SUSCEPTIBILITY AND RESISTANCE
Deciding whether any bacterium should be considered susceptible or resistant to any an-timicrobic involves an integrated assessment of in vitro activity, pharmacologic character-istics, and clinical evaluation. Any agent approved for clinical use has demonstrated in vitro its potential to inhibit the growth of some target group of bacteria at concentrations that can be achieved with acceptable risks of toxicity. That is, the minimal inhibitory con-centration (MIC) can be comfortably exceeded by doses tolerated by the patient. Use of the antimicrobic in animal models and then human infections must have also demon-strated a therapeutic response. Because the influence of antimicrobics on the natural his-tory of different categories of infection (eg, pneumonia, meningitis, diarrhea) varies, extensive clinical trials must include both a range of bacterial species and infected sites. These studies are important to determine whether what should work actually does work and, if so, to define the parameters of success and failure.
Once these factors are established, the routine selection of therapy can be based on known or expected characteristics of organisms and pharmacologic features of antimicro-bics. With regard to organisms, use of the term susceptible (sensitive) implies that their MIC is at a concentration attainable in the blood or other appropriate body fluid (eg, urine) using the usually recommended doses. Resistant, the converse of susceptible, im-plies that the MIC is not exceeded by normally attainable levels. As in all biological sys-tems, the MIC of some organisms lies in between the susceptible and resistant levels. Borderline strains are called intermediate, moderately sensitive, or moderately resis-tant, depending on the exact values and conventions of the reporting system. Antimicro-bics may be used to treat these organisms but at increased doses, perhaps to reach body compartments where pathogens are concentrated. For example, nontoxic antimicrobics such as the penicillins and cephalosporins can be administered in massive doses and may thereby inhibit some pathogens that would normally be considered resistant in vitro.
Furthermore, in urinary infections, urine levels of some antimicrobics may be very high, and organisms that are seemingly resistant in vitro may be eliminated.
Important pharmacologic characteristics of antimicrobics include dosage as well as the routes and frequency of administration. Other characteristics include whether the agents are absorbed from the upper gastrointestinal tract, whether they are excreted and concentrated in active form in the urine, whether they can pass into cells, whether and how rapidly they are metabolized, and the duration of effective antimicrobial levels in blood and tissues. Most agents are bound to some extent to serum albumin, and the pro-tein-bound form is usually unavailable for antimicrobial action. The amount of free to bound antibiotic can be expressed as an equilibrium constant, which varies for different antibiotics. In general, high degrees of binding lead to more prolonged but lower serum levels of an active antimicrobic after a single dose.
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