Problems With Antimicrobial Drugs

susceptible strains, and costs of therapy and lengths of hospital stay are greater.

Mechanisms of resistance act as follows:

• Naturally resistant strains. Some bacteria are innately resistant to certain classes of antimicrobial agent, e.g. coliforms and many other Gramnegative bacteria possess outer cell membranes which protect their cell walls from the action of certain penicillins and cephalosporins. Facultatively anaerobic bacteria (such as Escherichia colt) lack the ability to reduce the nitro group of metronidazole which therefore remains in an inactive form. In the course of therapy, naturally sensitive organisms are eliminated and those naturally resistant proliferate and occupy the biological space newly created by the drug.

• Spontaneous mutation brings about organisms with novel antibiotic resistance mechanisms. If these cells are viable, in the presence of the antimicrobial agent selective multiplication of the resistant strain occurs so that it eventually dominates as above.

• Transmission of genes from other organisms is the commonest and most important mechanism. Genetic material may be transferred, e.g. in the form of plasmids which are circular strands of DNA that lie outwith the chromosomes and contain genes capable of controlling various metabolic processes including formation of |3-lactamases (that destroy some penicillins and cephalosporins), and enzymes that inactivate aminoglycosides. Alternatively, genetic transfer may occur through bacteriophages (viruses which infect bacteria), particularly in the case of staphylococci.

Resistance is mediated most commonly by the production of enzymes that modify the drug, e.g. aminoglycosides are phosphorylated, p-lactamases hydrolyse penicillins. Other mechanisms include decreasing the passage into or increasing the efflux of drug from the bacterial cell (e.g. imipenem resistance in Pseudomonas aeruginosa), modification of the target site so that the antimicrobial binds less effectively (e.g. methicillin resistance in staphylococci), and bypassing of inhibited metabolic pathways (e.g. resistance to trimethoprim in many bacteria).

Limitation of resistance to antimicrobials may be achieved by:

• Avoidance of indiscriminate use by ensuring that the indication for, the dose and duration of treatment are appropriate

• Using antimicrobial combinations in appropriate circumstances, e.g. tuberculosis

• Constant monitoring of resistance patterns in a hospital or community (changing recommended antibiotics used for empirical treatment when the prevalence of resistance becomes high), and good infection control in hospitals (e.g. isolation of carriers, hand hygiene practices for ward staff) to prevent the spread of resistant bacteria

• Restricting drug use, which involves agreement between clinicians and microbiologists, e.g. delaying the emergence of resistance by limiting the use of the newest member of a group of antimicrobials so long as the currently-used drugs are effective; restricting use of a drug may become necessary where it promotes the proliferation of resistant strains.

Although clinical microbiology laboratories report microbial susceptibility test results as 'sensitive' or 'resistant' to a particular antibiotic, this is not an absolute predictor of clinical response. In a given patient's infection, variables such as absorption of the drug, its penetration to the site of infection, and its activity once there (influenced, for example, by protein binding, pH, concentration of oxygen, metabolic state of the pathogen, intracellular location and concentration of microbes) profoundly alter the likelihood that effective therapy will result.

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