies and academic centres, rather than by large pharmaceutical companies. Antibiotics that are currently in clinical development or at the preclinical stage, including both improved compounds related to approved drugs and new chemical classes as of 2011 are listed in Table 6.1.3.117
6.1-23

Table 6.1.3: Antibiotics that are currently in clinical development or at the preclinical stage Compound name BC-3205 BC-7013 CG400549 AF-1252 FAB-001 Delafloxacin TP-434 BC-3781 Solithromycin ACHN-490 CB183<comma>315 Ramoplanin GSK-1322322 JNJ-Q2 Nemonoxacin Oritavancin Dalbavancin Torezolid Radezolid Amadacycline Cethromycin Chemical class Pleuromutilin Pleuromutilin Triclosan New lead Triclosan Fluoroquinolone Tetracycline Pleuromutilin Ketolide Aminoglycoside Target Ribosome Ribosome FabI FabI FabI DNA gyrase Ribosome Ribosome Ribosome Ribosome Dev. stage Phase 1 Phase 1 Phase 1 Phase 1 Phase 1 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Route Oral Topical iv iv iv iv/oral iv/oral iv/oral iv/oral iv Oral Oral iv iv/oral Oral iv iv iv/oral iv/oral iv/oral Oral Developing company Nabriva Nabriva Crystal Genomics Affinium FAB Pharma Rib-X Tetraphase Nabriva Cempra Achaogen Cubist Nanotherapeutics GSK Furiex TaiGen/Warner The Medicine Co Durata Trius Rib-X Paratek Advanced Life Sciences
Lipopeptide Membrane Phase 2 Lipoglycodepsipeptide Cell wall Phase 2 New lead PDF Phase 2 DNA Phase Fluoroquinolone gyrase 2/3 DNA Phase Quinolone gyrase 2/3 Glycopeptides Cell wall Phase 3 Glycopeptides Cell wall Phase 3 Oxazolidinone Ribosome Phase 3 Oxazolidinone Ribosome Phase 3 Tetracycline Ribosome Phase 3 Ketolide Ribosome Phase 3
Source: Daniela Jabes, The antibiotic R&D pipeline: an update Current Opinion in Microbiology Volume 14, Issue 5, October 2011, Pages 564569116
Considering the attrition rate for antibiotics in development and commercial considerations, only a small number of the compounds listed in Table 6.1.3 are expected to reach the marketplace.
6.5
Optimization of antibiotic dosing regimens
Optimization of antimicrobial dosing regimens have made progress. Pharmacokinetic/pharmacodynamic parameters are not fully understood although there is research underway.118 Additionally, innovative ways to use old antibiotics to combat the issue of AMR is also being addressed, mostly through combination regimens119 but also through shortened treatment duration.120
6.1-24
7. What are the gaps between current research and potential research issues which could make a difference?
7.1 Need for Rapid and inexpensive diagnostics
Diagnostic tools have made major advancements although the cost still remains high for many of these tests.121122,123 (Annex 6.1.7). Diagnostics to detect S. pyogenes, urinary tract infections and bacterial and viral bronchitis are currently available although they are not always used by practitioners.124,125 Efforts to reduce these costs have been made, most notably with the Xpert MTB/RIF diagnostic test and its concessional pricing methods.126 Even though there are many obstacles preventing the development of AMR diagnostic tools, numerous initiatives have been developed by organizations such as the IMI.127 See Chapter 2. Improvements have been made regarding diagnostic tools but in low- and middle-income countries (LMIC), there are still few useful and context-appropriate diagnostics. Inexpensive and readily available diagnostic tools are now available for a variety of infectious diseases, the best known being rapid diagnostic tests for malaria.128 Some tools are able to distinguish between viral and bacterial infections while others are able to distinguish between bacterial species. (See Annex 6.1.7). However, point-of-care diagnostics remain an unmet need. The development and validation of new diagnostic tests can in principle help determine whether antibiotics should be prescribed at all and, if they are prescribed, such tools can help determine which antibiotics should be prescribed. Further, rapid diagnostics can help control the spread of infections if an infection is diagnosed early enough. Certainly, rapid diagnostics are being developed to determine the presence of resistant strains of clinically important bacteria.129 There is no doubt rapid diagnostics can be developed but there will be regulatory and other challenges to creating inexpensive diagnostics, particularly for use in low and middle income countries. The business environment poses both opportunity and challenge. From a business model, a diagnostic company will typically look at the total market; product value, project growth rates, the projected manufacturer market share, the competition, and alignment with overall strategy to determine if they want to pursue a particular diagnostic for a particular indication. For low- and middle-income countries, the issues of market failure (great patient need but inability to pay), as in pharmaceuticals, will be a key consideration. The widespread use of improved and cost effective diagnostic tools to identify bacterial infections which will benefit from treatment is still needed to reduce antibiotic misuse. More research may be needed to identify how these diagnostic products can most effectively be used to reduce inappropriate antimicrobial prescriptions.
7.2
Identifying the most urgent needs for new antibiotics
Efforts attempting to identify the most urgent needs for new antibiotics continue. A greater proportion of infections are caused by Grampositive pathogens although prevalence of Gramnegative infections is steadily increasing as shown in Figure 6.1.8. Surveillance has
6.1-25

revealed that the total burden of AMR Gram-positive pathogens is less than that for Gramnegative pathogens.9 This means that priority should be given to the development of Gram negative antibiotics.
Figure 6.1.8: Population-weighted, average percentage of resistant isolates among bacteria from bloodstream infections, EU, Iceland and Norway, 2002-2010
Source: Monnet DL. Update on EARS-NET AMR & HAI activities and workplan [for] 2012. [Presentation] Warsaw 2011 November 23-25 [cited 2012 July 11]; Available from: www.EARSnet.europa.eu/en/activities/diseaseprogrammes/ARHAI/Presentations2011Warsaw/ARHAI-networksmeeting_parallel-session-five-1-Dominique-Monnet-AMR-HAI-activities.pdf.130
Numerous incentives for medicine development have been proposed and implemented. 97 See Annex 6.1.22. The United States passed the Prescription Drug User Fee Act (PDUFA) V Act in July 2012 along with the controversial GAIN Act. The GAIN act will provide five additional years of market exclusivity, priority review and fast track status for antimicrobials targeted towards the most serious AMR pathogens.131 Priority review vouchers have been proposed to stimulate the antibiotic development pipeline, similar to those distributed by the FDA for neglected tropical diseases.132 Scientific opportunities for medicine development have been proposed. Open source innovations have been recommended by WHO and various other stakeholders.133
7.3
New therapeutic approaches
7.3.1 Alternatives to antimicrobials: Antivirulence medicines

Progress during the last five years is being made toward one alternative, the development of antivirulence drugs focusing on bacterial secretion systems. Secretion systems translocate macromolecules across the envelope of bacterial cells and in many cases directly into the host where these effectors modulate the defense response and thereby facilitate survival of the
6.1-26

pathogen. Antivirulence drugs would not kill but rather deprive bacteria of their virulence functions so that they can be eliminated by the immune system. Since antivirulence drugs would not impact vital cell functions it is believed that the development of resistance will be slow. Therefore, they would constitute a valuable alternative to antibiotics. Also, they may be used in combination therapies to augment the potency of antibiotics or to slow down the development of resistance.134, 135
7.3.2 Host-pathogen interactions

The production of cationic antimicrobial peptides (CAMPs) by an animal host is widespread.136 Significantly, these CAMPs are still highly effective against pathogens after millions of years of co-evolution. Antibiotics are usually designed to function at low concentrations through a defined high-affinity antimicrobial target a set of circumstances that makes it comparatively easy for bacteria to develop resistance. By contrast, CAMPs are released precisely at infected sites and are usually active at much higher concentrations than antibiotics. Moreover, many CAMPs have multiple antimicrobial activities. In theory, it can be argued that the evolution of the innate host defense systems has favored the design of antimicrobials that disturb many biological functions with low potency rather than blocking a specific high-affinity target such as enzymes for building bacterial cell walls. Such properties enable the host to control a much wider range of potential pathogens without creating the selection pressure for high-level resistance that is observed with potent, highaffinity antibiotics. Considering the high concentrations that are required for antimicrobial activity, it is thought that CAMPs might exhibit greater toxicity compared with the therapeutic antibiotics currently in use. CAMPs have a number of potential advantages as future therapeutics; in addition to their broad spectrum antimicrobial activity and rapid killing of microbes, they are unaffected by classical antibiotic resistance mechanisms. Moreover, CAMPs do not appear to induce antibiotic resistance CAMPs currently are being widely used as blueprints for the development of innovative therapeutic agents that may be used as antimicrobials, modifiers of inflammation, or in cancer therapy.137,138
7.3.3 Non-antibiotics
Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. Recent work has evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics. Non-antibiotics such as phytochemical flavonoids (galangin, quercetin and baicalein) and other compounds such as chlorpromazine, amitryptiline and trans-chlorprothixene were shown to reduce or reverse resistance of a variety of bacteria to antibiotics.139, 140
7.3.4 Use of Phage and Phage Therapy

Another alternative approach was recently demonstrated in a proof-of-concept trial in which bacteriophages were genetically engineered to reverse a pathogens drug resistance, thereby restoring its sensitivity to antibiotics.141
6.1-27

Another use of phage therapy would be use phage to directly kill specific bacteria and eliminate an individual patients infection without affecting the bodys communities of beneficial bacteria. Because phages attack bacteria by attaching to receptors on the bacterial cell surface that are often bacterial virulence factors, phage-resistant bacterial mutants (which lack these receptors) are often less pathogenic than phage-susceptible bacteria. Further, the development of phage-resistance can be forestalled altogether if phages are used in cocktails (preparations containing multiple types of phages) and/or in conjunction with antibiotics. An improved understanding of phages in vivo pharmacokinetics would also increase phages therapeutic value. For phage therapy to be useful in clinical settings, a patients specific etiological agent would need to be rapidly identified and matched to the relevant phage(s) in a comprehensive pre-existing database. New and interdisciplinary thinking involving bioinformaticists, health care professionals, and phage researchers, among others, would be required to make phage therapy practicable on a large-scale. Phage therapy has been extremely effective at treating a number of bacterial infections in controlled animal studies. In 2009, a double-blind Phase II clinical study showed phages to be safe and effective at treating chronic drug-resistant ear infections.142
7.3.5 Vaccines: Primary prevention of resistance

Several FDA approved vaccines addressing bacterial pathogens have been released. (Annex 6.1.24). Vaccines would be an ideal approach and there are several suggestive examples.143 The vaccine pipeline is extensive although many fail in the early stages. Currently, several vaccines are undergoing clinical trials.144 The possibility of targeting vaccines towards therapeutics remains a challenge. See also Section 9.1. It is interesting that the effect of vaccines leading to substitution of one resistant microbe with another of increasing resistance clones has been debated in relation to pneumococcal vaccines. Clearly, conjugate vaccines have had a major effect in reducing the absolute incidence of drug-resistant Streptococcus pneumoniae (DRSP) not only in immunised children, but also in their contacts. However, continued antibiotic exposure of pneumococci lacking a response to pneumococcal conjugate vaccines PCV has led to increasing resistance among these strains, which has reduced the overall impact of these vaccines.145 Thus, serotype replacement as observed for pneumococcal strains can undermine vaccine effectiveness. Nonetheless, it is possible to make vaccines virtually against any pathogen. The presence of antibiotics in the environment and host imposes a strong selective filter of resistances acquired through horizontal gene transfer (HGT) of plasmids, transposons and/or integrons or through mutations. Although antigenic variation could potentially be the mechanism behind the emergence of vaccine resistant strains, vaccines harbor several unique features that make them virtually resilient to resistance phenomena. First, protein-based vaccines usually contain multiple immunogenic epitopes implying that many mutations should accumulate before resistant strains rise. Vaccine-resistant bacteria have never been reported. By preventing infections, vaccines do not allow bacteria to replicate in the host, limiting the selection process of variants to the initial phases of the infection. By targeting bacterial pathogens, vaccines directly reduce the need for the use of antibiotics Vaccines also contribute to the reduction of antibiotic usage through the establishment of herd immunity by halting the levels of transmission of pathogenic bacteria to potentially
6.1-28

susceptible individuals and therefore limiting the numbers of infections in the overall population. However, no vaccines yet exist for the most important multi-drug resistant strains. There are several ongoing preclinical and clinical research programs on antibiotic resistant pathogens (Table 6.1.4). Development of novel vaccines against bacterial pathogens for which antibiotic therapies are still efficacious, including veterinary infections, would also contribute substantially to further prevent the emergence of antibiotic resistant strains.146
Table 6.1.4: Status of vaccine development against relevant nosocomial antibiotic resistant pathogenic bacteria Bacterial pathogen S. aureus Disease Skin and soft tissue infections, endocarditis, pneumonia, bacteremia, osteomyelitis, toxic shock syndrome Antibiotics associated diarrhea and colitis Chronic pulmonary infections in immunocompromised and cystic fibrosis patients, pneumonia, urinary tract infections (UTIs) Respiratory tract infections, bacteremia, meningitis, epiglottitis UTIs, diarrhea, hemolytic-uremic syndrome Pneumonia (bronchopneumonia and bronchitis), UTIs Neonatal meningitis, UTIs, endocarditis, bacteremia Pneumonia, UTIs, bacteremia Vaccines status and references Clinical trials147
C. difficile P. aeruginosa
Clinical trials148 Clinical trials149
H. influenzae
Licensed vaccine and Clinical trials150 Research and Clinical trials151 Research reported Research reported Research reported
Pathogenic E. coli K. pneumoniae E. faecium A. baumannii
8.
Conclusion
Collaborative, global and more concerted efforts are needed to address the public health threat that AMR poses. The EU should continue its extensive contributions and collaborations in this regard and can provide leadership in the following areas: Diagnostic and therapeutic tools: Development and use of cost-effective and point of care diagnostic tools to encourage prudent and appropriate antibiotic use. Priority development of antibiotics against Gram- negative bacteria. Replenishment of the antibiotic development pipeline, possibly using new business models for R&D, in order to develop new products with novel mechanisms of action to address the already heavy burden of AMR.
6.1-29

Health systems: Establishment and implementation of a multi-faceted approach using standardized surveillance coupled with appropriate antimicrobial stewardship campaigns at country level. Allocation of public funding to continue providing evidence/data on antimicrobial resistance to treatment for vaccine-preventable diseases in order to assess the potential impact of comprehensive vaccination policies in reducing antimicrobial resistance. Exploration of further possibilities for extending global cooperation. Prescription interventions: Promotion of strategies designed to modify physician antimicrobial-prescribing practices towards an approach based on simplicity rather than complexity. These strategies should take into account physicians limited knowledge of many of the specifics of the complex interaction between antibiotics and microbes. Approaches to encourage improved adherence to veterinary judicious use guidelines. Promotion of investment in research and development of future innovative vaccines capable of targeting and preventing antibiotic-resistant bacteria.
References
1
Chan M. Antimicrobial resistance in the European Union (EU) and the world - the EUs contributions to the solutions of the global antimicrobial resistance problem. [Keynote Address] Copenhagen: World Health Organization (WHO) Press; 14 March 2012 [cited 16 July 2012]; Available from: http://www.who.int/dg/speeches/2012/amr_20120314/en/index.html. World Health Organization (WHO). Antimicrobial resistance: no action today, no cure tomorrow. [Web Page]: WHO Press; 7 April 2011 [cited 20 July 2012]; Available from: http://www.who.int/world-health-day/2011/en/index.html. (WHO) WHO. Priority Medicines for Europe and the World: A Public Health Approach to Innovation. 2004. [cited 10 June 2012]; Available from: http://mednet3.who.int/ prioritymeds Nordberg P MD, Cars O. Antibacterial drug resistance. Priority medicines for Europe and the world: A public health approach to innovation. Geneva: World Health Organization; 2004. p. 40. [cited 4 June 2012]; Available from: http://apps.who.int/medicinedocs/documents/s16368e/s16368e.pdf Gerards M. International policy overview: antibiotic resistance. [Report] 2011 [cited 11 July 2012]; Available from: http://www.nationaalkompas.nl/object_binary/o12174_International-PolicyOverview_Antibiotic-Resistance_July2011.pdf. Laxminarayan R, Malani A. Extending the cure : policy responses to the growing threat of antibiotic resistance. Washington, DC: Resources for the Future; 2007 [cited 16 July 2012]; xiii, 175 p.]. Available from: http://www.loc.gov/catdir/toc/ecip0712/2007008949.html; http://digitalarchive.oclc.org/request?id%3Doclcnum%3A85817903; http://www.loc.gov/catdir/enhancements/fy0827/2007008949-b.html; http://www.loc.gov/catdir/enhancements/fy0827/2007008949-d.html; http://www.extendingthecure.org/report.
6.1-30
Hgglund G. Innovative incentives for effective antibacterials. [Conference Summary] 2009 [cited 2012 July 10]; Available from: http://www.se2009.eu/polopoly_fs/1.25861!menu/standard/file/Antibacterials5.pdf. Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Recommendations for future collaboration between the U.S. and EU. TATFAR. [Electronic Book]: The European Centre for Disease Prevention and Control (ECDC); 2011 [cited 18 July 2012]; Available from: http://ecdc.europa.eu/en/activities/diseaseprogrammes/tatfar/pages/index.aspx. Norrby R, Powell M, Aronsson B, Monnet DL, Lutsar I, Bocsan IS. The bacterial challenge: time to react - a call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. [Joint Technical Report]: European Center for Disease Prevention and Control (ECDC) & European Medicines Agency (EMA); 2009 [cited 6 July 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf. van de Sande-Bruinsma N, Grundmann H, Verloo D, Tiemersma E, Monen J, Goossens H, et al. Antimicrobial drug use and resistance in Europe. Emerging Infectious Diseases. 2008; 14:1722-30. Nugent R, Back E, Beith A. The race against drug resistance. [Electronic Book]: Center for Global Development; 2010 [cited 2012 July 12]; 116]. Available from: http://www.cgdev.org/content/publications/detail/1424207/. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. The Lancet Infectious Diseases. 2010; 10:597-602. MacLean RC, Hall AR, Perron GG, Buckling A. The population genetics of antibiotic resistance: integrating molecular mechanisms and treatment contexts. Nature Reviews Genetics. 2010; 11:40514. Sundqvist M, Geli P, Andersson DI, Sjolund-Karlsson M, Runehagen A, Cars H, et al. Little evidence for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use. The Journal of Antimicrobial Chemotherapy. 2010; 65:350-60. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Reviews Microbiology. 2010; 8:260-71. Wright GD. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Reviews Microbiology. 2007; 5:175-86. Canton R. Antibiotic resistance genes from the environment - a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Clinical Microbiology And Infection : The Official Publication Of The European Society Of Clinical Microbiology And Infectious Diseases. 2009; 15 Suppl 1:20-5. Wright GD. Antibiotic resistance in the environment - a link to the clinic? Current Opinion In Microbiology. 2010; 13:589-94. Soavi L, Stellini R, Signorini L, Antonini B, Pedroni P, Zanetti L, et al. Meticillin-resistant Staphylococcus aureus ST398, Italy. Emerging Infectious Diseases. 2010; 16:346-8. Smith TC, Male MJ, Harper AL, Kroeger JS, Tinkler GP, Moritz ED, et al. Meticillin-resistant Staphylococcus aureus (MRSA) strain ST398 is present in midwestern U.S. swine and swine workers. PloS One. 2009; 4:e4258. van Loo I, Huijsdens X, Tiemersma E, de Neeling A, van de Sande-Bruinsma N, Beaujean D, et al. Emergence of meticillin-resistant Staphylococcus aureus of animal origin in humans. Emerging Infectious Diseases. 2007; 13:1834-9.
10
11
12
13
14
15
16
17
18
19
20
21
6.1-31
22
Cortes P, Blanc V, Mora A, Dahbi G, Blanco JE, Blanco M, et al. Isolation and characterization of potentially pathogenic antimicrobial-resistant Escherichia coli strains from chicken and pig farms in Spain. Applied and Environmental Microbiology. 2010; 76:2799-805. Nisha AR. Antibiotic residues - a global health hazard. Veterinary World. 2008; 1:3. Turkyilmaz S, Tekbiyik S, Oryasin E, Bozdogan B. Molecular epidemiology and antimicrobial resistance mechanisms of meticillin-resistant Staphylococcus aureus isolated from bovine milk. Zoonoses and Public Health. 2010; 57:197-203. Poeta P, Costa D, Igrejas G, Rojo-Bezares B, Saenz Y, Zarazaga M, et al. Characterization of vanAcontaining Enterococcus faecium isolates carrying Tn5397-like and Tn916/Tn1545-like transposons in wild boars (Sus Scrofa). Microbial Drug Resistance. 2007; 13:151-6. Berger CN, Sodha SV, Shaw RK, Griffin PM, Pink D, Hand P, et al. Fresh fruit and vegetables as vehicles for the transmission of human pathogens. Environmental Microbiology. 2010; 12:2385-97. Chen MH, Wang SW, Hwang WZ, Tsai SJ, Hsih YC, Chiou CS, et al. Contamination of Salmonella Schwarzengrund cells in chicken meat from traditional marketplaces in Taiwan and comparison of their antibiograms with those of the human isolates. Poultry Science. 2010; 89:359-65. Levy SB, Fitzgerald GB, Macone A. 1976 Spread of antibiotic-resistant plasmids from chicken to chicken and from chicken to man Nature 260, 40 - 42 (04 March 1976); doi:10.1038/260040a0 [Harrison EM, Peterson GK, Holden MTG et al. Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel mecA homologue mecC. EMBO Molecular Medicine published online 25 MAR 2013. DOI: 10.1002/emmm.201202413] Verner-Jeffreys DW, Welch TJ, Schwarz T, Pond MJ, Woodward MJ, Haig SJ, et al. High prevalence of multidrug-tolerant bacteria and associated antimicrobial resistance genes isolated from ornamental fish and their carriage water. PloS One. 2009; 4:e8388. Allen HK, Cloud-Hansen KA, Wolinski JM, Guan C, Greene S, Lu S, et al. Resident microbiota of the gypsy moth midgut harbors antibiotic resistance determinants. DNA and Cell Biology. 2009; 28:10917. Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PloS One. 2010; 5:e9836 Gullberg E, Cao S, Berg OG, Ilback C, Sandegren L, Hughes D, et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathogens. 2011; 7:e1002158. Rice LB. 2011. Rapid Diagnostics and Appropriate Antibiotic Use Clin Infect Dis. (2011) 52 (suppl 4): S357-S360. doi: 10.1093/cid/cir051 at http://cid.oxfordjournals.org/content/52/suppl_4/S357.full?sid=78c3ce45-4011-4770-a1fc-6a7a2b96f90f U.S. Department of Health and Human Services. CDC now tracking antibiotic use in hospitals. [Press Release] 2011 [updated 14 November 2011; cited 17 July 2012]; Available from: http://www.cdc.gov/media/releases/2011/p1114_antibiotic_hospitals.html. WHO list of Critically Important Antimicrobials (CIA) 2011 [accessed 23 April 2013] Available from: http://www.who.int/foodborne_disease/resistance/cia/en/ Geffers C, Gastmeier P. Nosocomial infections and multidrug-resistant organisms in Germany: epidemiological data from KISS (the Hospital Infection Surveillance System). Deutsches Arzteblatt International. 2011; 108:87-93. Jean SS, Hsueh PR. High burden of antimicrobial resistance in Asia. International journal of Antimicrobial Agents. 2011; 37:291-5.
23 24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
6.1-32
39
Mattys A, Opila S. Research suggests hospital antimicrobial stewardship programs beneficial: antibiotic resistance and costs down. [Press Release] Boston, Massachusetts: Infectious Diseases Society of America (IDSA); 2011 [cited 11 July 2012]; Available from: www.idmeeting.org/press_releases/1103/AntibioticStewardship.pdf. Coenen S, Adriaenssens N, Versporten A, Muller A, Minalu G, Faes C, et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe (1997-2009). The Journal of Antimicrobial Chemotherapy. 2011; 66 Suppl 6:vi57-70. Dutil L, Irwin R, Finley R, Ng LK, Avery B, Boerlin P, et al. Ceftiofur resistance in Salmonella enterica serovar Heidelberg from chicken meat and humans, Canada. Emerging Infectious Diseases. 2010; 16:48-54. Boussat S, Demore B, Lozniewski A, Aissa N, Rabaud C. How to improve the collection and analysis of hospital antibiotic consumption: preliminary results of the ConsoRes software experimental implementation. Medecine et Maladies Infectieuses. 2012; 42:154-60. Cars O, Hedin A, Heddini A. The global need for effective antibiotics-moving towards concerted action. Drug Resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:68-9. WHO antimicrobial resistance facts and figures; 2013 [accessed 23 April 2013] Available from: http://www.euro.who.int/en/what-we-do/health-topics/disease-prevention/antimicrobialresistance/facts-and-figures. Livermore DM. 2002. Multiple Mechanisms of Antimicrobial Resistance in Pseudomonas aeruginosa: Our Worst Nightmare? Clin Infect Dis. (2002) 34 (5): 634-640. doi: 10.1086/338782 at http://cid.oxfordjournals.org.ezproxy.bu.edu/content/34/5/634.short See Verhegghe M, Pletinckx LJ, Crombe F et al. Methicillin-Resistant Staphylococcus aureus (MRSA) ST398 in Pig Farms and Multispecies Farms http://onlinelibrary.wiley.com.ezproxy.bu.edu/doi/10.1111/zph.12007/abstract First published online: 28 AUG 2012 ECDC TECHNICAL REPORT: Risk assessment on the spread of carbapenemase-producing Enterobacteriaceae (CPE); 2011 [accessed on 23 April 2013] Available from: http://EARSnet.europa.eu/en/publications/Publications/110913_Risk_assessment_resistant_CPE.pdf The Alliance for the Prudent Use of Antibiotics (APUA). Antibiotics should be assigned to a special drug class to preserve their power, says Alliance for the Prudent Use of Antibiotics (APUA). [Press Release] 2010 [cited 17 July 2012]; Available from: http://www.tufts.edu/med/apua/news/press_release_7-13-10.shtml. Alliance for the Prudent Use of Antibiotics (APUA). The cost of antibiotic resistance to U.S. families and the health care system - antibiotic-resistant infections cost the U.S. healthcare system over $20 billion each year. [Quick Reference Sheet] 2010 [cited 17 July 2012]; Available from: http://www.tufts.edu/med/apua/consumers/personal_home_5_1451036133.pdf. Sun L, Klein EY, Laxminarayan R. Seasonality and temporal correlation between community antibiotic use and resistance in the United States. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2012. China Daily News. China faces battle against antibiotic resistance. [News Article] Beijing: Xinhua News Agency; 2012 [updated 23 March 2012; cited 18 July 2012]; Available from: http://www.chinadaily.com.cn/china/2012-03/23/content_14893869.htm. NDM-1 A Cause for Worldwide Concern Robert C. Moellering, Jr., M.D N Engl J Med 2010; 363:2377-2379 December 16, 2010 DOI: 10.1056/NEJMp1011715 at http://www.nejm. http://www.nejm.org/doi/full/10.1056/NEJMp1011715 org/doi/full/10.1056/NEJMp1011715].
40
41
42
43
44
45
46
47
48
49
50
51
52
6.1-33
53
Updated risk assessment on the spread of New Delhi metallo--lactamase (NDM) and its variants within Europe at http://EARS-net.europa.eu/en/publications/Publications/Forms/EARSNET_DispForm.aspx?ID=775 and
Risk assessment on the spread of carbapenemase-producing Enterobacteriaceae (CPE) through patient transfer between healthcare facilities, with special emphasis on cross-border transfer. Stockholm: European Centre for Disease Prevention and Control (EARS-NET). EARS-NET, 2011.
54
World Health Organization (WHO). World health statistics. [Electronic Book] France: WHO Press; 2012 [cited 17 July 2012]; Available from: http://www.who.int/healthinfo/EN_WHS2012_Full.pdf. de Kraker ME, Wolkewitz M, Davey PG, Koller W, Berger J, Nagler J, et al. Clinical impact of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay related to meticillin-resistant Staphylococcus aureus bloodstream infections. Antimicrobial Agents And Chemotherapy. 2011; 55:1598-605. Lambert ML, Suetens C, Savey A, Palomar M, Hiesmayr M, Morales I, et al. Clinical outcomes of health-care-associated infections and antimicrobial resistance in patients admitted to European intensive-care units: a cohort study. The Lancet Infectious Diseases. 2011; 11:30-8. Kaki R, Elligsen M, Walker S, Simor A, Palmay L, Daneman N. Impact of antimicrobial stewardship in critical care: a systematic review. The Journal of Antimicrobial Chemotherapy. 2011; 66:1223-30. BURDEN of Resistance and Disease in European Nations; modified 2010 [accessed 23 April 2013]. Available from: http://www.eu-burden.info Boan D, Cook P, Crnich C, Kaye K, Nadzam D, Soule BM, et al. What every health care executive should know: the cost of antibiotic resistance. Soule BM, Weber S, editors. Oakbrook Terrace, IL: Joint Commission Resources; 2008. Foster SD. The economic burden of antibiotic resistance evidence from three recent studies. 2010 Annual Conference on Antimicrobial Resistance; Bethesda, MD: National Academy Press; 2010. Filice GA, Nyman JA, Lexau C, Lees CH, Bockstedt LA, Como-Sabetti K, et al. Excess costs and utilization associated with meticillin resistance for patients with Staphylococcus aureus infection. Infection Control And Hospital Epidemiology : The Official Journal Of The Society Of Hospital Epidemiologists Of America. 2010; 31:365-73. Roberts RR, Hota B, Ahmad I, Scott RD, 2nd, Foster SD, Abbasi F, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society of America. 2009; 49:1175-84. Anderson DJ, Kaye KS, Chen LF, Schmader KE, Choi Y, Sloane R, et al. Clinical and financial outcomes due to meticillin resistant Staphylococcus aureus surgical site infection: a multi-center matched outcomes study. PloS One. 2009; 4:e8305. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant Gram-negative bacteria. Antimicrobial Agents And Chemotherapy. 2010; 54:109-15. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and economic outcomes of vancomycinresistant enterococci. Archives of Internal Medicine. 2002; 162:2223-8. Evans HL, Lefrak SN, Lyman J, Smith RL, Chong TW, McElearney ST, et al. Cost of Gram-negative resistance. Critical Care Medicine. 2007; 35:89-95. Morales E, Cots F, Sala M, Comas M, Belvis F, Riu M, et al. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. BMC Health Services Research. 2012; 12:122.
55
56
57
58
59
60
61
62
63
64
65
66
67
6.1-34
68
Rubio-Terres C, Garau J, Grau S, Martinez-Martinez L. Cost of bacteraemia caused by meticillinresistant vs. meticillin-susceptible Staphylococcus aureus in Spain: a retrospective cohort study. Clinical Microbiology And Infection : The Official Publication Of The European Society Of Clinical Microbiology and Infectious Diseases. 2010; 16:722-8. Sanchez-Romero I, Asensio A, Oteo J, Munoz-Algarra M, Isidoro B, Vindel A, et al. Nosocomial outbreak of VIM-1-producing Klebsiella pneumoniae isolates of multilocus sequence type 15: molecular basis, clinical risk factors, and outcome. Antimicrobial Agents And Chemotherapy. 2012; 56:420-7. de Kraker ME, Davey PG, Grundmann H. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Medicine. 2011; 8:e1001104. Schwaber MJ, Navon-Venezia S, Kaye KS, Ben-Ami R, Schwartz D, Carmeli Y. Clinical and economic impact of bacteremia with extended- spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrobial Agents And Chemotherapy. 2006; 50:1257-62. Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrobial Agents And Chemotherapy. 2006; 50:43-8. European Surveillance of Antimicrobial Consumption Network (ESAC-Net); 2011 [accessed 24 April 2013] Available at: http://www.ecdc.europa.eu/en/activities/surveillance/esac-net/pages/index.aspx HALT-2; 2013 [accessed 23 April 2013] Available at: http://halt.wivisp.be/about/page/background.aspx European Parliament resolution of 27 October 2011 on the public health threat of antimicrobial resistance; 2011 [accessed 23 April 2013] Available at: http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-//EP//TEXT+TA+P7-TA-20110473+0+DOC+XML+V0//EN European Commission Recommendation of 27 October 2011 on the research Joint Programming Initiative The Microbial Challenge An Emerging Threat to Human Health; 2011 [accessed on 23 April 2013] Available at: http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2011:315:0001:0003:EN:PDF Communication from the Commission to the European Parliament and the Council - Action plan against the rising threats from Antimicrobial Resistance; 2011 [accessed on 23 April 2013] Available at: http://ec.europa.eu/dgs/health_consumer/docs/communication_amr_2011_748_en.pdf European Antibiotic Awareness Day; 2013 [accessed 23 April 2013] Available at: http://ecdc.europa.eu/en/EAAD/Pages/Home.aspx/ Cogliani C, Goossens H, Greko C. Restricting antimicrobial use in food animals: lessons from Europe - Banning nonessential antibiotic uses in food animals is intended to reduce pools of resistance genes. Microbe Magazine. 2011 June:274-9. (EU) EU. Ban on antibiotics as growth promoters in animal feed enters into effect. [Press Release] 2005 [cited 18 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/05/1687&format=HTML&aged=0&lang uage=EN. U.S. Food and Drug Administration (FDA). FDA's strategy on antimicrobial resistance - questions and answers. [Web Page] Silver Spring, MD [updated 11 April 2012; cited 7 July 2012]; Available from: http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/uc m216939.htm.
69
70
71
72
73
74
75
76
77
78
79
80
81
6.1-35
82
The Innovative Medicines Initiative; 2010 [accessed 23 April 2013] Available at: http://www.imi.europa.eu/ The Innovative Medicines Initiative - Combatting Bacterial Resistance in Europe (COMBACTE); 2013 [accessed 23 April 2013] Available at: http://www.imi.europa.eu/content/combacte) The Innovative Medicines Initiative - Translocation; 2013 [accessed on 23 April 2013] Available at: http://www.imi.europa.eu/content/translocation Initiatives to supportAMR related research in the EU - OIE Global Conference on the Responsible and Prudent Use of Antimicrobial Agents for Animals, Paris 13-15 March 2013 [accessed on 23 April 2013] Available at: http://www.oie.int/eng/A_AMR2013/Presentations/S8_4_Jean-CharlesCavitte.pdf European Commission (EC). Vision paper and basis for a strategic research agenda for NanoMedicine. [Electronic Book] Luxembourg: Office for Official Publications of the European Communities. 2005; [cited 17 July 2012]; Available from: http://cordis.europa.eu/nanotechnology/nanomedicine.htm#challenge; ftp://ftp.cordis.europa.eu/pub/nanotechnology/docs/nanomedicine_visionpaper.pdf. Ti Pharma. Pharmaceutical research projects. [Web Page] [cited 20 July 2012]; Available from: http://www.tipharma.com/pharmaceutical-research-projects/infectious-diseases/multidrugresistant-bacterial-pathogens.html. World Health Day; 2011 [accessed on 23 April 2013] Available at: http://www.who.int/world-healthday/2011/en/index.html Patient safety document: The evolving threat of antimicrobial resistance - Options for action; 2012 [accessed on 23 April 2013] Available at: http://www.who.int/patientsafety/implementation/amr/publication/en/ European strategic action plan on antibiotic resistance; 2012 [accessed 23 April 2013] Available at: (http://www.euro.who.int/__data/assets/pdf_file/0008/147734/wd14E_AntibioticResistance_111380.p df) Huttner B, Goossens H, Verheij T, Harbarth S, consortium C. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. The Lancet Infectious Diseases. 2010; 10:17-31. Chatterjee P, Fleck F. Mobilizing political will to contain antimicrobial resistance. Bulletin of the World Health Organization. 2011; 89:168-9. Resolution for the WHO regional committee for South-East Asia: PREVENTION AND CONTAINMENT OF ANTIMICROBIAL RESISTANCE; 2010 [accessed 23 April 2013] Available at: (http://repository.searo.who.int/bitstream/123456789/15013/1/sea-rc63-r4.pdf). Action on Antibiotic Resistance (ReAct). China and Sweden in fruitful summit on antibiotic resistance. [Press Release] Uppsala University, Sweden. 2009 [cited 12 July 2012]; Available from: http://www.reactgroup.org/uploads/what-we-do/react-activities/pressrelease-china-and-sweden-infruitful-summit.pdf. Hvistendahl M. China takes aim at rampant antibiotic resistance. Science. 2012; 336:795. Beijing Youth Daily. Of infectious diseases all network direct report from April 1. [News Article] 2004 [cited 17 July 2012]; Available from: http://www.china-ah.com/news/2004/12/14/30082.html. Zhang Y, Harvey K. Rational antibiotic use in China: lessons learnt through introducing surgeons to Australian guidelines. Australia and New Zealand Health Policy. 2006; 3:5. Regev-Yochay G, Raz M, Dagan R, Roizin H, Morag B, Hetman S, et al. Reduction in antibiotic use following a cluster randomized controlled multifaceted intervention: the Israeli judicious antibiotic
83
84
85
86
87
88
89
90
91
92
93
94
95 96
97
98
6.1-36
prescription study. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2011; 53:33-41.
99
Schwaber MJ, Lev B, Israeli A, Solter E, Smollan G, Rubinovitch B, et al. Containment of a countrywide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society of America. 2011; 52:848-55. Jarlier V, Carlet J, McGowen J, Goossens H, Voss A, Harbath S, et al. Priority actions to fight antibiotic resistance: results of an international meeting. Antimicrobial Resistance and Infection Control. 2012; 1. Ghafur A et al. Indian J Cancer. 2013 [accessed 23 April 2013] Available at: http://www.indianjcancer.com/preprintarticle.asp?id=104065 Combating Antimicrobial Resistance: Policy Recommendations to Save Lives; 2011 [accessed 23 April 2013] Available at: http://cid.oxfordjournals.org/content/52/suppl_5/S397.full.pdf Infectious Diseases Society of America (IDSA). The 10 x '20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2010; 50:1081-3. http://www.tufts.edu/med/apua/policy/other_initiatives_2_765224796.pdf
100
101
102
103
104 105
Guidance for Industry - The Judicious Use of Medically Important Antimicrobial Drugs in FoodProducing Animals; 2012 [accessed 23 April 2013] Available at: http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforI ndustry/UCM216936.pdf (FDA) US FDA. PDUFA V: Fiscal years 2013 - 2017. [Web Page] Washington, DC. 2012 [updated 19 July 2012; cited 20 July 2012]; Available from: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm272170.htm. Guidance for Industry - The Judicious Use of Medically Important Antimicrobial Drugs in FoodProducing Animals; 2012 [accessed 23 April 2013] Available at: http://www.paho.org/english/ad/dpc/cd/amr-saidi.htm Pan American Health Organization Antimicrobial resistance documents; 2013 [accessed 23 April 2013] Available at: http://new.paho.org/hq/index.php?option=com_content&view=article&id=6221&Itemid=4328&lang= en CenterWatch. FDA approved drugs for immunology/infectious diseases. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.centerwatch.com/drug-information/fda-approvals/drugareas.aspx?AreaID=7. So AD, Ruiz-Esparza Q, Gupta N, Cars O. 3Rs for innovating novel antibiotics: sharing resources, risks, and rewards. BMJ (Clinical Research Ed). 2012; 344:e1782. So AD, Gupta N, Brahmachari SK, Chopra I, Munos B, Nathan C, et al. Towards new business models for R&D for novel antibiotics. Drug Resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:88-94. Bergstrm R. EFPIA contributes to IMI 223,7 million programme to tackle antibiotic resistance. [Press Release]: European Federeation of Pharmaceutical Industries and Associations (EFPIA); 2012 [cited 18 July 2012]; Available from: http://www.efpia.eu/press-releases/efpia-contributes-imi%E2%82%AC2237-million-programme-tackle-antibiotic-resistance. PR Newswire. The antibiotic development pipeline and strategies to combat antibiotic resistance. [News Article]: United Business Media (UBM); 2012 [updated 18 January 2012; cited 20 July 2012];
106
107
108
109
110
111
112
113
6.1-37
Available from: http://www.prnewswire.com/news-releases/antibiotic-resistance-2012-theantibiotic-development-pipeline-and-strategies-to-combat-antibiotic-resistance-137553493.html.

114
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2009; 48:1-12. Infectious Disease Society of America (IDSA). Bad bugs, no drugs - as antibiotic discovery stagnates ... a public health crisis brews. [Electronic Book] 2004 [cited 18 July 2012]; Available from: http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/A ntimicrobial_Resistance/10x20/Images/Bad%20Bugs%20no%20Drugs.pdf#search=%22bad%20bugs% 22. Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? British Journal of Pharmacology. 2011; 163:184-94. Daniela Jabes, The antibiotic R&D pipeline: an update Current Opinion in Microbiology Volume 14, Issue 5, October 2011, Pages 564569 Available at: http://www.sciencedirect.com.ezproxy.bu.edu/science/article/pii/S1369527411001330# Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: do we ever learn? The Journal Of Antimicrobial Chemotherapy. 2008; 61:235-7. Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, MacGowan A, et al. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:107-17. Sandberg T, Skoog G, Hermansson AB, Kahlmeter G, Kuylenstierna N, Lannergrd A, Otto G, Settergren B, Ekman GS.Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012 Aug 4;380(9840):484-90. doi: 10.1016/S0140-6736(12)60608-4. Epub 2012 Jun 21 Brittain-Long R, Westin J, Olofsson S, Lindh M, Andersson LM. Access to a polymerase chain reaction assay method targeting 13 respiratory viruses can reduce antibiotics: a randomised, controlled trial. BMC Medicine. 2011; 9:44. Endimiani A, Hujer KM, Hujer AM, Kurz S, Jacobs MR, Perlin DS, et al. Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia? Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2011; 52 Suppl 4:S373-83. Levy SB, Choe J, Safwat N, Okeke IN, Tzubery T, Ldke G. Diagnostic innovation to contain resistance. The Alliance for the Prudent Use of Antibiotics (APUA); 7 September 2011 [cited 12 July 2012]; Available from: http://www.tufts.edu/med/apua/index_298_3070611776.pdf. Burkhardt O, Ewig S, Haagen U, Giersdorf S, Hartmann O, Wegscheider K, et al. Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. The European Respiratory Journal : Official Journal Of The European Society For Clinical Respiratory Physiology. 2010; 36:601-7. Madurell J, Balague M, Gomez M, Cots JM, Llor C. Impact of rapid antigen detection testing on antibiotic prescription in acute pharyngitis in adults. FARINGOCAT STUDY: a multicentric randomized controlled trial. BMC Family Practice. 2010; 11:25. Solelh V. Foundation for Innovative New Diagnostics (FIND) - negotiated prices for Xpert MTB/RIF and country list. [Web Page] 2010 [cited 18 July 2012]; Available from: http://www.finddiagnostics.org/about/what_we_do/successes/find-negotiatedprices/xpert_mtb_rif.html.
115
116
117
118
119
120
121
122
123
124
125
126
6.1-38
127
Okeke IN, Peeling RW, Goossens H, Auckenthaler R, Olmsted SS, de Lavison JF, et al. Diagnostics as essential tools for containing antibacterial resistance. Drug Resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:95-106. Malaria Rapid Diagnostic Tests; 2005 [accessed 24 April 2013] Available at: http://www.wpro.who.int/malaria/sites/rdt/ Rapid detection of extended-spectrum -lactamase producing Enterobacteriacae. Nordmann P. Dortet L, Poirel L Journal of Clinical Microbiology (September 2012). Published ahead of print 3 July 2012, doi: 10.1128/JCM.00859-12 J. Clin. Microbiol. September 2012 vol. 50 no. 9 3016-3022 Monnet DL. Update on EARS-NET AMR & HAI activities and workplan [for] 2012. [Presentation] Warsaw 2011 November 23-25 [cited 2012 July 11]; Available from: www.EARSnet.europa.eu/en/activities/diseaseprogrammes/ARHAI/Presentations2011Warsaw/ARHAInetworks-meeting_parallel-session-five-1-Dominique-Monnet-AMR-HAI-activities.pdf. Corker B. FDA user fee reauthorization including GAIN act to become law - GAIN act encourages development of new antibiotics to treat rising cases of drug-resistant infections. [Press Release] 26 June 2012 [cited 11 July 2012]; Available from: http://www.corker.senate.gov/public/index.cfm?p=News&ContentRecord_id=e30e2239-0434-4c158f16-58c0b64b3165. Palmer R. Congress vouches for priority review of childhood disease. Nature Medicine. 2012; 18:181. World Health Organization (WHO). Research and development to meet health needs in developing countries: strengthening global financing and coordination. [Electronic Book] Italy: WHO Press; 2012 [cited 18 July 2012]; Available from: http://www.who.int/phi/CEWG_Report_5_April_2012.pdf. [ C. Baron, B. Coombes Targeting bacterial secretion systems: benefits of disarmament in the microcosm Target. Disord Drug Targets, 7 (2007), pp. 1927 A.E. Clatworthy, E. Pierson, D.T. Hung A.E. Clatwo virulence: a new paradigm for antimicrobial therapy Chem Biol, 3 (2007), pp. 541548] Peschel A, Sahl H-G. (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nature Reviews/Microbiology 4: 529-536 at http://www.nature.com.ezproxy.bu.edu/nrmicro/journal/v4/n7/pdf/nrmicro1441.pdf. Peters BM, Shirtliff ME, Jabra-Rizk MA (2010) Antimicrobial Peptides: Primeval Molecules or Future Drugs? PLoS Pathog 6(10): e1001067. doi:10.1371/journal.ppat.1001067; Yanmei Li, Qi Xianga, Qihao Zhanga,, Yadong Huanga, Zhijian Sua, Overview on the recent study of antimicrobial peptides: Origins, functions, relative mechanisms and application. Peptides 37 (2012) 207215. Kristiansen JE, Thomsen VF, Martins A, Viveiros M, Amaral L. Non-antibiotics reverse resistance of bacteria to antibiotics. In Vivo. 2010; 24:751-4. Eumkeb G, Sakdarat S, Siriwong S. Reversing beta-lactam antibiotic resistance of Staphylococcus aureus with galangin from Alpinia officinarum Hance and synergism with ceftazidime. Phytomedicine: International Journal Of Phytotherapy And Phytopharmacology. 2010; 18:40-5. Edgar R et al. Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes. Applied and Environmental Microbiology, 2012, 78:744-51. Frontiers in Microbiology, Phage therapy: concept to cure Eric C. Keen* July 2012 | Volume 3 | Article 238 | 1-3 http://www.frontiersin.org/Antimicrobials,_Resistance_and_Chemotherapy/10.3389/fmicb.2012.00238/full
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
6.1-39
143
Zhou F et al. Pediatrics 2008; 121:253-260 (heptavalent pneumococcal conjugate vaccines (PCV7) against drug-resistant streptococcus pneumoniae (DRSP) led to a drop in antibiotic prescriptions); Whitney C. et al Seminars in Pediatric Infectious Diseases, Vol 15, No 2 (April), 2004: pp 86-93 (pneumococcal conjugate vaccine effective in preventing disease in young children and may be reducing the rate of disease in.adults); Haddy et al. The Pediatric Infectious Disease Journal Volume 24, Number 4, April 2005 ( case rates for invasive S. pneumoniae disease among children decreased significantly in the 2-year period after introduction of the heptavalent S. pneumonia protein conjugate vaccine). Fernebro J. Fighting bacterial infections-future treatment options. Drug resistance Updates : Reviews And Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:125-39. Gant CM, Rosingh AW, Lpez-Hontangas JL, et al. 2012. Serotype distribution and antimicrobial resistance of invasive pneumococcal disease strains in the Comunidad Valenciana, Spain, during the winter of 2009-2010: low PCV7 coverage and high levofloxacin resistance Antimicrob Agents Chemother. 2012 Sep;56(9):4988-9. doi: 10.1128/AAC.01201-12. Epub 2012 Jul 2 at http://www.ncbi.nlm.nih.gov/pubmed/22751535. [Vaccines and antibiotic resistance, Mishra R PN, Oviedo-Orta E. Prachi P et al. Current Opinion in Microbiology Volume 15, Issue 5, October 2012, Pages 596602 at http://dx.doi.org.ezproxy.bu.edu/10.1016/j.mib.2012.08.002, http://www.clinicaltrials.gov/ct2/results?term=Staphylococcus+and++vaccine] (http://www.clinicaltrials.gov (Search term Staphyloccous + and ++ vaccine) ) [http://clinicaltrials.gov/ct2/results?term=Clostridium+Difficile+vaccine] [http://clinicaltrials.gov/ct2/results?term=Pseudomonas+vaccine]
144
145
146
147
148 149 150
[http://www.clinicaltrials.gov/ct2/results?term=H.+influenzae+and+vaccine&recr=Open&no_unk=Y]
151
[http://www.clinicaltrials.gov/ct2/results?term=e.coli+vaccine]
6.1-40
Annexes
Annex 6.1.1: Annex 6.1.2: Annex 6.1.3: Annex 6.1.4: Annex 6.1.5: Annex 6.1.6: Annex 6.1.7: Annex 6.1.8: Annex 6.1.9: Annex 6.1.10: Annex 6.1.11: Annex 6.1.12: Annex 6.1.13: Annex 6.1.14: Annex 6.1.15: Annex 6.1.16: Annex 6.1.17: Annex 6.1.18: Annex 6.1.19: Annex 6.1.20: Annex 6.1.21: Annex 6.1.22: Annex 6.1.23: Annex 6.1.24: Examples of Global Activities and Publications Addressing Antimicrobial Resistance Correlation between Antibiotic Consumption and Resistance in Europe Correlation between Antibiotic Consumption and Resistance in the World Outpatient Antibiotic Consumption Examples of Campaigns Addressing the Issue of Antimicrobial Resistance Successful Campaigns for Prudent and Appropriate Antibiotic Use Examples of Diagnostics for Containing Antimicrobial Resistance Antibiotic Resistant Streptococcus pneumonia trends in Europe, 2005 and 2010 Antibiotic Resistant Escherichia coli trends in Europe, 2005 and 2010 Meticillin Resistant Staphylococcus aureus trends in Europe, 2005 and 2010 Antibiotic Resistant Enterococcus faecium trends in Europe, 2005 and 2010 Epidemiological Trends in the USA Epidemiological Trends in the World Examples of the Economic Impact of Antimicrobial Resistance Activity Review of the European Commission on Antimicrobial Resistance Press Release of IMI's 223.7 Programme to Combat Antibiotic Resistance European Commission Funded FP7 Projects on Antimicrobial Resistance Activity Review of the WHO and Antimicrobial Resistance Examples of Concerted Action Addressing Antimicrobial Resistance in Europe Examples of Public Private Partnerships Concerning Antimicrobial Resistance FDA Approved New Molecular Entity Antibiotics, 2004 2012 Incentives to Encourage Antimicrobial Research and Development Antibiotic Development Pipeline, 2011 Bacterial Vaccines Licensed for Distribution in the USA, 2005 2012
6.1-41
Annex 6.1.1: Examples of Global Activities and Publications Addressing Antimicrobial Resistance
This table presents several examples of global activities and actions concerning AMR. This is a brief overview of actions and is not inclusive of all of the efforts that have occurred since 2004. Organization Location Activity Purpose / Action (Year) WHO1 World Published: Priority Medicines for Europe Identify AMR as the greatest infectious disease to and the World public health if the appropriate drugs were not developed (2004) EMA & CHMP Europe Published: Final report from EMA / CHMP Discuss the antibiotic R & D pipeline Think - Tank Group on Think - Tank Group on Innovative Drug Formulate suggestions for future activities Innovative Drug Development conducted at the EMA Development2 (2004) ECDC3 Europe Visited: Several countries within Europe Discuss implementation of EC recommendations from 2001 (2006 2011) EU4 Europe Legislated: Ban antibiotics in poultry Ban the use of antibiotics in poultry farming farming
(2006) Meeting: Develop the ECDC / EMA Joint Working Group (2007) Legislated: Paediatric regulation (2007)
ECDC EMA ReAct5 EU

6
Europe
Discuss, plan and develop a group to formally produce a report concerning AMR and the gaps in antimicrobial R & D Ensure quality of medicines prescribed to children Foster prudent antimicrobial use
Europe
6.1-42
Organization
EU7
Location
Europe
Activity (Year) Legislated: AMR surveillance in pigs

(2008) Integrated: Suggestions by Think-Tank Group (2008) Legislated: Suggestions for antibiotic use (2008 / 2010) Published: Best - practice framework for the use of antimicrobials in food-producing animals (2008) Published: The bacterial challenge: time to react - A call to narrow the gap between multidrug - resistant bacteria in the EU and the development of new antibacterial agents (2009) Conference: Innovative incentives for effective antibacterials (2009) Presented: Suggestions for patient safety (2009) Annual summit: EU United States presidencies
Purpose / Action
Implement AMR surveillance and reporting strategies for Salmonella, Campylobacter and MRSA within pigs Plan to bolster the EU scientific network Encourage international communication concerning antimicrobial R & D AMR and its relationship with antibiotics within animals Encourage prudent use of antibiotics in animals within the EU
EMA Scientific Committees2
Europe
EC
8, 9
Europe
EPRUMA10
Europe
CHMP11 PDCO ECDC EMA ReAct Numerous AMR experts (Hosted by Swedish EU Presidency)12 EC12
Europe
Produce a report concerning gaps in antimicrobial drug R & D and the increasing prevalence of antimicrobial resistant bacteria
Europe
Develop and discuss incentives to stimulate antimicrobial drug R & D
Europe
Propose strategies to prevent AMR in HAIs
EU United States13
Europe / US
Discuss the human public health threats of AMR Establish TATFAR as a collaborative effort
6.1-43
(2009)
Organization
EMA14
Location
Europe
Activity (Year) Published: Road map to 2015

(2010) Conference: The global need for effective antibiotics-moving towards concerted action (2010) Legislated: Separate physician salary and drug sales at primary care level (2010) Conference: Collaboration for innovation the urgent need for new antibiotics (2011) Published: Recommendations for future collaboration between the US and EU
Purpose / Action
Discuss past, current and future actions of the EMA about the gaps in industry and antimicrobial R & D Further elaborate findings and discussions pertaining to those at the 2009 conference Innovative Incentives for Effective Antibacterials To discourage inappropriate use of antibiotics Part of the national campaign that was implemented in 2004 Discuss the need to develop the appropriate medicines to combat AMR Contribute ideas to the EUs official plan against AMR Issue 17 recommendations that could be implemented with opportunities for collaboration concerning AMR Provide a platform to potentially stimulate the antimicrobial development pipeline Discuss: Control strategies National surveillance Antibiotic stewardship Antibiotic use in food production Research needs Offers recommendations that would limit antibiotic use in animals
Numerous AMR experts (Hosted by ReAct)15
Europe
Ministry of Health
16
China
Numerous AMR experts (Hosted by ReAct)17
Europe
TATFAR
Europe / US
Numerous AMR experts (Hosted by the Australian Society for Infectious Diseases and the Australian Society for Antimicrobials)18 FDA Industry Australia (2011) Conference: Antimicrobial Resistance Summit - defining the problem - an international perspective
United States
(2011) Legislated: Guidance for antibiotics and use in animals
6.1-44
Others19
(2012)
Organization
FDA Industry Others20 Ministry of Health21
Location
United States China
Activity (Year) Legislated: PDUFA V GAIN Act

(2012) Legislated: Administrative Measures on Clinical Application of Antimicrobial Drugs (2012)
Purpose / Action
Offer incentives to stimulate the R & D pipeline for new innovative antimicrobials Stricter regulations concerning the prescription of antimicrobials Promote prudent antimicrobial use
Sources:
1. 2. 3. Kaplan W, Laing R. Priority Medicines for Europe and the World. Geneva, Switzerland: World Health Organization Press; 2004 [cited 9 July 2012]; Available from: http://whqlibdoc.who.int/HQ/2004/WHO_EDM_PAR_2004.7.pdf. European Medicines Agency (EMA). Final report from the EMA/CHMP think-tank group on innovative drug development. [Report] London. 2007 [updated 9 July 2012; cited 10 July 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004913.pdf. European Center for Disease Prevention and Control (ECDC). ECDC meeting report - training strategy for intervention epidemiology in the European Union (EU). [Report] 11-12 September 2007 [cited 6 July 2012]; Available from: http://ecdc.europa.eu/en/publications/Publications/0709_MER_Training_Strategy_for_Intervention_Epidemiology.pdf. Kyprianou M. Commission regulation (EC) number 1177/2006 of 1 August 2006 implementing Regulation (EC) number 2160/2003 of the European Parliament and of the council as regards requirements for the use of specific control methods in the framework of the national programmes for the control of salmonella in poultry. [Legislation]: Official Journal of the European Union; 2006 [cited 10 July 2012]; Available from: http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:212:0003:0005:EN:PDF. European Centre for Disease Prevention and Control (ECDC). ECDC and EMA publish joint technical report on the bacterial challenge - time to react. [Press Release] 17 September 2009 [cited 10 July 2012]; Available from: http://ecdc.europa.eu/en/press/news/Lists/News/ECDC_DispForm.aspx?List=32e43ee8%2De230%2D4424%2Da783%2D85742124029a&ID=309. European Medicines Agency (EMA). Paediatric Regulation. [Web Page] London [cited 10 July 2012]; Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsp&mid=WC0b01ac0580025b8b.
4.
5.
6.
6.1-45
7.
Kyprianou M. Commission decision of 20 December 2007 concerning a financial contribution from the community towards a survey on the prevalence of Salmonella spp. and meticillin-resistant Staphylococcus aureus in herds of breeding pigs to be carried out in the member states. [Legislation]: Official Journal of the European Union; 2007 [cited 10 July 2012]; Available from: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:014:0010:0025:En:PDF. Committee of Permanent Representatives. Doc. 9637/08: Antimicrobial resistance - adoption of council conclusions. Brussles. 2008 [cited 10 July 2012]; Available from: http://register.consilium.europa.eu/pdf/en/08/st09/st09637.en08.pdf. General Secretariat. CVO Conclusions on Antimicrobial Resistance (AMR). Brussels. Council of the European Union (EU); 2010 [cited 11 July 2012]; Available from: http://register.consilium.europa.eu/pdf/en/10/st14/st14867.en10.pdf.
8. 9.
10. European Feed Manufacturers' Federation (FEFAC). The European Platform for the Responsible Use of Medicines in Animals (EPRUMA). [Web Page] [cited 10 July 2012]; Available from: http://www.fefac.eu/links.aspx?CategoryID=1548. 11. Norrby R, Powell M, Aronsson B, Monnet DL, Lutsar I, Bocsan IS. The bacterial challenge: time to react - a call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. [Joint Technical Report]: European Center for Disease Prevention and Control (ECDC) & European Medicines Agency (EMA); 2009 [cited 6 July 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf. 12. Hagglund G. Innovative incentives for effective antibacterials. [Conference Summary] 2009 [cited 20 July 2012]; Available from: http://www.se2009.eu/polopoly_fs/1.25861!menu/standard/file/Antibacterials5.pdf. 13. Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Recommendations for future collaboration between the U.S. and EU. TATFAR. [Electronic Book]: The European Centre for Disease Prevention and Control (ECDC); 2011 [cited 18 July 2012]; Available from: http://ecdc.europa.eu/en/activities/diseaseprogrammes/tatfar/pages/index.aspx. 14. European Medicines Agency (EMA). Road map to 2015 - the EMAs contribution to science, medicines and health. [Electronic Book] 2011 [cited 11 July 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf. 15. Action on Antibiotic Resistance (ReAct). The Global Need for Effective Antibiotics. [Web Page] [cited 10 July 2012]; Available from: http://www.reactgroup.org/resource-centre/react-presentations/the-global-need-for-effective-antibiotics.html. 16. Hvistendahl M. China takes aim at rampant antibiotic resistance. Science. 2012; 336:795. 17. Action on Antibiotic Resistance (ReAct). Collaboration for innovation - the urgent need for new antibiotics. [Conference Procedings] Brussels. 18 October 2011 [cited 11 July 2012]; Available from: http://www.reactgroup.org/uploads/publications/react-publications/report-collaboration-for-innovation-october-2011.pdf. 18. Gottlieb T, Nimmo G. A call to urgent action to address the growing crisis of antibiotic resistance. [Conference] Sydney, Australia. 7-8 February 2011 [cited 11 July 2012]; Available from: http://www.antimicrobialsummit.com.au/.
6.1-46
19. United States Food and Drug Administration (FDA). The judicious use of medically important antimicrobial drugs in food-producing animals. [Guidance Document]: Center for Veterinary Medicine; 2012 [cited 6 July 2012]; Available from: http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM216936.pdf. 20. Corker B. GAIN act encourages development of new antibiotics to treat rising cases of drug-resistant infections. [Press Release]: Tennessee Senator Bob Corker; 26 June 2012 [cited 20 July 2012]; Available from: http://www.corker.senate.gov/public/index.cfm?p=News&ContentRecord_id=e30e2239-0434-4c15-8f1658c0b64b3165. 21. Rong M, Yang K, Yan JJ, Tan J, Schatz GB. Pharmaceuticals, medical devices, health care & life sciences. Reed Smith; 14 June 2012 [cited 11 July 2012]; Available from: http://www.jdsupra.com/post/documentViewer.aspx?fid=36f462ec-8aca-4545-bb1a-f90c74394f16.
6.1-47
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.2: Correlation between Antibiotic Consumption and Resistance in Europe
This figure confirms the 2004 reports assentation that resistance is directly proportional to antibiotic consumption. This figure provides an example within Europe in which the consumption of fluoroquinolones and penicillins is related to resistant E. coli and S. pneumonia strains, respectively.
Occurrence of fluoroquinolone resistant Escherichia coli against outpatient fluoroquinolone use in 17 European countries (with 95% confidence intervals)
Occurrence of penicillin resistant Streptococcus pneumonia against outpatient penicillin use in 17 European countries (with 95% confidence intervals)
Source: van de Sande-Bruinsma N, Grundmann H, Verloo D, Tiemersma E, Monen J, Goossens H, et al. Antimicrobial drug use and resistance in Europe. Emerging Infectious Diseases. 2008; 14:1722-30.
6.1-48
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.3: Correlation between Antibiotic Consumption and Resistance in the World
This figure shows the positive relationship between several antibiotic prescription rates and resistant Gramnegative infection rates in several Singapore hospitals. These findings suggest that antimicrobial usage may be directly related to resistance. Incidence density of respective resistant microbes and prescription volumes over three years
Source: Hsu LY, Tan TY, Tam VH, Kwa A, Fisher DA, Koh TH. Surveillance and correlation of antibiotic prescription and resistance of Gram-negative bacteria in Singaporean hospitals. Antimicrobial Agents and Chemotherapy. 2010; 54:1173-8.
6.1-49
Annex 6.1.4: Outpatient Antibiotic Consumption
These figures represent various outpatient antibiotic use in several European countries and Latin America. Figure 1 offers a comparison of several European countries outpatient antibiotic use in 2002 and 2009. Figure 2 shows antibiotic consumption in eight Latin America n countries in 2007. Figure 1 Total outpatient antibiotic use in 26 European countries in 2002
1
Total outpatient antibiotic use in 28 European countries in 20092
6.1-50
Figure 23 Antibiotic utilization in eight Latin American countries, by therapeutic class, 2007
Sources:
1. 2. World Health Organization (WHO). Essential medicines annual report. [Pamphlet] 2004 [cited 20 July 2012]; Available from: http://apps.who.int/iris/bitstream/10665/69157/1/WHO_EDM_2005.1_eng.pdf. European Centre for Disease Prevention and Control (ECDC). Annual epidemiological report - reporting on 2009 surveillance data and 2010 epidemic intelligence data. [Electronic Book] 2011 [cited 12 July 2012]; Available from: http://ecdc.europa.eu/en/publications/Publications/1111_SUR_Annual_Epidemiological_Report_on_Communicable_Diseases_in_Europe.pdf. Wirtz VJ, Dreser A, Gonzales R. Trends in antibiotic utilization in eight Latin American countries, 1997-2007. Revista panamericana de salud publica = Pan American Journal of Public Health. 2010; 27:219-25.
3.
6.1-51
Annex 6.1.5: Examples of Campaigns Addressing the Issue of Antimicrobial Resistance

This table offers several examples of campaigns addressing the issue of AMR. These campaigns differ from one another in their target audience, budgets, locations and intervention strategy used. Some of these campaigns run several times throughout the year while others run periodically. This table is not inclusive of all of the campaigns that have occurred since 2004.
Location (Year) Belgium Organization Belgian Antibiotic Policy Coordination Committee1 Name of Campaign (Budget)* Antibiotics are ineffective for the common cold, acute bronchitis and flu Intervention Strategy Numerous interventions targeting wide demographics Various media types Seminars Academic workshops Distributes herbal remedies Website Numerous interventions targeting wide demographics Various media types Seminars Numerous interventions targeting wide demographics Various media types Seminars Numerous interventions targeting wide demographics Various media types Numerous interventions targeting wide demographics Various media types Seminars
(2000 Current) Germany (2007 Current) Greece
Private organization
(400 000/year) Informational campaign on antibiotic resistance Unavailable For the prudent use of antibiotics
Government - Department of Health
(2001 2003) Luxemburg
Government - Department of Health2
Unavailable Awareness campaign for the appropriate use of antibiotics (50 000/year) Antibiotics, use them in an adequate way (60 000/year) Antibiotics are not automatic
(2004 -2009) Portugal (2004 2007) France
Department of Health Numerous professional societies Industry (Pfizer)2 French Social Insurance System3
(2002 Current)
(4 million/year)
6.1-52
Location (Year) Italy: Emilia Romagna (2007 2008) England (2001 Current) Europe (2008 Current) Europe (2010 Current) United States (2003 Current) United States: Arkansas (2000 Current) Canada: British Columbia (2005 Current) Canada (1996 2006)
Organization Government - Department of Health2
Name of Campaign (Budget)* Project children and antibiotics for appropriate antibiotic use in children (227 500/year) Antibiotic campaign (600 000/year) European antibiotic awareness day (3 000/2009) e-Bug (1 865 358/2010 2013)6 Get smart: know when antibiotics work (US$ 1.6 million/2003) Save the antibiotic don't use it when you don't need it! (US$ 30 000/year) Do bugs need drugs?
Intervention Strategy Focus on prescribing behavior No mass media
Government - Department of Health2 EC WHO Others4 EC Health Protection Agency5 CDC7
Numerous interventions targeting wide demographics Various media types Numerous interventions targeting wide demographics Various media types Develop an interactive website geared towards schools Numerous interventions targeting wide demographics Various media types Academic programme
Government - Department of Health Private sponsor2 Government - Department of Health2
Numerous professional societies Industry (Pfizer)8
(CA$ 460 000/year) National information programme on antibiotics (CA$ 300 000/year)
Numerous interventions targeting wide demographics Various media types Seminars Various media types Letters
6.1-53
Location (Year) Australia
Organization Agency of the department of health9
Name of Campaign (Budget)* Common colds need common sense, not antibiotics (AU$ 800 000/2007) Antibiotic campaign Unavailable
Intervention Strategy Numerous interventions targeting wide demographics Various media types Academic workshops Numerous interventions targeting wide demographics Various media types
(2000 - 2008) Israel (2001, 03, & 06)
Health Organization Government10
* Budget costs are not current PPP adjusted. Budget costs are current year indicated within the parenthesis.
Sources:
1. 2. 3. 4. 5. 6. Borg MA. National cultural dimensions as drivers of inappropriate ambulatory care consumption of antibiotics in Europe and their relevance to awareness campaigns. The Journal of Antimicrobial Chemotherapy. 2012; 67:763-7. Huttner B, Goossens H, Verheij T, Harbarth S, consortium C. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. The Lancet Infectious Diseases. 2010; 10:17-31. Cars O. Defining the problem - an international perspective. [Presentation] Sydney, Australia: Action on Antibiotic Resistance (ReAct); 2011 [cited 6 July 2012]; Available from: www.antimicrobialsummit.com.au/images/pdfs/slides/otto_cars.pdf. Borg M, Zarb P. National Antibiotic Committee (NAC) annual report. [Report] 2009 [cited 6 July 2012]; Available from: https://ehealth.gov.mt/download.aspx?id=4664. Patel M. e-Bug Project Information. [Web Page]: European Commission (EC); [cited 12 July 2012]; Available from: http://www.ebug.eu/partners/partner_home.html. European Commission (EC). e-Bug - development and dissemination of a school antibiotic and hygiene education pack and website across Europe. [Web Page] [updated 1 March 2012; cited 11 July 2012]; Available from: http://ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/projects/034_en.html. Rudavsky S. Parents asked to fight overuse of antibiotics. Globe Newspaper Company; 7 October 2003 [cited 12 July 2012]; Available from: http://www.boston.com/yourlife/health/diseases/articles/2003/10/07/parents_asked_to_fight_overuse_of_antibiotics/.
7.
6.1-54
8. 9.
National Information Program on Antibiotics (NIPA). National report card on antibiotic resistance. [Newsletter]: Mount Sinai Hospital: Department of Microbiology; 2006 [cited 12 July 2012]; Available from: http://microbiology.mtsinai.on.ca/ic/nipa/2006NIPAreportcard.pdf. Weekes LM, Mackson JM, Artist MA, Wutzke S. An ongoing national programme to reduce antibiotic prescription and use. Microbiology Australia. 2007:3.
10. Hemo B, Shamir-Shtein NH, Silverman BG, Tsamir J, Heymann AD, Tsehori S, et al. Can a nationwide media campaign affect antibiotic use? The American Journal of Managed Care. 2009; 15:529-34.
6.1-55
Annex 6.1.6: Successful Campaigns for Prudent and Appropriate Antibiotic Use
The table presented below is a brief overview of campaigns targeted against AMR. The outcomes of these campaigns were considered successful if antibiotic consumption, antibiotic prescription, and or prevalence rates decreased.
Name of Campaign
Antibiotic management teams
1
Location
Belgium France France France Greece Luxembourg New Zealand Portugal Spain United States United States Israel
Year
2002 Current 1993 - Current 2001 - Current 2001 - Current 2001 - 2003 2004 - 2009 1999 - Current 2004 - 2007 2006 - 2008 1995 - 2002 2003 - Current 2007 - Current
Outcome
Successful implementation of AMR control strategies Reduced MRSA rates Reduced antibiotic consumption Reduced antibiotic prescription Decreased antibiotic prescription Decreased antibiotic use Decreased antibiotic prescription Decreased antibiotic consumption Decreased antibiotic consumption Decreased antibiotic prescription Decreased antibiotic prescription Decreased antibiotic prescription
Assistance Publique-Hpitaux de Paris MRSA control programme2 Keep Antibiotics Working3 Antibiotics are not automatic anymore4 For the prudent use of antibiotics5 Awareness campaign for the appropriate use of antibiotics5 Wise use of antibiotics5 Antibiotics, use them in an adequate way5 Campaign for the responsible use of antibiotics5 Campaign for the appropriate antibiotic use in the community5 Get smart: know when antibiotics work5 Task force on antimicrobial resistance and infection control5,
6
Sources:
1. Van Gastel E, Costers M, Peetermans WE, Struelens MJ, Hospital Medicine Working Group of the Belgian Antibiotic Policy Coordination Committee. Nationwide implementation of antibiotic management teams in Belgian hospitals: a self-reporting survey. The Journal of Antimicrobial Chemotherapy. 2010; 65:576-80. Jarlier V, Trystram D, Brun-Buisson C, Fournier S, Carbonne A, Marty L, et al. Curbing meticillin-resistant Staphylococcus aureus in 38 French hospitals through a 15-year institutional control program. Archives of Internal Medicine. 2010; 170:552-9.
2.
6.1-56
3. 4. 5. 6.
Sabuncu E, David J, Bernede-Bauduin C, Pepin S, Leroy M, Boelle PY, et al. Significant reduction of antibiotic use in the community after a nationwide campaign in France, 2002-2007. PLoS Medicine. 2009; 6:e1000084. Huttner B, Harbarth S. "Antibiotics are not automatic anymore"--the French national campaign to cut antibiotic overuse. PLoS Medicine. 2009; 6:e1000080. Huttner B, Goossens H, Verheij T, Harbarth S, Consortium C. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. The Lancet Infectious Diseases. 2010; 10:17-31. Schwaber MJ, Lev B, Israeli A, Solter E, Smollan G, Rubinovitch B, et al. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011; 52:848-55.
6.1-57
Annex 6.1.7: Examples of Diagnostics for Containing Antimicrobial Resistance

The table presented below offers a brief overview of several diagnostic tools. These tools may detect a specific pathogen, a specific strain or strains of a pathogen or distinguish between a viral and bacterial infection. This list is not comprehensive of all of the diagnostic tools currently available.
Product Name Manufacturer Pathogen(s) of Interest Turn Around Time Cost* (Year) 69.62 / test3 (2010) US$ 45.00 / assay5 (2006) US$ 37.50 / test1 (2011) US$ 16.86 / test8 (2011) 29.95 / test10 (2009) US$ 47.37 / test12 (2008) US$ 35.00 / test14 (2002) US$ 35 / test14 (2002) US$ 35 / test14 (2002) US$ 35 / test14 (2002)
GeneXpert System (Xpert MRSA) GeneXpert System (Xpert GBS) GeneXpert System (Xpert C. difficile) GeneXpert System (GeneXpert MTB/RIF Assay) SmartCycler System (Smart GBS) AMPLIFIED MTD Test (Mycobacterium Tuberculosis Direct) AccuProbe MYCOBACTERIUM TUBERCULOSIS Complex Culture Identification Test AccuProbe MYCOBACTERIUM AVIUM Complex Culture Identification Test AccuProbe MYCOBACTERIUM GORDONAE Culture Identification Test AccuProbe MYCOBACTERIUM KANSASII Culture Identification Test
Cepheid
MRSA
66 minutes or less1, 2
Cepheid
S. agalactiae (GBS)
30 minutes4
Cepheid
C. difficile
45 minutes6
Cepheid
M. tuberculosis complex Rifampicin resistance S. agalactiae (GBS) M. tuberculosis complex
128 minutes7
Cepheid Gen - Probe Inc.
26 hours9 3.5 hours11
Gen - Probe Inc.
M. tuberculosis complex
50 minutes13
Gen - Probe Inc.
M. avium
50 minutes13
Gen - Probe Inc.
M. gordonae
50 minutes13
Gen - Probe Inc.
M. kansasii
50 minutes13
6.1-58
Product Name
Manufacturer
Pathogen(s) of Interest
Turn Around Time
Cost* (Year) US$ 19.71 / specimen15 (2002) US$ 25.00 / test1 (2011) 56.22 / test3 (2010) US$ 27.00 / test1 (2011) US$ 35.00 / test19 (2008) 12.65 / test21 (2008) US$ 21.50 / test23 (2010) US$ 26.00 / test25 (2010) 12.71 / test21 (2008) 2.08 / test3 (2010) 6.00 / test21 (2008) 150-200 / test29 (2012) 4.04 / sample31 (2005)
AccuProbe GROUP B STREPTOCOCCUS Culture Identification Test ProGastro Cd Detection Kit BD GeneOhm MRSA ACP Assay BD GeneOhm Cdiff Assay BD GeneOhm StaphSR Assay Phoenix Automated Microbiology System BD ProbeTec ET System
Gen - Probe Inc.
S. agalactiae (GBS)
50 minutes13
Gen - Probe Inc. Becton -Dickinson Becton-Dickinson Becton-Dickinson Becton-Dickinson
C. difficile MRSA C. difficile C. difficile toxin B S. aureus MRSA Several bacterial and viral pathogens
3 hours1 2 hours16 1 hour17 2 hours18 12 hours20
Becton-Dickinson
C. trachomatis N. gonorrhoeae S. agalactiae (GBS) Several bacterial and viral pathogens MRSA Several bacterial pathogens Several bacterial and viral pathogens Several bacterial and viral pathogens
2 hours22
BD GeneOhm StrepB Assay Vitek Chromogenic agar (MRSA-ID) API system identification LightCycler SeptiFast Test MagNA Pure
Becton-Dickinson bioMrieux bioMrieux bioMrieux Roche Roche
1 hour24 5 8 hours21 18 hours26 24 hours27 6 hours28 5.5 hours30
6.1-59
Product Name
Manufacturer
Pathogen(s) of Interest
Turn Around Time
Cost* (Year) US$ 29.00 / test32 (2012) US$ 9.00 / test32 (2012) US$ 10.00 / test32 (2012) US$ 13.00 / test32 (2012) US$ 17.00 / test32 (2012) 1.43 / test21 (2008) US$ 35.00 / test34 (2011) 12.00 / test35 (2010) US$ 25.00 / test36 (2011) 15.00 / test37 (2011) US$ 14.46 / test38 (2010) US$ 54 / test14 (2002) US$ 45.00 / test41 (2012)
Alere BinaxNOW Legionella Urinary Antigen Card Alere PBP2a Test BinaxNOW S. aureus Test C. DIFF QUIK CHEK COMPLETE Alere BinaxNOW Antigen Card S. pneumoniae
Alere Inc. Alere Inc. Alere Inc. Alere Inc Alere Inc Bruker Daltonik GmbH GenoType
L. pneumophila S. aureus S. aureus C. difficile toxins A & B S. pneumoniae Several bacterial pathogens
15 minutes32 24 hours32 30 minutes32 30 minutes32 15 minutes32 6 minutes / 1 isolate21
Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry GenoType Mycobacterium CM/AS
M. tuberculosis complex 30 most common non-Tuberculosis mycobacteria species M. tuberculosis complex
5 hours33
Hyplex TBC PCR Test
BAG Health Care GmbH AusDiagnostics 3M
6 hours35
Easy-Plex Assay BacLite Rapid MRSA
12 Gram - positive pathogens MRSA
3 hours36 5 hours37
MicroScan 40 SI MicroSeq 500 System Verigene GP Blood Culture Nucleic Acid Test (BC-GP)
Siemens Applied Biosystems Nanosphere
Several bacterial and viral pathogens Several bacterial and viral pathogens Several various Gram - positive pathogens
48 hours38 1 -2 days39 4 hours40
6.1-60
* Costs are not current PPP adjusted. Costs are current year indicated within the parenthesis.
Sources:
1. 2. 3. Irvine B, Claremont BioSolutions. A fully integrated assay and platform for detecting Clostridium difficile. [Pamphlet]: International Innovation; 2011 [cited 12 July 2012]; Available from: https://www.claremontbio.com/v/vspfiles/downloadables/press/international_innovations_interview.pdf. Cepheid. Xpert MRSA - redefining active MRSA management. [Web Page] 2011 [cited 29 June 2012]; Available from: http://www.cepheid.com/tests-andreagents/clinical-ivd-test/xpert-mrsa/. Wassenberg MW, Kluytmans JA, Box AT, Bosboom RW, Buiting AG, van Elzakker EP, et al. Rapid screening of meticillin-resistant Staphylococcus aureus using PCR and chromogenic agar: a prospective study to evaluate costs and effects. Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2010; 16:1754-61. Cepheid. Xpert GBS - revolutionizing group B Streptococcus testing. [Web Page] 2011 [cited 12 July 2012]; Available from: http://www.cepheid.com/tests-andreagents/clinical-ivd-test/xpert-gbs/. Boschert S. Point-of-care group B Strep test gets approved. [Magazine Article]: www.familypracticenews.com; 15 September 2006 [cited 2 July 2012]; Available from: http://www.skinandallergynews.com/fileadmin/content_pdf/fpn/archive_pdf/vol36iss18/73867_main.pdf. Cepheid. Xpert C. difficile - detection of Clostridium difficile in 45 minutes. [Web Page] 2011 [cited 12 July 2012]; Available from: http://www.cepheid.com/tests-and-reagents/clinical-ivd-test/xpert-c-difficile. Miller MB, Popowitch EB, Backlund MG, Ager EP. Performance of Xpert MTB/RIF RUO assay and IS6110 real-time PCR for Mycobacterium tuberculosis detection in clinical samples. Journal of Clinical Microbiology. 2011; 49:3458-62. (WHO) WHO. Rapid implementation of the Xpert MTB/RIF diagnostic test - technical and operational 'How-to'; practical considerations. [Electronic Book] Geneva, Switzerland: WHO Press; 2011 [cited 12 July 2012]; Available from: http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf. Cepheid. Smart GBS - Better Group B Streptococcus answers. [Web Page] 2011 [cited 12 July 2012]; Available from: http://www.cepheid.com/tests-andreagents/clinical-ivd-test/smart-gbs.
4. 5. 6. 7. 8. 9.
10. Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness. Health Technology Assessment. 2009; 13:1-154, iii-iv. 11. Gen-Probe Incorporated. Amplified MTD (Mycobacterium Tuberculosis Direct) test. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.genprobe.com/global/products-services/amplified-mtd. 12. Guerra RL, Hooper NM, Baker JF, Alborz R, Armstrong DT, Kiehlbauch JA, et al. Cost-effectiveness of different strategies for amplified Mycobacterium tuberculosis direct testing for cases of pulmonary tuberculosis. Journal of Clinical Microbiology. 2008; 46:3811-2.
6.1-61
13. Gen-Probe Incorporated. Products & Services - Microbial Infectious Diseases - Culture Identification. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.gen-probe.com/global/products-services/culture-identification. 14. Cloud JL, Neal H, Rosenberry R, Turenne CY, Jama M, Hillyard DR, et al. Identification of Mycobacterium spp. by using a commercial 16S ribosomal DNA sequencing kit and additional sequencing libraries. Journal of Clinical Microbiology. 2002; 40:400-6. 15. Overman SB, Eley DD, Jacobs BE, Ribes JA. Evaluation of methods to increase the sensitivity and timeliness of detection of Streptococcus agalactiae in pregnant women. Journal of Clinical Microbiology. 2002; 40:4329-31. 16. Becton-Dickinson and Company. BD GeneOhm MRSA ACP Assay. [Web Page] Franklin Lakes, N J2012 [cited 12 July 2012]; Available from: http://www.bd.com/geneohm/english/products/mrsa/acpassay/. 17. Becton-Dickinson and Company. BD GeneOhm Cdiff Assay. [Web Page] Franklin Lakes, NJ2012 [cited 12 July 2012]; Available from: http://www.bd.com/geneohm/english/products/md/cdiff/. 18. Becton-Dickinson and Company. BD GeneOhm StaphSR Assay. [Web Page] Franklin Lakes, NJ2012 [cited 12 July 2012]; Available from: http://www.bd.com/geneohm/english/products/md/staphsr/. 19. Finn R. Clinical & practice management: rapid MRSA blood test gets green light from FDA. [Web Page]: American College of Emergency Physicians News; 2008 [cited 12 July 2012]; Available from: http://www.acep.org/content.aspx?id=35928. 20. Mittman SA, Huard RC, Della-Latta P, Whittier S. Comparison of BD Phoenix to Vitek 2, MicroScan MICroSTREP, and Etest for antimicrobial susceptibility testing of Streptococcus pneumoniae. Journal of Clinical Microbiology. 2009; 47:3557-61. 21. Seng P, Drancourt M, Gouriet F, La Scola B, Fournier PE, Rolain JM, et al. Ongoing revolution in bacteriology: routine identification of bacteria by matrixassisted laser desorption ionization time-of-flight mass spectrometry. Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2009; 49:543-51. 22. Noguchi Y. [Pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections]. Nihon Rinsho = Japanese Journal of Clinical Medicine. 2009; 67:173-6. 23. Duffy G. STI control strategy in Pacific island countries 2009-2013. [Discussion Paper]: Sexually Transmitted Infection Working Group; 2010 [cited 4 July 2012]; Available from: http://lyris.spc.int/read/attachment/69088/6/MWP_R7_H_Ph2_Discuss-Paper_STI-Test-Tx_Jan10_16Apr10.doc. 24. Becton-Dickinson and Company. BD GeneOhm StrepB Assay. [Web Page] Franklin Lakes, NJ2012 [cited 12 July 2012]; Available from: http://www.bd.com/geneohm/english/products/gbs/strepb/. 25. Riedlinger J, Beqaj SH, Milish MA, Young S, Smith R, Dodd M, et al. Multicenter evaluation of the BD Max GBS assay for detection of group B streptococci in prenatal vaginal and rectal screening swab specimens from pregnant women. Journal of Clinical Microbiology. 2010; 48:4239-41.
6.1-62
26. bioMerieux SA. chromID MRSA. [Web Page] 2012 [cited 12 July 2012]; Ava ilable from: http://www.biomerieux-diagnostics.com/servlet/srt/bio/clinicaldiagnostics/dynPage?open=CNL_CLN_PRD&doc=CNL_PRD_CPL_G_PRD_CLN_21&pubparams.sform=10&lang=en. 27. bioMerieux SA. bioMerieux Products - API features & specs. [Web Page] 2009 [cited 12 July 2012]; Available from: http://www.biomerieuxusa.com/servlet/srt/bio/usa/dynPage?open=USA_PRD_LST&doc=USA_PRD_LST_G_PRD_USA_5&pubparams.sform=0&lang=en. 28. Mancini N, Clerici D, Diotti R, Perotti M, Ghidoli N, De Marco D, et al. Molecular diagnosis of sepsis in neutropenic patients with haematological malignancies. Journal of Medical Microbiology. 2008; 57:601-4. 29. Afshari A, Schrenzel J, Ieven M, Harbarth S. Bench-to-bedside review: Rapid molecular diagnostics for bloodstream infection - a new frontier? Critical Care. 2012; 16:222. 30. Dubska L, Vyskocilova M, Minarikova D, Jelinek P, Tejkalova R, Valik D. LightCycler SeptiFast technology in patients with solid malignancies: clinical utility for rapid etiologic diagnosis of sepsis. Critical Care. 2012; 16:404. 31. Rours GI, Verkooyen RP, Willemse HF, van der Zwaan EA, van Belkum A, de Groot R, et al. Use of pooled urine samples and automated DNA isolation to achieve improved sensitivity and cost-effectiveness of large-scale testing for Chlamydia trachomatis in pregnant women. Journal of Clinical Microbiology. 2005; 43:4684-90. 32. Clinical Lab Products (CLP) Magazine. Tech Guide - Microbiology Testing Products. Allied Media; 2012 [cited 4 July 2012]; Available from: http://www.clpmag.com/issues/articles/2012-06_04.asp. 33. Hain Lifescience GmbH. Microbiology products - GenoType Mycobacterium CM/AS. [Web Page] [cited 12 July 2012]; Available from: http://www.hainlifescience.de/en/products/microbiology/mycobacteria/genotype-mycobacterium-cmas.html. 34. Ngeow YF, Wong YL, Ng KP, Ong CS, Aung WW. Rapid, cost-effective application of Tibilia TB rapid test for culture confirmation of live and heat-killed Mycobacterium tuberculosis. Journal of Clinical Microbiology. 2011; 49:2776-7. 35. Hofmann-Thiel S, Turaev L, Hoffmann H. Evaluation of the hyplex TBC PCR test for detection of Mycobacterium tuberculosis complex in clinical samples. BMC Microbiology. 2010; 10:95. 36. O'Sullivan M. Molecular diagnostics: clinical interpretation and impact. [Presentation]: Westmead Hospital, Centre for Infectious Diseases and Microbiology; 18 March 2011 [cited 12 July 2012]; Available from: http://www.cidmpublichealth.org/resources/pdf/symposiums/march-18-2011/matthew-osullivan.pdf. 37. Fwity B, Lobmann R, Ambrosch A. Evaluation of a rapid culture-based screening test for detection of meticillin resistant Staphylococcus aureus. Polish Journal of Microbiology / Polskie Towarzystwo Mikrobiologow = The Polish Society of Microbiologists. 2011; 60:265-8. 38. Barman P, Sengupta S, Singh S. Study of a novel method to assist in early reporting of sepsis from the microbiology laboratory. Journal of Infection in Developing Countries. 2010; 4:822-7.
6.1-63
39. Conway M. Rapid microbiology newsletter - identification of mycobacterium using 16S ribosomal DNA sequencing. [Newsletter] 2004 [cited 12 July 2012]; Available from: http://www.rapidmicro.org/04JanuaryNewsletter.pdf. 40. Anderson C, Kaul K, Voss B, Thomson RB. Evaluation of the Verigene Gram-Positive Blood Culture test (BC-GP). [Poster Presentation]: Nanosphere Incorporated; 2012 [cited 12 July 2012]; Available from: http://www.nanosphere.us/sites/nanosphere.us/files/literature/Anderson%20Poster%20ASM%202012.pdf. 41. Nanosphere. Company overview. [Presentation Slides] 2012 [cited 12 July 2012]; Available from: http://www.sec.gov/Archives/edgar/data/1105184/000119312512216667/d348931dex992.htm.
6.1-64
Annex 6.1.8: Antibiotic Resistant Streptococcus pneumonia trends in Europe, 2005 and 2010
These figures represent the burden of antimicrobial resistant S. pneumoniae trends in Europe in 2005 and 2010. Figure 1 Proportion of penicillins (R+I) resistant Streptococcus pneumoniae isolates in participating countries 2005 2010
This report has been generated from data submitted to TESSy, The European Surveillance System on 2012-07-04. Page: 1 of 1. The report reflects the state of submissions in TESSy as of 2012-07-04 at 16:00. (www.rivm.nl/earss)
6.1-65
Figure 2 Proportion of macrolides (R+I) resistant Streptococcus pneumoniae isolates in participating countries 2005 2010
Source: (Netherlands) RvVeM. European Antimicrobial Resistance Surveillance System (EARSS) database. [Database; Statistics] Bilthoven, Netherlands: RIVM; Available from: www.rivm.nl/earss.
6.1-66
Annex 6.1.9: Antibiotic Resistant Escherichia coli trends in Europe, 2005 and 2010
These figures represent the burden of antimicrobial resistant E. coli trends in Europe in 2005 and 2010. Figure 1 Proportion of fluoroquinolones (R+I) resistant Escherichia coli isolates in participating countries, 2005 and 2010 2005 2010
This report has been generated from data submitted to TESSy, The European Surveillance System on 2012-07-09. Page: 1 of 1. The report reflects the state of submissions in TESSy as of 2012-07-09 at 16:00
6.1-67
Figure 2 Proportion of carbapenems (R+I) resistant Escherichia coli isolates in participating countries, 2005 and 2010 2005 2010
6.1-68
Figure 3 Proportion of third generation cephalosporins (R+I) resistant Escherichia coli isolates in participating countries in 2005 and 2010 2005 2010
6.1-69
Figure 4 Proportion of resistant Escherichia coli isolates to third generation cephalosporins in participating countries in 2005 versus 2010
30.00%
25.00% Proportion of Resistant Isolates
20.00%
15.00%
10.00%
2005
2010
5.00%
0.00%
Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Luxembourg Malta Netherlands Norway Poland Portugal Romania Slovenia Spain Sweden United Kingdom Country This report has been generated from data submitted to TESSy, The European Surveillance System on 2012-07-04. Page: 1 of 1. The report reflects the state of submissions in TESSy as of 2012-07-04 at 16:00. (www.rivm.nl/earss) Source: (Netherlands) RvVeM. European Antimicrobial Resistance Surveillance System (EARSS) database. [Database; Statistics] Bilthoven, Netherlands: RIVM; Available from: www.rivm.nl/earss.
6.1-70
Annex 6.1.10: Meticillin Resistant Staphylococcus aureus trends in Europe, 2005 and 2010
These figures represent the burden of antimicrobial resistant S. aureus trends in Europe in 2005 and 2010. Figure 1 Proportion of meticillin resistant Staphylococcus aureus isolates in participating countries, 2005 and 2010 2005 2010
6.1-71
Figure 2 Proportion of meticillin resistant Staphylococcus aureus isolates in participating countries in 2005 versus 2010
70.0% 60.0% Proportion of Resistant Isolates 50.0% 40.0% 30.0% 2005 20.0% 10.0% 0.0% Austria Belgium Bulgaria Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Luxembourg Malta Netherlands Norway Poland Portugal Romania Slovenia Spain Sweden United Kingdom 2010
Country This report has been generated from data submitted to TESSy, The European Surveillance System on 2012-07-04. Page: 1 of 1. The report reflects the state of submissions in TESSy as of 2012-07-04 at 16:00. (www.rivm.nl/earss)
6.1-72
Figure 3 Trends in the proportion of meticillin resistant Staphylococcus aureus in Europe*1

60
Proportion of meticillin resistance in S. aureus
50
40 30 20 10 0 2004 2007 2010
Country
*Only countries reporting 500 cases or more per year were included.
Source: (Netherlands) RvVeM. European Antimicrobial Resistance Surveillance System (EARSS) database. [Database; Statistics] Bilthoven, Netherlands: RIVM; Available from: www.rivm.nl/earss.
6.1-73
Annex 6.1.11: Antibiotic Resistant Enterococcus faecium trends in Europe, 2005 and 2010
These figures represent the burden of antimicrobial resistant E. faecium trends in Europe in 2005 and 2010. Figure 1 Proportion of vancomycin resistant Enterococcus faecium isolates in participating countries, 2005 and 2010 2005 2010
6.1-74
Figure 2 Proportion of high level gentamicin resistant Enterococcus faecium isolates in participating countries, 2005 and 2010 2005 2010
6.1-75
Figure 3 Proportion of aminopenicillins (R+I) resistant Enterococcus faecium isolates in participating countries, 2005 and 2010 2005 2010
This report has been generated from data submitted to TESSy, The European Surveillance System on 2012-07-11. Page: 1 of 1. The report reflects the state of submissions in TESSy as of 2012-07-11 at 16:00 Sources: (Netherlands) RvVeM. European Antimicrobial Resistance Surveillance System (EARSS) database. [Database; Statistics] Bilthoven, Netherlands: RIVM; Available from: www.rivm.nl/earss.
6.1-76
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.12: Epidemiological Trends in the USA
These figures represent epidemiological trends of resistant bacterial pathogens and their respective antibiotics throughout the United States. The table provided provides a brief summary of AMR pathogens and their trends in the United States.
Figure 1 Resistance of meticillin-resistant Staphylococcus aureus isolates to clindamycin, ciprofloxacin, gentamicin and sulfamethoxazole / trimethoprim in outpatient areas of hospitals, United States, 199920061
6.1-77

Figure 2 Frequency of AMR among intensive care unit patients between the International Infection Control Consortium (INICC) study and U.S. National Healthcare Safety Network (NHSN), 2003 20082
90 80 70 Percent Resistance 60 50 40 30 20 10 0 S. aureus K. pneumoniae A. baumannii P. aeruginosa AMR Pathogen S. aureus isolates resistant to meticillin K. pneumonia isolates resistant to ceftazidime or ceftriaxone A. baumannii resistant to imipenem P. aeruginosa resistant to piperacillin INICC NHSN
6.1-78

Table 1 Epidemiological Trends in Multidrug Resistant Organisms in the United States3 Pathogen(s) of Interest Gram-positive MRSA Trend Increasing proportion of CA-MRSA strain USA3004,
5
Vancomycin resistant Enterococcus
C. difficile
Gram-negative bacilli ESBL producers K. pneumoniae carbapenemase producers NDM-1 producers
Decreasing rate of bloodstream infections for adults6, 7 No change in rate of bloodstream infections for children6 Overall rate of MRSA infection increasing for children8 Increasing prevalence among patients with inflammatory bowel disease for adults9 Outbreaks in pediatric ICUs with prevalence similar to that of adult ICUs for children10 Increasing incidence of healthcare-associated CDI for adults11 Increasing incidence of hospitalizations for children12 Increasing prevalence of community-associated clone ST131 for adults13 Endemic to northeastern U.S.A but incidence increasing nationwide for adults14 Five U.S.A cases have been reported to the CDC, all linked to travel or hospitalization in South Asia for adults First case in a pediatric patient reported in Los Angeles in April 201115
Sources 1. 2. Klein E, Smith DL, Laxminarayan R. Community-associated meticillin-resistant Staphylococcus aureus in outpatients, United States, 1999-2006. Emerging Infectious Diseases. 2009; 15:1925-30. Rosenthal VD, Maki DG, Jamulitrat S, Medeiros EA, Todi SK, Gomez DY, et al. International Nosocomial Infection Control Consortium (INICC) report, data summary for 2003-2008, issued June 2009. American Journal of Infection Control. 2010; 38:95-104 e2. Prabaker K, Weinstein RA. Trends in antimicrobial resistance in intensive care units in the United States. Current Opinion in Critical Care. 2011; 17:472-9. Freitas EA, Harris RM, Blake RK, Salgado CD. Prevalence of USA300 strain type of meticillinresistant Staphylococcus aureus among patients with nasal colonization identified with active surveillance. Infection Control and Hospital Epidemiology: the Official Journal of the Society of Hospital Epidemiologists of America. 2010; 31:469-75. Carey AJ, Della-Latta P, Huard R, Wu F, Graham PL, 3rd, Carp D, et al. Changes in the molecular epidemiological characteristics of meticillin-resistant Staphylococcus aureus in a neonatal intensive care unit. Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2010; 31:613-9.
3. 4.
5.
6.1-79

6. 7. Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S, Gershman K, et al. Health care-associated invasive MRSA infections, 2005-2008. Journal of the American Medical Association. 2010; 304:641-8. Burton DC, Edwards JR, Horan TC, Jernigan JA, Fridkin SK. Meticillin-resistant Staphylococcus aureus central line-associated bloodstream infections in US intensive care units, 1997-2007. Journal of the American Medical Association. 2009; 301:727-36. Gerber JS, Coffin SE, Smathers SA, Zaoutis TE. Trends in the incidence of meticillin-resistant Staphylococcus aureus infection in children's hospitals in the United States. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America. 2009; 49:65-71. Nguyen GC, Leung W, Weizman AV. Increased risk of vancomycin-resistant enterococcus (VRE) infection among patients hospitalized for inflammatory bowel disease in the United States. Inflammatory Bowel Diseases. 2011; 17:1338-42.
8.
9.
10. Milstone AM, Maragakis LL, Carroll KC, Perl TM. Targeted surveillance to identify children colonized with vancomycin-resistant Enterococcus in the pediatric intensive care unit. Infection Control and Hospital Epidemiology: the Official Journal of the Society of Hospital Epidemiologists of America. 2010; 31:95-8. 11. Dubberke ER, Butler AM, Yokoe DS, Mayer J, Hota B, Mangino JE, et al. Multicenter study of Clostridium difficile infection rates from 2000 to 2006. Infection Control and Hospital Epidemiology: the Official Journal of the Society of Hospital Epidemiologists of America. 2010; 31:1030-7. 12. Zilberberg MD, Tillotson GS, McDonald C. Clostridium difficile infections among hospitalized children, United States, 1997-2006. Emerging Infectious Diseases. 2010; 16:604-9. 13. Johnson JR, Johnston B, Clabots C, Kuskowski MA, Castanheira M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America. 2010; 51:286-94. 14. Kitchel B, Rasheed JK, Patel JB, Srinivasan A, Navon-Venezia S, Carmeli Y, et al. Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolates in the United States: clonal expansion of multilocus sequence type 258. Antimicrobial Agents and Chemotherapy. 2009; 53:3365-70. 15. Mochon AB, Garner OB, Hindler JA, Krogstad P, Ward KW, Lewinski MA, et al. New Delhi metallo-beta-lactamase (NDM-1)-producing Klebsiella pneumoniae: case report and laboratory detection strategies. Journal of Clinical Microbiology. 2011; 49:1667-70.
6.1-80
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.13: Epidemiological Trends in the World
These figures present the epidemiological trends of various antimicrobial resistant bacterial pathogens throughout various countries and regions in the world.
Figure 1 Rates of extended-spectrum -lactamase (ESBL)-producing Klebsiella pneumoniae strains amongst Asian countries1
Figure 2* Trends in the incidence of penicillin-resistant and penicillin-intermediate S. pneumoniae, 2000 -20092
* PISP: penicillin-intermediate S. pneumoniae
6.1-81

Figure 3** Trends in the prevalence of the predominant antimicrobial resistant bacteria in China, 2000 to 2009 (a) Gram-positive bacteria; (b) Gram-negative bacteria2
**MRSA: meticillin-resistant S. aureus; VRE: vancomycin-resistant enterococcus; PNSP: penicillin nonsusceptible S. pneumoniae; ESBL (+) EC: extended-spectrum -lactamase-producing E. coli; CPR-REC: ciprofloxacin-resistant E. coli; IMI-R PA: imipenem-resistant P. aeruginosa; IMI-R AB: imipenem-resistant A. baumannii.
6.1-82

Figure 4 Prevalence of antimicrobial resistance among respective bacterial pathogen and antibiotics in South Africa3
100 % Resistant: S. aureus 80 60 40 20 0
Antibiotic Tested 100 80 60 40 20 0
% Resistant: K pneumoniae
Antibiotics Tested 100 80 60 40 20 0
% Resistant P. aeruginosa
Antibiotics Tested
6.1-83

Sources:
1. 2. Jean SS, Hsueh PR. High burden of antimicrobial resistance in Asia. International Journal of Antimicrobial Agents. 2011; 37:291-5. Xiao YH, Giske CG, Wei ZQ, Shen P, Heddini A, Li LJ. Epidemiology and characteristics of antimicrobial resistance in China. Drug Resistance Updates : Reviews and Commentaries In Antimicrobial And Anticancer Chemotherapy. 2011; 14:236-50. Nyasulu P, Murray J, Perovic O, Koornhof H. Antimicrobial resistance surveillance among nosocomial pathogens in south africa - systematic review of published literature. Journal of Experimental and Clinical Medicine. 2012; 4:8-13.
3.
6.1-84
Annex 6.1.14: Examples of the Economic Impact of Antimicrobial Resistance

This table presents a brief summary of the economic impact of AMR. The economic impact of AMR may be attributed to direct costs, increased labor costs, increased hospital length of stay, additional treatment and or other factors.
Study Location Description United States1 Review; Presentation United States2. Review Pathogen of Interest Description Non-AMR versus AMR Several AMR pathogens MSSA versus MRSA Non-AMR versus AMR Infections MSSA versus MRSA Surgical Site Infections Susceptible Gram-negative versus Resistant Gram-negative HAI Control Treatment costs* (Year) US$ 15 104 per patient (2007) US$ 15 923 per patient (2004 2006) US$ 24 794 per patient (2009) US$ 75 353 per patient (2003) US$ 106 293 per patient (2008) Hospital LOS AMR Treatment costs* (Year) US$ 25 380 per patient (2007) US$ 34 657 per patient (2004 2006) US$ 53 863 per patient (2009) US$ 99 466 per patient (2003) US$ 144 414 per patient (2008) Hospital LOS Additional Burden Treatment costs* (% change) US$ 10 276 per patient (+ 40%) US$ 18 734 per patient (+ 54%) US$ 29 069 per patient (+ 54%) US$ 24 113 per patient (+ 25%) US$ 38 121 per patient (+ 29.3%)** Hospital LOS (% change) 4.3 days per patient (+ 47%) 10 days per patient (+ 66%) 11 days per patient (+ 46%) 5.6 days per patient (+ 23.6%) 5 days per patient (+ 23.8%)**
4.7 days per patient
9 days per patient
5 days per patient
15 days per patient
United States3 Primary
31 days per patient
36 days per patient
6.1-85
Study Location Description United States6 Primary Pathogen of Interest Description Non-AMR versus Vancomycin resistant (Enterococci)
Control Treatment costs* (Year) US$ 31 915 per patient (1993 1997) Hospital LOS
AMR Treatment costs* (Year) US$ 52 449 per patient (1993 1997) 13 days per patient US$ 80 500 per patient (1996 2000) 9 597 per patient (2005 2006) 29 days per patient Hospital LOS
Additional Burden Treatment costs* (% change) US$ 20 534 per patient (+ 39%) US$ 50 896 per patient (+ 63%) 5 614 per patient (+ 59%) 1 205.75 per patient (+ 11%) Unavailable Hospital LOS (% change) 6.2 days per patient (+ 73%) 16 days per patient (+ 55%) 13.9 days per patient (+ 36%) 2 days per patient (+ 8%) 29 days per patient (+ 80.5%) Unavailable
Spain8 Primary
Spain9 Primary
Susceptible Gram-negative versus Resistant Gram-negative Surgical Site Infections Non-AMR versus AMR P. aeruginosa MSSA versus MRSA Non-AMR versus AMR K. pneumoniae MRSA Outbreak in 32 hospitals
US$ 29 604 per patient (1996 2000) 3 983 per patient (2005 2006) 9 839.25 per patient (2006) Unavailable
39 days per patient
11 045 per patient (2006) Unavailable
Spain10 Primary
7 days per patient (2009) Unavailable
36 days per patient (2009) Unavailable
United11 Kingdom Primary Europe12 Primary
Unavailable
500 000 total costs (1991 1993) 44 million total (2007)
Unavailable
MRSA
Unavailable
Unavailable
255 683 days total
Unavailable
Unavailable
6.1-86
Study Location Description Europe12 Primary Europe13 Surveillance Data Pathogen of Interest Description Cephalosporin-resistant E. coli Third-generation Several AMR pathogens
Control Treatment costs* (Year) Unavailable Hospital LOS
AMR Treatment costs* (Year) 18.1 million total (2007) Unavailable Hospital LOS
Additional Burden Treatment costs* (% change) Unavailable Hospital LOS (% change) Unavailable
Unavailable
120 065 days total Unavailable
Unavailable
Unavailable
910 million per year ---------------1.5 billion total costs (2007) US$ 13 000 30 000 per patient (+ 50%) US$ 30 093 per patient (+ 57%) Unavailable
2.5 million days total
South Africa & United States Simulation Israel15 Primary
14
Non-MDR TB versus MDR TB (Conventional therapy) Non- ESBL versus ESBL (Enterobacteriaceae) Non-MDR versus MDR (P. aeruginosa)
US$ 13 000 - 30 000 per patient (1998) US$ 16 877 per patient (2000 2003) Unavailable
Unavailable
US$ 26 000-60 000 per patient (1998) US$ 46 970 per patient (2000 2003) Unavailable
Unavailable
Unavailable
5 days per patient
11 days per patient
6 days per patient (+ 56%) 10 days per patient (+ 50%)
Israel16 Primary
10 days per patient (2005)
20 days per patient (2005)
* Costs are not current PPP adjusted. Costs are current year indicated within the parenthesis. ** Multivariate analysis
6.1-87
Sources:
1. 2. Foster SD. The economic burden of antibiotic resistance evidence from three recent studies. 2010 Annual Conference on Antimicrobial Resistance; Bethesda, MD: National Academy Press; 2010. Filice GA, Nyman JA, Lexau C, Lees CH, Bockstedt LA, Como-Sabetti K, et al. Excess costs and utilization associated with meticillin resistance for patients with Staphylococcus aureus infection. Infection Control And Hospital Epidemiology : The Official Journal Of The Society Of Hospital Epidemiologists Of America. 2010; 31:365-73. Roberts RR, Hota B, Ahmad I, Scott RD, 2nd, Foster SD, Abbasi F, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America. 2009; 49:1175-84. Anderson DJ, Kaye KS, Chen LF, Schmader KE, Choi Y, Sloane R, et al. Clinical and financial outcomes due to meticillin resistant Staphylococcus aureus surgical site infection: a multi-center matched outcomes study. PloS One. 2009; 4:e8305. Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant Gram-negative bacteria. Antimicrobial Agents And Chemotherapy. 2010; 54:109-15. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and economic outcomes of vancomycin-resistant enterococci. Archives Of Internal Medicine. 2002; 162:2223-8. Evans HL, Lefrak SN, Lyman J, Smith RL, Chong TW, McElearney ST, et al. Cost of Gram-negative resistance. Critical Care Medicine. 2007; 35:89-95. Morales E, Cots F, Sala M, Comas M, Belvis F, Riu M, et al. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. BMC Health Services Research. 2012; 12:122. Rubio-Terres C, Garau J, Grau S, Martinez-Martinez L. Cost of bacteraemia caused by meticillin-resistant vs. meticillin-susceptible Staphylococcus aureus in Spain: a retrospective cohort study. Clinical Microbiology And Infection : The Official Publication Of The European Society Of Clinical Microbiology And Infectious Diseases. 2010; 16:722-8.
3.
4. 5. 6. 7. 8. 9.
10. Sanchez-Romero I, Asensio A, Oteo J, Munoz-Algarra M, Isidoro B, Vindel A, et al. Nosocomial outbreak of VIM-1-producing Klebsiella pneumoniae isolates of multilocus sequence type 15: molecular basis, clinical risk factors, and outcome. Antimicrobial Agents And Chemotherapy. 2012; 56:420-7. 11. Cox RA, Conquest C, Mallaghan C, Marples RR. A major outbreak of meticillin-resistant Staphylococcus aureus caused by a new phage-type (EMRSA-16). The Journal Of Hospital Infection. 1995; 29:87-106. 12. de Kraker ME, Davey PG, Grundmann H. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Medicine. 2011; 8:e1001104.
6.1-88
13. Norrby R, Powell M, Aronsson B, Monnet DL, Lutsar I, Bocsan IS. The bacterial challenge: time to react - a call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. [Joint Technical Report]: European Center for Disease Prevention and Control (ECDC) & European Medicines Agency (EMA); 2009 [cited 6 July 2012]; Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf. 14. Wilton P, Smith RD, Coast J, Millar M, Karcher A. Directly observed treatment for multidrug-resistant tuberculosis: an economic evaluation in the United States of America and South Africa. The International Journal Of Tuberculosis And Lung Disease : The Official Journal Of The International Union Against Tuberculosis And Lung Disease. 2001; 5:1137-42. 15. Schwaber MJ, Navon-Venezia S, Kaye KS, Ben-Ami R, Schwartz D, Carmeli Y. Clinical and economic impact of bacteremia with extended- spectrum-betalactamase-producing Enterobacteriaceae. Antimicrobial Agents And Chemotherapy. 2006; 50:1257-62. 16. Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrobial Agents And Chemotherapy. 2006; 50:43-8.
6.1-89
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.15: Activity Review of the European Commission on Antimicrobial Resistance
This table presents a review of the European Commissions activities concerning AMR. Activities include projects, publications, consultations, general communication, Eurobarometers, press documents, conferences and collaborative efforts.
Projects Project Title European Surveillance of Antimicrobial Consumption (ESAC I)2 European Antimicrobial Resistance Surveillance System (EARSS)3 European Committee on Antimicrobial Susceptibility Testing (EUCAST)4 Antibiotic Resistance and Prescribing in European Children (ARPEC)5 European Surveillance of Antimicrobial Consumption (ESAC II)2 Improving Patient Safety in Europe (IPSE)6 Implementing Antibiotic Strategies for Appropriate Use of Antibiotics in Hospitals in Member States of the European Union (ABS International)7 Burden of Disease and Resistance in European Nations8 Development and Dissemination of a School Antibiotic and Hygiene Education Pack and website across Europe (EBUG PACK)9 Publications Publication Title The European Community Strategy Against Antimicrobial Resistance10 Research strategy to address the knowledge gaps on the antimicrobial resistance effects of biocides11 2nd report from the Commission to the Council on the implementation of the Council Recommendation (2002/77/EC) on the prudent use of antimicrobial agents in human medicine12 Antimicrobial resistance surveillance in Europe 2009. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net)13 Antimicrobial resistance surveillance in Europe 2010. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net)14 Consultations Consultation Title Stakeholder Consultation on the Transatlantic Task Force on antimicrobial resistance15 Public Consultation on the SCENIHR preliminary report on Effects of the Active Substances in Biocidal Products on Antibiotic Resistance16 Call for information on assessment of the Antibiotic Resistance Effects of Biocides17 General Communication Title of Communication Communication from the Commission to the European Parliament and the Council - Action plan against the rising threats from Antimicrobial Resistance18 Video message from Commissioner Dalli - Conference: combatting Antimicrobial Resistance - Time for joint action19 Years Funded / EC Contribution* 2001 2004 / 533 440 2003 2006 / 734 142 2004 -2007 / 355 680 2009 2012 / 698 994 2004 2007 / 880 606 2005 2008 / 1 006 916 2005 2007 / 798 598 2007 2010 / 1 139 412 2005 2008 / 1 865 358
Year 2004 2010 2010
2010 2011
Year 2010 2008 2008
Year 2011
2012
6.1-90

Eurobarometers Title of Eurobarometer Year Les antibiotiques: EUROBAROMETER 58.220 2003 21 Antimicrobial Resistance: EUROBAROMETER 72.5 2010 Press Documents Title of Press Release Year EU acts to combat resistance to antibiotics22 2006 23 Employment, Social Policy, Health and Consumer Affairs Council 2008 Androulla Vassiliou, Member of the European Commission, responsible for 2008 24 Health, Europe for Patients, Launch for the ''Europe for Patients'' Campaign Androulla Vassiliou, Member of the European Commission, responsible for 2008 25 Health, Speech at the launch of the European Antibiotic Awareness Day EU Health Prize for Journalists26 2009 Launching the first EU health prize for journalists, part of the Europe for 2009 Patients campaign27 Winners of the EU Health Journalism Prize announced at an award ceremony 2009 in Brussels28 Commission paper lays foundations of discussion to tackle the problem of anti2009 29 microbial resistance Employment, Social Policy, Health and Consumer Affairs Council 30 2009 Almost 40% of Europeans are aware of the issue of overuse of antibiotics, says 2009 a survey31 World Health Day: fight against antimicrobial resistance must continue on a 2011 global scale32 Action Plan against antimicrobial resistance: Commission unveils 12 concrete 2011 actions for the next five years33 Preparation of Agriculture and Fisheries Council, 18 June 2012 - Antimicrobial 2012 34 Resistance and human health to be discussed EU Health Prize for Journalists - Ben Hirschler and Kate Kelland won 1st prize 2012 35 for their article on antimicrobial resistance. "When the drugs don't work" Conferences Title of Conference Year The Microbial Threat to Patient Safety in Europe 36 2009 37 Conference on Antimicrobial resistance 2010 Combating Antimicrobial Resistance - Time for Joint Action38 2012 Collaborative Efforts Name of Organization Year 39 Transatlantic task force on urgent antimicrobial resistance - TATFAR 2010 European Centre for Disease Prevention and Control 1 Several Efforts European Food Safety Authority1 Several Efforts * EC contributions are not current PPP adjusted. EC contributions are current year as indicated. Sources: 1. 2. European Commission (EC). Antimicrobial resistance policy. [Web Page] [cited 11 July 2012]; Available from: http://ec.europa.eu/health/antimicrobial_resistance/policy/index_en.htm. Goossens H. Update and highlights of the ESAC project. [Presentation] Belgium: University of Antwerp; 2007 [cited 6 July 2012]; Available from: www.esac.ua.ac.be/download.aspx?c=*ESAC2OUD&n=21750&ct=016020&e=35327. European Commission (EC). EARSS - The European antimicrobial resistance surveillance system. [Web Page] [updated 1 March 2012; cited 11 July 2012]; Available from:
3.
6.1-91

http://ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/projects/033_en.html. 4. European Commission (EC). EUCAST - European committee on antimicrobial susceptibility testing. [Web Page] [updated 1 March 2012; cited 11 July 2012]; Available from: http://ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/projects/039_en.html. Sharland M. Antibiotic resistance and prescribing in European children (ARPEC). [Project Summary]: European Commission (EC); 2009 [cited 11 July 2012]; Available from: http://ec.europa.eu/eahc/projects/database.html?prjno=20091101. European Commission (EC). IPSE - Improving patient safety in Europe. [Web Page] [updated 1 March 2012; cited 11 July 2012]; Available from: http://ec.europa.eu/research/health/infectiousdiseases/antimicrobial-drug-resistance/projects/052_en.html. European Commission (EC). ABS Iinternational - Implementing antibiotic strategies (ABS) for appropriate use of antibiotics in hospitals in member states of the European Union [Web Page]: Research & Innovation - Health; [updated 1 March 2012; cited 11 July 2012]; Available from: http://ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/projects/016_en.html. European Commission (EC). EU-funded FP6 research projects on antimicrobial drug resistance. [Electronic Book] Luxembourg: Publications Office of the European Union; 2010 [cited 21 July 2012]; Available from: http://ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/pdf/fp6-projects-amrd_en.pdf. European Commission (EC). e-Bug - development and dissemination of a school antibiotic and hygiene education pack and website across Europe. [Web Page] [updated 1 March 2012; cited 11 July 2012]; Available from: http://ec.europa.eu/research/health/infectious-diseases/antimicrobialdrug-resistance/projects/034_en.html.
5.
6.
7.
8.
9.
10. Bronzwaer S, Lonnroth A, Haigh R. The European community strategy against antimicrobial resistance. [Electronic Article] January 2004 [cited 21 July 2012]; Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=441. 11. Scientific committee on emerging and newly identified health risks (SCENIHR). Research strategy to address the knowledge gaps on the antimicrobial resistance efforts of biocides. [Electronic Article]: European Commission (EC); 2010 [cited 21 July 2012]; Available from: http://bookshop.europa.eu/is-bin/INTERSHOP.enfinity/WFS/EU-Bookshop-Site/en_GB//EUR/ViewPublication-Start?PublicationKey=NDAS09002. 12. European Commission (EC). The prudent use of antimicrobial agents in human medicine. 2010 [cited 21 July 2012]; Available from: http://ec.europa.eu/health/antimicrobial_resistance/docs/amr_report2_en.pdf. 13. European Centre for Disease Prevention and Control (ECDC). Annual report of the European Antimicrobial resistance surveillance network (EARS-Net). [Report] 2009 [cited 21 July 2012]; Available from: http://ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=580. 14. European Center for Disease Prevention and Control (ECDC). Annual report of the European antimicrobial resistance surveillance network (EARS-Net). [Report] 2010 [cited 21 July 2012]; Available from: http://ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=774. 15. Stakeholder consultation on the transatlantic task force on antimicrobial resistance (TATFAR). European Commission (EC); 23 February 2011 [cited 21 July 2012]; V3:[Available from: http://ec.europa.eu/health/antimicrobial_resistance/docs/antimicrobial_cons01_report_en.pdf.
6.1-92

16. Scientific committee on emerging and newly identified health risks (SCENIHR). Effects of the active substances in biocidal products on antibiotic resistance. [Report]: European Commission (EC); 2008 [cited 21 July 2012]; Available from: http://ec.europa.eu/health/archive/ph_risk/committees/04_scenihr/docs/scenihr_biocides_commen ts.pdf. 17. Scientific committee on emerging and newly identified health risks (SCENIHR). Effects of the active substances in biocidal products on antibiotic resistance. 4 November 2008 [cited 21 July 2012]; Available from: http://ec.europa.eu/health/archive/ph_risk/committees/04_scenihr/docs/scenihr_o_020.pdf. 18. Directorate general for health & consumers. Communication from the commission to the European parliament and the council - action plan against the rising threats from antimicrobial resistance. European Commission (EC); 2011 [cited 21 July 2012]; Available from: http://ec.europa.eu/dgs/health_consumer/docs/communication_amr_2011_748_en.pdf. 19. European Commission (EC). Antimicrobial resistance videos. 2012 [updated 20 July 2012; cited 21 July 2012]; Available from: http://ec.europa.eu/health/antimicrobial_resistance/videos/index_en.htm. 20. Eurobarometre Special. Les antibiotiques. European Commission (EC); November 2003 [cited 21 July 2012]; Available from: http://ec.europa.eu/public_opinion/archives/ebs/ebs_183.3_fr.pdf. 21. Eurobarometer. Antimicrobial resistance. European Commission (EC); April 2010 [cited 21 July 2012]; Available from: http://ec.europa.eu/health/antimicrobial_resistance/docs/ebs_338_en.pdf. 22. European Union (EU). EU acts to combat resistance to antibiotics. [Press Release]: Europa; 2006 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/06/323. 23. Council of the European Union. Employment, social policy, health and consumer affairs council. [Web Page] 2008 [cited 21 July 2012]; Available from: http://www.consilium.europa.eu/press/press-releases/employment,-social-policy,-health-andconsumer-affairs?BID=79&lang=en. 24. Vassiliou A. Launch for the ''Europe for patients'' campaign. [Speech] Brussels. 30 September 2008 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=SPEECH/08/475&format=HTML&aged= 0&language=EN. 25. Vassiliou A. Speech at the launch of the 1st European Antibiotic Awareness Day. 18 November 2008 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=SPEECH/08/628&format=HTML&aged= 0&language=EN&guiLanguage=en. 26. European Union (EU). EU health prize for journalists. 17 February 2009 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=MEMO/09/69&format=HTML&aged=0 &language=en. 27. European Commission (EC). Launching the first EU health prize for journalists, part of the Europe for patients campaign. [Press Release] 17 February 2009 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/09/272&format=HTML&aged=0&lan guage=EN&guiLanguage=en. 28. European Commission (EC). Winners of the EU Health Journalism Prize announced at an award ceremony in Brussels. [Press Release] 30 October 2009 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/09/1661&format=HTML&aged=0&la nguage=EN&guiLanguage=en.
6.1-93

29. European Commission (EC). Commission paper lays foundations of discussion to tackle the problem of anti-microbial resistance. [Press Release] 18 November 2009 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/09/1732&format=HTML&aged=0&la nguage=EN&guiLanguage=en. 30. European Commission (EC). Employment, social policy, health and consumer affairs council, 30 November and 1 December 2009, Brussels. [Press Release] 27 November 2009 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=MEMO/09/528&format=HTML&aged=0 &language=EN&guiLanguage=en. 31. European Commission (EC). Almost 40% of Europeans are aware of the issue of overuse of antibiotics, says a survey. [Press Release] 9 April 2010 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/10/412&format=HTML&aged=0&lan guage=EN&guiLanguage=en. 32. European Commission (EC). World Health Day: fight against antimicrobial resistance must continue on a global scale. [Press Release] 6 April 2011 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/11/448&format=HTML&aged=0&lan guage=EN&guiLanguage=en. 33. European Commission (EC). Action plan against antimicrobial resistance: Commission unveils 12 concrete actions for the next five years. [Press Release] 17 November 2011 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=IP/11/1359&format=HTML&aged=0&la nguage=EN&guiLanguage=en. 34. European Commission (EC). Preparation of agriculture and fisheries council, 18 June 2012. [Memo] 15 June 2012 [cited 21 July 2012]; Available from: http://europa.eu/rapid/pressReleasesAction.do?reference=MEMO/12/442&type=HTML. 35. European Commission (EC). EU Health Prize for Journalists - 2011 winners. [Web Page] 2012 [updated 19 July 2012; cited 21 July 2012]; Available from: http://ec.europa.eu/healtheu/journalist_prize/2011/winners/index_en.htm. 36. Ministry of Health of the Czech Republic. The microbial threat to patient safety in Europe conference. [Pamphlet] 15-16 April 2009 [cited 21 July 2012]; Available from: http://ec.europa.eu/health/ph_systems/docs/ev_20090415_en.pdf. 37. Seguridad del Paciente. International conference on patient safety: healthcare associate infection and antimicrobial resistance. [Web Page] 2010 [updated 2 March 2012; cited 21 July 2012]; Available from: http://www.seguridaddelpaciente.es/index.php/langen/informacion/eventos/international-conferences-patient-safety/v-conference.html. 38. Ministry of Health, EU-Commission. Combating antimicrobial resistance - time for joint action. [Conference] 14-15 March 2012 [cited 21 July 2012]; Available from: http://eu2012.dk/en/Meetings/Conferences/Mar/~/media/4FB3323763E54A009A75C0E2C89BFF1C. ashx. 39. European Commission (EC). Transatlantic task force on urgent antimicrobial resistance - TATFAR. [Web Page] 2010 [updated 20 July 2012; cited 21 July 2012]; Available from: http://ec.europa.eu/health/antimicrobial_resistance/policy/tatfar/index_en.htm.
6.1-94
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.16: Press Release of IMI's 223.7 Programme to Combat Antibiotic Resistance
This is the press release that describes the launch of IMIs 223.7 million programme against AMR.
6.1-95
Source: Initiative IM. IMI launches 223.7 million programme for combatting antibiotic resistance. Brussels2012 May 24 [cited 2012 8 June 2012]; Press Release]. Available from: http://www.imi.europa.eu/content/press-releases.
6.1-96
Annex 6.1.17: European Commission Funded FP7 Projects on Antimicrobial Resistance

This table provides a list of European Commission funded projects concerning AMR. The contributions listed are not representative of the total budget for each project but rather the contribution amount from the European Commission itself.
Project Title Multidrug resistance and the evolutionary ecology of insect immunity (EVORESIN)1 The Integron Cassette Dynamics and the Integrase Gene Expression (ICADIGE)2 Preserving old antibiotics for the future : assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics (AIDA)3 New antimicrobials (NAM)4 European multicenter network to evaluate pharmacokinetics, safety and efficacy of Meropenem in neonatal sepsis and meningitis (NEOMERO)5 Biofilm Alliance (BALI)6 Knowing the enemy: unravelling a novel regulatory system involved in bacterial virulence (CSS AND VIRULENCE)7 Impact of Specific Antibiotic Therapies on the prevalence of hUman host ResistaNt bacteria (SATURN)8 A comprehensive dissection of pneumococcal-host interactions (PNEUMOPATH)9 Translational research on combating antimicrobial resistance (TROCAR)10 Detecting and eliminating bacteria using information technologies (DEBUGIT)11 The Ecology of Antibiotic Resistance (ARISE)12 Integrated whole blood acoustophoresis and homogeneous nucleic acid detection cartridge for rapid sepsis diagnostics (ACUSEP)13 Nano-structured copper coatings, based on Vitolane technology, for antimicrobial applications (CUVITO)14 Revealing Antibiotic Resistance Evolution (RARE)15 An integrated tool-kit for the clinical evaluation of microbial detection and antibiotic susceptibility point-of-care testing technologies (TEMPOTEST-QC)16 Chips for Life (C4L)17 A stealth attack tool for preventing clinical drug resistance through a unique self-regenerating surface (BACATTACK)18 Training and Research AImed at Novel Antibacterial Solutions in Animals and People (TRAIN-ASAP)19 Years Funded / EC Contribution* 2010 2015 / 1 292 502 Unavailable / 193 594 2011 - 2016 / 5 999 860 2008 2012 / 1 425 693 2010 2013 / 5 900 000 2011 2016 / 2 999 709 2012 2016 / 100 000 2010 2014 / 5 999 436 2009 2012 / 2 999 839 2009 2012 / 2 999 444 2008 2011 / 6 414 915 2012 2017 / 1 900 000 2010 2013 / 2 870 410 2010 2013 / 1 000 000 2012 2016 / 100 000 2010 2013 / 3 064 462 2012 2014 / 2 876 300 2012 2015 / 2 990 698 2012 2015 / 3 515 586
6.1-97
Project Title Identification and validation of novel drug targets in Gram-negative bacteria by global search: a trans-system approach (ANTIPATHOGN)20 Investigating sRNAs as the master on/off switch of Vibrio cholerae virulence (VCSRNAHV)21 The effects of antibiotic administration on the emergence and persistence of antibiotic-resistant bacteria in humans and on the composition of the indigenous microbiotas at various body sites (ANTIRESDEV)22 Role of Biotransformation on the Dynamics of Antimicrobial Resistance (ROBODAR)23 Novel approaches to bacterial target identification, validation and inhibition (NABATIVI)24 New high-quality mined nanomaterials mass produced for plastic and wood-plastic nanocomposites (MINANO)25 The population biology of drug resistance: Key principles for a more sustainable use of drugs (PBDR)26 Development of new nanocomposites using materials from mining industry (NANOMINING)27 Tracing antimicrobial peptides and pheromones in amphibian skin (TAPAS)28 Membrane-active peptides across disciplines and continents: An integrated approach to find new strategies to fight bacteria, dengue virus and neurodegeneration (MEMPEPACROSS)29 Surface functionalization of cellulose matrices using cellulose embedded nano-particles (SURFUNCELL)30 Microbial translocation across host barriers (MICROTRANS)31 The role of peptidoglycan in bacterial cell physiology: from bacterial shape to host-microbe interactions (PGNFROMSHAPETOVIR)32 Preventing community and nosocomial spread and infection with MRSA ST 398 - instruments for accelerated control and integrated risk management of antimicrobial resistance (PILGRIM)33 Rendering environmental pathogens sensitive to antibiotics prior to infection (RESTORING SENSITIVIT)34 Occurrence, distribution and cost of antibiotic resistance in marine sediment bacteria (MARIBACT) 35
* EC contributions are not current PPP adjusted. EC contributions are current year as indicated by initial funding year.
Years Funded / EC Contribution* 2009 2013 / 5 943 961 2009 2011 / 50 000 2009 2013 / 5 368 088 2011 2015 / 100 000 2009 2013 / 5 506 000 2010 2013 / 1 494 447 2011 2016 / 2 272 403 2010 2013 / 1 800 000 2008 2013 / 900 000 2010 2014 / 181 800 2008 2012 / 5 472 795 2010 2015 / 1 499 710 2008 2013 / 1 650 000 2009 2011 / 2 993 824 2010 2014 / 100 000 2010 2013 / 45 000
6.1-98
Sources:
1. Rolff JO. Multidrug resistance and the evolutionary ecology of insect immunity (EVORESIN). [Web Page]: European Commission (EC) Community Research and Development Information Service (CORDIS); 2010-2015 [updated 26 June 2012; cited 12 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/96082_en.html. Rosso M-l. The integron cassette dynamics and the integrase gene expression (ICADIGE). [Web Page]: European Commission (EC); [updated 4 June 2012; cited 12 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/103886_en.html. Van Oijen W. Preserving old antibiotics for the future : assessment of clinical efficacy by a harmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics (AIDA). [Web Page]: European Commission (EC); 2011-2016 [updated 31 May 2012; cited 12 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/101361_en.html. Risteli L. New antimicrobials (NAM). [Web Page]: European Commission; 2008-2012 [updated 25 May 2012; cited 12 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/86714_en.html. Faggion S. European multicenter network to evaluate pharmacokinetics, safety and efficacy of Meropenem in neonatal sepsis and meningitis (NEOMERO). [Web Page]: European Commission; 2010-2013 [updated 4 June 2012; cited 12 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/93635_en.html. Groen FJM. Biofilm alliance (BALI). [Web Page]: European Commission; 2011-2016 [updated 18 April 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/102212_en.html. Jimenez-Arroyo E. Knowing the enemy: unravelling a novel regulatory system involved in bacterial virulence (CSS AND VIRULENCE). [Web Page]: European Commission; 2012-2016 [updated 7 March 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/102703_en.html. Harbarth SJ. Impact of specific antibiotic therapies on the prevalence of human host resistant bacteria (SATURN). [Web Page]: European Commission; 2010-2014 [updated 5 March 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/92565_en.html. Adams M. A comprehensive dissection of pneumococcal-host interactions (PNEUMOPATH). [Web Page]: European Commission (EC); 2009-2012 [updated 29 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/91044_en.html.
2. 3.
4. 5. 6. 7. 8. 9.
10. Gomis R. Translational research on combating antimicrobial resistance (TROCAR). [Web Page]: European Commission (EC); 2009-2012 [updated 21 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/88877_en.html. 11. Verguts J. Detecting and eliminating bacteria using information technologies (DEBUGIT). [Web Page]: European Commission; 2008-2011 [updated 21 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/85484_en.html. 12. Kishony R. The ecology of antibiotic resistance (ARISE). [Web Page]: European Commission; 2012-2017 [updated 8 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/101427_en.html.
6.1-99
13. Sarkilahti E. Integrated whole blood acoustophoresis and homogeneous nucleic acid detection cartridge for rapid sepsis diagnostics (ACUSEP). [Web Page]: European Commission; 2010-2013 [updated 1 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/97060_en.html. 14. McConnell D. Nano-structured copper coatings, based on Vitolane technology, for antimicrobial applications (CUVITO). [Web Page]: European Commission; 2010-2013 [updated 1 February 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/97537_en.html. 15. Eran A. Revealing antibiotic resistance evolution (RARE). [Web Page]: European Commission; 2012-2016 [updated 31 January 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/97537_en.html. 16. Van Der Velden R. An integrated tool-kit for the clinical evaluation of microbial detection and antibiotic susceptibility point-of-care testing technologies (TEMPOTEST-QC). [Web Page]: European Commission; 2010-2013 [updated 26 January 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/93642_en.html. 17. Leclipteux T. Chips for life (C4L). [Web Page]: European Commission; 2012-2014 [updated 22 December 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/102035_en.html. 18. Lejre A-lH. A stealth attack tool for preventing clinical drug resistance through a unique self-regenerating surface (BACATTACK). [Web Page]: European Commission; 2012-2015 [updated 19 December 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/101807_en.html. 19. Kristoffersen I. Training and research aimed at novel antibacterial solutions in animals and people (TRAIN-ASAP). [Web Page]: European Commission; 20122015 [updated 14 December 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/101660_en.html. 20. Schustakowitz K. Identification and validation of novel drug targets in Gram-negative bacteria by global search: a trans-system approach (ANTIPATHOGN). [Web Page]: European Commission; 2012-2015 [updated 1 December 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/91036_en.html. 21. Bartle E. Investigating sRNAs as the master on/off switch of Vibrio cholerae virulence (VCSRNAHV). [Web Page]: European Commission; 2009-2011 [updated 31 October 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/92827_en.html. 22. Wilson M. The effects of antibiotic administration on the emergence and persistence of antibiotic-resistant bacteria in humans and on the composition of the indigenous microbiotas at various body sites (ANTIRESDEV). [Web Page]: European Commission; 2009-2013 [updated 12 October 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/92468_en.html. 23. Akman ML. Role of biotransformation on the dynamics of antimicrobial resistance (ROBODAR). [Web Page]: European Commission; 2011-2015 [updated 12 October 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/99976_en.html. 24. Pedrazzi MR. Novel approaches to bacterial target identification, validation and inhibition (NABATIVI). [Web Page]: European Commission; 2009-2013 [updated 21 September 2012; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/90762_en.html.
6.1-100
25. Heino J. New high-quality mined nanomaterials mass produced for plastic and wood-plastic nanocomposites (MINANO). [Web Page]: European Commission; 2010-2013 [updated 24 August 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/98066_en.html. 26. Bonhoeffer LS. The population biology of drug resistance: key principles for a more sustainable use of drugs (PBDR). [Web Page]: European Commission; 20112016 [updated 26 July 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/99462_en.html. 27. Rozwalka T. Development of new nanocomposites using materials from mining industry (NANOMINING). [Web Page]: European Commission (EC); 2010-2013 [updated 8 June 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/99312_en.html. 28. Bossuyt F. Tracing antimicrobial peptides and pheromones in the amphibian skin (TAPAS). [Web Page]: European Commission (EC); 2008-2013 [updated 16 March 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/88362_en.html. 29. Pinta-Gago M. Membrane-active peptides across disciplines and continents: An integrated approach to find new strategies to fight bacteria, dengue virus and neurodegeneration (MEMPEPACROSS). [Web Page]: European Commission (EC); 2010-2014 [updated 15 February 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/96370_en.html. 30. Ribitsch V. Surface functionalisation of cellulose matrices using cellulose embedded nano-particles (SURFUNCELL). [Web Page]: European Commission (EC); 2008-2012 [updated 28 January 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/89660_en.html. 31. Lecuit M. Microbial translocation across host barriers (MICROTRANS). [Web Page]: European Commission; 2010-2015 [updated 24 January 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/96590_en.html. 32. Boneca I. The role of peptidoglycan in bacterial cell physiology: from bacterial shape to host-microbe interactions (PGNFROMSHAPETOVIR). [Web Page]: European Commission (EC); 2008-2013 [updated 11 January 2011; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/87435_en.html. 33. Stark K. Preventing community and nosocomial spread and infection with MRSA ST 398 - instruments for accelerated control and integrated risk management of antimicrobial resistance (PILGRIM). [Web Page]: European Commission (EC); 2009-2011 [updated 7 October 2010; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/88867_en.html. 34. Ron E. Rendering environmental pathogens sensitive to antibiotics prior to infection (RESTORING SENSITIVIT). [Web Page]: European Commission (EC); 20102014 [updated 24 September 2010; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/96103_en.html. 35. Edgren L. Occurrence, distribution and cost of antibiotic resistance in marine sediment bacteria (MARIBACT). [Web Page]: European Commission (EC); 20102013 [updated 4 June 2010; cited 13 July 2012]; Available from: http://cordis.europa.eu/projects/rcn/94587_en.html
6.1-101
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.18: Activity Review of the WHO and Antimicrobial Resistance
This table provides a summary of the activities conducted by the WHO concerning AMR. These efforts and activities include events, publications and policy briefs.
Events1 Title of Event The 4th Session of the Codex ad hoc Intergovernmental Task Force on Antimicrobial Resistance 2nd meeting of the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (WHO AGISAR) The 3rd Session of the Codex ad hoc Intergovernmental Task Force on Antimicrobial Resistance First Meeting of the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) Global Patient Safety Challenge: Tackling Antimicrobial Resistance. Third International Consultation on Antimicrobial Resistance Global Patient Safety Challenge: Tackling Antimicrobial Resistance. Second International Consultation on Antimicrobial Resistance Global Patient Safety Challenge: Tackling Antimicrobial Resistance. First International Consultation on Antimicrobial Resistance The 2nd session of the Codex ad hoc Intergovernmental Task Force on Antimicrobial Resistance Publications Title of Publication The evolving threat of antimicrobial resistance - Options for action2 WHO Guidelines on Hand Hygiene in Health Care3 Core Components for Infection Prevention and Control Programmes. Report of the Second Meeting of the Informal Network on Infection Prevention and Control in Health Care4 Medicines Use in Primary Care in Developing Countries: Fact Book summarizing Results from Studies Reported between 1990 and 20065 Community Based Surveillance of Antimicrobial Use and Resistance in Resource Constrained Settings: Report on Five Pilot Projects6 Progress report on 2007 Rational Use of Medicines Resolution7 Joint WHO CDC Conference on Health Laboratory Quality Systems8 Policy and procedures of the WHO/NICD Microbiology External Quality Assessment Programme in Africa9 How to Improve the Use of Medicines by Consumers10 WHO Operational Package for Assessing, Monitoring and Evaluating Country Pharmaceutical Situations11 Secretariats report on RUM12 Progress report: WHA A60/28 Progress reports on technical and health matters Improving the containment of antimicrobial resistance13 Discussion: Report on Progress of Implementation of Resolution on Antimicrobial Resistance adopted by the Assembly in 200514 Resolution WHA: 10.1615 Developing Pharmacy Practice: A Focus on Patient Care16 Resolution WHA: 58.2715 Year 2010 2010
2009 2009 2009 2009 2008 2008
Year 2012 2009 2009
2009 2009 2009 2008 2007 2007 2007 2007 2007 2007 2007 2006 2005
6.1-102

Policy Briefs Fact sheet N255: Campylobacter17 Policy Package To Combat Antimicrobial Resistance18 Ensure uninterrupted access to essential medicines of assured quality19 Commit to a comprehensive, financed national plan with accountability and civil Society engagement20 Strengthen surveillance and laboratory capacity21 Regulate and promote rational use of medicines, including in animal husbandry and ensure proper patient care22 Reduce use of antimicrobials in food-producing animals23 Enhance infection prevention and control24 Foster innovations and research and development for new tools25 Year 2011 2011 2011 2011 2011 2011 2011 2011 2011
Sources:
1. World Health Organization (WHO). WHO Meetings: Antimicrobial Resistance. [Web Page]: WHO Press; 2012 [cited 12 July 2012]; Available from: http://www.who.int/drugresistance/AMR_DC_WHO_Meetings/en/index.html. Grayson ML, Heymann D, Pittet D, Grundmann H, OBrien TF, Stelling JM, et al. The evolving threat of antimicrobial resistance. [Electronic Book] Geneva, Switzerland: World Health Organization (WHO) Press; 2012 [cited 11 July 2012]; Available from: http://whqlibdoc.who.int/publications/2012/9789241503181_eng.pdf. World Health Organization (WHO). WHO guidelines on hand hygiene in health care: first global patient safety challenge - clean care is safer care. [Electronic Book]: 12 July 2012; 2009; Available from: http://whqlibdoc.who.int/publications/2009/9789241597906_eng.pdf. World Health Organization (WHO). Report of the second meeting informal network on infection prevention and control in health care. [Electronic Report] Geneva, Switzerland: WHO Document Production Services; 2008 [cited 21 July 2012]; Available from: http://www.who.int/drugresistance/DC_Infection_Prevention/en/index.html. World Health Organization (WHO). Medicines use in primary care in developing and transitional countries. [Electronic Book]: WHO Press; 2009 [cited 12 July 2012]; Available from: http://apps.who.int/medicinedocs/documents/s16073e/s16073e.pdf. World Health Organization (WHO). Community-based surveillance of antimicrobial use and resistance in resource-constrained settings - report on five pilot projects. [Electronic Book] Geneva, Switzerland: WHO Press; 2009 [cited 12 July 2012]; Available from: http://www.who.int/drugresistance/DC_Antimicrobial_Resistance/en/index1.html. Sixty-Second World Health Assembly. Progress report on 2007 rational use of medicines resolution. Geneva, Switzerland: World Health Organization Press; 9 April 2009 [cited 12 July 2012]; Available from: http://www.who.int/drugresistance/AMR_DC_Resolutions/en/index.html. World health Organization (WHO). Joint WHOCDC conference on health laboratory quality systems. [Conference Procedings] Lyon, France. 2008 [cited 12 July 2012]; Available from: http://www.who.int/drugresistance/DC_Antimicrobial_Resistance/en/index1.html. World Health Organization (WHO). Policies and procedures of the WHO/NICD microbiology external quality assessment programme in Africa. [Electronic Book]: WHO Press; 2007 [cited 12 July 2012]; Available from: http://whqlibdoc.who.int/hq/2007/who_cds_epr_lyo_2007.3_eng.pdf.
2.
3.
4.
5.
6.
7.
8.
9.
10. Chetley A, Hardon A, Hodgkin C, Haaland A, Fresle D. How to improve the use of medicines by consumers. [Electronic Book] Geneva, Switzerland: World Health Organization Press; 2007 [cited 12 July 2012]; Available from: www.who.int/drugresistance/Manual2_HowtoImprove.pdf.
6.1-103

11. World Health Organization (WHO). WHO Operational package for assessing, monitoring and evaluating country pharmaceutical situations - guide for coordinators and data collectors. [Electronic Book] Geneva, Switzerland: WHO Press; 2007 [cited 12 July 2012]; Available from: http://apps.who.int/medicinedocs/documents/s14877e/s14877e.pdf. 12. World Health Organization (WHO). Progress in the rational use of medicines. [Conference Report] Geneva, Switzerland: WHO Press; 22 March 2007 [cited 12 July 2012]; Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA60/A60_24-en.pdf. 13. World Health Organization (WHO). Sixtieth World Health Assembly - progress reports on technical and health matters. Geneva, Switzerland: WHO Press; 5 April 2007 [cited 12 July 2012]; Available from: http://apps.who.int/medicinedocs/index/assoc/s16339e/s16339e.pdf. 14. World Health Organization (WHO). Discussion: Report on progress of implementation of resolution on antimicrobial resistance adopted by the assembly in 2005. Geneva, Switzerland: WHO Press; 2007 [cited 21 July 2012]; Available from: http://soapimg.icecube.snowfall.se/stopresistance/Report%20on%20progress%20impl%20amr.pdf. 15. World Health Organization (WHO). Sixtieth World Health Assembly - resolution WHA 60.16: progress in the rational use of medicines. Geneva, Switzerland: WHO Press; 23 May 2007 [cited 21 July 2012]; Available from: http://apps.who.int/gb/ebwha/pdf_files/WHASSA_WHA60Rec1/E/reso-60-en.pdf#page=27. 16. Wiedenmayer K, Summers RS, Mackle CA, Gous AGS, Everard M, Tromp D. Developing pharmacy practice - a focus on patient care. [Handbook] The Netherlands: World Health Organization & International Pharmaceutical Federation; 2006 [cited 21 July 2012]; Available from: http://apps.who.int/medicinedocs/en/m/abstract/Js14094e/. 17. (WHO) WhO. Fact sheet N255 - Campylobacter. [Web Page]: WHO Press; October 2011 [cited 12 July 2012]; Available from: http://www.who.int/mediacentre/factsheets/fs255/en/index.html. 18. World Health Organization (WHO). World Health Day - policy package to combat antimicrobial resistance. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/world-health-day/2011/presskit/WHDIntrototobriefs.pdf. 19. World Health Organization (WHO). World Health Day - ensure uninterrupted access to essential medicines of assured quality. [Pamphlet]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/entity/world-health-day/2011/presskit/whd2011_fs3_essmed.pdf. 20. World Health Organization (WHO). World Health Day - commit to a comprehensive, financed national plan with accountability and civil society engagement. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/entity/world-healthday/2011/presskit/whd2011_fs1_natplan.pdf. 21. World Health Organzation (WHO). World Health Day - strengthen surveillance and laboratory capacity. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/entity/world-health-day/2011/presskit/whd2011_fs2_labcapa.pdf. 22. World Health Organization (WHO). World Health Day - regulate and promote rational use of medicines, including in animal husbandry, and ensure proper patient care. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/world-healthday/2011/presskit/whd2011_fs4_animal.pdf. 23. World Health Organization (WHO). World Health Day - reduce use of antimicrobials in foodproducing animals. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/world-health-day/2011/presskit/whd2011_fs4d_subanimal.pdf. 24. World Health Organization (WHO). World Health Day - enhance infection prevention and control. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/world-health-day/2011/presskit/whd2011_fs5_prevcontr.pdf.
6.1-104

25. World Health Organization (WHO). World Health Day - foster innovations and research and development for new tools. [Policy Brief]: WHO Press; 7 April 2011 [cited 12 July 2012]; Available from: http://www.who.int/world-health-day/2011/presskit/whd2011_fs6_newtool.pdf.
6.1-105
Annex 6.1.19: Examples of Concerted Action Addressing Antimicrobial Resistance in Europe

This table presents a brief summary of concerted efforts to address AMR. These efforts are not inclusive of the efforts that have been taken since 2004.
Participant EC1 Location Europe Initiative Name / Founding Year (Annual Budget / Year)* ESAC / 2004 (2 201 516 / 2004 - 2007) EARS-Net / 2004 (4.9 million / 2010) Think-Tank Group / 2004 Unavailable EPRUMA / 2005 Unavailable ECDC / 2005 (50 million / 2010)2 Joint Working Group / 2008 (46 000 / 2008) IMI / 2008 (2 billion / 2008 2017) TATFAR / 2009 Unknown ARPEC / 2009 (698 994 / 2009 2012) Purpose / Action Consolidate the continuous collection of comprehensive antibiotic consumption data Perform surveillance in Europe concerning AMR and the health threats it poses to humans Encourage stakeholders to casually discuss their perspectives concerning antibiotic R & D Promote collaboration amongst different stakeholders Encourage prudent use of antibiotics in animals Develop and implement best practices for both animal and public health Identify, assess and communicate human related health threats Enhance Europes defense system against such threats Formally produce a report concerning AMR and the gaps in antibiotic R & D Propose recommendations to address AMR Stimulate drug R & D in Europe through private-public partnerships Provide the necessary resources for drug R & D Encourage international collaboration to combat AMR Formulate recommendations concerning AMR Provide opportunities for stakeholder collaboration AMR and antibiotic consumption surveillance targeted towards European children Better understand AMR in the younger population
European Parliament EC2 EMA CHMP3 EU EISA Others4 EU (27 member states) EEA (three countries)5 ECDC EMA ReAct6 EU EFPIA7 US Health and Human Services EC Others8 EC ESPID Others9
Europe
Europe
Europe
Europe
Europe
Europe
United States Europe Europe
6.1-106
Participant SWAB ECDC Professional societies10 EU EFPIA
Location Europe
Initiative Name / Founding Year (Annual Budget / Year)* E-learning module / 2010 Unavailable
Purpose / Action Develop an e-learning tool to promote continuous education about AMR and prudent antibiotic use Stimulate antimicrobial drug development Stimulate antimicrobial development pipeline Present collaborative opportunities between the public and private sector
Europe
IMI / 2008
(2 billion / 2008 -2017)
*Budget costs are not current PPP adjusted. Budget costs are current year indicated within the parenthesis.
Sources:
1. 2. 3. 4. 5. 6. 7. Goossens H. Update and highlights of the ESAC project. [Presentation] Belgium: University of Antwerp; 2007 [cited 6 July 2012]; Available from: www.esac.ua.ac.be/download.aspx?c=*ESAC2OUD&n=21750&ct=016020&e=35327. European centre for Disease Prevention and Control (ECDC). Transparency. 2012 [cited 12 July 2012]; Available from: http://ecdc.europa.eu/en/aboutus/transparency/Pages/Transparency.aspx. Eurpoean Medicines Agency (EMA). Medicines and emerging science. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000339.jsp&mid=WC0b01ac05800baed8. European Platform for the Responsible Use of Medicines in Animals (EPRUMA). [Web Page]: IFAH-Europe; 2010 [cited 12 July 2012]; Available from: http://www.epruma.eu/. European Center for Disease Prevention and Control (ECDC). [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.ecdc.europa.eu/en/Pages/home.aspx. SE-Stockholm: produce a report on the gap between multidrug-resistant bacteria in the EU and development of novel antibacterial medicinal products. Supplement to the Official Journal of the European Union. 2008; S179:3. European Commission (EC). Innovative Medicines Initiative (IMI). 2010 [cited 12 July 2012]; Available from: http://www.imi.europa.eu/content/mission.
6.1-107
8.
Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Recommendations for future collaboration between the U.S. and EU. TATFAR. [Electronic Book]: The European Centre for Disease Prevention and Control (ECDC); 2011 [cited 18 July 2012]; Available from: http://ecdc.europa.eu/en/activities/diseaseprogrammes/tatfar/pages/index.aspx. Welcome to Antibiotic Resistance and Prescribing in European Children (ARPEC). [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.arpecstudy.eu/.
9.
10. (SWAB) SWA. E-learning module. [Web Page] 2011 [cited 12 July 2012]; Available from: http://www.swab.eu/landingpages/swab.
6.1-108
Annex 6.1.20: Examples of Public Private Partnerships Concerning Antimicrobial Resistance

This table presents several examples of public private partnerships that have been formed to address the issue of AMR. These collaborative efforts address AMR from multiple perspectives such as the development of new antimicrobials, diagnostics, open platforms and other efforts.
Location Netherlands1 Europe2 United Kingdom3 Public Organization Government Affiliates (Benefactor) EC* (Benefactor) National Government (Benefactor) Institute for the Promotion of Innovation by Science and Technology in Flanders (Benefactor) OSEO Innovation (Benefactor) TATFAR University Medical Center Groningen & Erasmus University Medical Center Erasmus Medical Center, University Medical Center Groningen & University Medical Center Utrecht Private Organization Pfizer (Recipient) Unavailable Unavailable Amount** (Year Issued) 7.95 million (2012) 223.7 million (2012) 500,000 (2012) Purpose Develop anti-infectives as an alternative to antibiotics for animals IMI has issued its annual call for proposals to develop tools against antimicrobial resistance Research relating to extended spectrum lactamases
Netherlands4
arGEN-X (Recipient)
1.3 million (2011)
Research and development of human monoclonal antibodies from the SIMPLE Antibody platform
France5 Europe & United States6 Europe7
Deinove (Recipient) Unavailable TI Pharma / Pepscan Therapeutics
US$ 1.8 million (2010) Unavailable (2009) 600 000 (2012)
Research and development for multidrug-resistant infections Publicize funding opportunities to EU & United States research communities Identification of immunodominant cell surface-exposed targets in multidrug-resistant bacterial pathogens
Europe8
TI Pharma / IQ Corporation, Pepscan Presto BV
Unavailable (2007)
Develop a medicine that attacks MRSA on several fronts
6.1-109
Location
Public Organization Biomedical Advanced Research and Development Authority (Benefactor) NIAID (Benefactor) NIAID (Benefactor) NIAID (Benefactor) NIAID (Benefactor) Department of Defense (Benefactor) Department of Health and Human Services (Benefactor) Department of Defense (Benefactor) Council for Scientific and Industrial Research (Benefactor) More than 25 groups (Benefactor)
Private Organization
Amount** (Year Issued) US$ 94 million (2011) US$ 3.8 million (2011) US$ 299 867 (2011) US$ 151 529 (2011) US$ 828 940 (2011) US$ 29.5 million (2010) US$ 64 million (2010) US$ 41 million (2007) US$ 12 million (2008) US$ 70 million (2003)
Purpose
United States9 United States10 United States11 United States11 United States11 United States12 United States13 United States14 India15 World16
GlaxoSmithKline (Recipient) Sequella (Recipient) Novobiotic Pharmaceuticals, LLC (Recipient) Immuven, Inc. (Recipient) Cubrc, Inc. (Recipient) Trius Therapeutics (Recipient) Achaogen Inc. (Recipient) GlaxoSmithKline (Recipient) Samir Brahmachari (Recipient) Eli Lilly and Company (Recipient)
Develop antibiotic against Gram-negative pathogens
Develop antibiotics for C. diff Research for novel antibiotics concerning AMR Research and development for T cell receptors to prevent MRSA infections Develop broad spectrum antibiotics Develop new antibiotics against potential bioterroristic microbes Develop antibiotics for the plague and tularemia infections Develop antibiotics concerning Gram-negative pathogens Created the Open Source Drug Discovery project to re-annotate the Mycobacterium tuberculosis genome Funds activities and issues concerning MDTR
*The Innovative Medicines Initiative (IMI) is composed of the European Commission and the pharmaceutical industry.
** Costs are not current PPP adjusted. Costs are current year indicated within the parenthesis.
6.1-110
Sources:
1. Watt Publishing Co. Asia poultry farmers may benefit from infectious disease initiative: Public-private collaboration seek to develop antibiotic alternatives. . [News Article]: WATTAgNet.com; 27 June 2012 [cited 13 July 2012]; Available from: http://www.wattagnet.com/Asia_poultry_farmers_may_benefit_from_infectious_disease_initiative.html. Taylor L. EU/industry 223.7M-euro fund to tackle antibiotic resistance. [News Article]: PharmaTimes Online; 24 May 2012 [cited 13 July 2012]; Available from: http://www.pharmatimes.com/article/12-05-24/EU_industry_223_7M-euro_fund_to_tackle_antibiotic_resistance.aspx. Department of Health U. Government makes 500,000 available for new research into antibiotic-resistant bacteria. [Press Release] 2012 [cited 13 July 2012]; Available from: http://mediacentre.dh.gov.uk/2012/02/07/govt-500k-research-antibiotic-resistant-bacteria. FlandersBio. arGEN-X is awarded 1.3 million IWT grant to advance proprietary simple antibody platform for addressing challenging disease targets. [Press Release] 19 December 2011 [cited 13 July 2012]; Available from: http://flandersbio.be/news/argen-x-is-awarded-13-million-iwt-grant-to-advance-proprietarysimple-antibody-platform/. Business Wire. Deinoves antibiotics project receives 1.35 million from OSEO. [Press Release] P aris: Bloomberg L. P.; 2010 [cited 13 July 2012]; Available from: http://www.bloomberg.com/apps/news?pid=conewsstory&tkr=5D8:GR&sid=aGhrxL.PpCno. Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Recommendations for future collaboration between the U.S. and EU. TATFAR. [Electronic Book]: The European Centre for Disease Prevention and Control (ECDC); 2011 [cited 18 July 2012]; Available from: http://ecdc.europa.eu/en/activities/diseaseprogrammes/tatfar/pages/index.aspx. Hagglund G. Innovative incentives for effective antibacterials. [Conference Summary] 2009 [cited 20 July 2012]; Available from: http://www.se2009.eu/polopoly_fs/1.25861!menu/standard/file/Antibacterials5.pdf. Corker B. GAIN act encourages development of new antibiotics to treat rising cases of drug-resistant infections. [Press Release]: Tennessee Senator Bob Corker; 26 June 2012 [cited 20 July 2012]; Available from: http://www.corker.senate.gov/public/index.cfm?p=News&ContentRecord_id=e30e2239-0434-4c15-8f1658c0b64b3165. Kaustinen K. Drug Discovery News - GSK awarded $94 million BARDA contract. [News Article] Rocky River, OH: Old River Publications LLC; 7 September 2011 [cited 13 July 2012]; Available from: http://www.drugdiscoverynews.com/index.php?newsarticle=5348.
2. 3. 4.
5. 6.
7. 8.
9.
10. Klein AS. Sequella awarded $4.6 million in new NIH grants to expand anti-infectives pipeline: Company has $4.8 million in non dilutive R&D funding for 2011 and $3.3 million committed for 2012-2015. [Press Release] BusinessWire.com: Berkshire Hathaway Co.; 4 April 2011 [cited 21 July 2012]; Available from: http://www.businesswire.com/news/home/20110404006080/en/Sequella-Awarded-4.6-million-NIH-Grants-Expand.
6.1-111
11. Research Portfolio Online Reporting Tools (RePORT). National Institutes of Health: reports, data, and analysis of NIH research activities. [Database Report]: U.S. Department of Health & Human Services; 2012 [updated 13 June 2012; cited 13 July 2012]; Available from: http://report.nih.gov/categorical_spending_project_listing.aspx?FY=2011&ARRA=N&DCat=Antimicrobial%20Resistance. 12. Fikes BJ. Trius receives $29.5 million contract to find microbe antibiotics. [News Article] Escondido, CA: North County Times; 20 September 2010 [cited 13 July 2012]; Available from: http://www.nctimes.com/article_bb6141ed-f20b-5016-b00e-96a2bacab749.html. 13. BARDA funds drug development for biothreats, antibiotic resistance. [News Release]: U.S. Department of Health & Human Services Press Office; 2010 [updated 3 January 2011; cited 13 July 2012]; Available from: http://www.hhs.gov/news/press/2010pres/08/20100830a.html. 14. Newswire Association LLC. GlaxoSmithKline awarded U.S. Department of Defense Contract to pursue novel antibacterial research program. [Press Release] Drugs.com18 September 2007 [cited 13 July 2012]; Available from: http://www.drugs.com/news/glaxosmithkline-awarded-u-s-department-defense-contractpursue-novel-antibacterial-research-program-6857.html. 15. "Jacqueline". Open source drug discovery. [Op-ed Article] skepchick.org8 March 2012 [cited 13 July 2012]; Available from: http://skepchick.org/2012/03/opensource-drug-discovery/. 16. Eli Lilly and Company - Newsroom. Lilly foundation commits US $30 million to the Lilly MDR-TB partnership. [Press Release] Lille, France: PRNewswire; 27 October 2011 [cited 13 July 2012]; Available from: http://newsroom.lilly.com/releasedetail.cfm?releaseid=618389.
6.1-112
Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance Annex 6.1.21: FDA Approved New Molecular Entity Antibiotics, 2004 2012
The table and figure below show the number and type of new molecular antibiotics that have been FDA approved from 2004 2012. Table 11
Drug Name (FDA Application) Ketek (NDA #021144) Tindamax (NDA #021618) Xifaxan (NDA #021361) Tygacil (NDA #021821) Altabax (NDA #022055) Doribax (NDA #022106) Besivance (NDA #022308) Vibativ (NDA #022110) Teflaro (NDA #200327) Dificid (NDA #201699) Active Ingredients Telithromycin Tinidazole Rifaximin Tigecycline Retapamulin Doripenem Besifloxacin Hydrochloride Telavancin Hydrochloride Ceftaroline Fosamil Fidaxomicin Review Classification Standard Standard Standard Priority Standard Standard Standard Standard Standard Priority Company Sanofi Aventis Us Mission Pharma Salix Pharms Wyeth Pharms Inc. Glaxo Grp Ltd Janssen Pharms Bausch And Lomb Theravance Inc. Cerexa Optimer Pharms Approval Date 04/01/2004 05/17/2004 05/25/2004 06/15/2005 04/12/2007 10/12/2007 05/28/2009 09/11/2009 10/29/2010 05/27/2011
Figure 1
FDA Approved New Molecular Entity Antibiotics, 2004 2012

New Molecular Entity Antibiotics 5 4 3 2 1 0 2004 2005 2006 2007 2008 Year 2009 2010 2011 2012
Source: CenterWatch. FDA approved drugs for immunology/infectious diseases. [Web Page] 2012 [cited 12 July 2012]; Available from: http://www.centerwatch.com/drug-information/fdaapprovals/drug-areas.aspx?AreaID=7.
6.1-113
Annex 6.1.22: Incentives to Encourage Antimicrobial Research and Development

This table presents a list of incentives that may potentially stimulate the antimicrobial development pipeline. Many of these incentives are proposed. Some of these incentives have been successfully implemented.
Name of Incentive Special Population Limited Medical Use Drugs1 Description Special approval process for drugs targeted towards the most serious infections where limited therapeutic options are available Marketed towards only affected population Encourage prudent antibiotic use Review FDAs current review process and make recommendations to improve FDAs efficiency FDA seeks external assistance in reviewing evidence concerning the regulatory affairs of antimicrobial clinical trials Extended patent length of antimicrobial drug Providing value in the early stages of R & D to the industry via: Tax credits Grants Direct Funding PPP Push incentive by encouraging PPPs Provides funding in the early stages Extending exclusivity periods Storage for clinical specimens to spur diagnostic R & D Housing specimens to eliminate the redundancy for several stakeholders to collect the same types of specimens s Flexible and alternative clinical trial design Discover supporting data that would standardize optimal antibiotic use Status (Location) Proposed ( United States)
Institute of Medicine Review of FDA AntiInfective Clinical Trial Design1 Foundation for the National Institutes of Health Initiative1 GAIN Act1 Push Incentive1, 2
Proposed ( United States) Implemented ( United States) Implemented ( United States) Proposed (Several)
IMI1 Pull Incentive1 Centralized specimen biorepository1, 2 Cancer Human Bio-Bank by the National Cancer Institute1 Continuous review of legal framework3 Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance3
Implemented (EU) Proposed (Several) Proposed (Several) Implemented ( United States) Proposed (Several) Implemented ( United States)
6.1-114
Name of Incentive Open Source (Indias Open Source Drug Discovery)3 Needs driven approach Neglected Diseases Initiative (DNDi)2, 3 The Urgent Need: Regenerating Antibacterial Drug Discovery and Development4
Strategies to Address Antimicrobial Resistance Act5 Antibiotic Innovation and Conservation Fee5 Improving lead identification and chemistry Partnership: Rare and Neglected Diseases Program and Rapid Access to Intervention Development Program2 South-South platforms European and Developing Countries Clinical Trials Partnership African Network for Drugs and Diagnostics Innovation2 Separate incentives from drug sales6
Description Open source technology that provides non-proprietary methods for drug discovery Participants are rewarded accordingly Utilize the target product profile to focus on the needs in settings where resources are lacking Expanding pharmacokinetics & pharmacodynamics to expedite antimicrobial development Special / alternative review process for antimicrobials Conditional approval Extended use of surrogate markets Formally create a specialized team within the Department of Health and Human Services addressing AMR Antibiotic fees in which 75% of proceeds would go towards antibiotic R & D and 25% towards stewardship programmes Broad access to compound collections Access to the proprietary information behind these collections
Status (Location) Proposed (Several) Implemented (India) Proposed (Several) Implemented (Several) Proposed (United Kingdom)
Proposed ( United States) Proposed ( United States) Proposed (Several) Implemented ( United States)
Clinical trials to be conducted in Southern countries
Proposed (Several) Implemented (Europe / Africa) Implemented (Several)
Provide incentives that separate the financial return from the sales of the drug Discourage monopoly protection on antibiotics
Proposed (Several)
6.1-115
Sources:
1. Infectious Diseases Society of America (IDSA). Statement of the IDSA: Promoting anti-infective development and antimicrobial stewardship through the U.S. Food and Drug Administration Prescription Drug User Fee Act (PDUFA) Reauthorization. [Electronic Article] 8 March 2012 [cited 13 July 2012]; Available from: http://www.idsociety.org/uploadedfiles/idsa/policy_and_advocacy/current_topics_and_issues/advancing_product_research_and_development/bad_bugs_no_d rugs/statements/idsa%20pdufa%20gain%20testimony%20030812%20final.pdf. So AD, Gupta N, Brahmachari SK, Chopra I, Munos B, Nathan C, et al. Towards new business models for R&D for novel antibiotics. Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy. 2011; 14:88-94. Alvan G, Edlund C, Heddini A. The global need for effective antibiotics A summary of plenary presentations. Drug Resistance Updates. 2011; 14:70-6. Finch R, Discovery BWPoTUNRAD, Development. Regulatory opportunities to encourage technology solutions to antibacterial drug resistance. The Journal of Antimicrobial Chemotherapy. 2011; 66:1945-7. Kuehn BM. Proposals seek to reduce resistance, boost development of new antibiotics. Journal of the American Medical Association. 2011; 305:1845-6. So AD, Ruiz-Esparza Q, Gupta N, Cars O. 3Rs for innovating novel antibiotics: sharing resources, risks, and rewards. BMJ (Clinical Research Ed). 2012; 344:e1782.
2. 3. 4. 5. 6.
6.1-116
Annex 6.1.23: Antibiotic Development Pipeline, 2011

These tables present a summary of the antibiotic development pipeline as of 2011. These tables demonstrate the lack of antibiotics within the R & D pipeline. Moreover, these tables show that the development pipeline for Gramnegative pathogens is incredibly limited. Table 1 New antibacterial drugs in clinical development1
6.1-117
Table 2 Antibacterial compounds in development2
6.1-118
6.1-119
Sources:
1. 2. Jabes D. The antibiotic R&D pipeline: an update. Current Opinion In Microbiology. 2011; 14:564-9. Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? British Journal of Pharmacology. 2011; 163:184-94.
6.1-120
Annex 6.1.24: Bacterial Vaccines Licensed for Distribution in the USA, 2005 2012 This chart provides a summary of the FDA approved vaccines for distribution within the US from 2005 2012. As shown, many of these vaccines do not address AMR pathogens, especially Gramnegative pathogens.
Year Licensed* 2005 Trade Name Adacel Indication Booster immunization against tetanus, diphtheria and pertussis as a single dose in individuals 11 through 64 years of age. Booster immunization against tetanus, diphtheria and pertussis as a single dose in individuals 10 years of age and older. Active immunization of individuals 9 months through 55 years of age for the prevention of invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y and W-135. Active immunization against diphtheria, tetanus, pertussis and poliomyelitis as the fifth dose in the diphtheria, tetanus and acellular pertussis (DTaP) vaccine series and the fourth dose in the inactivated poliovirus vaccine (IPV) series in children 4 through 6 years of age whose previous DTaP vaccine doses have been with INFANRIX and/or PEDIARIX for the first three doses and INFANRIX for the fourth dose. For active immunization against diphtheria, tetanus, pertussis, poliomyelitis and invasive disease caused by H. influenzae type b when administered to children 6 weeks through 4 years old. Use in adults 60 years of age and older for active immunization for the prevention of tetanus and diphtheria. For active immunization for the prevention of invasive disease caused by H. influenzae type b when administered as a booster dose in children 15 months through 4 years old. Bacteria of Interest C. diphtheriae, C. tetani, & B. pertussis C. diphtheriae, C. tetani, & B. pertussis N. meningitidis serogroups A, C, Y & W-135 Sponsor Sanofi Pasteur, Ltd GlaxoSmithKli ne Biologicals Sanofi Pasteur, Inc
2005
Boostrix
2007
Menactra
2008
KINRIX
C. diphtheriae, C. tetani, & B. pertussis
GlaxoSmithKli ne Biologicals
2008
Pentacel
C. diphtheriae, C. tetani, B. pertussis & H. influenzae type b C. diphtheriae tetani & C.
Sanofi Pasteur Limited Sanofi Pasteur, Ltd GlaxoSmithKli ne Biologicals, S.A.
2008
TENIVAC
2009
Hiberix
H. influenzae type b
6.1-121
Year Licensed*
Trade Name MenomuneA/C/Y/W-135
Indication For active immunization against invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y and W-135. Menomune A/C/Y/W135 in persons 2 years of age and older. For active immunization to prevent invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y and W-135 when administered to individuals 2 through 55 years of age. Active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F in persons 50 years of age or older. Active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, for use in children 6 weeks through 5 years of age. Active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F for use in children 6 weeks to 5 years old. Indicated for active immunization to prevent invasive disease caused by N. meningitidis serogroups C and Y and H. influenzae type b for children 6 weeks of age through 18 months of age.
Bacteria of Interest N. meningitidis serogroups A, C, Y & W-135 N. meningitidis serogroups A, C, Y & W-135
Sponsor Sanofi Pasteur Inc Novartis Vaccines and Diagnostics, Inc
2009
2010
Menveo
2010
Prevnar 13
S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 4, 6B, 9V, 14, 18C, 19F, & 23F
Wyeth Pharmaceutica ls Inc
2012
MenHibrix
N. meningitidis serogroups C and Y & H. influenzae type b
GlaxoSmithKli ne Biologicals
*The year licensed is according to the most recent modification(s) of the: o Components of the vaccine o Indication
*This search was completed on 28 June 2012 via http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm (Updated 20 June 2012)
6.1-122

BP6 1amr

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

BP6 1amr

Uploaded by

Copyright:

Available Formats

Priority Medicines for Europe and the World "A Public Health Approach to Innovation"

Background Paper 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Why does the problem persist?

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

New variants of resistance have continued to emerge

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Transmission of antibiotic-resistant bacteria

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Antibiotic misuse continues to be a challenge

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

3.1.1 Escherichia coli

Source: EARS-NET interactive database. 2

Source: EARS-NET Net database.

3.1.3 Carbapenem resistance in Pseudomonas aeruginosa

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Source: EARS-NET Net database.

3.1.4 Staphylococcus aureus

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Source: EARS-NET Net database.

3.1.5 Emerging carbapenemase-producing bacteria in Europe.

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Antibiotic resistance in other regions

3.2.1 The Americas

3.2.2 Asia and the World

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

The disease and economic burdens of antibiotic resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

What are the current policy initiatives regarding AMR control?

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

World Health Organization

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

FDA Approved New Molecular Entity Antibiotics, 2004 - 2012

Are incentives insufficient for the pharmaceutical industry?

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Public resources for basic and applied research

What is in the current antibiotic pipeline?

Figure 6.1.7: Antimicrobials in development as of 2011 Gramnegative versus Gram positive

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Optimization of antibiotic dosing regimens

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Identifying the most urgent needs for new antibiotics

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

New therapeutic approaches

7.3.1 Alternatives to antimicrobials: Antivirulence medicines

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

7.3.2 Host-pathogen interactions

7.3.4 Use of Phage and Phage Therapy

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

7.3.5 Vaccines: Primary prevention of resistance

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance

Clinical trials148 Clinical trials149

Pathogenic E. coli K. pneumoniae E. faecium A. baumannii

Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance