This report gives a comprehensive overview of global antibiotic resistance, the antibiotics pipeline and new strategies to target resistance mechanisms. It identifies 109 antibiotics in the development pipeline, approximately 70% of which are in early development (Preclinical and Phase 1). In contrast, there are just 9 candidates at Phase 3, while there are 31 at Phase 2. These developments are being progressed by 66 companies, of which nine (14%) are major international corporations and 57 (86%) are Small/Medium Sized Enterprises (SMEs).

While antibiotics are effective for the majority of infections, increasing resistance in some pathogens threatens to undermine the few remaining drugs that are still effective against them. This is evident in the case of Klebsiella pneumoniae. Since 2005, there has been a significant decrease of susceptibility to carbapenems in invasive Klebsiella pneumoniae, causing concerns due to the lack of therapeutic options for treating these infections.
Antibiotic resistance is a long-evolved trait in prokaryotes. The extensive capabilities of the resistome, together with the ability of bacteria to establish new mutant variants in response to man-made antibiotics, suggest that antibiotic resistance will remain an ever-present threat. It is therefore not so much a question of whether a pathogen will become resistant to an antibiotic, but when. However, the development of new drugs and targeting mechanisms provide an opportunity to “reset the clock” on resistance levels in particular pathogens.
In the last decade, the capacity to target pathogens has also been undermined by a lack of innovation, which has seen a 60% fall in the numbers of new approvals and few novel molecules. However, as this report has shown, this trend is changing. Today, there are more than 100 candidate antibiotics in development, of which half are in the clinical pipeline. While there are several promising candidates at Phase 3 which offer hope of new approvals in the coming years, Phase 2 developments are now substantial, suggesting the emergence of a new era in the types of antibiotics and the strategies that will be available to target pathogens in the future.

Background
In Europe, 25,000 people die every year from drug-resistant infections and in 2009 there were 440,000 new cases of MDR tuberculosis, in 69 countries. These figures, and rising resistance levels seen in global surveillance programmes, show that antibiotic resistance has reached a critical point, as human and economic costs escalate. Many pathogens are now completely resistant to beta lactam antibiotics and MDR resistant Gonorrhoeal strains have emerged.
Resistance is a familiar problem in drug therapy, however there are unique aspects to antibiotic resistance in bacterial pathogens. This is because bacteria have evolved genetic and phenotypic attributes, which specifically enable them to withstand antibiotics, which they produce naturally. In consequence, bacteria have established a diverse pool of genes (the “resistome”) that protect them against antibiotics used therapeutically, to target them. Killing pathogens is the goal of antibiotic therapy, but there is now a need to extend the capabilities of anti-bacterial therapies; to develop drugs that both destroy pathogens and also undermine resistance mechanisms in more effective ways.

Antibiotic resistance is now a global healthcare threat and today’s armoury of antibiotics is increasingly limited. For some pathogens, the choice of available drugs is now greatly reduced. Increasing mortality from infections caused by resistant strains, and the strong link between resistant pathogens and increasing levels of hospital-acquired infections, together with escalating healthcare costs, have put antibiotic resistance at the top of the healthcare agenda.
Despite its importance, pathogenomics (genome research on pathogenic microorganisms) is still at an early stage in its development, compared to human genome research. While bacterial genomes and phenotypes are being mapped, much less information is available on the horizontal spread of virulence genes across bacterial populations, an area that has fundamental relevance to keeping pace with the emergence of new resistant strains and the therapeutic strategies that can be used to target them. However, important initiatives are moving forward, notably the ERA-NET Pathogenomics programme and the development of the LLNL database.
According to the US Centers for Disease Control and Prevention, 1.7 million patients per year in the US acquire an infection while in hospital, resulting in 99,000 (5.8%) deaths. In 1992, deaths from hospital-acquired infections in the US were 13,300, showing a 670% increase over a decade, equivalent to around a 20% annual growth during that time. The CDC also report that 70% of bacteria responsible for hospital-acquired infections are resistant to at least one of the antibiotics that were once used to treat them.
In a report from the US state of Pennsylvania, state-wide hospitals reported 19,154 cases in which patients acquired an infection while staying in hospital, a rate of 12.2 cases per 1000 patients. The hospital costs associated with this patient group averaged $185,260 per patient, giving overall hospital costs of around $3.5 billion. By comparison, hospital costs for patients who did not acquire an infection were $32,389, around 17% of that seen in the case of patients who acquired an infection.
In the US, it is reported that between 50–60% of all hospital-acquired infections are caused by antibiotic resistant bacteria. While little has been published on the relationship between antibiotic resistance and subsequent infection rates and prevalence, increases in both are an inevitable consequence of longer treatment times (durations of infection), due to antibiotic resistance. Also, the more time that is required to eradicate a pathogen from a patient, the higher the probability the pathogen will spread, particularly within the hospital environment, where patients and healthcare workers are in close proximity.
Based on these figures, estimates of the cost of hospital-acquired infections, as a proportion of the general population, suggest a figure of $28.0 million/million of general population in the UK and $22.3 million/million of population in the US. The average of these two figures is approx $25 million/million of general population. Based on this average figure, hospital-acquired infections in the USA, Canada, Australia, Japan and Europe (population = 1.3 billion) is approximately $32.5 billion.

The antibiotic development pipeline: small and medium sized companies take the helm

Killing pathogens is the goal of antibiotic therapy, however there is an urgent need to develop antibiotic therapies that undermine resistance mechanisms in more effective ways. The last decade has seen a 60% reduction in the numbers of new antibiotic approvals, but recent years have also seen unprecedented innovation in the development of new antibiotics and there are now over 100 candidates in the pipeline. Many of these are novel molecular classes that target pathogens in new ways, compared to existing drugs. Moreover, some of these candidates may enable the direct targeting of microbial resistance mechanisms.

Of 113 antibiotics in the development pipeline, 73% are being developed by small and medium sized companies

Today there are more than 200 marketed antibiotics for the treatment of bacterial and fungal infections and these fall into thirty different classes. Notably, 87 (>40%) are beta lactams (carbapenems, cephalosporins, monobactams and penicillins). These are some of the findings of a market study by Biopharm Reports, which identified 113 candidate antibiotics in the development pipeline, of which 60% are early stage (Preclinical and Phase 1). Promisingly, later stage molecules (Phase 2, Phase 3, and those filed with the Regulatory authorities or under Regulatory review), represent 40% of the pipeline. Of these, 24 antibiotics or combinations are at Phase 3 or filed/under review. These molecules are being progressed by 80 companies, of which 77 (73%) are small to medium sized enterprises (SMEs), offering important opportunities for new commercial collaborations.

Surveillance
Surveillance studies by The European Antimicrobial Resistance Surveillance System (EARSS) in Europe, by the Active Bacterial Core surveillance (ABCs) Project in the US and by China's National Center for Antimicrobial Resistance, show steadily increasing levels of antibiotic resistance in 35 countries, amongst all human pathogen groups.
EARSS is a European surveillance network and collects antibiotic susceptibility/resistance data on six major pathogens, that cause invasive infections. These are Streptococcus pneumoniae, Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. In surveillance studies carried out since 2001, isolate data from over 900 laboratories serving 1400 hospitals in up to 28 countries, have been evaluated.
Overall, European findings show that resistance of Escherichia coli has continued in recent years, with the highest percentage of cases being up to 83% for aminopenicillins; a high frequency of multi-drug resistant Klebsiella pneumoniae in southern, central and eastern Europe and in half of the reporting countries, combined resistance to third-generation cephalosporins, fluoroquinolones and aminoglycosides) is greater than 10 %; the United Kingdom has shown a consistent reduction of resistant proportions in Klebsiella. pneumoniae for all antibiotics under surveillance, and in some countries (Germany, Greece, Italy and the UK) glycopeptide resistance in Enterococcus faecium is decreasing; aminoglycoside resistance in Enterococcus faecalis is stabilising in Europe at a level of 25–50 %; Streptococcus pneumoniae is not susceptible to penicillin and this remains generally stable in Europe; pseudomonas aeruginosa resistance to fluoroquinolones, carbapenems and combined resistance have been reported by many countries, especially in southern and eastern Europe; there has been a significant decrease of susceptibility to carbapenems in invasive Klebsiella pneumoniae over the period 2005–2010, causing concerns due to the lack of therapeutic options for these infections; with the exception of stabilisation for some pathogens (e.g. MRSA) in some countries, antibiotic susceptibility continues to decline and there are significant concerns regarding the emergence of carbapenem resistance in Klebsiella pneumonia, due to a lack of alternative treatment options.
Outside of Europe, the largest increases in antibiotic resistance are being seen in Asia, South America and Africa and for some bacteria, in North America.

In antibiotic resistance studies carried out in China, Kuwait and the US, the highest resistance levels were seen in China, followed by Kuwait and then the US. In China, mean resistance for hospital-acquired infections were as high as 41% (range 23% to 77%) and for community-acquired infections were 26% (range 15% to 39%). China also showed the highest rate of increase of antibiotic resistance (22%) between 1994 and 2000, followed by Kuwait (17% from 1999 to 2003) and the US (6% from 1999 to 2002).
Marketed Antibiotics
This report identifies 209 marketed antibiotics for the treatment of bacterial and fungal infections. These fall into around thirty different groups, namely, aminocyclitols, aminoglycosides, beta lactams (carbapenems, cephalosporins (Generations 1-4), monobactams and penicillins), cyclic lipopeptides, folate antagonists, fluoroquinolones, glycopeptides, immunomodulators, ketolides, lincosamides, macrocyclics, macrolides, mycobacterials, nitrofurans, oxazolidinones, peptides, pleuromutilins, polypeptides, pyridopyrimidines, quinolones, streptogramins, sulphonamides and tetracycline and others.
Of these 209 marketed antibiotics, 87 (42%) are classified as beta lactams (carbapenems, cephalosporins, monobactams and penicillins).
The mode of action, or mechanisms, of currently marketed drugs can be put into five categories. More than 50% of these antibiotics affect cell walls or membranes (e.g. cell wall synthesis, cell wall integrity), while around one quarter exert their disruptive effects on protein synthesis (e.g. via interaction with one or more of the ribosomal subunits). Other “mechanistic” groups include molecules that target DNA (e.g. bacterial DNA transcription-associated enzymes), folate antagonists (which exert their effects via the folate coenzyme cycle) and others.
The 209 marketed antibiotics listed, are represented by 76 different companies, of which 60% are large international corporations and 40% are Small/Medium Sized Enterprises (SMEs). The vast majority of these antibiotics are now available as generic brands and in multiple formulations.
The emergence of antibiotic resistance, combined with the lack of innovation in the development of new antibiotic molecules has increased greatly the challenge of treating and eradicating certain infecting pathogens. According to a recent study, the approval of new antibiotics in the US has fallen in recent decades by 60%; from 30 during the decade 1983 to 1992, to 12 over the period 1998 and 2009.
Although recent years have seen the launch of some new antibiotics (e.g. linezolid, tigecycline and daptomycin), the listing of marketed antibiotics shows that many of these drugs are very long established. While beta lactams have seen the greatest innovation of all antibacterial classes, these molecules represent more than 40% of antibiotics used. This has exacerbated the problems of increasing resistance to these antibiotics.
It is notable that almost 70% of all antibiotics used in the clinic fall into just five different classes; the beta lactams, quinolones, aminoglycosides and macrolides and tetracyclines. Many of the antibiotics in these groups have been used for decades to treat broad spectrum of pathogens, and this has driven resistance levels seen today.

Antibiotics Pipeline
The rate of growth of antibiotic resistant bacteria over the last two decades, coupled with an evident fall in the numbers of new antibiotics being approved during this time, has long raised concerns over the future treatment of infections. Whilst antibiotics that offer different bactericidal mechanisms have been developed over the last 60 years, the increasing difficulty of treating infections today is defined by the resistance attributes of bacterial pathogens and it is here that discovery and innovation are now focusing. This strategy is generating new molecular classes to which pathogens have shown little resistance, alongside others (such as lactamases inhibitors), that directly target resistance mechanisms.
This report identifies 109 candidate antibiotics in the clinical pipeline, approximately 70% of which are in early development (Preclinical and Phase 1). In contrast, there are just 9 candidates at Phase 3, while there are 31 at Phase 2. These pipeline developments are being progressed by 66 companies, of which nine (14%) are major international corporations and 57 (86%) are Small/Medium Sized Enterprises (SMEs).

Table Of Contents

Executive Summary

Chapter 1 Introduction (p.18)

1.1 Antibiotic Resistance
1.2 Resistance Mechanisms
1.3 The Resistome
1.4 Pathogenomics
1.5 Strategies and Targets
1.6 The Cost of Antibiotic Resistance
1.7 Global Surveillance
1.8 This Report

Chapter 2 Antibiotic Resistance, Global Trends (p.27)

2.1 Antibiotic Resistance
2.2 Europe
2.2.1 Carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa (2005 to 2010)
2.2.2 Escherichia coli
2.2.3 Streptococcus pneumoniae
2.2.4 Staphylococcus aureus
2.2.5 Enterococcus faecalis
2.2.6 Klebsiella pneumoniae
2.2.7 Pseudomonas aeruginosa
2.3 Other Countries
2.4 China
2.5 USA
2.6 Kuwait
2.7 Discussion

Chapter 3 Marketed Antibiotics (p.63)

3.1 Marketed Antibiotics
3.2 Mechanisms
3.3 Companies
3.4 Sulphonamides
3.5 Beta Lactams (penicillins, cephalosporins, carbapenems, monobactams)
3.6 Aminoglycosides
3.7 Tetracyclines
3.8 Quinolones/Fluoroquinolones
3.9 Macrolides
3.10 Combinations
3.11 Folate antagonists
3.12 Mycobacterials
3.13 Glycopeptides
3.14 Others
3.15 Discussion

Chapter 4 Pipeline Antibiotics (p.86)

4.1 Pipeline Antibiotics
4.2 Companies
4.3 Phase 3
4.4 Phase 2
4.5 Phase 1
4.6 Preclinical
4.7 Discussion

Chapter 5 Discussion (p.106)

5.1 Background
5.2 Mechanisms
5.3 Multiple Activities
5.4 Marketed Antibiotics
5.5 Antibiotics Pipeline
5.6 Circumventing Resistance
5.7 Resistance Mutations
5.8 Virulence
5.9 Conclusions

References (p.120)



Tables

Table 2.1 EARSS Surveillance Programme: Countries and Country codes
Table 3.1 Developers or companies with marketed antibiotics for bacterial or fungal
Infections (Source: Biopharm Reports, 2013). The top 11 companies are indicated in blue
Table 3.2 Approved/marketed sulphonamide drugs, which exert their bactericidal effects through folate inhibition (Source: Biopharm Reports, 2013).
Table 3.3 Approved/marketed beta lactam antibiotics, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.4 Approved/marketed penicillins, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.5 Approved/marketed cephalosporins, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.6 Approved/marketed 1st, 2nd, 3rd and 4th generation cephalosporins, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.7 Approved/marketed carbapenems and one monobactam (Aztreonam), which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.8 Approved/marketed aminoglycosides, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2013).
Table 3.9 Approved/marketed tetracyclines, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2013).
Table 3.10 Approved/marketed quinolones and fluoroquinolones, which exert their bactericidal effects through the inhibition of DNA transcription (Source: Biopharm Reports, 2013).
Table 3.11 Approved/marketed macrolides, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2013).
Table 3.12 Approved/marketed combination antibiotics, which exert their bactericidal
effects through the combined effects of both molecules (Source: Biopharm Reports, 2013).
Table 3.13 Approved/marketed folate antagonists, which exert their bactericidal
effects through the inhibition of the folate cycle (Source: Biopharm Reports, 2013).
Table 3.14 Approved/marketed mycobacterials, which exert their mycocidal effects through multiple mechanisms (Source: Biopharm Reports, 2013).
Table 3.15 Approved/marketed glycopeptides, which exert their bactericidal effects through the inhibition cell wall synthesis (Source: Biopharm Reports, 2013).
Table 3.16 Other approved/marketed antibiotics, which exert their bactericidal effects through multiple mechanisms (Source: Biopharm Reports, 2013).
Table 3.17 Other approved/marketed antibiotics, which exert their bactericidal effects through multiple mechanisms (Source: Biopharm Reports, 2013).
Table 4.1 Companies with pipeline bacterial ICorps = blue (Source: Biopharm Reports, 2013)
Table 4.2 Antibiotics in Phase 3 Development (Source: Biopharm Reports, 2013)
Table 4.3 Antibiotics in Phase 2 Development (Source: Biopharm Reports, 2013)
Table 4.4 Antibiotics in Phase 1 Development (Source: Biopharm Reports, 2013)
Table 4.5 Antibiotics in preclinical development (Source: Biopharm Reports, 2013)



Figures

Figure 2.1 Escherichia coli: trends of resistance to aminopenicillin by country, 2007-2010
Figure 2.2 Escherichia coli: trends of resistance to third-generation cephalosporins by country, 2007-2010
Figure 2.3 Escherichia coli: trends of resistance to fluoroquinolones by country, 2007-2010
Figure 2.4 Escherichia coli: trends of resistance to aminoglycosides by country, 2007-2010
Figure 2.5 Escherichia coli: trends of combined resistance (resistant to fluoroquinolones,
third-generation cephalosporins and aminoglycosides) by country, 2007-2010
Figure 2.6 Streptococcus pneumoniae: trends of non-susceptibility to penicillin by country, 2007-2010
Figure 2.7 Streptococcus pneumoniae: trends of non-susceptibility to macrolides by country, 2007-2010
Figure 2.8 Staphylococcus aureus: trends of resistance to meticillin (MRSA) by country, 2007-2010
Figure 2.9 Enterococcus faecalis: trends of high-level resistance to aminoglycosides by country, 2007-2010
Figure 2.10 Enterococcus faecium: trends of resistance to vancomycin by country 2007-2010
Figure 2.11 Klebsiella pneumoniae: trends of resistance to third-generation cephalosporins by country, 2007-2010
Figure 2.12 Klebsiella pneumoniae: trends of resistance to fluoroquinolones by country, 2007-2010
Figure 2.13 Klebsiella pneumoniae: trends of resistance to aminoglycosides by country, 2007-2010
Figure 2.14 Klebsiella pneumoniae: trends of resistance to carbapenems by country, 2007-2010
Figure 2.15 Klebsiella pneumoniae: trends of combined resistance (third-generation cephalosporins, fluoroquinolones and aminoglycosides) by country, 2007-2010
Figure 2.16 Pseudomonas aeruginosa: trends of resistance to piperacillin±tazobactam by country, 2007-2010
Figure 2.17 Pseudomonas aeruginosa: trends of resistance to ceftazidime by country, 2007-2010
Figure 2.18 Pseudomonas aeruginosa: trends of resistance to fluoroquinolones by country, 2007-2010
Figure 2.19 Pseudomonas aeruginosa: trends of resistance to aminoglycosides by country, 2007-2010
Figure 2.20 Pseudomonas aeruginosa: trends of resistance to carbapenems by country, 2007-2010
Figure 2.21 Pseudomonas aeruginosa: trends of combined resistance (R to three or more antibiotic classes among piperacillin±tazobactam, ceftazidime, fluoroquinolones, aminoglycosides and carbapenems) by country, 2007-2010
Figure 2.22 Antibiotic resistance of Staphylococcus, Streptococcus, Escherichia coli and Enterococcus in the US, Egypt and Tunisia 2.1
Figure 3.1 Current fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2013).
Figure 3.2 Current fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2013).
Figure 3.3 Bactericidal mechanisms of fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2013).
Figure 3.4 Companies with pipeline bacterial antibiotics, by size (Source: Biopharm Reports, 2013)
Figure 3.5 New US antibiotic approvals from 1983 to 2009
Figure 4.1 The Antibiotics Drug Development Pipeline. (Source: Biopharm Reports, 2013).
Figure 4.2 Companies with pipeline bacterial antibiotics, by size (Source: Biopharm Reports, 2013)
Figure 5.1 Current fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2013).
Figure 5.2 The Antibiotics Drug Development Pipeline. (Source: Biopharm Reports, 2013).

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