colitis, helped to catalyze the emergence of resistance, and is now tentatively associated in the pathogenesis of certain chronic diseases, including atopy, asthma and – perhaps – certain forms of cancer. This article briefly reviews these trends and suggests that the current strategy of nonspecific therapy is fundamentally unsound because it damages the microflora and – consequently – the human symbiont. The essay argues for the development of immunotherapy and pathogen-specific therapies, especially with regard to bacterial and fungal diseases, and suggests possible routes to that future.

1.
The Problematic Status Quo

Current antimicrobial therapy is largely pathogen-specific for viral diseases and nonpathogen-specific for bacterial, fungal, and parasitic diseases (Casadevall, 1996). Although some of the latter diseases are sometimes treated with pathogen-specific drugs, such as the use of isoniazid for tuberculosis, the overwhelming majority of compounds targeting bacteria, fungi, and parasitic diseases have activity against multiple microbes. Furthermore, these compounds target both pathogenic and nonpathogenic microbes. This current antimicrobial paradigm is currently in use at a time of significant upheaval in the therapy of microbial diseases, which is the only field of medicine in which one can argue that therapeutic options have declined over time. For example, in the 1950s Jawetz noted that the then currently available antimicrobial drugs were satisfactory for the treatment of bacterial diseases (Jawetz, 1956). However, in recent years the field of infectious diseases has seen dramatic increases in antimicrobial resistance, an increasing prevalence of bacterial and fungal superinfections in treated individuals, a relatively low therapeutic efficacy of antimicrobial therapy in individuals with impaired immunity, the emergence of new infectious diseases, and the reemergence of older microbial diseases, often with highly resistant microbes such as XDR-Tb. Given this status quo, it behooves us to ask the questions: How did we get here? What are the consequences of the choices made then and now? Can we do better and how do we get there?

2.
How Did We Get Here?

Effective antimicrobial therapy can be dated to the introduction of serum therapy in the 1890s, which, for the first time, provided physicians with the ability to intervene and cause a favorable outcome for an infectious disease. Serum therapy was developed against numerous bacterial and viral diseases, including pneumococcal pneumonia, meningococcal meningitis, erysipelas, anthrax, and measles (for reviews, see refs Casadevall and Scharff, 1994; Casadevall and Scharff, 1995; Buchwald and Pirofski, 2003). The heyday of serum therapy was the 1930s, but the modality was rapidly abandoned because serum could not compete with small-molecule antimicrobial therapy, such as sulfonamides and



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement