Environmentally Mediated Antimicrobial Resistance

Antimicrobial resistance is the result of nearly inseparable interactions among the drug, the microorganism, and the environment in which they are brought together. Characteristics of the antimicrobial agents, other than the mode and spectrum of activity, include important aspects of each drug's pharmacologic attributes. However these factors are beyond the scope of this text. Microorganism characteristics are discussed in subsequent sections of this chapter (see discussion of Microorganism-Mediated Antimicrobial Resistance). The impact that environment has on antimicrobial activity is considered here, and its importance cannot be overstated.

Environmentally mediated resistance is defined as resistance that directly results from physical or chemical characteristics of the environment that either directly alter the antimicrobial agent or alter the microorganism's normal physiologic response to the drug. Examples of environmental factors that mediate resistance include pH, anaerobic atmosphere, cation (e.g., Mg*+ and Ca"*) concentrations, and thymidine content.

Several antibiotics are affected by the pH of the environment. For instance, the antibacterial activities of erythromycin and aminoglycosides diminish with decreasing pH, whereas the activity of tetracycline decreases with increasing pH.

Aminoglycoside-mediated shutdown of bacterial protein synthesis requires intracellular uptake across the cell membrane. Much of this aminoglycoside uptake is driven by oxidative processes, so that in the absence of oxygen, uptake, and hence activity, is substantially diminished.

Aminoglycoside activity is also affected by the concentration of cations such as Ca"* and Mg++ in the environment. This effect is most notable with P. aeruginosa. As shown in Figure 11-1, an important step in antimicrobial activity is the adsorption of the antibiotic to the bacterial cell surface. Aminoglycoside molecules have a net positive charge and, as is true for most gram-negative bacteria, the outer membrane of P. aeruginosa has a net negative charge. This electrostatic attraction facilitates attachment of the drug to the surface before internalization and subsequent inhibition of protein synthesis (Figure 11-7). However calcium and magnesium cations compete with the aminoglycosides for negatively charged binding sites on the cell surface. If the positively charged calcium and magnesium ions outcompete aminoglycoside molecules for

P. aeruginosa

AG++ AG++

Figure 11-7 Cations (Mg41 and Ca44) and aminoglycosides (AG**) compete for the negatively charged binding sites on the outer membrane surface of Pseudomonas aeruginosa. Such competition is an example of the impact that environmental factors (e.g., cation concentrations) can have on the antibacterial activity of aminoglycosides.

these sites, less drug will be taken up and antimicrobial activity will be diminished. For this reason, aminoglycoside activity against P. aeruginosa tends to decrease as environmental cation concentrations increase.

The presence of certain metabolites or nutrients in the environment can also affect antimicrobial activity. For example, enterococd are able to use thymine and other exogenous folic add metabolites to circumvent the activities of the sulfonamides and trimethoprim, which are folic add pathway inhibitors (see Figure 11-6), In essence, if the environment supplies other metabolites that a microorganism can use, the activities of antibiotics that target pathways for producing those metabolites are greatly diminished, if not entirely lost. In the absence of the metabolites, full susceptibility to the antibiotics may be restored.

Information regarding environmentally mediated resistance is used to establish standardized testing methods that minimize the impact of environmental factors so that microorganism-mediated resistance (see the following discussion) is more accurately determined. Of importance, testing conditions are not established to recreate the in vivo physiology of infection but are set to optimize detection of resistance expressed by microorganisms. This is an extremely important point and a major reason why susceptibility testing results cannot be used to predict the clinical outcome of patients undergoing antimicrobial therapy.

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