Antibiotics became widely available in the 1940's and 1950's and were touted as "magic bullets" and "wonder drugs." Indeed these drugs treated many infectious diseases with great success. The news is not all good and some believe we are entering a "post antibiotic era." Antibiotics have been used with great abandonment and to treat viral infections against which they have no effect. We dump antibiotics into livestock feed and consume drug resistant microbes that get into the food chain. We were lulled into a false sense of security, believing we could eradicate diseases that have since reemerged as multi-drug resistant forms. Vaccine research was abandoned for pills. As a result of these factors we have placed selection pressure on microbes to outwit antibiotics. How does selection pressure work? Imagine the following scenario. You are prescribed a weeks course of antibiotics. By the fourth day of treatment you begin feeling better as the antibiotics kill off the offending microbes. Believing you are well you stop taking the drugs. At this point, susceptible microbes have been eliminated but any mutant or resistant forms that are left behind are now free to multiply. Within a couple of days you are sick again and the original antibiotic will no longer work. Time to get a new drug.....if there's one available!

Socioeconomic factors contributing to drug resistance

• Growing populations of elderly and immunocompromised
• Increased homelessness
• Lack of access to adequate health care
• Crowded institutions (Prisons, Homeless centers)
• Increased reliance on day care centers
• Developing countries-reliance on "injectables"
• Over dependence & frequent use of "over the counter" medications'

Common resistance mechanisms utilized by microbes

1. Enzyme inactivation

• Among the most common mechanisms of drug resistance
• Beta-lactamases destroy Beta-lactam rings of penicillins & cephalosporins.
  • Commonly encoded on resistance plasmids (most patient isolates).
  • Penicillinases secreted by Staphylococcus aureus (MRSA) and Neiserria gonorrhea
  • Found in periplasmic space of Gram negatives
• Aminoglycoside-modifying enzymes-most common form of resistance to these types of antibiotics
  • Commonly encoded on resistance plasmids
  • Modification of enzyme leads to reduced transport of drugs across the cell membrane so that the drug fails to bind to ribosomes

2. Altered target: drug can no longer bind

Often due to chromosomal resistance

Examples:

• Penicillin binding proteins-MRSA, penicillin-resistant S. pneumoniae, N. gonorrhea
• DNA gyrase-resistance to quinolones
• Dihydrofolate reductase (DHFR) enzyme leads to altered metabolic pathway-trimethoprim
• RNA polymerase-rifampin

3. Altered membrane permeability

• Can involve changes in membrane composition or loss of porin channels

4. Efflux pumps drive antibiotics out of cell

• Mediated by plasmids
• Main mechanism of resistance to tetracycline used by gram positive& negative organisms

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How do microbes become resistant to antibiotics?

Inherent resistance

Some microbes may naturally lack a recognizable target. For example, mycoplasma are small bacteria that lack cell walls. Other microbes are naturally impermeable to an antibiotic. For example, the lipopolysaccharide outer membrane of gram negatives is impermeable to Penicillin G.

Acquisition of drug resistance

1. Chromosomal

• Spontaneous mutations/accumulation of point mutations
• Can be induced by selection pressure
• Can impart "cross resistance" to similar classes of drugs
• Important but not the most common form of resistance in patient isolates

2. Conjugation

• Donor transmits genetic information (a free gift) to a recipient cell via sex pili.
• Some cells release diffusable pheromones & "ask for sex"
• Often involves "plasmid-sharing"
  • circular strands of dsDNA-extrachromosomal
  • transferred between same or different species
  • R factor plasmids or MDR plasmids carry genes for resistance to one or multiple agents

3. Transformation

 This phenomenon was first described by Frederick Griffith in the 1920's when working with pneumococci. Organisms take up fragments of "naked DNA" that can recombine with the chromosome of the recipient cell. The cell being transformed must be in a state of competence. That is, the cell wall must be transiently permeable to allow entry of the nucleic acid into the cell. Transformation has been observed in pneumococci, Neisseria gonorrhea and Hemophilus influenza.

4. Transduction

Bacteriophages infect bacteria and package bacterial DNA into new virions. Following lysis of the host cell virions infect more bacterial cells. Nucleic acid (prophage DNA) can be incorporated into the host chromosome in a state of lysogeny (also known as phage conversion). The incorporated DNA replicates along with the bacterial DNA.

Examples:

• Diphtheria toxin in Corynebacteria
• Toxic shock toxin of S. aureus

5. Transposons

• Small mobile genetic elements with insertion sequences ("jumping genes")
• Can move between chromosomes and plasmids
• Can carry antibiotic resistance genes

 

Minimizing drug resistance: What can be done?

Focus on PREVENTING infection

• Develop vaccines
  • May take 15 years minimum
  • Not always seen as economically viable
• Disrupt transmission
  • Nosocomial: increased infection control; hand-washing; barrier & isolation precautions; air flow control
  • Community: increased hygiene & sanitation. Problems: absenteeism discouraged from work, day care centers.

More prudent use of antibiotics

• Reduce selective pressure
• Limit drug availability
• Limit use in farm animals

Rapid diagnosis & susceptibility testing to assure appropriate drug use

Improve surveillance and tracking of drug resistance

Combination therapy

• Slows but does not eliminate selection pressure

Develop new drugs:

• Easier said than done!
• May take 7 or more years
• May not be "profitable"
• Incentives may be needed

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