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.

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

In memoriam Bill Craig

The PK/PD world has lost a leader and pioneer. Dr. William A. Craig has passed away Wednesday March 11, 2015. Bill Craig was instrumental in founding the International Society of Anti-InfectivePharmacology (ISAP). As current president of ISAP, I published an editorial in AAC with all past presidents and the president-elect of ISAP as coauthors. This orbituary has been recently published.

 

G7 summit June 2015

The leaders of the G7 agreed on concrete steps with regard to antimicrobial drug resistsance to respond to some of the most pressing issues in the world:

“Antimicrobials play a crucial role for the current and future success of human and veterinary medicine. We fully support the recently adopted WHO Global Action Plan on Antimicrobial Resistance. We will develop or review and effectively implement our national action plans and support other countries as they develop their own national action plans.

We are strongly committed to the One Health approach, encompassing all areas — human, and animal health as well as agriculture and the environment. We will foster the prudent use of antibiotics and will engage in stimulating basic research, research on epidemiology, infection prevention and control, and the development of new antibiotics, alternative therapies, vaccines and rapid point-of-care diagnostics. We commit to taking into account the annex (Joint Efforts to Combat Antimicrobial Resistance) as we develop or review and share our national action plans.”

Let’s hope that real action will follow the nice words.

Antibiotic research and development: business as usual?

My recent publication in the Journal of Antimicrobial Chemotherapy describes the problem of global resistance, the dry antibacterial R&D pipelines and the new IMI-funded, multistakeholder, €9.4 million DRIVE-AB (Driving Re-InVEstment in R&D and responsible AntiBiotic use) project with a consortium, composed of 14 public and 9 private partners from 12 countries.

New approved antibiotics

Which antibiotics has the FDA approved in the last year? Will they help combat antibiotic resistance?

In a blog published on the CDDEP website I give an overview of how the six new approvals will help treat resistant bacteria in certain patient populations. I summarise each antibiotic, give expert detail and context for these new drugs that have been in development for years and even decades. Though we will have six new antibiotics available based on known antibacterial drug classes or approaches, they will not provide a solution to the treatment of infections caused by extensively or pan drug-resistant bacteria.

COMBACTE-MAGNET launched

I am partner of the newly launched project COMBACTE-MAGNET. The European Innovative Medicines Initiative’s (IMI) program New Drugs for Bad Bugs (ND4BB) leads the efforts to  combat antibiotic resistance in Europe by tackling the scientific, regulatory, and business challenges that are hampering the development of new antibiotics. The 7 year, €167 million project will investigate a new approach to preventing respiratory infections in patients in intensive care units and new treatment options for patients with life-threatening infections caused by multi-drug resistant bacteria.

It will be exciting to be part of this important project that will perform clinical trials and describe the epidemiology of antibiotic resistance and healthcare associated infections.