WHO priority pathogen list for R&D published

The WHO priority pathogen list for R&D was recently published. I contributed my R&D expertise to this intense work. The list should prioritise and guide R&D of new antibiotics, as part of WHO’s efforts to address growing global resistance to antimicrobial drugs. The process was based on collecting all available evidence to develop criteria that were used in a multi-criteria decision analysis technique vetted by a group of international experts.

The list is an important step to spur governments to put in place policies that incentivize basic science and R&D by both publicly funded agencies and the private sector investing in new antibiotic discovery.

List

Antibacterial innovation in European SMEs

This analysis provides a current snapshot of the innovation potential for antibacterial R&D among European small and medium-sized enterprises (SMEs). It has been recently published in Nature Reviews Drug Discovery. The report shows that far more effective coordination and well-targeted support by public and philanthropic funders will be crucial to sufficiently fill antibiotic R&D pipelines according to priorities based on the greatest public health needs.

Ursula Theuretzbacher: Antibacterial innovation in European SMEs. Nature Reviews Drug Discovery 2016, 15:812–813

Council of the European Union: Next steps to combat antimicrobial resistance

On 17 June, 2016, the Council of the European Union published conclusions on the next steps for the EU to combat antimicrobial resistance (AMR) under a One Health approach. The role of the Council is to serve as the voice of the EU member governments. The Council welcomes other international and regional initiatives, such as the declaration by the G7 on Antimicrobial Resistance and the decision to put antimicrobial resistance on the agenda of the G20.

In its conclusions to combat AMR, the Council has adopted a One Health approach, which considers the importance of intricate interactions between human, animal, and environmental health in addressing AMR. The conclusions also state the importance of research and development into new antimicrobials, as evidenced by item 16 below, where the Council recognizes the accomplishments of DRIVE-AB in this area:

16. UNDERLINES that in order to stimulate the development of new antimicrobials, alternative therapies and (rapid) diagnostics, EU and global coordination and cooperation on research programmes and incentives are needed and RECOGNISES the work done by the Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving reinvestment in research and development and responsible antibiotic use), the proposals of the Antimicrobial Resistance Review team and the Joint Programming Initiative on Antimicrobial Resistance among others.

DRIVE-AB is a publi-private-partnership supported by the the Innovative Medicines Initiative of the EU and developes new economoic models to stimulate antibiotic R&D.

Conference to stimulate innovation in antibiotic R&D

On Thursday 2 June, 2016, the DRIVE-AB consortium, which is developing new economic models to stimulate antibiotic innovation and ensure global access to and sustainable use of antibiotics, held the “Stimulating innovation, sustainable use and global access to antibiotics” conference in Amsterdam.

Global leaders agree on the need to maintain a steady supply of new antibiotics for all as a critical part of the strategy to address antibiotic resistance and that new reward models are necessary to achieve this goal. While basic frameworks have been proposed, the DRIVE-AB consortium seeks a level of granularity that other initiatives have not, moving beyond discussions to concrete plans for policy implementation.

DRIVE-AB shared its preliminary proposals at the event, which attracted more than 180 high-level decision-makers and policy experts, economists, regulatory and public health experts and representatives of pharmaceutical companies and research institutions from around the world. The conference featured keynote speakers and panellists from the World Health Organization, the European Commission, the European Investment Bank, and the US Centers for Disease Control and Prevention, to name a few. The participation of a diverse group of stakeholders at the conference illustrates the level of global interest in the outcomes of DRIVE-AB, and will help the consortium secure the buy-in of stakeholders who can help to implement new incentive policies.

More….

DRIVE-AB Conference in Amsterdam

The DRIVE-AB Conference Stimulating innovation, sustainable use and global access to antibiotics will take place on 2 and 3 June 2016 in Amsterdam. This conference, generously funded by the Government of the Netherlands and organized by the IMI DRIVE AB consortium, will bring together about 150 invited decision-makers and policy influencers from around the world to explore current and proposed efforts to address antibiotic resistance. The main goal of the meeting is to move beyond discussions and instead identify key policies that can be implemented globally to both stimulate the innovation of critically-needed new treatments and ensure their availability and responsible use. Input from the conference will help inform DRIVE AB’s policy recommendations to the European Commission—an important part of growing global discussion on how to manage the looming public health threat of resistance.

Presenting at TATFAR meeting in Luxembourg

The Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) identifies and adopts recommendations for collaborations between the US and the EU to respond to the growing challenges posed by antimicrobial resistance. The biennial in-person TATFAR meeting will take place October 22-23, 2015 in Luxembourg City and I have been invited to present my views in the expert workshop “How do we keep new antibiotics effective? Balancing access and conservation”.

My slides will be available on the AIDA website after the meeting.

G7 Health Ministers address antibacterial resistance

The G7 Health Ministers discussed antibacterial resistance during the G7-Meeting in Berlin on 8 and 9 October 2015.

The “Berlin Declaration on AMR” includes strong committments to:

  • Improve the coordination between global initiatives and  joint international efforts encompassing human and animal health, agriculture and the environment.
  • National AMR Action Plans will take into account the requirements of the WHO Global Action Plan.
  • Support other countries with the development and implementation of their National Action Plans, building global capacity to combat AMR and coordinating activity.
  • Three-fold approach to AMR: improving infection prevention and control; conserving the effectiveness of existing and future antimicrobials; engaging in research to optimise such approaches and to develop new antimicrobials, vaccines, treatment alternatives and rapid diagnostic tools.
  • Pool the national efforts in order to share best practices and promote the prudent use of antimicrobials among all relevant stakeholders.
  • Increase awareness among the general public of the impact of AMR .
  • Call on all countries to enforce the availability of antibiotics by prescription only.
  • Strengthen antibiotic stewardship programs for professionals.
  • Ensure the production of high quality antimicrobials in human and veterinary medicine.
  • Strengthen surveillance systems on AMR and antimicrobial consumption.
  • Inform research prioritization and encourage the research and development of new antimicrobials, vaccines, alternative treatment options and diagnostics.
  • Explore innovative economic incentives to enhance the research and development of new antibiotics, other therapeutic options, and diagnostics, e.g. a global antibiotic research fund and a market entry reward mechanism for truly new antibiotics targeting the most important pathogens and most needed for global public health.
  • Explore the feasibility and need of setting up a global antibiotic product development partnership.
  • Encourage international cooperation on antimicrobial stewardship and regulatory dialogue on the approval and regulation for antibiotics.

DRIVE-AB supports this initiative and will provide scientific data to inform the decisions regarding antibiotic stewardship (metrics to define the prudent antibiotic use) and innovative economic incentives to encourage research and development of new antibiotics.

Where are new antibiotics coming from?

While most big pharma companies left the field of antibiotic drug discovery, small companies—mostly backed by academic institutions—are stepping in to drive research and early clinical development in the antibiotics field. Most small companies face serious hurdles when focusing on antibacterial drug R&D.  These challenges are not only financial limitations but also scientific problems, shortage of experienced personnel, dependence on external support, lack of appropriate diagnostics, the need for R&D short cuts, and IP issues in collaborations may impact directly on these companies.

My recent  GEN Exclusives article in Genetic Engineering & Biotechnology News (GEN), a widely read biotech publication and online portal highlights some of my activites related to antibiotics R&D in small companies.

An in-depth analysis of the role of small companies in anitbiotics R&D can be found on the DRIVE-AB website. The EU project DRIVE-AB (Driving reinvestment in research and development and responsible antibiotic use) is funded by the Innovative Medicines Initiative (IMI) to find ways policymakers can stimulate innovation, responsible use and global access to antibiotics to meet public health needs. A central objective of DRIVE-AB is to engage with all interested stakeholders including small companies.

New economic models to incentivice antibiotics R&D should strongly consider the contributions of small companies and publicly funded research institutions.

Global antibacterial resistance: The never-ending story

New resistance mechanisms evolve, resistant bacteria are spreading quickly in some parts of the world. The topic of resistance finds increasingly interest as physicians are confronted with infections caused by multi-drug resistant, extensively- drug resistant and even pan-drug resistant bacteria without any therapeutic option.

The new Journal of Global Antimicrobial Resistance focuses on the global spread of antibiotic-resistant microbes. It has received its first Impact Factor despite not being indexed yet by PubMed. My paper, published 2 years ago, is the most-cited paper from this new journal: Global antibacterial resistance: The never-ending story.

Revived old antibiotics: Nitrofurantoin

Bacterial resistance increases and old antibiotics are being revived to expand therapy options or ease the selection pressure for commonly used drugs. Nitrofurantoin was commercialized in an era predating requirements for robust methodology in drug development. Despite the drug’s resurgence and widespread consumption, uncertainties persist regarding PK/PD relationships, dosing, efficacy and toxicity. The re-developing process of a revived antibiotic in an academic setting starts with a systematic review to identify knowledge gaps and select the most important non-clinical and clinical studies.

The EU-funded AIDA project (FP7 HEALTH.2011.2.3.1-1—Preserving Old Antibiotics for the Future) is systematically “re-developing” some old antibiotics and includes vital PK, PD studies and PK/PD analysis as well as 3 randomized controlled clinical trials.

One of the studied drugs in nitrofurantoin for uncomplicated lower urinary tract infections caused by multi-drug resistant bacteria. The current body of clinical knowledge is unclear. For this reason we performed a structured, systematic review and meta-analysis of controlled clinical trials to evaluate nitrofurantoin’s efficacy and toxicity when given short term (≤14 days) for the treatment of UTI.

This study has just been published in the Journal of Antimicrobial Chemotherapy.

Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW: Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Jun 11.

OBJECTIVES: Nitrofurantoin’s use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin’s efficacy and toxicity in the treatment of lower UTI.
METHODS: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials.
RESULTS: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin’s clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare.
CONCLUSIONS: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.