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

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.

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.

Re-development of old antibiotics

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to ‘re-develop’ these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today’s standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance.

The recently published paper REVIVING OLD ANTIBIOTICS describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

Theuretzbacher U, Van Bambeke F, Cantón R, Giske CG, Mouton JW, Nation RL, Paul M, Turnidge JD, Kahlmeter G: Reviving old antibiotics. J Antimicrob Chemother. 2015 Jun 10. pii: dkv157

Progress on colistin

The European Medicines Agency recommended updating and harmonising the Summary of Product Characteristics of nationally approved colistin products throughout the EU to reflect what is currently known. The recommendations focus mainly on optimising dosing schedules but will also review the quality of the products and the way the potency of colistimethate sodium is measured and tested. Details here. This is a great success given the administrative challenges as the products have not been approved under the EU regulatory framework and knowledge is still evolving about how to use this drug.

In spring 2013 an expert conference in Prato summarised the current knowledge on polymyxin drugs and laid the ground for awareness and the need to update the information: The Lancet Infectious Diseases, 21 October 2014

R.L. Nation, J. Li, O. Cars, W. Couet, M.N. Dudley, K.S. Kaye, J.W. Mouton, D. L. Paterson, V. H. Tam, U. Theuretzbacher, B.T. Tsuji, J.D. Turnidge: Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.

Reviving old antibiotics: Colistin SPCs

Colistin is arguably the first case in the antibacterial field where substantial “re-development” activities have been driven by academic and clinical investigators, rather than a sponsoring company. As a result of these activities, there is rapidly evolving new non-clinical and clinical knowledge on colistin. My recently published study investigated the variation and accuracy of information in the summary of product characteristics (SPCs) of intravenous colistin products approved in the European Union. This study highlights the challenges of integrating new rapidly evolving scientific knowledge into approved SPCs in Europe.

More information on regulatory issues of colistin: http://epasg.escmid.org

Reviving old antibiotics: Colistin terminology

Multidrug resistance is a growing health crisis and old antibiotics such as colistin  are being used increasingly as a last-line therapy against infections caused by Gram-negative bacteria that are resistant to other available antibiotics. Colistin was never developed according to current regulatory standards and regional differences in approved product characteristics and labeling is confounding the appropriate clinical use of colistin worldwide. A serious problem is the confusing terminology of describing the contents of parenteral vials and corresponding doses of the administered prodrug  colistin colistin methanesulfonate (CMS) that may lead to lethal dosing errors.

The experts of The Prato Polymyxin Consensus recently published a letter to the editor of Clinical Infectious Diseases that recommends a consistent global approach on reporting of colistin doses and labeling.