Wednesday, November 2, 2011

Antibiotics resistance: when enough is enough!

There is a general concern on the spread of bacteria resistant to antibiotics. The scientific community is well aware of the problem already since the isolation of Staphylococcus aureus resistant to methicillin (MRSA) in the late 1990s. The list of bacteria resistant to virtually all drugs is increasing nearly every month and the top ten killers superburgs include Pseudomonas, Acinetobacter, Clostridium, Mycobacterium, Enterococcus and Klebsiella. The general public is also aware of the increasing isolation of multidrug resistant bacteria since it makes often headlines at the news. However, I should say that their awareness is not enough. Public and mass media maybe missing the big picture: in the XXI century patients are dying in our hospitals due to the lack of treatments for infections.

There is also high-level political concern on this issue mostly due to the costs of inefective treatments. National goverments worldwide as well as private foundations do actively support research groups working on antibiotic resistance. Surprisingly, the investment in this area of research is just a tiny fraction of the amount devoted to Biomedicine. This is somewhat surprising considering that infection diseases are the first cause of global death. Could it be that tax-payers money is not supporting research in the most important cause of death worldwide?

Making this scenario worst, there is a significant reduction in the investment in research and development of antibiotics by the pharmaceutical industry. In 2004, only 1.6%  of drugs in clinical development by the world´s largest 15 largest drug companies were antibiotics. The competition of generic drugs and the short duration of antibiotics regimens make them less profitable than drugs for chronic use. To complicate a bit more the problem, regulatory agencies have raised the bar for approval of new formula hence discouraging antibiotic developers. Only four new antibiotics, discovered already in the 1970s, have reached the market in the last ten years and just for the treatment of Gram positive multidrug bacteria (half of the problem). The increasing rate of resistance predicts that none of them will be a blockbuster. On the whole, we maybe facing what Dr. David Shlaes called a "perfect storm".

Clearly there is an urgent need for new antibacterials, but what are we doing? In my view, not much. Just as an example, if you check the 2010 Table of Contents of the flagship journal of the American Society for Microbiology for antibiotics research, Antimicrobial Agents and Chemotherapy, you will find out that nearly 90% of the papers are devoted to epidemiological studies and molecular mechanisms of resistance and just a mere 10% to new drugs/treatments. I am not saying that this is not important but it is as if we think that by going several times to the MD to get a diagnosis we will get cured.

Some actions are easy to implement to reduce the resistance rate. Just to mention three of them widely accepted and recommened by several clinical guidelines:
  • Medicine professionals should wash hands more often and be aware of the spreading of resistant bacteria via contaminated clothes.
  • Antibioctics should only be used to treat bacterial infections.
  • In Hospitals, antibiotic regimens should be changed according to MICs determination by the clinical microbiology lab.
However, the time is ripe to really tackle the problem using new drug discovery paradigms. Among others, one of the most promising approaches is based on identifying and targeting host factors important for infection as well as pathogen determinants involved in disease progression. This drug discovery programm is built upon the enormous potential of on-going basic research done at Academia. It is expected that these studies will identify targets to be used as host-directed drug therapy which will efficiently eliminate the invading pathogen. It is already accepted that host cell factors are essential in the infection processes and it has meanwhile been shown in many cases, both in vitro and in living animals carrying specific genetic defects, that absence of critical host cell functions can prevent an infection. Importantly, although pathogens express different virulence determinants in all cases they confrontthe same host background. Therefore, targets identified for particular host-pathogen interplay could be extrapolated to other systems.

On the other hand, several studies indicated that existing drugs, used for purposes unrelated to antimicrobial activity, may influence viral and bacterial infections. This illustrates another way to significantly speed-up the drug-development process: since the factors to be targeted by a treatment are from the (human) host, drug and application development for infectious diseases could be cut short significantly or even bypassed by tapping into the arsenal of drugs that have already been approved for use in humans (e.g. off-label use). A prominent example is Gleevec, an inhibitor originally developed as an anti-cancer drug, and its application for treatment of certain viral infections.

In my view, major international concerted efforts are required to solve this global health problem. An strong partneship between academic groups and pharmaceutical indutries well funded for a suficient period of time (five to eight years) should produce already new targets/drugs and, even in the worst scenario, will generate invaluable knowledge on prevalent diseases. Definetely a win-win strategy.

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