Nongenetic Origin of Drug Resistance

Active replication of bacteria is required for most antibacterial drug actions. Consequently, microorganisms that are metabolically inactive (nonmultiplying) may be phenotypically resistant to drugs. However, their offspring are fully susceptible. Example: Mycobacteria often survive in tissues for many years after infection yet are restrained by the host’s defenses and do not multiply. Such “persisting” organisms are resistant to treatment and cannot be eradicated by drugs. Yet if they start to multiply (eg, after suppression of cellular immunity in the patient), they are fully susceptible to the same drugs.

Microorganisms may lose the specific target structure for a drug for several generations and thus be resistant. Example: Penicillin-susceptible organisms may change to cell wall deficient L forms during penicillin administration. Lacking cell walls, they are resistant to cell wall-inhibitor drugs (penicillins, cephalosporins) and may remain so for several generations. When these organisms revert to their bacterial parent forms by resuming cell wall production, they are again susceptible to penicillin.

Microorganisms may infect the host at sites where anti microbials are excluded or are not active. Examples: Aminoglycosides such as gentamicin are not effective in treating Salmonella enteric fevers because the salmonellae are intra cellular and the aminoglycosides do not enter the cells. Similarly, only drugs that enter cells are effective in treating Legionnaires’ disease because of the intracellular location of Legionella pneumophila.

Genetic Origin of Drug Resistance

Most drug-resistant microbes emerge as a result of genetic change and subsequent selection processes by antimicrobial drugs.

A. Chromosomal Resistance

This develops as a result of spontaneous mutation in a locus that controls susceptibility to a given antimicrobial drug. The presence of the antimicrobial drug serves as a selecting mechanism to suppress susceptible organisms and favor the growth of drug-resistant mutants. Spontaneous mutation occurs with a frequency of 10⁻¹²–10⁻⁷ and thus is an infrequent cause of the emergence of clinical drug resistance in a given patient. However, chromosomal mutants resistant to rifampin occur with high frequency (~10⁻⁷–10⁵). Consequently, treatment of bacterial infections with rifampin as the sole drug often fails. Chromosomal mutants are most commonly resistant by virtue of a change in a structural receptor for a drug. Thus, the P 12 protein on the 30S subunit of the bacterial ribosome serves as a receptor for streptomycin attachment. Mutation in the gene controlling that structural protein results in streptomycin resistance. Mutation can also result in the loss of PBPs, making such mutants resistant to β-lactam drugs.

B. Extrachromosomal Resistance

 Bacteria often contain extrachromosomal genetic elements called plasmids. Their features are described in Chapter 7.

Some plasmids carry genes for resistance to one—and often several—antimicrobial drugs. Plasmid genes for antimicrobial resistance often control the formation of enzymes capable of destroying the antimicrobial drugs. Thus, plasmids determine resistance to penicillins and cephalosporins by carrying genes for the formation of β-. Plasmids code for enzymes that acetylate, adenylate, or phosphorylate various aminoglycosides; for enzymes that determine the active transport of tetracyclines across the cell membrane; and for others.

Genetic material and plasmids can be transferred by transduction, transformation, and conjugation. These processes are discussed in Chapter 7.

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مواضيع ذات صلة

Antimicrobial Chemoprophylaxis

Drug–Pathogen Relationships

Measurement of Antimicrobial Activity

Clinical Implications of Drug Resistance

Resistance to Sulfonamide

Control of Antibiotics Overuse

International Distribution of Antibiotics: A Scandinavian Example

Rediscovery of Penicillin by a Basic Scientific Approach

Penicillin: the First Antibiotic

Sulfonamide: the First Antibacterial Agent Acting Selectively

Drug elimination

Drug distribution