Antimicrobial resistance is the result of nearly inseparable interactions involving the drug, the microorganism, and the environment in which they coexist. 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. The environmental impact on antimicrobial activity is considered here, and its importance cannot be overstated.
Environmentally mediated resistance is defined as resistance directly resulting 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 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. Most of the aminoglycoside uptake is driven through oxidative processes in the cell. In the absence of oxygen, uptake (and hence the activity of the aminoglycoside) is substantially diminished.
Aminoglycoside activity is also affected by the concentration of cations in the environment, such as calcium and magnesium (Ca++ and Mg++). This effect is most notable with P. aeruginosa. As shown in Figure 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 2). 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 these sites, the amount of the drug taken up is decreased and antimicrobial activity is diminished. For this reason, aminoglycoside activity against P. aeruginosa tends to decrease as environmental cation concentrations increase.
Fig1. The basic steps required for antimicrobial activity and strategic points for bacterial circumvention or interference (marked by X) of antimicrobial action, leading to resistance.
Fig2. Cations (Mg++ and Ca++) and aminoglycosides (AG++) compete for the negatively charged binding sites on the outer mem brane 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.
The presence of certain metabolites or nutrients in the environment may also affect antimicrobial activity. For example, enterococci are able to use thymine and other exogenous folic acid metabolites to circumvent the activities of the sulfonamides and trimethoprim, which are folic acid pathway inhibitors (see Figure 3). In essence, if the environment supplies other metabolites for the microorganism, 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.
Fig3. Bacterial folic acid pathway indicating the target enzymes for sulfonamide and trimethoprim activity. (Modified from Katzung BG: Basic and clinical pharmacology, Norwalk, Conn, 1995, Appleton & Lange.)
Information about environmentally mediated resistance is used to establish standardized testing methods that minimize the impact of environmental factors, allowing more accurate determination of microorganism mediated resistance mechanisms. It is important to note that in vitro, testing conditions are not established to recreate the in vivo physiology of infection, but rather are set to optimize detection of resistance expressed by microorganisms.
