Development of new antibiotics : taking off finally ?

List of abbreviations ABSSSI: acute bacterial skin and skin structure infections AMR: antimicrobial resistance ANRESIS: Swiss Antibiotic Resistance Surveillance database BARDA: Biomedical Advanced Research and Development Authority BLI: β-lactamase inhibitor CABP: community-acquired bacterial pneumonia CHMP: Committee for Medicinal Products for Human Use cIAI: complicated intra-abdominal infection CRE: carbapenem-resistant Enterobacteriaceae cUTI: complicated urinary tract infections EFPIA: European Federation of Pharmaceutical Industries and Associations EMA: European Medicines Agency ESBL: extended spectrum β-lactamase EU: European Union FDA: Food and Drug Administration FNIH: Foundation for the National Institutes of Health GAIN: Generating Antibiotic Incentives Now Gram‒: Gram-negative. Gram+: Gram-positive HAP: hospital-acquired pneumonia IMI: Innovative Medicine Initiative JPI-AMR: Joint Programming Initiative on Antimicrobial Resistance KPC: Klebsiella pneumoniae carbapenemase MDR: multi-drug resistant MRSA: meticillin resistant Staphylococcus aureus NA: not applicable ND4BB: New Drugs for Bad Bugs NIBR: Novartis Institute for Biomedical Research PDR: pan-drug resistant QIDP: Qualified Infectious Disease Product R&D: research and development SME: small and medium enterprises VAP: ventilator-associated pneumonia VRSA: vancomycin-resistant Staphylococcus aureus WAAAR: World Alliance against Antimicrobial Resistance WHO: World Health Organization XDR: extensively drug resistant fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges. Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i.e. multiresistant Gram-negative bacteria. Of the three new antibiotics with pending authorisation in Switzerland for systemic treatment of severe infections, oritavancin and tedizolid target Grampositive pathogens, while only ceftolozane+tazobactam partially covers multiresistant Gram-negative pathogens. Among six antibiotics currently in phase III of clinical development, delafloxacin and solithromycin will also be useful mostly for Gram-positive infections. Importantly, the four other compounds are active against multiresistant Gram-negative pathogens: ceftazidime+avibactam, meropenem+RPX7009, eravacycline and plazomicin. The three last compounds are also active against carbapenemresistant Enterobacteriaceae (CRE). A few compounds active against such pathogens are currently in earlier clinical development, but their number may decrease, considering the risk of failure over the course of clinical development. At last, through public and political awareness of pathogens with high public health impact and unmet medical need, development of innovative economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again.


Introduction
Although antimicrobial resistance (AMR) existed well before humans started to use antibiotics to treat infections, the menace of a post-antibiotic era threatening modern day medicine is closer to reality than ever before [1,2].Based on modelling studies, the impact of AMR was recently quantified as potentially causing the death of 300 million people during the next 35 years and having so much impact as to decrease the world gross domestic product by 2-3.5% compared with what it should be by 2050 [3,4].Although these crude predictions are based on large uncertainty and may overestimate the future health-economic impact of AMR [5], experts and policy makers agree that AMR should be considered a serious public health threat.Both common and rare pathogens found in hospitals and in the community have seen their resistance rates increase dramatically in recent decades.As reported by the World Health Organization (WHO), more than 50% of Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus are reported as resistant to commonly used antibiotics in many parts of the world [6].Several levels of acquired resistance to antibacterial agents have been defined.Multidrug resistant (MDR) pathogens are resistant to at least one antibiotic in three or more antibiotic classes, extensively drug resistant (XDR) pathogens are resistant to at least one antibiotic in all but one or two antibiotic classes and pandrug resistant (PDR) pathogens are resistant to all antibiotics in all clinically relevant antibiotic classes [7].The causes of such a rise in resistance are multiple, from natural evolution to antibiotics overuse in patients and farm animals [8].In Switzerland, the overall prevalence of MDR among E. coli isolates at a single hospital in 2011 was still low (6.5%) compared with the numbers reported by the WHO and was similar in the community (5.7%), hospital (7.8%) and specialised outpatient clinic (5.3%) settings [9].However, using data from the Swiss Antibiotic Resistance Surveillance database (ANRESIS) [10], Kronenberg et al. also showed that the prevalence of MDR increased significantly between 2004 and 2011 from 1% to 5.8% for E. coli and from 1.1% to 4.4% for K. pneumoniae [11].Unfortunately, development of new antibiotics against these resistant bacteria did not progress at the same speed, and even lagged behind.This worrisome trend leaves physicians with a limited therapeutic arsenal for an increasing number of resistant pathogens and the absence of therapy for some PDR pathogens.Although a few new antibiotics might be available in Switzerland in the next couple of years, these new agents are not based on completely new mechanisms of action as they do not attack new bacterial targets.Nevertheless, through modified economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again, as we describe in this narrative review.

The crisis of antibiotic research and development
During the flourishing years of antibiotic development in the 1940s and 50s, 12 different classes of antibiotics were discovered, but only seven have been discovered since, the last one being the lipopeptides in the 1980s [12].Despite this discovery void, the panel of antibiotics available for clinicians to treat susceptible infections still remains large.Many of these antibiotic compounds belong to a known class, but were chemically modified from the original compound to increase the number of susceptible pathogens or to be insensitive to a particular mechanism of resistance.This flourishing era was followed by a steep decline in numbers of new antibiotics approved during the 1990s and 2000s.Indeed, difficulties in the development of new anti-biotics spanning the whole spectrum of drug development appeared: drug discovery challenges [12], regulatory hurdles [13,14], difficulties in conducting clinical trials [15] and economic disincentives [16,17].It also led large pharmaceutical companies to desert this area for more lucrative and less scientifically and economically challenging therapeutic areas, like cardiology and oncology [18].Although this inverse trend (increasing AMR rates / decreasing availability of efficient antibiotics) has been known for a long time, many alerts and calls to action were needed to raise the awareness around the problem and trigger policy initiatives.

MDR pathogens with unmet medical need
The starting point to raising awareness around the AMR issue and setting priorities for R&D of new antibiotics was to define resistant pathogens for which the highest unmet medical need exists or, in other words, resistant pathogens that have the potential to pose the most serious threat to public health.A first list of six key pathogens was created in 2008 under the acronym "ESKAPE pathogens" [19]: Enterococcus faecium, S. aureus, K. pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species.In 2014, the United States Food and Drug Administration (FDA) released a final list of a total of 21 target pathogens (table 1) with high unmet medical need [20].As highlighted in the table, the unmet need is highest for XDR or PDR strains [21].Importantly, this list shows that AMR is not a problem restricted to the healthcare setting only, but that common community-acquired infections such as urinary tract infections, gonorrhoea and tuberculosis are increasingly caused by MDR or XDR pathogens.Since January 2012, when the Generating Antibiotic Incentives Now (GAIN) act came into effect in the United States, development of a new antibiotic agent active against one or several pathogens on this list allows a Qualified Infectious Disease Product (QIDP) designation to be obtained.This offers several incentives such as priority review of the new drug application file by the FDA and an economic incentive in the form of 5 additional years of market exclusivity if a marketing authorisation is obtained.Other economic incentives have been put in place recently in the United States.Funds from the Biomedical Advanced Research and Development Authority (BARDA), which are public, nonrefundable funds given to companies to develop specific compounds for potential bioterrorism threats, are now extended to compounds active against MDR, XDR and PDR pathogens [22].Consequently, the overall United States budget for 2016 to fight AMR almost doubled to about 1.2 billion dollars.
will leading to policy, legal and regulatory changes if our society wants to keep up with the issue.Essential determinants impacting R&D of new antibiotics are displayed in figure 1. Thanks to the mobilisation and lobbying activities of several independent initiatives, awareness of the AMR problem has finally risen since 2010 and the second step of concerted action is advancing.The initiatives that have played a key role in raising global awareness on AMR include the independent global network ReAct [23], the World Alliance against Antimicrobial Resistance (WAAAR) [24] and Antibiotic Action [25].Although the bulk of multidrug resistance might lie outside of these regions, the United States and the European Union (EU) are key regions for pharmaceutical companies to register a new drug.New regulatory guidance for infections caused by bacteria with high unmet medical need (i.e., in this case MDR, XDR and PDR bacteria) have been issued by the European Medicines Agency (EMA) and the FDA [26,27], with the aim to facilitate the approval of new antibiotics.A new risk/benefit balance must be found between approving new antibiotics with limited clinical data, because of the high unmet need, and ensuring patients are treated with new antibiotics that are safe and efficacious.This kind of trade-off has been successfully applied in drug development, for example, to orphan diseases [28,29].Furthermore, potential new regulatory pathways being discussed for new antibiotic agents include (1) the Limited Population Drug Approval mechanism [30] and (2) the tiered approach in which different amounts of clinical data are required on the basis of the level of unmet medical need and pathogen-based indications are pursued rather than conventional disease-based indications [31].Methodological investigations on how to ameliorate trial design for antibiotics are also being addressed by different consortia involving the academic, private and regulatory sectors, such as the Foundation for the National Institutes of Health (FNIH) biomarkers consortium [32] and the COMBACTE project [33], part of the Innovative Medicine Initiative (IMI)'s New Drug for Bad Bugs (ND4BB) programme [34].IMI is a public-private partnership between the EU and the European Federation of Pharmaceutical Industries and Associations (EFPIA).Its ND4BB programme launched in 2013 aims to promote R&D of new antibiotics: the TRANSLOCATION and ENABLE projects focus on the discovery stage, the COMBACTE, COMBACTE-MAGNET, COMBACTE-CARE project include clinical trials with new compounds and the sharing of clinical de-Table 1: Qualified infectious disease product (QIDP) qualifying pathogens: pathogens that have the highest unmet medical need.

Community acquired
Acinetobacter species 1  Gram-X X Enterobacteriaceae 1 (especially Citrobacter, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Salmonella, Serratia marcescens, Shigella) Cryptococcus species NA X 1 Key unmet need due to high and increasing prevalence of XDR or PDR strains [21] 2 Unmet need primarily for blood, bone and prosthesis infections and not for skin infection.
NA = Not applicable.[36], such public-private partnerships are an important contribution to a wealth of measures that can be implemented to support the R&D of new antibacterials.Rapid diagnostic test development is another key area and has been recently incentivised through a prize [37].

Review article: Current opinion
Other initiatives include the Joint Programming Initiative on Antimicrobial Resistance (JPI-AMR) in the EU [38] and an independent review on AMR commissioned by the United Kingdom government in July 2014 [39].The latter initiative aims to deliver a list of priority action items that should be agreed internationally to tackle AMR.Last but not least, the recent WHO action plan on antimicrobial resistance (adopted in May 2015) [40] will without a doubt foster attention and trigger a series of actions at a global level.

Current systemic compounds active against MDR pathogens recently or in the process of being registered
What is the current pipeline status and are any new antibiotic agents likely to reach Swiss pharmacies in the next 2 years?First, as listed in table 2, five systemic compounds have been approved since May 2014 in the United States (ceftolozane+tazobactam [41], oritavancin [42], tedizolid [43], dalbavancin [42] and ceftazidime+avibactam [44]).All had QIDP designation, meaning they are active against at least one of the pathogens with high unmet medical need (table 1).Four of these five new antibiotics or antibiotic combinations have pending marketing authorisations at the EMA and three of them (ceftolozane+tazobactam, oritavancin and tedizolid) have been submitted to the Swiss Agency for Therapeutic Products (Swissmedic).One new antibiotic agent, ceftobiprole [45], was approved in the EU at the end of 2013 and in Switzerland at the end of 2014, after unusually long regulatory approval delays [46].Importantly, four of these six compounds have activity mainly against Gram-positive pathogens and will, therefore, be useful for treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections.As MRSA infection rates are decreasing in many parts of Europe [47,48], these new compounds are enlarging our arsenal but clearly not tackling the key emerging resistant Gram-negative pathogens.Only ceftolozane+tazobactam, which has a submission pending in Switzerland, partially covers MDR Gramnegative pathogens such as extended spectrum β-lactamase (ESBL)-producing strains.Importantly for MDR Gram-negative infections, ceftazidime-avibactam was approved in January 2015 in the United States for complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), but restricted to patients who have limited treatment options [49].Avibactam is the first new β-lactamase inhibitor (BLI) approved in two decades.Using the new regulatory guidance and QIDP designation registration process, the antibiotic combination was approved on the basis of data for ceftazidime alone, supplemented by in-vitro and phase II data for ceftazidime+avibactam in the targeted indications [49].Phase III trials are planned to be completed in 2015 [50].Although the label is currently restricted because of the limited availability of data, it will help to preserve use of the drug and development of resistance.It remains to be seen whether, once data from ongoing phase III or postmarketing studies are available for broad spectrum antibiotics such as ceftazidime+avibactam, pharmaceutical companies will try to expand the label, leaving it to countries' public health systems to decide upon and put in place conservation measures for these precious new antibiotics.

Current systemic compounds active against MDR pathogens in phase III and their potential use in Switzerland
As of June 2015, six compounds are in phase III for the systemic treatment of severe bacterial infections.They all have QIDP designation.While delafloxacin [51] and solithromycin [52] will most likely play a role in management of Gram-positive infections [53], four of the six other compounds that could be available in Switzerland within the next 3-5 years have activity against MDR Gram-negative pathogens with key unmet medical needs (table 2 and [21]): ceftazidime+avibactam [44], meropenem+RPX7009 [54,55], eravacycline [56] and plazomicin [57].Notably, three of these are also active against carbapenem-resistant Enterobacteriaceae (meropenem+RPX7009, eravacycline and plazomicin).
In Switzerland, there are a few published small-scale outbreaks [58] and reports of imported cases of carbapenemresistant Enterobacteriaceae (CRE) from endemic countries [58][59][60][61][62][63].Thus, the need for new therapeutic agents is so far very limited, but this will likely change in the coming years as more and more infections with CRE will occur with the global spread of XDR/PDR Gram-negative bacteria [64].As current treatment options for CRE are limited to, for example, colistin, fosfomycin, tigecycline or combination therapies [65], compounds active against such XDR bacteria such as eravacycline, plazomicin or meropenem+RPX7009 will hopefully be available to treat patients by that time.
The need is very different in Switzerland for ESBL-producing strains, which are now widely present in the community.Indeed, local studies have shown that carriage of ESBLs is observed in 5.8% of screened healthy people [66] and 4.8% of patients at admission [67].Most ESBLproducing Enterobacteriaceae are resistant to fluoroquinolones and cotrimoxazole, limiting orally available therapeutic options for more severe ESBL infections.Fosfomycin and nitrofurantoin remain highly active for uncomplicated UTI, which led to new Swiss treatment guidelines for uncomplicated UTI: the recommended first-line antibiotic changed from a quinolone agent to fosfomycin or nitrofurantoin [68,69].

The current early antibiotics development pipeline: overview of promising compounds in phase I and II of clinical development
As listed in the inventory of antibiotics in clinical development kept by the Pew Charitable Trusts antibiotics and innovation project [70], there are currently 37 antibiotics overall in clinical development from phase I to registration for systemic bacterial infections (including Clostridium difficile infection).Ten compounds are in phase I and 18 in phase II.All of these have QIDP designation, meaning that they are active against at least one QIDP-qualifying pathogen.Based on published calculated failure rates for all therapeutic areas [71,72], only 1 in 9 or 10 compounds entering phase I can be expected to obtain market approval.This ratio could be even smaller for innovative antibiotics displaying new mechanisms of action.As mentioned earlier, pharmaceutical companies massively left the antibiotics field in the 1990s.Importantly, some of the large pharmaceutical companies that had left are back in the antibiotics R&D field.In Switzerland, the two largest Swiss pharmaceutical companies Novartis and Hoffmann-La Roche have restarted R&D activities for antibiotics.Roche started a partnership in 2013 with Polyphor to develop RG7929 (POL7080), a compound active against MDR Gram-negative bacteria and in particular MDR P. aeruginosa [73].Two phase II clinical trials with this compound Since 2010, awareness around the AMR issue has dramatically increased and actions have started to be called for or implemented.R&D of new antibiotics is a key component of all programmes aiming at fighting AMR, but it has lagged owing to a plethora of scientific, regulatory and eco-nomic challenges.During past years, regulatory guidance has been updated and economic incentives have started to be put in place.This is encouraging both large and small pharmaceutical companies to slowly re-enter the antibiotics field.As R&D is a long process, the real effect of all these measures and restarting R&D activities will only be assessable in 5-10 years in terms of new antibiotics available to treat patients infected with MDR, XDR and PDR pathogens.As AMR is a global issue, coordinated action will now become key in order to optimise the use of resources to develop new antibiotics, as well as to allow their appropriate distribution (where they are most needed in terms of patterns of AMR) and use (to prevent development of AMR).

Figure 1
Figure 1 Essential determinants impacting the research and development (R&D) of new antibiotics.QIDP = qualified infectious disease product.

Figures (large format) Figure 1
Figures (large format) phases I to III, and the DRIVE-AB project, which started in October 2014, aims to develop new economic models for antibiotics while preserving their use[35].With a total budget for infectious diseases of over 710 million euros Swiss Med Wkly.2015;145:w14167 Swiss Medical Weekly • PDF of the online version • www.smw.chvelopment costs from

Table 2 :
Late-stage pipeline: systemic antibiotics recently approved, in registration or in phase III of clinical development.