FEATURE: WHO releases global priority pathogens list towards prioritizing antibiotic R&D
On February 27th, the WHO published a preliminary list of antibiotic-resistant “priority pathogens” towards guiding R&D of novel antibiotics to be aligned with public health priorities. The list includes 12 bacterial families determined by through a collaboration with the Division of Infectious Diseases at the University of Tübingen in Germany and the WHO “that pose the greatest threat to human health.” Through a coordinating group of international experts in the fields of infectious disease, clinical microbiology, R&D, public health, and infection control, a multi-criteria decision analysis technique was established. The following criteria were chosen by these experts for prioritization: “all-cause mortality, healthcare and community burden, prevalence of resistance, 10- year trend of resistance transmissibility in hospital and community settings, treatability and current pipeline.”
These pathogens were also separated into three categories according to their urgency for novel treatments - critical, high, and medium.
Critical: This group includes multi-drug resistant bacterial pathogens that particularly impact hospitals, nursing homes, and patients dependent on ventilators and blood catheters. Critical pathogens include Acinetobacter, Pseudomonas, and Enterobacteriaceae such as Klebsiella, E. coli, Serratia, and Proteus. These pathogens have become increasingly resistant to multiple antibiotics such as carbapenems and third-generation cephalosporins.
High: This group contains bacterial pathogens that are becoming increasingly resistant to treatment and also cause more common illnesses such as food poisoning due to Salmonella or Campylobacter as well as gonorrhea.
Medium: This group includes other resistant bacterial pathogens that are becoming resistant to first-line treatments including Streptococcus pneumoniae as well as Haemophilus influenzae.
The list also specifically emphasizes the threat of multi-drug resistant gram-negative pathogens that can pass along these resistant genetic traits to other bacteria. Additionally, it also points to specific pathogens affecting pediatric populations and other common diseases with a high mortality burden including Salmonella typhi, Neisseria gonorrhoeae, and ESBL-producing Enterobacteriaceae. The WHO began embarking on these efforts as part of their “global development and stewardship framework” in an effort to provide direction to ongoing antibiotic R&D efforts including the WHO/Drugs for Neglected Diseases Initiative (DNDi) Global Antibiotic R&D Partnership (GARDP) among others.The expert group also called for public awareness campaigns and antibiotic stewardship programs to be implemented globally, targeting stakeholders in both health care and community facilities. They also call for sustainable financing for both education as well as innovation of tools to support the prudent use of antibiotics are urgently needed. The developers of this list do acknowledge certain limitations including the lack of data on the frequency and burden of drug-resistant infections to specific bacteria in health care and community settings as well as on community-acquired infections, especially in low- and middle-income countries. They also note the lack of surveillance data in food animals and products and the need for coordinated human and animal surveillance systems.Developing countries also stressed the important role governments will need to play in the regulation aspect for tackling antimicrobial resistance and the need to ensure affordable access to medicines, vaccines and diagnostics. Member States further highlighted the importance of looking at the animal health and agricultural aspects as key challenge areas.
FEATURE: Boston Consulting Group releases follow-up report of recommendations on antibiotic R&D for German Ministry of Health
In a follow-up to an October 2015 report, the Boston Consulting Group has completed a second report, titled Breaking through the Wall: A Call for Concerted Action on Antibiotics Research and Development, for the German Federal Ministry of Health. This 2017 follow-up focuses on four out of the original ten potential levers for enhancing innovation of the antibiotics R&D pipeline. These four levers include target product profiles to guide funding towards areas of clinical need and three funding vehicles positioned at different points in the pharmaceutical value chain—a Global Research Fund upstream in the R&D pipeline, a Global Development Fund to support clinical trial testing, and a Global Launch Reward that will help ensure returns on investment. In composite, their recommendations give shape to a proposed policy initiative, a Global Union for Antibiotics Research and Development or GUARD--not to be mistaken with GARDP, the Global Antibiotic Research and Development Partnership, incubated by the Drugs for Neglected Diseases Initiative (DNDi) with the support of the World Health Organization.
The report describes target product profiles as “a proprietary planning tool used in industry to guide product development and to inform regulatory body and investors.” Target product profiles have also been used by product development partnerships, such as DNDi and the Medicines for Malaria Venture. By contrast to these product development partnerships, BCG opted not to set desired price levels within their target product profiles. Instead, it has proposed to use “differentiated pricing and access requirements for new drugs in all funding contracts entered into with GUARD.” This would open the door to their proposal for a partial delinkage approach—where the company’s return on investment is divorced from the price and quantity of drug sold, just not in higher-income countries.
Of the three funding vehicles, the size of the Global Launch Reward dwarfs the financial commitments proposed for the other two funds, but as an insurance mechanism, a company realizing operating profits would have obligation to repay the reward. The Global Launch Reward would offer $1 billion payment, in installments contingent on meeting “access, quality, and good stewardship conditions,” for “high-need antibiotics.” These installments would be front-loaded, but paid out over an eight-year period. A fraction of operating profits would be returned to GUARD, but for antibiotics with low to medium profit potential, likely only a fraction of the reward will be recouped. Once the product’s patent expires, the company would no longer be obliged to repay the reward, and in no case would the company pay back more than what was received. Importantly, BCG maintains that 1) a partial delinkage model would allow recipients not to “forgo the profit potential of marketing the antibiotic in question which lowers the required capital for GUARD significantly” and 2) “high prices in developed markets are acceptable (and in some cases even desirable).” BCG also envisions that these arrangements would give GUARD leverage over price differentiation and stewardship of other products in the portfolio of awarded companies. What is unclear is how access and stewardship conditions might work under such arrangements and why placing such responsibilities in the hands of drug companies, as opposed to providers in the healthcare delivery system, makes sense.
By comparison, the annual budget for the Global Research Fund would come to $200 million, and this would be divided across a portfolio of basic research and preclinical projects of varying risk. While the report acknowledges the value of collaboration in research (e.g., substance libraries, standardized methodologies, a digital platform and so on), the Global Research Fund focuses on individual projects and less so the innovation platform for the field.The Global Development Fund—also $200 million per year--would offer partial support of multiple clinical trials through a mechanism of forgivable loans. Loan repayment would only begin if and when a drug candidate came to market or were sold to another company. So the Global Development Fund would assume the risk of early-stage development, and where failure rates are high, a financing scheme of forgivable loans would be tantamount to grants. It does not appear that receiving payout from the Global Research Fund or the Global Development Fund would necessarily diminish later payout from the Global Launch Reward to the same company for that product. Alternatively, instead of repaying the debt in cash, GUARD could share in revenues generated, or the debt could be assumed by a new company spun off by an academic institution.
As an important guiding principle, the report stipulates that “direct funding from the pharmaceutical industry should, if at all, only be accepted under the condition that it is not directly allocated to projects, but to GUARD as a whole. This is to avoid situations in which organizations other than GUARD and the researcher/developer have a claim to a scientific or clinical outcome.” Of note, apart from this project for the German Federal Ministry of Health, BCG has received funding from a range of pharmaceutical company clients itself.
Through these four levers, GUARD seeks to bring one high-need antibiotic to market every year “in a steady state.” For this to be possible, funding commitments would need to be secured from a group of “country champions.” The report also notes that such an effort will require at least five years of a “ramp-up phase.” Besides continuous monitoring of performance indicators across all four levers, the report also calls for biennial strategic reviews to be conducted. These reviews would include a transparent and comprehensive evaluation of the GUARD portfolio and evaluation of the broader antibiotic drug pipeline.
Policy Updates on AMR
Health Care Without Harm (HCWH) Europe Executive Director, Anja Leetz attended the Third International German Forum at the Chancellory in Berlin on February 22-23. For two days, 120 global experts discussed improving the use of antibiotics, using the potential of information and communications technology, and fighting neglected tropical diseases and mental health. As well as joining the discussions, Anja shared HCWH Europe's most recent leaflets - one on pharmaceutical pollution (also available in German) and another concerning antimicrobial resistance (AMR). On the second day, all experts came together to present Dr. Angela Merkel with their findings. During the debate, Anja urged the chancellor to push for clear policies that will provide more transparency on the use of antibiotics, for both human and veterinary use and clear goals with a reduction of overuse and the promotion of rational use. Cross-posted from Health Care Without Harm Europe's February 2017 Newsletter
The Alliance to Save Our Antibiotics received 2nd Prize for the European Commission’s EU Health Award for NGOs fighting Antimicrobial Resistance. 26 candidate NGOs from 10 European Union Member States were considered for this prize, which “aims to reward outstanding initiatives by NGOs which have significantly reduced the threat of antimicrobial resistance (AMR) to human health.” Vytenis Andriukaitis, the Commissioner for Health and Food Safety, awarded this 2nd Prize of €15,000 to the Alliance for their campaign efforts to end the routine use of antibiotics and curb use of critically-important antibiotics in food animal production through a combination of “peer-reviewed reports, public advocacy, and lobbying, public campaigning and media work, and solutions-facing work in partnership with the livestock and food retail sector.” The Alliance to Save Our Antibiotics is a coalition of over 60 European-wide organizations across the health, medical, environmental, farming, and animal welfare sectors. The organization is also a member of the Antibiotic Resistance Coalition, a coalition of over 25 leading civil society and intergovernmental organizations working together to address the global threat of AMR. First prize for the EU Health Award was awarded to the European Consumer Organization (BEUC), while 3rd prize was given to the World Alliance against Antibiotic Resistance (WAAR).
The Medicines Patent Pool announced in late January that it had successfully signed a license with Johns Hopkins University for clinical development of sutezolid, a multi-drug resistant tuberculosis (TB) drug candidate. This license culminated after over two years of advocacy from a coalition of civil society organizations including Universities Allied for Essential Medicines (UAEM), Médecins Sans Frontières (MSF), and Treatment Action Group (TAG) calling for Johns Hopkins to license the drug to the Medicines Patent Pool to ensure affordable access to this promising treatment in development countries. Sutezolid is an oxazolidinone antibiotic is more potent and less toxic than the commercially-available drug linezolid, and is currently in Phase IIa clinical development. This announcement marks the first ever TB drug license the Medicines Patent Pool has signed with an American university. Mario Raviglione, Director of the Global TB Programme at the WHO stated that “THE MPP-Johns Hopkins University agreement is an extraordinary step as it seeks to jump-start currently stalled development on a compound that showed promise in early stage trials.” UAEM, MSF, TAG, Public Citizen, and others also issued a statement lauding this announcement, but also expressing concern around the lack of affordability provisions within the final agreement. The current scarcity of treatment options to treat TB makes the inclusion of sutezolid a very exciting prospect to help decrease deaths due to TB, and especially so for drug-resistant TB.
The World Health Organization (WHO) and Health Action International (HAI) have published a manual to help healthcare and pharmacy students cope with pressure from the pharmaceutical industry entitled Understanding and Responding to Pharmaceutical Promotion. The report argues that while medicines can be crucial for attaining or maintaining health, they also need to be used responsibly. This publication is the result of growing concerns that the pharmaceutical industry’s influence over treatment choices through exerting pressure on healthcare professionals, particularly regarding prescriptions. Despite this, WHO/HAI state that very few medical and pharmacy training programs spend more than a day on this subject. This publication is meant as a companion to the 1994 manual Guide to Good Prescribing to “assist teachers and health-care professionals to teach medical and pharmacy students about pharmaceutical promotion.”
The European Centre for Disease Prevention and Control (ECDC) released the annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net), which included concerning results, particularly around resistance to Gram-negative pathogens. In this report, the agencies examined antimicrobial resistance data across 30 EU/EEA countries. The already high resistance data shows an increase across multiple regions of the EU, with a significant increase of third-generation cephalosporin resistance to E. coli and K. pneumoniae. A significant fraction of these resistant pathogens was associated with extended-spectrum beta-lactamase (ESBL) enzymes. Trends between 2012 and 2015 showed that third-generation cephalosporin resistance in combination with resistance to other drug classes including fluoroquinolones and aminoglycosides have increased. These concerning trends within the EU/EEA countries, particularly regarding invasive bacteria where an effective antibiotic is the most important and sometimes only possible treatment, show the urgent need for strategies for control and prevention of drug resistance, a task that requires the effort of all sectors of the health system.
The Fleming Fund has recently released a roadmap for low- and middle-income countries to participate in the WHO Global Antimicrobial Surveillance System (GLASS) program. This fund is £265 million initiative financed by the UK Government to strengthen AMR surveillance and laboratory capacity in developing countries. The purpose of the manual is to be a guideline targeted for low- and middle-income countries, as they may be unlikely to have the necessary resources or capacity to implement the components of GLASS. This modified roadmap “allows for flexibility across different systems, but has sufficient standardization of core protocols to ensure that data will be valid and comparable.” The manual would help ensure that AMR surveillance programs can provide data to make further evidence-based interventions at the local, national, and international levels of policy.
During a satellite event at the World Economic Forum’s annual meeting in Davos, Switzerland in late January, AdvaMedDx, the industry association representing the world’s leading diagnostic manufacturers, announced a global stakeholder initiative stressing the role of diagnostics tests in the fight against AMR.Here, signatories from the diagnostics industry committed to “building a long-term economic case for diagnostics as a public good in the fight against drug-resistant infections; establishing public-private partnerships to develop health systems and create wide-scale access to diagnostics; working to ensure effective global utilization of diagnostics; and advocating for research and development investments, funding, simplified regulatory processes and sustainable reimbursement policies to encourage development.” Andrew Fish, AdvaMedDx’s Executive Director, explained that the purpose of this new initiative is “to not only drive a better understanding of diagnostics’ role in antimicrobial resistance, but to ultimately improve use of diagnostics worldwide to counter this problem.” Partners include the British In Vitro Diagnostics Association, the Brazilian Chamber for In Vitro Diagnostics, MedTech Europe, Micronics, Philips Healthcare, QuantuMDx Group, and Thermo Fisher Scientific. Fish further explained that diagnostic tests need to be adjusted to the resources available, and that point-of-care tests will be especially important in areas with limited laboratory and equipment access.
The Center for Global Development (CGD) has proposed a global treaty to reduce the use of antibiotics in livestock production. The authors note that “drug resistant superbugs do not respect borders. To date, however, there has been little concrete action at the global level.“ While acknowledging multiple unknowns in food animal consumption and animal species treated with antibiotics as well as general questions about resistance development and spread, the CGD emphasizes the importance of action in the animal sector for human health, They also state that such an intervention would have a high benefit-cost ratio. The proposal for the treaty leans on the Montreal Protocol, where countries agreed on the reduction of ozone-depleting chlorofluorocarbons (CFCs). Despite a large number of unknown variables, a global agreement was achieved on the basis of the protection of a global public good, continuous research, and immediate action. As AMR has similar significant urgency, the CGD calls for such a global treaty to address the use of antimicrobials in livestock as a crucial aspect in the fight against rising drug resistance.
The British Cattle Veterinary Association (BCVA) recommends a reduction of antibiotics used in cattle production in the United Kingdom. The BCVA points out that preventive use of antibiotics in cattle should be avoided and not be seen as a solution for addressing animal welfare and husbandry problems. Instead, novel management and prevention strategies should be implemented to overcome these issues. They also call for third and fourth generation cephalosporins, fluoroquinolones and colistin, all of them designated as critically important antibiotics by the World Health Organization, to only be used in rare cases and after sensitivity testing where no other treatment option is available. Additionally, the group also recommends that the common practice of antibiotic use in dry cow teat sealants to be replaced by other established non-antibiotic options. According to the BCVA statement, a herd health plan with documentation of and strategies for good herd management practices, including disease control and prevention measures would be an important step in the direction of prudent drug use and healthy livestock production.
The meeting of the 21st WHO Expert Committee on the Selection and Use of Essential Medicines will be held at WHO Headquarters in Geneva, Switzerland, from March 27-31, 2017. The purpose of the meeting will be to revise and update the WHO Model List of Essential Medicines (EML), including Essential Medicines for Children (EMLc). Applications to be considered for inclusion of new medicines, and changes to or deletion of currently listed medicines in the EML and EMLc, were available for public review and comment online until February 24th. Five applications focused on antibiotics were submitted, reviewing treatments for priority infectious syndromes, pediatric infections, and for specific sexually transmitted infections as well as on antibiotic awareness campaigns. Comments will be published online together with all other documents relating to the meeting of the Expert Committee.
The European Commission has announced an open public consultation on its 2011-2016 action plan against AMR. Input is being solicited by individuals, administrations, associations, and other organizations through an online questionnaire. The 2016 evaluation of its action plan concluded that the EU can best support the fight against AMR by supporting member states, making the EU “a best practice region on AMR”, boosting research, development, and innovation, and help form the AMR global agenda. The EC is planning to launch a “Commission communication on a One Health action plan to support Member States in the fight against antimicrobial resistance (AMR)” by mid-2017 and will use this consultation to collect views and feedback for the current proposals process. The consultation period started in late January and will remain open until April 27th.
From the Research Bench
The European Commission has announced the first ever recipient of its Horizon Prize on Better Use of Antibiotics. Conceived in 2015, the prize has been positioned to catalyze a response to growing concerns around AMR in the hope of discouraging misuse of antibiotics through technological innovation. In reward, €1 million was offered for a rapid diagnostic that would determine whether an established upper airway infection determine would require antibiotic therapy or could be treated without antibiotics. On February 6th, Commissioner Carlos Moedas announced the winner of Horizon Prize to be Minicare HNL, a joint research effort between Philips Electronics from the Netherlands and a Swedish research-based company, P&M Venge AB. The winning technology combines Philips’ Minicare platform developed for point-of-care diagnostics and Human Neutrophil Lipocalin HNL, a novel biomarker that inhibits bacterial growth by binding iron. Minicare NHL’s contribution was a finger-prick test that can nearly instantaneously determine whether an airway infection is bacterial or viral. By rapidly diagnosing the etiology, a provider would immediately know whether or not a patient can be treated safely without antibiotics. The runners-up for the EU Horizon Prize were ImmunoPoc and PulmoCheck.
Twostudies conducted in China on bacterial resistance to last-resort antibiotics not only suggests far more resistance than expected but also that resistance is being spread by flies. Cardiff University’s Tim Walsh and his team found that a third of Escherichia coli bacteria sampled from chicken farms and retail meat products were resistant to carbapenem drugs. Additionally, a quarter of strains were also found to be resistant to colistin - both carbapenems and colistin are considered to be last line antibiotics used only when all other drugs fail. Despite the drug not being used often to treat people, researchers also found colistin resistance in 1% of hospital patients in two large cities, concluding that the resistance originated in poultry farms. Each year in China, 8000 tonnes of colistin is fed to chickens and pigs for growth promotion. On the chicken farms, the team found that while only half of the bacteria sampled were resistant to colistin, almost all carried the colistin-resistant gene mcr-1, suggesting a far greater ability for the resistance to spread than has previously been thought. Furthermore, Walsh and his colleagues discovered that the resistant genes are being carried by migrating swallows, which could bring the resistance with them to Southeast Asia, and, perhaps most worryingly, by flies, concluding that “their ability to contaminate the environment has immense public health concerns.” According to Walsh, in the summer months, these flies can carry these resistant pathogens to various locations.
Ethnobotanist Cassandra Quave and her colleagues at Emory Universityhave discovered an extract in the berries of the Brazilian peppertree able to disarm antibiotic-resistant bacteria. In clinical trials performed on mice, the researchers were able to show that the flavone-rich extract prevented methicillin-resistant Staphylococcus aureus (MRSA) from taking collective action by repressing a gene that allows the bacteria to communicate with each other. “It essentially disarms the MRSA bacteria, preventing it from excreting the toxins it uses as weapons to damage tissues,” Quave says. “The body’s normal immune system then stands a better chance of healing a wound,” adding that in the Amazon, traditional healers have used the Brazilian peppertree to treat skin infections for centuries. The peppertree extract seems to not harm the skin’s normal, healthy bacterial flora. Additionally, as it does not kill MRSA pathogens, but only blocks it, researchers hope is that the extract would not promote antimicrobial resistance.
Public health researchers at University of Maryland School of Medicine, along with collaboration with researchers in Mali, have modeled the impact of a salmonella vaccine in young children in sub-Saharan Africa. Using this model, they estimate that with a three-dose vaccine series (or two with a booster shot) that this vaccine covering two of the most common types of salmonella can prevent 73% of the cases and 43% of the mortalities. However, the authors are quick to note that these findings do have limitations, including the lack of data on pediatric populations that could help identify where the disease is occurring but not detected through surveillance methods. Additionally, by focusing only on cases admitted to the hospital, the overall burden in the pediatric population was not modeled as it did not include those children who were not ill enough to be taken into the hospital.
In a recent study published in Nature Ecology & Evolution, researchers have found that antibiotics may accelerate bacterial reproduction. In their study, Escherichia coli was exposed to doxycycline, and subsequently, the growth rate, carrying capacity, and drug efflux rate increased. Speculation from the researchers who took part in the study includes a hypothesis that losing viral DNA stops the E. coli from destroying itself causing the bacterial cells to grow more quickly when the increase in pump DNA allows them to resist the antibiotic, which creates an evolutionary force change on two regions of the E. coli genome. Professor Robert Beardmore, of the University of Exeter and lead author of the study, stated in a press release that the “research suggests there could be added benefits for E. coli bacteria when they evolve resistance to clinical levels of antibiotics.”
Published in Nature Communications, scientists discovered a gene that prevents tuberculosis (TB) strains from mutating into drug-resistant forms. In a partnership between Centro Nacional de Biotecnología in Madrid and the University of Sussex in Brighton, researchers call this gene NucS. The gene reduces mutation rates in mycobacteria, the microbe that causes TB. Using a genetic screen to individually known out 11,000 genes in mycobacteria, the researchers tested the modified strains against rifampicin, a common antibiotic used to treat TB. Drug-resistant strains of TB have been reported in 105 countries, so such a discovery could play an important role in understanding the development of antimicrobial resistance in patients within these affected countries. In an accompanying press release, Professor Jesus Blázquez from Centro Nacional de Biotecnología emphasized that it is “vital that we take advantage of this and work towards exploiting this discovery to help doctors and microbiologists to predict and prevent the development of antibiotic resistance during treatments.”
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Note: The ARC Newsletter will periodically capture key meetings and developments, as well as news and resources, on antibiotic resistance for Coalition members and partners. This newsletter is prepared and published through ReAct North America/Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health. The ARC Declaration on Antibiotic Resistance can be found here. Please share items for consideration for inclusion in future newsletters by writing to Reshma Ramachandran at email@example.com.