Alternative Strategies for Antimicrobial Therapy

ALTERNATIVE STRATEGIES FOR ANTIMICROBIAL THERAPY

INTRODUCTION

Most of us have no notion of what life would be like without antibiotics. Penicillin was discovered in 1928 and after a lengthy developmental period became available for clinical use in the 1940s. Then followed what is often referred to as the golden era of antibiotic discovery which brought us the cephalosporins, the tetracyclines, the macrolides, the aminoglycosides, the 4-quinolones, etc. (Table 27.1). It is interesting to note that the impact of antibiotic discovery was sufficient to halt the development of virtually all other antimicrobial therapies being pursued at that time. The fact that Alexander Fleming in the early years had flagged up the probability of resistance development in bacterial pathogens was largely ignored because of the constant stream of new agents on to the market. There is anecdotal evidence that in 1967 the US Surgeon General stated ‘… it is time to close the book on infectious disease, declare the war against pestilence won…’. Whether or not he actually said this is debatable, but it represented a widely held view at the time that the stream of antibiotic discovery would never dry up. However, we now know that is precisely what has happened.

At present we are faced with two major issues—we have seen an inexorable rise in the incidence of antibiotic resistance among the most important bacterial pathogens, while at the same time the development of novel antibacterial antibiotics has all but stopped. Some clinical isolates from species such as Pseudomonas aeruginosa, Acinetobacter baumannii, Enterococcus faecium and Mycobacterium tuberculosis are resistant to virtually every antibiotic we have at our disposal. It is not appropriate here to discuss the issue of antibiotic resistance, other than to say it is an almost inevitable event occurring as a consequence of the bacterial cell’s remarkable adaptability to environmental change. Without this ability to adapt to their environment bacteria would not still be thriving 3.5 billion years after first emerging on to what was at that time an extremely hostile earth. Suffice it to say there is very little we can do to stop this process.

The second issue of antibiotic discovery and development is, of course, under our control. We have the scientific ingenuity to devise novel approaches to circumvent the resistance mechanisms put in place by these bacteria. Unfortunately, the driving force behind drug discovery is not based on altruism but has a financial imperative. The cost of bringing a new chemical entity to the market has been estimated as $800 million or more, while the process of development takes about 8 years. Antibiotics simply do not generate sufficient revenue to justify this initial outlay of time and cost, and not surprisingly the focus for the large pharmaceutical companies has switched to those medicines which patients will take long-term such as statins, antidepressants and antihypertensives. The market for antiviral agents, particularly those to treat HIV/AIDS, remains buoyant simply because the patients will be taking the medicines for the remainder of their lives.

All this poses the question, ‘How in the near future will clinicians be able to treat patients with infections caused by multiresistant bacterial pathogens?’ In reality this is a question which is relevant today but will only become more pressing in the future. Some respected authorities in the field have already expressed the view that we are on the verge of entering a postantibiotic era.

This article examines a range of alternative therapeutic strategies available for the management of infectious disease (Table 27.2). As we will see, a number of the techniques to be described have a very long history, some of them going back many centuries. Some of these have very little chance of ever moving from the fringes of medicine, some may have the potential to be useful but in reality suffer from the same developmental issues as conventional antibiotics, some are niche approaches which may find relevance in specific clinical areas, while a few may offer a realistic alternative, or at least an adjunct, to antibiotics.