Background Paper 6.1 Antimicrobial resistance - World Health

122 Pages·2013·4.45 MB·English

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. Introduction ................................................................................................................................................. 5
2. Why does the problem persist? ................................................................................................................ 6
2.1 New variants of resistance have continued to emerge .................................................................. 7
2.2 Transmission of antibiotic-resistant bacteria .................................................................................. 8
2.3 Antibiotic misuse continues to be a challenge ................................................................................ 9
3. 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. The disease and economic burdens of antibiotic resistance ............................................................ 16
5. What are the current policy initiatives regarding AMR control? .................................................... 17
5.1 European Union ................................................................................................................................ 17
5.2 World Health Organization ............................................................................................................ 19
5.3 World .................................................................................................................................................. 20
5.4 The Americas ..................................................................................................................................... 21
6. Research into the past and present pharmaceutical interventions: what can be learnt? ............. 22
6.1 Antibiotic development ................................................................................................................... 22
6.2 Are incentives insufficient for the pharmaceutical industry? .................................................... 22
6.3 Public resources for basic and applied research ........................................................................... 23
6.4 What is in the current antibiotic pipeline? .................................................................................... 23
6.5 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 Need for Rapid and inexpensive diagnostics ............................................................................... 25
7.2 Identifying the most urgent needs for new antibiotics ................................................................ 25
7.3 New therapeutic approaches .......................................................................................................... 26
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Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
7.3.1 Alternatives to antimicrobials: Antivirulence medicines ....................................................... 26
7.3.2 Host-pathogen interactions ......................................................................................................... 27
7.3.3 Non-antibiotics ............................................................................................................................. 27
7.3.4 Use of Phage and Phage Therapy .............................................................................................. 27
7.3.5 Vaccines: Primary prevention of resistance .............................................................................. 28
8. 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 Korinsek–Porta, Eric Georget, Drs. Louis Kazis, David Rosenbloom:, Dr. Sean
Devlin

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Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
Acronyms

AMR Antimicrobial resistance
CGD Centre for Global Development
CDC US Centers for Disease Control and Prevention
CHMP Committee for Medicinal Products for Human Use
EARS-NET-Net European Antimicrobial Resistance Surveillance System
Network
EC European Commission
EARS-NET European Centre for Disease Prevention and Control
EEA European economic area
EMA European Medicines Agency
ESBL Extended-spectrum beta-lactamase
ESPID European Society for Paediatric Infectious Diseases
EPRUMA European Platform for the Responsible Use of Medicines in
Animals
EU European Union
FDA US Food and Drug Agency
GAIN Generating antibiotic incentives now
GBS Group B streptococcal septicemia
HAI Hospital acquired infection
IDSA Infectious Diseases Society of America
IMI Innovative Medicines Initiative
LOS Length of stay
MDR TB Multidrug – resistant tuberculosis
MRSA Meticillin – resistant Staphylococcus aureus
NDM – 1 New Delhi metallo-lactamase 1
NIAID National Institute of Allergy and Infectious Diseases
OSDD Open source drug discovery
PDCO Paediatric Committee
PDUFA Prescription Drug User Fee Act
PPP Public private partnerships
R & D Research and development
ReAct Action on Antibiotic Resistance
TATFAR Transatlantic Taskforce on Antimicrobial Resistance
USA United States of America
WHO World Health Organization

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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).

1 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” interchangeably 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.
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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-
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Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
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 non-
inferiority 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 Gram-
positive 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 (NDM–1) 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
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Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
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 non-
therapeutic 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 beta-
lactams (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
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“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
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Update on 2004 Background Paper, BP 6.1 Antimicrobial resistance
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. Epidemiological trends

3.1 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-
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