Some pathogens are naturally resistant to certain chemotherapeutic drugs. Resistance can occur through mutation, adaptation, or gene transfer. The mechanisms accounting for innate and acquired resistance are essentially the same. Spontaneous mutation in bacterial cells occurs at a frequency of approximately one per million cells. Such mutations may confer resistance to the chemotherapeutic drug. Spontaneous mutation is not a major concern unless the use of the drug results in selection and proliferation of resistant mutant pathogens in the patient.
Resistance to an antibiotic can be the result of one or more mechanisms. Alterations in the lipopolysaccha-ride structure of gram-negative bacilli can affect the uptake of lipophilic drugs. Similarly, changes in porins can affect the uptake of hydrophilic drugs. Once the drug enters the cell, it may be enzymatically inactivated. Some bacteria possess pumps that remove drugs from the bacterial cytosol. The antibiotic also may be ineffective as a result of mutation of genes coding for the target site (e.g., penicillin-binding proteins, DNA gyrase, or ribosomal proteins).
It is clinically important to understand the nature of the mechanism of resistance to an antibiotic drug. For example, the p-lactam resistance of Streptococcus pneu-moniae is due to the appearance of altered penicillin-binding proteins. Thus, the use of a combination of a p-lactam and a penicillinase inhibitor, such as clavulanate, will not overcome streptococcal p-lactam resistance, because the mechanism of resistance is not due to the production of a penicillinase.
Multiple resistance may occur. Such resistance is recognized as a major problem in controlling bacterial infections and may be either chromosome or plasmid mediated. Plasmids (extrachromosomal genetic elements), which code for enzymes that inactivate antimicrobials, can be transferred by conjugation and transduction from resistant bacteria to previously sensitive bacteria. Such a transfer can also occur between unrelated species of bacteria. Enzymes coded by plasmids (e.g., penicillinase, cephalosporinase, and acetylases) that are specific for a given antimicrobial inactivate the drug either by removal or addition of a chemical group from the molecule or by breaking a chemical bond. Transposons are segments of genetic material with insertion sequences at the end of the gene; these sequences allow genes from one organism to be easily inserted into the genetic material of another organism. Some of these transposons code for antibiotic resistance.
In vitro laboratory tests of sensitivity of a microorganism to specific antimicrobial agents are used to predict efficacy in vivo. Often, it is enough to identify the causative pathogen in culture; the general resistance pattern of the pathogen and local patterns of resistance of the pathogen may then allow proper choice of chemotherapy. It is sometimes helpful to measure the antibiotic sensitivity of the specific isolated pathogen. Generally, a battery of tests against a selection of possible antibiotic drugs is employed.
Some organisms, such as Staphylococcus aureus, Neisseria gonorrhoeae, and Haemophilus influenzae, may produce p-lactamase and therefore be resistant to penicillin and its congeners. Testing for p-lactamase production by isolates enables an early decision on the use of penicillin and congeners in treatment of the disease.
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