Antibiotic Resistance 2012: The Antibiotic Development Pipeline and Strategies to Combat Antibiotic Resistance

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Overview

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).

Conclusions

While antibiotics are effective for the major 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 resistance 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.

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).

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.

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).

Mechanisms

Given the resistance patterns that pathogens have evolved to existing drugs, the development of agents that target them in new ways is vital. For example, Cubist's marketed antibiotic daptomycin has a unique mechanism, based on the disruption of multiple areas of membrane function. Daptomycin is active against glycopeptide-resistant Enterococci, including methicillin-resistant Staphylococcus aureus.

Multiple Activities

Antibiotics directed against multiple bacterial targets are well established and include combined antibiotic formulations (e.g. Pfizer's Rifampicin/Trimethoprim) and drugs such as GSK's Augmentin and Timentin, which co-formulate lactamase inhibitors. These drugs are able to overwhelm the ability of pathogens to establish resistance mechanisms. Many new "multiple targeting" drugs are also being developed. For example, Theravance is developing the drug TD-1792, a heterodimer that combines the anti-bacterial activities of a glycopeptide and a beta-lactam, in one molecule. This drug is currently at Phase 1. Achillion have developed an agent (ACH-702) which shows multiple target inhibition of DNA replication enzymes and potent broad-spectrum activity against multi-drug-resistant bacteria. This antibiotic is reported to target gyrase, topoisomerase IV and primase, and is currently in late stage pre-clinical development.

Circumventing Resistance

Broadly, bacteria develop resistance in two ways; either by preventing the antibiotic from reaching the target (efflux, blocking the movement of the drug to the target, changing the target) or by changing the antibiotic in some way (e.g. inactivation of ß-lactams by lactamases). One example of how bacteria are able to protect themselves by changing the target is seen in the case of vancomycin resistance, due to the VanA gene cluster. This adaptive change results from a relatively minor modification of Lipid II, a molecule that is involved in the delivery of the building blocks of cell wall synthesis. Vancomycin works by blocking the delivery of these building blocks. However, this minor adaptive change in Lipid II is able to block the activity of the antibiotic, without loss of its function in cell wall synthesis. However, today's development pipeline list new antibiotic candidates that targets a sites which may not allow ready adaptation by the bacterium.

Virulence

A number of companies and groups are also investigating the potential to target bacterial virulence, the ability of the pathogen to invade, overcome defence mechanisms, and cause infection. Quorum sensing is integral to the virulence process and in biofilm formation. Quorum sensing is the mechanism by which bacteria regulate gene expression, in response to changes in the prevailing population. This mechanism is based on the release of chemical messengers (autoinducers), the levels of which fluctuate within bacterial cell populations. Processes that are regulated through quorum sensing include symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm formation. The importance of quorum sensing in the regulation of bacterial populations makes this mechanism a potential target for antimicrobiol agents. Today's pipeline includes molecules developed to target quorum sensing.

1.1 Antibiotic Resistance1.2 Resistance Mechanisms1.3 The Resistome1.4 Pathogenomics1.5 Strategies and Targets1.6 The Cost of Antibiotic Resistance1.7 Global Surveillance1.8 This Report

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

2.1 Antibiotic Resistance2.2 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 Countries2.4 China2.5 USA2.6 Kuwait2.7 Discussion

Chapter 3 Marketed Antibiotics (p.63)

3.1 Marketed Antibiotics3.2 Mechanisms3.3 Companies3.4 Sulphonamides3.5 Beta Lactams (penicillins, cephalosporins, carbapenems, monobactams)3.6 Aminoglycosides3.7 Tetracyclines3.8 Quinolones/Fluoroquinolones3.9 Macrolides3.10 Combinations3.11 Folate antagonists3.12 Mycobacterials3.13 Glycopeptides3.14 Others3.15 Discussion

Chapter 4 Pipeline Antibiotics (p.86)

4.1 Pipeline Antibiotics4.2 Companies4.3 Phase 34.4 Phase 24.5 Phase 14.6 Preclinical4.7 Discussion

Chapter 5 Discussion (p.106)

5.1 Background5.2 Mechanisms5.3 Multiple Activities5.4 Marketed Antibiotics5.5 Antibiotics Pipeline5.6 Circumventing Resistance5.7 Resistance Mutations5.8 Virulence5.9 Conclusions

References (p.120)

Table 3.1 Developers or companies with marketed antibiotics for bacterial or fungal

Infections (Source: Biopharm Reports, 2012). 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, 2012).

Table 3.3 Approved/marketed beta lactam antibiotics, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2012).

Table 3.4 Approved/marketed penicillins, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2012).

Table 3.5 Approved/marketed cephalosporins, which exert their bactericidal effects through the inhibition of cell wall synthesis (Source: Biopharm Reports, 2012).

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, 2012).

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, 2012).

Table 3.8 Approved/marketed aminoglycosides, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2012).

Table 3.9 Approved/marketed tetracyclines, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2012).

Table 3.10 Approved/marketed quinolones and fluoroquinolones, which exert their bactericidal effects through the inhibition of DNA transcription (Source: Biopharm Reports, 2012).

Table 3.11 Approved/marketed macrolides, which exert their bactericidal effects through the inhibition of protein synthesis (Source: Biopharm Reports, 2012).

Table 3.12 Approved/marketed combination antibiotics, which exert their bactericidal

effects through the combined effects of both molecules (Source: Biopharm Reports, 2012).

Table 3.13 Approved/marketed folate antagonists, which exert their bactericidal

effects through the inhibition of the folate cycle (Source: Biopharm Reports, 2012).

Table 3.14 Approved/marketed mycobacterials, which exert their mycocidal effects through multiple mechanisms (Source: Biopharm Reports, 2012).

Table 3.15 Approved/marketed glycopeptides, which exert their bactericidal effects through the inhibition cell wall synthesis (Source: Biopharm Reports, 2012).

Table 3.16 Other approved/marketed antibiotics, which exert their bactericidal effects through multiple mechanisms (Source: Biopharm Reports, 2012).

Table 3.17 Other approved/marketed antibiotics, which exert their bactericidal effects through multiple mechanisms (Source: Biopharm Reports, 2012).

Table 4.1 Companies with pipeline bacterial ICorps = blue (Source: Biopharm Reports, 2012)

Table 4.2 Antibiotics in Phase 3 Development (Source: Biopharm Reports, 2012)

Table 4.3 Antibiotics in Phase 2 Development (Source: Biopharm Reports, 2012)

Table 4.4 Antibiotics in Phase 1 Development (Source: Biopharm Reports, 2012)

Table 4.5 Antibiotics in preclinical development (Source: Biopharm Reports, 2012)

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, 2012).

Figure 3.2 Current fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2012).

Figure 3.3 Bactericidal mechanisms of fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2012).

Figure 3.4 Companies with pipeline bacterial antibiotics, by size (Source: Biopharm Reports, 2012)

Figure 3.5 New US antibiotic approvals from 1983 to 2009

Figure 4.1 The Antibiotics Drug Development Pipeline. (Source: Biopharm Reports, 2012).

Figure 4.2 Companies with pipeline bacterial antibiotics, by size (Source: Biopharm Reports, 2012)

Figure 5.1 Current fully approved/marketed antibiotics for the treatment of bacterial and fungal infections (Source: Biopharm Reports, 2012).

Figure 5.2 The Antibiotics Drug Development Pipeline. (Source: Biopharm Reports, 2012).

Figure 5.3 Companies with pipeline bacterial antibiotics, by size (Source: Biopharm Reports, 2012)

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