Evolution of Resistance
Microbes circumvent antimicrobials in many ways. The mechanism associated with drug resistance may involve synthesis of antagonists to the drug, altered cell permeability, elimination of the drug, decreasing or removing the binding site for the drug, or shutting down the metabolic pathway on which the drug acts. One simple mechanism used in many microbes is the synthesis of chemicals or enzymes that inhibit the action of the antimicrobial or deactivate it. Altering or decreasing the number of pores on the microbial cell surface can reduce the permeability of the cell to a drug significantly. Similarly, pumps at the cell surface that can actively pump the antimicrobial out the bacterial cell are effective against many antimicrobials.
Each antimicrobial drug has a very specific molecular target, and antimicrobial resistance mechanisms may involve modifications to the target. Examples of these modifications include changing the structure of a membrane chemical in gram-negative bacteria, adding an additional protein to ribosomes to alter the shape of a subunit, and altering binding sites on enzymes involved in DNA processing to reduce their binding with an antimicrobial.
In many cases, resistance involves the substitution of one nucleotide in the gene, leading to a corresponding amino acid substitution that renders the microbe resistant. As new antibiotics are developed, microbes evolve mechanisms to circumvent them, and researchers in turn seek new ways to circumvent the microbial resistance.
Because of their broad-spectrum effectiveness and wide usage, several resistance strategies have evolved to evade quinolones. There are cell surface pumps that when highly expressed reduce the cellular concentration of quinolones below an effective threshold, allowing DNA gyrase, an enzyme that assists in uncoiling the chromosome for replication and transcription, to continue functioning despite their presence. Direct mutations to the gene coding for DNA gyrase can alter the binding sites of quinolones on the resultant enzyme, thus reducing quinolone effectiveness. And there are genes spread on plasmids that code for proteins that stabilize DNA gyrase in the presence of quinolones.
One of the greatest concerns doctors have about prescribing antimicrobials is that they will not be as effective as they should be because the pathogen has developed resistance to the drug. The more antimicrobials are used, the greater the chances that at least some of the organisms will become resistant and, therefore, no longer be able to be treated with the medicine. As such, medical professionals have started to implement antibiotic stewardship to help improve the usage of antibiotics in increasing human health while decreasing resistance and costs of using them.
According to the Centers for Disease Control and Prevention, many hospitals are implementing antibiotic stewardship programs. Hospitals are where antibiotic resistance often starts. These hospital programs have dedicated the necessary human, financial, and information resources to making sure they are successful. Additionally, these programs often have a single point of contact who is responsible for the success and outcomes of the program. Other characteristics of a hospital program include education of clinicians about drug resistance, drug expertise about the particular antibiotics, tracking of the prescribing of antibiotics by doctors and hospitals, and reporting the findings from different studies about antibiotic use to other doctors and medical professionals.
One of the factors that should be studied by an antibiotic stewardship program is how often and for how long patients are given antibiotics. If it is found that some doctors are using (or abusing) antibiotics too much, they should be restricted from prescribing more until an analysis of their patient can be conducted. This is puts the doctor in a difficult position because many patients insist on being prescribed an antibiotic. This analysis should investigate if the patient has an infection that requires antibiotics and, if so, if the patient is on the correct antimicrobials and for the correct length of time.
Regular updates and continuing education of prescribers and pharmacists should be done to make sure that information is current information. Antibiotic stewardship programs should provide regular updates on antibiotic prescribing, antibiotic resistance, and infectious disease management that address issues that impact the local prescription of antibiotics, as well as any nationwide problems. Hospital staff should be regularly updated on how the facility as a whole is doing as far as antibiotic use. This can work as a catalyst to improve prescribing practices, particularly if there are large variations in the patterns of use among similar patient-care locations.