Introducing Yesterday's Phage Therapy in Today's Medicine

Jean-Paul Pirnay; Gilbert Verbeken; Thomas Rose; Serge Jennes; Martin Zizi; Isabelle Huys; Rob Lavigne; Maia Merabishvili; Mario Vaneechoutte; Angus Buckling; Daniel De Vos

Disclosures

Future Virology. 2012;7(4):379-390. 

In This Article

Spreading Antibiotic Resistance: A Universal Threat

The worldwide emergence of 'superbugs' and a dry antibiotic pipeline threaten modern society with a return to the preantibiotic era, when bacterial infections were the primary cause of morbidity and mortality.[1] A recent estimate indicates that 400,000 people in Europe were infected with multidrug-resistant (MDR) bacteria during 2007, with 25,000 attributable deaths.[2] In hospitals in both the developed and the developing world, the majority of nosocomial outbreaks are caused by a small group of pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species, hereafter referred to as the 'ESKAPE bugs').[3] These ESKAPE bugs are increasingly prevalent and resistant to most of our antimicrobial agents, threatening patients' lives and confronting society with huge socioeconomic costs. To date, MDR pathogens, such as highly drug-resistant A. baumannii (often associated with military operations in the Middle East[4]), NDM-1-producing Enterobacteriaceae,[5] panresistant P. aeruginosa clones[6] and methicillinresistant S. aureus (MRSA),[7] have been mostly associated with hospital outbreaks.

In addition, community-associated MRSA infections and specific Escherichia coli outbreaks demonstrate that the community as a whole is increasingly threatened by virulent antibiotic-resistant pathogens. Community-associated MRSA infections arise in otherwise healthy individuals and are more virulent and transmissible than are traditional hospital-associated MRSA strains,[8] and the recent outbreak of enteroaggregative Shiga toxin/verotoxin-producing E. coli strain O104:H4 in Germany[9] caused over 4000 cases of diarrhea – 3167 without hemolytic–uremic syndrome (16 deaths) and 908 with hemolytic–uremic syndrome (34 deaths).[10] These cases demonstrate that infectious agents are not confined to hospitalized patients, but are actually deeply settled in our environment.

For rapidly evolving, genetically versatile bacteria such as Pseudomonas, it has turned out to be quite easy to develop mechanisms to avoid the toxicity of antibiotics, which have remained more or less 'static' for the last decade. More reflection on the biological role of antibiotics in nature as secondary metabolites would have revealed that resistance evolution was inevitable. Also, in nature, bacteria are constantly outsmarting toxins produced by competitors. However, the difference is that these natural competitors in turn react by selection towards adjusted toxins. The biological phenomenon of antibiotic resistance is typically an emergent characteristic of a dynamic, highly complex and self-organizing system that evolves at the edge of chaos.[11,12] Moreover, the rate of resistance evolution has been exacerbated by the overuse and misuse of antimicrobial agents in both clinical and agricultural contexts.[13–15]

Due to the complexity of the antibiotic resistance issue and the immense research and development costs and time-frames of developing new antibiotics, for which resistance will inevitably occur, the pharmaceutical industry is not keen to continue with the development of new molecules. Moreover, even if pharmaceutical companies succeed in developing and marketing highly active antibiotics, authorities, sensitized by past experiences concerning the rapid emergence of resistance, are likely to withhold these new antibiotics as third-line last-rescue drugs, thereby limiting the market and consequently the commercial interest of the pharmaceutical companies. As the industry antibiotic pipeline is virtually dry and infectious diseases – major causes of morbidity and mortality – are steadily on the increase, new initiatives are urgently needed.

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