Antimicrobial resistance: the example of Staphylococcus aureus.

In the early 1970s, physicians were finally forced to abandon their belief that, given the vast array of effective antimicrobial agents, virtually all bacterial infections were treatable. Their optimism was shaken by the emergence of resistance to multiple antibiotics among such pathogens as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The evolution of increasingly antimicrobial-resistant bacterial species stems from a multitude of factors that includes the widespread and sometimes inappropriate use of antimicrobials, the extensive use of these agents as growth enhancers in animal feed, and, with the increase in regional and international travel, the relative ease with which antimicrobial-resistant bacteria cross geographic barriers (1–3). The irony of this trend toward progressively more resistant bacteria is that it coincides with a period of dramatically increased understanding of the molecular mechanisms of antimicrobial resistance. Unfortunately, while this insight has resulted in the identification of novel drug targets, it has not yet resulted in effective new chemotherapeutic agents. This paradox stands in sharp contrast to the dramatic progress made in antiviral (notably antiretroviral) therapy in the past ten years, where a number of newly discovered molecular targets have resulted in clinically effective therapeutic agents. Nowhere has this issue been of greater concern than with the Gram-positive bacteria pneumococci, enterococci, and staphylococci. Multidrug resistance is now the norm among these pathogens. S. aureus is perhaps the pathogen of greatest concern because of its intrinsic virulence, its ability to cause a diverse array of life-threatening infections, and its capacity to adapt to different environmental conditions (4, 5). The mortality of S. aureus bacteremia remains approximately 20–40% despite the availability of effective antimicrobials (6). S. aureus is now the leading overall cause of nosocomial infections and, as more patients are treated outside the hospital setting, is an increasing concern in the community (7, 8). S. aureus isolates from intensive care units across the country and from blood culture isolates worldwide are increasingly resistant to a greater number of antimicrobial agents (4, 8). Inevitably this has left fewer effective bactericidal antibiotics to treat these often life-threatening infections (Figure ​(Figure1). 1). As rapidly as new antibiotics are introduced, staphylococci have developed efficient mechanisms to neutralize them (Table ​(Table11). Figure 1 S. aureus infections in intensive care units in the National Nosocomial Infections Surveillance System. Data include the total number of infections from 1987 to 1997. Isolates were tested for sensitivity to the following antimicrobial agents: gentamicin, . Table 1 Mechanisms of S. aureus resistance to antimicrobialsA Recent reports of S. aureus isolates with intermediate or complete resistance to vancomycin portend a chemotherapeutic era in which effective bactericidal antibiotics against this organism may no longer be readily available (9, 10). This review will focus on the emergence of antimicrobial resistance in S. aureus. It will review the historical evolution of resistant strains, their spread, the molecular mechanisms of resistance for selected antibiotics, and progress toward the development of alternative drug targets or novel approaches for therapeutic or prophylactic intervention.