Dead bugs don't mutate: susceptibility issues in the emergence of bacterial resistance - Perspectives - Editorial

Emerging Infectious Diseases, Jan, 2003 by Charles W. Stratton

The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/ lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.

**********

As the 19th century drew to a close, the work of Joseph Lister ushered in the antimicrobial era. Lister was among the first scientists to appreciate the implications of Pasteur's theory that microorganisms are involved in human disease (1). Accordingly, he examined the inhibitory effect of various chemicals on the growth and viability of bacteria and directly applied the results to the practice of medicine by using phenol (as well as heat) to sterilize surgical instruments. After this early example of infection control through antisepsis, the next step was inevitable: when chemicals with antibacterial activity were discovered, they were soon used in the treatment of infected patients. The ensuing clinical success was so dramatic that these agents were hailed as miracle drugs. By the second half of the 20th century, the practice of medicine enjoyed almost complete dominance over infectious bacteria (2).

Ironically, these same miraculous drugs now jeopardize the miracle, as evidenced by the widespread emergence of antibacterial resistance in the last decade (3-7). For example, methicillin-resistant Staphylococcus aureus strains have recently appeared in community-acquired infections (8), and Streptococcus pneumoniae strains resistant to both penicillins and macrolides (the antibacterial agents used most frequently for pneumococcal infections) have become prevalent throughout the world. Indeed, rates of S. pneumoniae resistance to penicillin now exceed 40% in many regions, and a high proportion of these strains are also resistant to macrolides. Moreover, the trend is growing rapidly. Whereas 10.4% of all S. pneumoniae isolates were resistant to penicillin and 16.5% resistant to macrolides in 1996, these proportions rose to 14.1% and 21.9%, respectively, in 1997 (9). A more recent susceptibility study conducted in 2000-2001 showed that 51.5% of all S. pneumoniae isolates were resistant to penicillin and 30.0% to macrolides (10).

The urgent need to curtail proliferation of antibacterial-resistant bacteria has refocused attention on the proper use of antibacterial agents. That the use of any antibacterial agent or class of agents over time will result either in the development of resistance to these agents or in the emergence of new pathogenic strains that are intrinsically resistant is now widely accepted. An example of the development of resistance is the mutation of S. pneumoniae to produce a multidrug-resistant strain (11). An example of a new resistant pathogenic strain is exemplified by the emergence of Enterococcus gallinarum as a nosocomial pathogen due to its intrinsic resistance to vancomycin (12). Keeping these phenomena in check requires a comprehensive strategy that includes, whenever possible, the selection of antibacterial agents in dosages sufficient to be bactericidal (13). A bactericidal effect is desired because, to put it succinctly, dead bugs don't mutate. In other words, if microbial pathogens causing infection are killed by antimicrobial therapy, rather than inhibited, mutations that might already exist or occur under the selective pressure of the antimicrobial agent are less likely to be promulgated. This principle will be briefly reviewed in relation to respiratory tract infections.

Clinical Relevance of Bacteriostatic versus Bactericidal Activity

All of the effects of antimicrobial agents against microbes, including the delineation of microbial resistance, are based upon the results of in vitro susceptibility testing. Most of these susceptibility tests only measure bacteriostatic activity even though the agent being tested may have bactericidal activity. Thus, the clinical relevance of susceptibility testing itself could be questioned. Numerous authors have extensively reviewed this issue over the years (14-16). These authors point out the paucity of studies that have critically evaluated the effectiveness of antimicrobial therapy with results of in vitro susceptibility tests. Such critical evaluations are not easily done, as susceptibility tests do not take into account the normal host defense mechanisms. However, the detection of resistance is somewhat predictive of poor outcome, although in the normal host this may be less clinically important due to the interaction of host defenses (17,18).