The World Health Organization (WHO) states that we are in “a race against time to develop new antibiotics”, one of the most important health challenges facing the world today (OMS, 2014). The overuse of available antibiotics in human, veterinary and agricultural fields has favored the selection of highly resistant microbes (so-called « superbugs ») and “the speed with which bacteria develop new resistance can dampen the enthusiasm of anyone”. The situation for severe infections is alarming, some of them becoming untreatable by current antibiotics due to new resistant and emergent pathogens (pan-resistant bacteria e.g. MRC-1), particularly Gram negative bacteria (high prevalence of Pseudomonas aeruginosa-, Escherichia coli- and Klebsiella pneumoniae-resistant strains in EU, US and Asia). The crisis is amplified by a growing number of immuno-compromised populations at risk of catching severe infections in hospitals and home-settings (elderly>65 years, newborns, diabetics, chemotherapy patients).
Moreover, the decline of new antibiotic approvals and the disengagement in the late 90s of “Big Pharma” from the antibiotic area due to low return on investment make the situation highly critical: no new antibiotic classes have been discovered over the last three decades!
Medical, social and economic burden of nosocomial infections
Nosocomial infections are a major burden with increased prevalence (5.5 million/year) and mortality associated to expensive health-care costs, around 30-45 billion US$ for US, 7 billion € for Europe. Notably, severe pneumonia (HAP, hospital-acquired pneumonia and VAP, ventilated-associated pneumonia) represent the 1st hospital acquired-infection, the 6th cause of death and the major cause of sepsis (Decision Resources 2010 and presentation of the IDSA to the House Committee on Energy and Commerce’s Subcommittee on Health in 2012).
Without major intervention, by 2050 antibiotic resistance is expected to kill about 10 million people annually (more than cancer) according to a recent analysis, called « The Review on Antimicrobial Resistance, » commissioned in 2014 by the UK government.
The battle against antibiotic resistant bacteria
There is an urgent medical and economic need to propose innovative solutions to combat increasingly hard-to-treat nosocomial infections. Worldwide health programs have started to preserve our most efficient antibiotics by a more rational use, with holistic approaches (in animals and humans) and to find new specific antimicrobials targeting the lastest emergent strains (amongst these programs are FP7, IMI ND4BB, JPIAMR, ERANET, EUROSTARS for Europe and BARDA, NIH NIAID, FDA, Obama’s budget for ID in US). However, antibiotics are medicines with only temporary use: by targeting pathogen growth, they induce the development of various resistance mechanisms by the bacteria set up to counteract antibiotic efficacy. Besides novel antibiotics, all preventive approaches and alternative strategies to antibiotics, are eagerly expected by patients and clinicians to fight AMR and nosocomial infections.
Europe is taking the lead in AMR with two key initiatives: BEAM alliance and EUCAST, creating a global consensus for antimicrobial breakpoint to combat AMR in future drugs
- BEAM: Biopharmaceutical companies from Europe innovating in Anti Microbial resistance
The BEAM co-founder, F Séjourné (CEO of DaVolterra) identified about 100 projects within the portfolio of BEAM members, yielding 65 new antibacterial compounds of which 22 at clinical stages.
The BEAM Alliance wants to improve the regulatory, investment, and commercial environments in Europe to promote research, development, approval and market viability of new medicines fighting AMR. By accurate analyses of the global crisis situation of R&D in AMR and deep evaluation of the portfolio (drugs and strategies) of its members, on 30 September 2015, Beam alliance published a position paper sent to European Health institutions and press releases on key measures necessary to stimulate antimicrobial research across Europe.
The BEAM Alliance urges European and national public authorities to take three key short term actions with immediate effect: (1) create a specific fund dedicated to small and medium biopharmas developing innovative antibacterial products, (2) enhance market incentives to increase the return on investment for products tackling antimicrobial resistance through the creation of a special status (antibacterial products are not standard drugs), (3) simplify regulatory pathways for products tackling antimicrobial resistance (the orphan drug regulatory status represents a successful example to favour new drug development).
In this context, VibioSphen, a SME healthcare biotechnology company in the field of infectious diseases, joined the BEAM alliance in September 2015 to support the AMR battle. It focuses its activities on the challenge of antibiotic resistance and nosocomial infections by developing high value preclinical infectious models (CRO) and innovative therapeutic solutions complementary to antibiotics (R&D). Using specific immune modulator treatments able to enhance host defenses and to control infection/inflammation development, VibioSphen offers a novel therapeutic solution adjunctive to antibiotics to tackle nosocomial pneumonia, without inducing pathogen resistance.
- EUCAST : European Committee on Antimicrobial Susceptibility Testing
EUCAST mission targets the standardization of the definition of resistance for each relevant antimicrobial agent and species throughout Europe and the rest of the world. The goal is to create a global consensus for antimicrobial breakpoint to combat antibiotic resistance in future drugs.
An antimicrobial breakpoint is the agreed concentration at which the growth of bacterium is inhibited— minimum inhibitory concentration (MIC)—which essentially defines at what dose each bacteria is considered susceptible or resistant to antimicrobial therapy. Essentially, the breakpoint is a man-made decided concentration defining the dose required to inhibit bacterial growth in relevant clinical infections. The breakpoint is published on the EUCAST website for consultation.
Gunnar Kahlmeter (Communications officer and past President of ESCMID and CDC), on behalf of ESCMID and EUCAST, underlined the importance of developing antimicrobial breakpoints to fight globally resistance in a recent article published in Pharmaceutical Processing online: “Breakpoints of new agents are vital in harmonization of a global definition of resistance and the point at which increased dosages are needed to treat patients”
Together with EMA, EUCAST has determined breakpoints for more than 10 new agents and continues with several compounds. Companies in the process of developing new antimicrobial agents are encouraged to seek contact with EUCAST early in the development cycle to obtain advice on the procedure.
Having common system and protocols to determine the defining and measuring of resistance is the ultimate goal of EUCAST and its members. Throughout Europe, 90 percent of countries are now following the EUCAST categorization of bacteria as susceptible or resistant to new and existing antimicrobial agents (the UK British Society for Antimicrobial Chemotherapy (BSAC) recommended all UK laboratories to adopt EUCAST by end of 2015). EUCAST AMR definition extends to several non-European countries including Australia, New Zealand, South Africa, and Morocco. “Previous to EUCAST, it would have been particularly complicated to use a common system given that there were seven different systems in place”. Everyone agrees that international unity would be beneficial to all. In USA, there are still two sets of breakpoints, those decided by FDA as part of the registration process and those recommended by CLSI (Clinical Laboratory Standards Institute). A group of U.S. scientists now works as an integral part of EUCAST.
The emergence of multi-drug resistant bacteria represents a worldwide public health crisis which urgently demands the development of new antibiotics and preventive or alternative/complementary strategies to antimicrobials. Because AMR bacteria have no boundaries, the situation requires also a global consensus for antimicrobial breakpoint definitions with unified values for resistance between countries to tackle AMR worldwide and efficiently cure infected patients. The Beam alliance and EUCAST are two active EU institutions involved in these challenges.
- Antimicrobial resistance at dangerous levels
A new report from the World Health Organization warns of the dangers of antibiotics’ overuse. But it also highlights how the worrying trend might be reversed. (26.03.2012)
- WHO: widespread confusion about antibiotic resistance and what causes it
There is widespread misunderstanding about the correct use of antibiotics worldwide, a report by the World Health Organization says. It calls antibiotic resistance one of the « greatest challenges for public health. » (16.11.2015)
- Carbapenem-resistant and colistin-resistant Escherichia coli co-producing NDM-9 and MCR-1.
Yao X, Doi Y, Zeng L, Lv L, Liu JH. Lancet Infect Dis. 2016 Jan 29. S1473-3099(16)00057-8
- Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.
Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. Lancet Infect Dis. 2016 Feb;16(2):161-8
- SMEs exact their toll. Insight Europe, European Biotechnology, Winter Edition, Vol 14, 6-8 2015
- http://beam-alliance.eu/.30 September 2015. Publication of the Alliance’s Position Paper; Download the position paper, the English press release, the French press release
- Developing antimicrobial breakpoint. Gunnar Kahlmeter of ESCMID & EUCAST Pharmaceutical Processing online article
- EUCAST- Breakpoint tables for interpretation of MICs and zone diameters. EUCAST: Breakpoint table v 5.0 2015 published