WHAT IS ANTIMICROBIAL RESISTANCE AND WHY SHOULD WE CARE?

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.

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

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

Resistance – Not Just Against Antibiotics

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

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

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

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

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.

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

Increasing Resistance . . .

Decreasing New Drug Approvals

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

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

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

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

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

Horizontal Gene Transfer

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

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.

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

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.

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

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

Public Health Concerns How can we help?

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)

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

If You Do Require Antibiotics, Follow the Instructions

Be Cautious in Environments Where Resistant Organisms are Prevalent

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!

Don’t Take Antibiotics for Viral Illness

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!

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

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

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

Antibacterial Resistance 1 2 Peroxide Bleach Dial antibacterial soap Neosporin Alcohol Lysol 6 3 5 4

Additional Resources Evolution of Antibiotic Resistance from PBS (good evolution tie-in) - http://www.pbs.org/wgbh/evolution/library/10/4/l_104_03.html CDC Educational Activities to Promote Appropriate Use of Antimicrobial Agents in Animals - http://www.cdc.gov/narms/get_smart.htm Multi-level Antimicrobial Susceptibility Testing Resources (MASTER) - case studies and more - http://wwwn.cdc.gov/dls/master/default.aspx General Antibiotic Information – http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Antibiotics.html