Changing the Therapeutic Paradigm in Antibacterial Drug Therapy and Discovery
from: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms (Edited by: Alita A. Miller and Paul F. Miller). Caister Academic Press, U.K. (2011)
At the beginning of the 21st century the therapeutic paradigm for the treatment of infectious diseases can be summarized by three words: kill the bug. In other words, the overwhelming majority of therapeutic interventions against microbial diseases are designed to help the host by damaging the microbe directly and/or interfering with its ability to replicate in tissue (Casadevall, 2006). This strategy has been termed the second age of antimicrobial therapy and was preceded by the era of serum therapy, which differed in the fundamental manner that serum was primarily an immunotherapeutic agent than enhanced host defenses (Casadevall, 2006). First and second age therapeutics differed in other ways including the chemistry of the therapeutic agent, their specificity and the form of manufacturing (Table 1). Second age therapeutics have been were tremendously successful and brought numerous drugs to the market that have saved countless lives. However, there are major trends at work that have significantly reduced the overall efficacy of second age therapeutics including widespread antimicrobial resistance, the emergence of new pathogenic microbes for which there are few drugs available and an epidemic of immunocompromised hosts where antimicrobial therapy is often less effective. Microbe-targeting strategies are limited in that they neglect the host; consequently, there are very few treatment strategies that aim to achieve a therapeutic outcome by enhancing host defenses. Microbe-targeting strategies include both microbe-specific and -non-specific drugs, each of which can put tremendous selection pressure on microbes that often result in the emergence of resistance. Non-specific microbe-targeting strategies have the additional problem that they can select for resistance in non-targeted microbes and their effects on host flora can have a variety of unintended deleterious consequences on host homeostasis. This chapter will consider these strategies in light of their historical development and analyze the advantages and disadvantages of specific and non-specific antimicrobial strategies read more ...