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Antibiotic Resistance 2013: The Antibiotics Development Pipeline And Strategies To Combat Antibiotic Resistance

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 AntibioticsThis 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.

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