prioritization of pathogens to guide discovery, research and development of new antibiotics for ...

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PRIORITIZATION OF PATHOGENS
TO GUIDE DISCOVERY,
RESEARCH AND DEVELOPMENT
OF NEW ANTIBIOTICS
FOR DRUG-RESISTANT
BACTERIAL INFECTIONS,
INCLUDING TUBERCULOSIS
1
PRIORITIZATION OF PATHOGENS
TO GUIDE DISCOVERY,
RESEARCH AND DEVELOPMENT
OF NEW ANTIBIOTICS
FOR DRUG-RESISTANT
BACTERIAL INFECTIONS,
INCLUDING TUBERCULOSIS
PRIORITIZATION OF PATHOGENS
TO GUIDE DISCOVERY,
RESEARCH AND DEVELOPMENT
OF NEW ANTIBIOTICS
FOR DRUG-RESISTANT
BACTERIAL INFECTIONS,
INCLUDING TUBERCULOSIS
WHO/EMP/IAU/2017.12
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Foreword
further increases the burden of infectious diseases.
Low-income countries are particularly vulnerable
because of conditions that enable the spread of these
diseases, such as poor sanitation, lack of control of
and guidance on antibiotic use, inadequate health-
care services and systems, and limited or inadequate
infection control measures.
Middle- and upper-middle-income countries are not
free of the burden of drug resistance, however. BRICS
countries (Brazil, Russian Federation, India, China and
South Africa) and several European countries face
major epidemics of multidrug-resistant infections
caused by common Gram-negative bacteria and
multidrug-resistant-TB (MDR-TB), with devastating
public health and economic consequences. Sadly, the
pipeline for new antibiotics currently includes only a
small number of novel compounds in development.
In the past 20 years, only two new antibiotic classes,
both active only against Gram-positive bacteria, have
received global regulatory approval by international
regulatory agencies. In the same time period, no new
Infectious diseases are among the top 10 causes of antibiotics against Gram-negative bacteria have been
death and the leading cause of disability-adjusted life approved. In addition, only two completely new drugs
years worldwide. Among these, acute lower respiratory for MDR-TB treatment (bedaquiline and delamanid)
tract infections, diarrhoeal diseases and tuberculosis have reached the market in over 70 years.
(TB) are responsible for significant global morbidity
and mortality. The overall burden of communicable In 2016, at the high-level meeting of the UN General
diseases is strongly linked to poverty and, as a result, Assembly on antimicrobial resistance, Heads of State
the African continent still suffers from the highest directed an unprecedented level of attention to curbing
mortality from infectious diseases. the spread of infections that are resistant to antimicrobial
medicines. They reaffirmed their commitment to
The reasons for the emergence and re-emergence stopping the misuse of antimicrobial medicines
of infectious diseases worldwide include a in human health, animal health and agriculture,
breakdown of public health measures in the face of and recognized the need for stronger systems to
epidemic transitions, increasing international travel, monitor drug-resistant infections and the amounts
immigration for political, social and economic of antimicrobials used in humans and animals. In the
reasons, microbe adaptation and ability to change, wake of the increasing global awareness of the need
and transmission of several pathogens between for new antibiotics, Member States highlighted market
animals and humans. Of great concern is the global failures, and called for new incentives for investment
emergence of resistance of infectious pathogens to in research and development of new, effective and
many first-line medicines. affordable medicines, rapid diagnostic tests, and other
important therapies to replace those that are losing
Equitable access to medicines is another major concern
their effectiveness. In response to this and in line with
in many low- and middle-income countries where
the Global Action Plan on Antimicrobial Resistance to
common, treatable infections like pneumonia and TB
support the identification of pathogens of greatest
are still associated with high numbers of deaths, often in
concern, WHO developed a priority list of antibiotic-
children. The emergence of pathogenic microbes with
resistant bacteria to underpin renewed efforts for the
drug resistance, not only to the most commonly used
research and development of new antibiotics.
antibiotics but also to second-line, “reserve” medicines,
2016 was also the first year of implementation of development of new antibiotics to treat drug-resistant
the WHO End TB Strategy, which was adopted by bacterial infections and TB. It is acknowledged that
the World Health Assembly in 2014 and aimed at viral, fungal and parasitic infections may well need a
attaining universal access to TB prevention, diagnosis similar strategy in the near future. The development
and treatment. Global TB care and control measures of new antibiotics to tackle the serious problem of
saved an estimated 49 million lives between 2000 and drug-resistant infections needs to be prioritized
2015, yet widespread MDR-TB threatens to reverse in the global political agenda of world leaders and
the gains made from decades of effort to contain the health policy-makers. It also needs to be linked to
TB epidemic. MDR-TB was declared a global crisis by the development of appropriate health-care delivery
WHO in 2014, 21 years after TB had been declared services and to proper stewardship to safeguard the
a global emergency (in 1993) and despite greatly use of current and future medicines. This challenge
improved cure rates in patients with drug-susceptible cannot be simplified in a “one size fits all” approach.
TB. The TB emergency prompted the establishment The only possible defence against the threat of
of new financing mechanisms to support countries antimicrobial resistance and the (very real) possibility
in tackling the TB epidemic, most notably the Global of a post-antibiotic era is a global and coordinated
Fund and Unitaid. However, investment in research effort by all stakeholders. This document reflects
and development for TB has major gaps in the funding the commitment and contribution of WHO and
needed to develop new tools that would help achieve its partners to help establish priorities for critically
the targets of the WHO End TB Strategy. needed research and development on new antibiotics
against drug-resistant bacterial infections and TB, in
The overall goal of the following report is to present
line with our mission of ensuring health for all.
the priority pathogens to be targeted for research and
Dr Tedros Adhanom Ghebreyesus
WHO Director-General
Contents
Acknowledgements 8
Executive summary 10
Introduction 14
Section 1: Tuberculosis 15
1.1 A top infectious disease killer 15
1.2 MDR-TB: a global public health crisis and health security threat 17
1.3 Arduous, toxic and limited treatment options 21
1.4 Profound human suffering and health service dilemmas 21
1.5 Critical gaps in investment in research and development 22
Section 2: Ranking of other drug-resistant bacterial infections 25
2.1 Background 25
2.2 Selection of prioritization methodology 29
2.3 Multi-criteria decision analysis: methodology for the prioritization exercise 39
2.3.1 Expert group selection 40
2.3.2 Selection of antibiotic-resistant bacteria to be prioritized 40
2.3.3 Selection of criteria for prioritization 44
2.3.4 Data extraction and criteria synthesis into the MCDA model 46
2.3.5 Summary of the evidence assessment methods: 62
strengths and limitations
2.3.6 Summary of the evidence 64
2.3.7 Ranking 75
2.4 Survey results 76
2.5 Ranking of other drug-resistant bacterial infections: overall results 79
2.6 Conclusions 80
References 83
Acknowledgements
The development of this report was a collaborative Advisory group
process between the WHO Department of Essential
∞ Marco Cavaleri: European Medicines Agency,
Medicines and Health Products (EMP) and the WHO
London, UK
Global Tuberculosis Programme (GTB), overseen by
∞ Edward M. Cox: US Food and Drug
Suzanne Hill (Director, EMP) and Mario Raviglione
Administration, Washington, USA
(Director, GTB).
∞ Paul Hansen: University of Otago, Dunedin, New
The report comprises two main sections. Zealand
Section 1 describes the current situation with respect ∞ Chris R. Houchens: Antibacterials Program
to TB and was prepared by Karin Weyer (WHO, GTB). Biomedical Advanced Research and Development
Authority, Washington, USA
Sections 2 reports the methods and results of the
∞ M. Lindsay Grayson: Austin Health, University of
multi-criteria decision analysis used to prioritize other
Melbourne, Melbourne, Australia
antibiotic-resistant bacteria and was prepared by
∞ Dominique L. Monnet: European Centre for
Evelina Tacconelli (Tübingen University Hospital, DZIF
Disease Prevention and Control, Stockholm,
Partner Center, Germany), and Nicola Magrini (WHO
Sweden
EMP) in collaboration with members of the WHO
Priority Pathogens List (PPL) coordinating, advisory and ∞ Marc Ouellette: Laval University and Canadian
working groups. The contributions of the following Institutes for Health Research, Québec, Canada
individuals are gratefully acknowledged: ∞ Kevin Outterson: Combating Antibiotic Resistant
Bacteria Biopharmaceutical Accelerator, Boston
University, Boston, USA
Coordinating group
∞ Jean Patel: Centers for Disease Control and
∞ Yehuda Carmeli: Tel Aviv University, Tel Aviv, Israel
Prevention, Atlanta, USA
∞ Elena Carrara: Tübingen University Hospital, DZIF
Center, Tübingen, Germany
Working group
∞ Stephan Harbarth: Geneva University Hospitals
Aaron O. Aboderin (Nigeria), Seif S. Al-Abri (Oman),
and Faculty of Medicine, Geneva, Switzerland
Nordiah Awang Jalil (Malaysia), Nur Benzonana
∞ Gunnar Kahlmeter: Central Hospital, Växjö,
(Turkey), Sanjay Bhattacharya (India), Adrian John Brink
Sweden
(South Africa), Francesco Robert Burkert (Germany),
∞ Jan Kluytmans: University Medical Center, Otto Cars (Sweden), Giuseppe Cornaglia (Italy), Oliver
Utrecht, Amphia Hospital, Breda, the Netherlands James Dyar (Sweden), Alexander W. Friedrich (the
Netherlands), Ana C. Gales (Brazil), Sumanth Gandra
∞ Marc Mendelson: Groote Schuur Hospital,
University of Cape Town, Cape Town, South (India), Christian G. Giske (Sweden), Debra A. Goff
Africa (USA), Herman Goossens (Belgium), Thomas Gottlieb
(Australia), Manuel Guzman Blanco (Venezuela),
∞ Céline Pulcini: Nancy University Hospital, Lorraine
Waleria Hryniewicz (Poland), Deepthi Kattula (India),
University, EA 4360 APEMAC, Nancy, France
Timothy Jinks (UK), Souha S. Kanj (Lebanon), Lawrence
∞ Alessia Savoldi: Tübingen University Hospital, DZIF Kerr (USA), Marie-Paule Kieny (WHO), Yang Soo
Center, Tübingen, Germany
Kim (South Korea), Roman S. Kozlov (Russia), Jaime
∞ Nalini Singh: Children’s National Health System, Labarca (Chile), Ramanan Laxminarayan (USA), Karin
George Washington University, Washington, USA Leder (Australia), Leonard Leibovici (Israel), Gabriel
Levy Hara (Argentina), Jasper Littman (Germany),
∞ Ursula Theuretzbacher: Center for Anti-infective
Surbhi Malothra-Kumar (Belgium), Vikas Manchanda
Agents, Vienna, Austria
8
(India), Lorenzo Moja (WHO), Babacar Ndoye (Senegal), For all experts, advice was provided in their personal
Angelo Pan (Italy), David Paterson (Australia), Mical Paul capacity. The views in this report do not necessarily
(Israel), Haibo Qiu (China), Pilar Ramon-Pardo (USA), reflect and should not be interpreted as being the
Jesús Rodríguez-Baño (Spain), Maurizio Sanguinetti official position of any agency or institution.
(Italy), Sharmila Sengupta (India), Mike Sharland (UK),
Funding provided by the Government of Germany
Massinissa Si-Mehand (WHO), Lynn L. Silver (USA),
for the development of the Priority Pathogens List is
Wonkeung Song (South Korea), Martin Steinbakk
gratefully acknowledged.
(Norway), Jens Thomsen (United Arab Emirates), Guy
E. Thwaites (UK), Jos van der Meer (the Netherlands),
Nguyen Van Kinh (Vietnam), Silvio Vega (Panama), Maria
Virginia Villegas (Colombia), Agnes Wechsler-Fördös
(Austria), Heiman F. L. Wertheim (the Netherlands),
Evelyn Wesangula (Kenya), Neil Woodford (UK), Fidan
O. Yilmaz (Azerbaijan), Anna Zorzet (Sweden).
9
Executive summary
Antimicrobial resistance is one of the most complex for new antibiotics, and to support the implementation
global health challenges today. The world has long of the Global Action Plan on Antimicrobial Resistance,
ignored warnings that antibiotics and other medicines WHO developed a priority pathogens list (PPL) of
are losing their effectiveness after decades of overuse antibiotic-resistant bacteria to support research and
and misuse in human medicine, animal health and development into new and effective drugs. This action
agriculture. Common illnesses like pneumonia, post- also followed recommendations in the 2016 United
operative infections, diarrhoeal and sexually transmitted Nations report of a high-level panel on the global
diseases, as well as the world’s largest infectious response to health crises, which emphasized the
disease killers – tuberculosis (TB), HIV and malaria – threat posed to humanity from a number of under-
are increasingly becoming untreatable because of the researched antibiotic-resistant bacteria that urgently
emergence and spread of drug resistance. require enhanced and focused investment in research
and development.
Worsening antimicrobial resistance could have serious
public health, economic and social implications. The 2016 was also the first year of implementation of the
threat of antimicrobial resistance is also becoming WHO End TB strategy, which was adopted by the World
a key consideration for programmes addressing Health Assembly in 2014. The End TB Strategy serves
maternal and child health, sexual and reproductive as the core strategic document for all WHO Member
health, foodborne diseases, water and sanitation, and States on TB prevention, control and elimination,
infection prevention and control. The World Bank including the prevention and management of TB drug
has warned that antimicrobial resistance could cause resistance. The End TB strategy is an evolution of the
more economic damage than the 2008 financial crisis. 2006 WHO Stop TB Strategy and its predecessor,
And although the 21st century is being shaped by the 1995 WHO DOTS Strategy, which Member States
technology and innovation, humans could soon find started to implement after WHO declared TB a global
themselves in an era where simple infections once health emergency in 1993. Twenty-one years later, in
again kill millions every year. 2014, multidrug-resistant TB (MDR-TB) was declared a
global public health crisis by WHO, with a call urging
The past three years have seen unprecedented
increased investment in research and development,
global political momentum to address antimicrobial
especially for new drugs and diagnostics.
resistance: in 2015, governments adopted a global
action plan at the World Health Assembly and in 2016 Prioritization of pathogens for research and
passed a political declaration at the United Nations development is highly challenging given the absence
General Assembly. Antimicrobial resistance has made of established criteria defining the impact of pathogens
it onto the agendas of the G7 and G20 groups and is a on human health. As a result, no consensus exists
core component of the Global Health Security Agenda. on the most effective methodology to develop
prioritization in infectious diseases. Ranking antibiotic-
WHO is working closely with the Food and Agriculture
resistant organisms to direct future research and
Organization of the United Nations and the World
development requires a detailed identification and
Organization for Animal Health in leading global efforts
integration of extensive information that defines the
against antimicrobial resistance and ensuring that the
burden of antimicrobial resistance (microbiological,
necessary momentum is consolidated and sustained.
epidemiological, and clinical). Moreover, communicable
These efforts are guided by an ad-hoc interagency
diseases differ in clinical presentation and duration
coordination group established in 2017. A global
(e.g. acute versus chronic), treatment approaches (e.g.
development and stewardship framework to combat
multidrug versus single drug therapy), and etiology (e.g.
antimicrobial resistance is being drafted to support
bacterial, viral, fungal).
the development of new antimicrobial medicines,
diagnostics, vaccines and other tools. The diversity of communicable diseases is a major
challenge for prioritization of pathogens. As a
One of the gravest global concerns about antimicrobial
result, the scope and focus of the work underlying
resistance currently is that antibiotic resistance has
this document was agreed beforehand to allow
emerged in so many pathogens, including TB. In 2016, in
the deliverables requested by Member States to be
the wake of the increasing global awareness of the need
10