1. WHAT IS ANTIMICROBIAL RESISTANCE AND WHY SHOULD WE CARE?

2. What is an antibiotic?
An antibiotic is a drug targeted to bacterial (prokaryotic) cells.
Humans can take antibiotics to eliminate bacterial infections in the body while leaving their eukaryotic cells unharmed.
Antibiotics are useless for treating viral infections as the virus is living inside your eukaryotic cells.

3. Resistant versus Susceptible
Susceptible organisms are killed by a particular antibiotic
Resistant organisms survive in the presence of the antibiotic

4. Selective Pressures
The dots represent a genetically diverse bacteria population
A few organisms have a spontaneous resistance mutation but their proliferation is controlled by the competition in the population
The use of the antibiotic acts as a selective force, wipes out the susceptible population, leaving only resistant organisms behind

5. Resistance – Not Just Against Antibiotics

6. Antibiotic Mechanisms of Action
Bactericidal: directly kill bacteria
Bacteriostatic: prevents growth of bacteria so that the immune system can then kill the bacteria

7. Spectrum of Action Broad: effective against many species
Narrow: effective against a more narrow range of species

8. How Does Resistance Develop?
Bacteria develop resistance to an antibiotic based on spontaneous mutations that occur.
Further, there are ways that bacteria with these resistance genes can seek out bacteria lacking the resistance and pass the genes on to them.
Conjugation
Transformation
Transduction

9. How long has resistance been a problem?
Drug
Year deployed
Year resistance observed
Penicillin
1943
1946
Streptomycin
1959
Tetracycline
1948
1953
Erythromycin
1952
1988
Vancomycin
1956
Methicillin
1960
1961
Ampicillin
1972
Note that resistance can sometimes be selected for within a year of a new drug being released. The more the drug is used, the bigger the problem

10. Developmental History of Antibiotics
Huge research in 40s and 50s - researchers though infections were conquered.
Resistance noted in 50s and 60s but thought to be no big deal because tons of new drugs were coming out.
By 1970, all the major classes of drugs were out and new drugs were only slight modifications of old drugs.

11. Developmental History of Antibiotics
Research slowed way down. It took 30 years to get a new class of drugs!
Resistance started becoming a major problem in the late 80s . Oopsie – we didn’t plan for this!
Very few drugs released in the 90s and 00s
Resistance is now a huge problem, particularly with hospital acquired infections where there is an extremely high level of resistance

12. Increasing Resistance . . .

13. Decreasing New Drug Approvals

14. Why aren’t new antibiotics being developed?
On average, it takes about $800 million to develop a new drug
The process takes about 10 years
The pressure to make money is tremendous when the drug comes out
This leads to mass marketing, overuse of the drug, and selection for resistance
Often, this process is a financial loss for the pharmaceutical companies who can make a lot more money on developing drugs for chronic conditions

15. What perks do pharmaceutical companies want?
The pharmaceutical companies want to cut deals if we want them to develop new antibiotics
Some things they want are:
Longer exclusivity
Fast track FDA approval
Tax breaks
Subsidies

16. Just How Do Bacteria Resist the Effects of an Antibiotic?
There are two options:
Do something to the antibiotic
Do something to prevent the antibiotic from working

17. Mechanisms for Acquiring Resistance
Inherent:
Natural resistance to a drug with no genetic modification required
Example: a drug designed to prevent crosslinking of peptidoglycan will not be effective on Gram negative organisms due to their normal cell wall structure
Acquired:
Resistance to a drug comes from genetic modification

18. Methods for Acquired Resistance
Vertical Gene Transfer:
Bacterium with a resistance gene reproduces via binary fission
All progeny will have the resistance gene
Horizontal Gene Transfer:
Bacterium with a resistance gene passes that gene to other cells by means other than binary fission
Examples: conjugation, transformation, transduction

19. Horizontal Gene Transfer

20. Both Vertical and Horizontal Gene Transfer Lead to the Same End Result

21. What happens when people develop infections that are resistant to antibiotics?
Let’s say you had a bacterial infection that your immune system couldn’t fight off on its own. The course of treatment for this infection would be antibiotics. Now, if the bacteria causing your infection are resistant to the antibiotic used, then the bacteria won’t be eliminated and the infection continues. This can be fatal if the bacteria can’t be killed.
Keep in mind that we only have a limited number of different antibiotics and if the bacteria become resistant to all of them then we literally will have no cure.

22. Notorious Resistant Bugs
Staphylococcus aureus: MRSA, VRSA, LRSA
Enterococcus species (VRE)
Streptococcus pneumoniae
Streptococcus pyogenes
Escherichia coli
Klebsiella pneumoniae
Acinetobacter baumanni
Clostridium difficile
Pseudomonas aeruginosa
Mycobacterium tuberculosis: MDR, XDR

23. Multiple Resistance Problems
Recent studies show that some bacteria produce an acetyltransferase enzyme that can modify all sorts of antibiotics and render them useless.
The active site on this enzyme appears flexible so it can bind to many antibiotics and then break them down.
There should be some very interesting developments in this area.

24. Costs of Resistance
Between 5 – 10% of all hospitalized patients acquire a nosocomial infection
This costs more than $5 billion annually!
In general, a nosocomial infection leads to:
3 times the length of a normal hospital stay
3 times the cost
5 times increased risk of death

25. Major Points People are not resistant to antibiotics – bacteria are!
On our survey, more than 50% of us stated “true” to the statement “People are becoming increasingly resistant to antibiotics”!
Antibiotic resistance is the result of mutations and normal evolution
Selective pressures increase the number of antibiotic resistant bacteria in a population
Our goal is to limit the spread of antibiotic resistant bacteria

26. Public Health Concerns
How can we help?

27. Notes
The first thing to understand is that we cannot do anything to end resistance.
It is evolution, it happens naturally, and it won’t be stopped
Our efforts have to be at reducing the selective pressures and slowing the rate of spread of antibiotic resistant organisms
Right now we have a vicious cycle at work (see next slide)

28. Culture and Do Susceptibility Testing
How often are antibiotics prescribed with no culturing at all?
Culturing is cheap, quick, and can make sure we use the most effective antibiotic for your particular infection

29. If You Do Require Antibiotics, Follow the Instructions

30. Be Cautious in Environments Where Resistant Organisms are Prevalent

31. Don’t Self-Medicate!
More than 50% of us say we have saved antibiotics from a time we were sick and taken them at a later date or shared them!

32. Don’t Take Antibiotics for Viral Illness

33. Precautions in Clinical Settings
Use protocols to encourage hand washing (bare below elbows)
Use caution with items that may be moved from patient to patient
Keep uniforms in the clinical setting
Wash lab coats and scrubs!

34. Be cautious about the use of antibiotics in animals other than humans

36. And . . . When We Run Out of Antibiotics, At Least We Have Alternatives

37. Other Forms of Resistance
Don’t forget that there are major drug resistant problems with microbes other than bacterial
Yeasts and other fungi can exhibit high levels of resistance to antimicrobial drugs
Viruses are notorious for their development of resistance to antiviral drugs

38. Antibacterial Resistance1 2
Peroxide
Bleach
Dial antibacterial soap
Neosporin
Alcohol
Lysol 6 3 5 4

39. Additional Resources
Evolution of Antibiotic Resistance from PBS (good evolution tie-in) -
CDC Educational Activities to Promote Appropriate Use of Antimicrobial Agents in Animals -
Multi-level Antimicrobial Susceptibility Testing Resources (MASTER) - case studies and more -
General Antibiotic Information –