gA European and global strategy is urgently needed to address the lack of new antibiotics to treat multidrug-resistant bacterial infection, according to a new European report. The document titled “The bacterial challenge: time to react, a call to narrow the gap between multidrug-resistant bacteria in the EU, and the development of new antibacterial agents,” was drafted jointly by the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMEA) with input from the international network Action on Antibiotic Resistance.
The document suggests that although MRSA remains the most common multidrug-resistant bacterium in the EU, the total number of cases of common antibiotic-resistant Gram-positive bacteria (mostly MRSA and vancomycin-resistant Enterococcus faecium) is actually comparable to that of common, antibiotic-resistant Gram negative bacteria (third-generation cephalosporin-resistant E. coli and K. pneumoniae and carbapenem-resistant P. aeruginosa).
Overall, it was estimated that in 2007 approximately 25,000 patients in the EU, Iceland, and Norway died from infection due to any of these selected five antibiotic-resistant bacteria. Two thirds of the deaths were due to Gram-negative bacteria. Moreover, infections caused by these five antibiotic-resistant bacteria resulted in estimated annual in-hospital costs of more than €900 million (about $1.33 billion), outpatient care costs of some €10 million (approximately $14.75 million), and societal costs including productivity losses of about €1.5 billion (roughly $2.21 billion).
The authors further state that multidrug resistance among Gram-negative bacteria has been increasing relentlessly and there is “particular concern regarding the paucity of new agents with activity against Gram-negative bacteria that have reached the market in the last decade.” Unfortunately, the report notes, those that have been marketed don’t show efficacy against Gram-negative bacteria with resistance to most or all beta-lactam drugs.
The study, initiated in 2008, also suggests that since the 1970s, only three systemically administered antibiotics (quinupristindalfopristin, linezolid, and daptomycin) including two from new classes (oxazolidinones and lipopeptides) have been marketed in the EU to treat infections caused by multidrug-resistant Gram-positive bacteria. Other systemically administered antibiotics reaching the EU market during this period belong to existing classes of antibiotics and are ineffective against the majority of organisms already resistant to other agents in the same class.
New antibacterials in development were identified through a data search carried out in March 2008. This highlighted 167 new antibacterial agents, 90 of which appeared to demonstrate in vitro activity in a “best case” scenario (based on actual data or based on known class properties or mechanisms of action) against at least one organism in the panel of bacteria selected for their public health importance. Of these 90 agents, 24 were new presentations of licensed antibacterial agents and 66 were new active substances.
Of the 66 new active agents, 27 were assessed as having either a new target or a new mechanism of action, thus potentially offering a benefit over existing antibiotics. Of these 27 agents, there were 15 that could be administered systemically, including 13 for which actual data indicated in vitro activity against at least one of the selected bacteria, and two additional agents for which activity was assumed due to known class properties or mechanisms of action.
Of the 15 agents with systemic administration, eight were judged to have activity against at least one of the selected Gram-negative bacteria, but only four had activity based on actual data. The other four had assumed activity based on known class properties or mechanisms of action.
The authors, led by Bo Aronsson, M.D., for the EMEA, and Dominique Monnet for the ECDC, conclude, “Multidrug-resistant Gram-negative bacteria constitute a major challenge for the future. Therefore, the lack of systemically administered agents with activity against Gram-negative bacteria displaying new mechanisms of action found in this study is particularly worrisome, and more so when the high attrition rates for agents in early stages of clinical development is taken into consideration.
“In fact, it is unclear if any of these identified agents will ever reach the market, and if they do, they may be indicated for use in a very limited range of infections. Even if a public health driven approach for R&D of antibacterial agents is commenced in the near future the burden of resistance will inevitably increase during the next years. Therefore, a European and global strategy to address this serious problem is urgently needed, and measures that spur new antibacterial drug development need to be put in place."