Chapter 20: Antibiotic Resistance

What is the most important problem associated with infectious disease today?

The rapid development of resistance to antibiotics

What will antibiotic resistance force us to do?

To change the way we view disease and the way we treat patients

Antibiotic resistance is not a matter of ____, but _________

if, when

What is the driving force behind the need to develop new antibiotics?

Resistance

What happens if antibiotics become useless?

Threat of the healthcare system as we know it

What is a warning from the United Nations regarding antibiotic resistance?

According to recent estimates, in 2019, 1.27 million deaths were directly attributed to drug-resistant infections globally. By 2050, up to 10 million deaths could occur annually. If unchecked, AMR (antimicrobial resistance) could shave $2.4 trillion off GDP annually and push 24 million more people into extreme poverty in the next day

Who said this and when: The message of this World Health Day is loud and clear. The world is on the brink of losing these miracle cures. In the absence of urgent corrective and preactive actions the world is heading towards a post-antibiotic era, in which many common infections will no longer have a cure, and once again, kill unabated.

WHO in 2011

What does the presence of too much antibiotic prompt the microbe to do?

Adjust to its environment and become resistant to the drug present (it is a matter of survival)

Antibiotics' use has not been without what?

Consequence

What are 3 factors in the development of antibiotic resistance (which is part of the natural world)?

1. Considerable potential for rapid spontaneous mutation (mutation happens)

2. Some of these mutations are for antibiotic resistance

3. These mutations are selected for (evolution of microbes is rapid from antibiotic exposure)

Development of Microbial Resistance to Antibiotics is ____________________

INEVITABLE

Why is antibiotic resistance inevitable?

1. Mutation happens (every organism with nucleic acid can mutate)

2. Evolution via artificial selection (called this bc humans do it)

Another fact about antibiotic resistance: Resistance occurs naturally as a part of what?

"Microbial chemical warfare"; bacteria fight each other using antibiotics

Mutations occur that allow an organism to do what?

Survive otherwise lethal antibiotics

Resistant cells continue to divide after the other cells of the microbe have died; then the resulting population becomes more resistant via what?

Vertical gene transfer

What does the ability to resist antibiotics come from?

Genes and relies on mutation to generate new mechanisms of resistance

What are 7 factors that are involved in the development of antibiotic resistance (according to the book)?

1. Bacterial growth and mutation rates

2. Plasmids and conjugation

3. Inappropriate clinical use of antibiotics

4. Use of antibiotics in the food chain

5. Immunocompromised population

6. Health care facilities

7. Lifestyle

What is an example of how microbial resistance happens (with penicillin)?

1. Penicillin is added; sensitive organisms are killed

2. Resistant P cells multiply (survive and undergo division)

What happens to bacterial cells that have developed resistance?

Are not killed off; they continue to divide, resulting in a completely resistant population

What 2 things cause a rapid increase in resistance to antibiotics?

Mutation and evolutionary pressure

What do bacteria have genetic material on?

Plasmids

plasmids transferred between bacteria via conjugation

Horizontal gene transfer

What happens if the resistance gene is present on the plasmid or chromosome?

The receiving bacteria will also get the resistance gene

Genetic material is transferred into the chromosome via what?

Resistance islands

Site where resistance genes accumulate in the recipient bacterium and are constantly maintained

Resistance islands

Where is selection pressure highest?

Where antibiotics are used most intensively AKA Hospitals

What can further exacerbate the development of resistant strains?

Modern technology and sociology

Who can carry resistant bacteria and what can they do?

Travelers carry resistant bacteria

- They travel with several or many other people

- Other people are infected with the resistant bacteria

- The process is repeated and the resistant bacteria spread

What are 6 instances of inappropriate use of antibiotics that contribute to antibiotic resistance?

1. Giving antibiotics for viral UTIs

2. Pts feeling better and decide not to finish antibiotic treatment

3. Pts using outdated drugs

4. Pts using antibiotics that were prescribed for something else

5. Sharing antibiotics between family and friends

6. Discarding unused drugs into landfill and water sources, introducing abx to the environment

Why should we use narrow spectrum antibiotics when possible?

As to not disrupt more of the normal flora of our bodies

There are more _______________ in the world today

large cities

What does having more large cities in the world today mean for the development of resistance?

- Large numbers of people in relatively small areas

- Passing antibiotic-resistant pathogens is easier

- Many large urban populations have poor sanitation

Urban living makes passing both ______________ and ________________ pathogens more possible

resistant, nonresistant

Why is the passing of resistant and nonresistant pathogens even worse in developing countries?

Sanitation is poor, health care is widely unavailable, and poverty is a huge issue in treatment possibilities (Cholera organisms becoming resistant)

_____________ for elderly also account for easy spread and resistance

Care homes

________ is also a source of infection that could affect the development of resistance

Food

How is food also a source of infection that could affect the development of resistance?

- More meals are prepared outside the home

- Contamination goes unnoticed until infection has started

- As the number of foodborne infections increases, so does the use of antibiotics (causes an increase in the development of resistance)

What is an example of contamination going unnoticed until infection has started?

Outbreaks of E. coli O157 in spinach and lettuce in the US

Antibiotics promote growth in livestock, but also do what?

Exposes the surrounding environment and water to the antibiotic (which creates evolutionary pressure for the antibiotic to create resistance)

How do hormones and antibiotics in food also affect the health of humans?

Abnormal digestion, weight gain in children; diabetes; chronic infection

What is an important social change in the development of resistance?

the increase in the number of people who are immunocompromised

What 2 things does an increase in the number of immunocompromised people necessitate and foster?

- Necessitates increased use of antibiotics

- Fosters development of resistance

What are immunocompromised populations that are growing?

HIV/AIDS patients surviving longer, transplant recipients, cancer patients, patients taking immune modulating drugs for Crohn's disease, MS, rheumatoid arthritis, psoriasis, etc. (Remicade, Embrel, Humira [TNF], Tremfya, Skyrizi, Ilumya [IL23], Stelera [IL12/23], etc.)

The clinical success of antibiotics led to what 3 things?

1. Increasing efforts to discover new antibiotics

2. Modification of existing drugs

3. Development of antibiotics with broader spectra

What is effort regarding antibiotics now targeted towards?

Prevention of wide-spread resistance in the first place

What 2 things are we trying to do about antibiotic resistance?

1. Slow it down (rate)

2. Try to keep resistance levels low (level)

What is true for every antibiotic regarding antibiotic resistance?

For every antibiotic, there are antibiotic resistance mechanisms

We need better ___________________ of antibiotics

stewardship

Resistance develops at different _________

rates

What are 4 examples of how resistance develops at different rates?

1. Several groups of antibiotics were used for many years before resistance was seen

2. Resistance to penicillin was seen in only 3 years

3. Some semi-synthetic forms of penicillin (ampicillin) had relatively long time before resistance developed

4. Other semi-synthetic forms (methicillin) lasted only a year before resistance developed

What was the short interval between use of methicillin and the development of resistance directly related to?

Increased use

The ________________________ of a drug is based on how quickly resistance develops

therapeutic life span

What happens the more an antibiotic is used?

The more quickly resistance occurs (so we have to limit rate of resistance by limiting antibiotic use)

Antibiotics are only available with a prescription. Why no OTC antibiotics?

Would be even more abused/overused

Steps can be taken to lengthen the ____________________ of antibiotics

therapeutic lifespan

What is the most important contributing factor for resistance?

Overuse

What is a good example of the overuse of antibiotics?

Prescribing antibiotics that don't kill viruses for the common cold

What do antibiotics destroy and what does this cause?

Destroy the normal flora, so opportunistic pathogens that are resistant survive and can take hold

How can you resist the patient as a "customer" demanding antibiotics (say, for a viral respiratory infection)?

There is NOT a customer relationship as in "the customer is always right" in healthcare

_____________ are ideal reservoirs for the acquisition of resistance

Hospitals

3 reasons hospitals are ideal reservoirs for the acquisition of resistance

1. A population of people with compromised health

2. A high concentration of organisms, many of which are extremely pathogenic

3. Large amounts of different antibiotics are constantly in use (so large selective pressure)

What does the increased use of antibiotics in hospitals lead to?

Resistance

The hospital is a place where resistance can develop ___________ and ______________

rapidly, spread

In hospitals, there is a large number of ________________ and _____________________________

antibiotics and immunocompromised patients

Resistance can be transferred by bacteria ______________ genes, as they are ___________________________

swapping, hyper-promiscuous

Where can swapping genes be easily accomplished?

in a hospital setting

What do health care works who don't follow infection control protocols do?

Aid in increasing resistance

Plasmids containing genes for resistance can integrate into what?

The chromosome

What do plasmids containing genes integrating into the chromosome form?

Resistance islands, where resistance genes accumulate and are stably maintained

What 2 ways can genes for resistance be passed?

1. Vertically: from one generation of bacteria to the next

2. Horizontally: between bacteria of the same generation and to bacteria of a different species

What is the major cause of rapid increase in resistant populations?

Inappropriate use of antibiotics

Why is there a need to modify old antibiotics and discover new antibiotics?

Development of resistance occurs quickly

What are 6 guidelines that can be used to increase the useful life span of drugs?

1. Optimal use of all antibacterial drugs

2. Control of certain antibiotic classes and selective use of broad-spectrum antibiotics

3. Use of antibiotics in rotation or cyclic patterns

4. Use of combination therapy

5. Evaluation of routes of resistance

6. Implementation of global changes

involves culturing the infective agent and isolating/identifying each organism involved in the clinical disease presentation

Susceptibility testing

In susceptibility testing, what is a list of drugs formed based on?

Identity of the pathogen

What is susceptibility testing tested using?

The Kirby Bauer method or disk diffusion

_______________ used for testing for single compounds, as well as effectiveness of different compounds

Disk diffusion

more advanced diffusion test that permits the determination of the minimal inhibitory concentration; use of a gradient scale

E test

the lowest antibiotic concentration that prevents visible pathogen growth

Minimal inhibitory concentration

used to determine whether an antibiotic is microbial or microbistatic

Dilution test

used to determine minimum bactericidal concentration

Broth test

Why do we work on the concentration of antibiotics?

Since the higher concentration used, the more quickly resistance will develop; trying to find the lowest concentration possible that still works in fighting the organism

Microorganisms producing antibiotic substances have what?

Autoprotective mechanisms

What is an example of an autoprotective mechanism that organisms that produce antibiotics have?

Transmembrane proteins that pump out the freshly produced antibiotic so that it doesn't accumulate (if it did, it would kill the organism producing it)

What are genes that code for transmembrane protein pumps closely linked to and what does this mean?

Genes that code for antibiotic resistance, so when genes for antibiotic production are turned on so are pump genes

What are 4 mechanisms that bacteria use to become antibiotic-resistant?

1. Inactivation of the antibiotic

2. Efflux pumping of the antibiotic

3. Modification of the antibiotic target

4. Alteration of the pathway

What does inactivation of antibiotics involve?

Enzymatic breakdown of antibiotic molecules

What is a good example of inactivation of an antibiotic?

Beta-lactamase

Where is beta-lactamase secreted?

Into the bacterial periplasmic space

What does beta-lactamase do?

Attacks the antibiotic as it approaches its target (its target = bacterial cell wall)

How many forms of beta-lactamase are there?

More than 190

The 2 bacterial genes involved with beta-lactamase activity can be:

1. Embedded in the bacterial chromosome

2. Carried on either plasmids or transposons

What are the 2 genes involved with beta-lactamase activity usually?

Turned off and only turned on in the presence of molecule's beta-lactam ring

Production of resistance factors such as beta-lactamase can be _____________________

genetically regulated

What were created in attempts to obtain antibiotics that are not affected by beta lactamase?

Next gen cephalosporins such as cefotaxime and ceftazidime

Use of ___________________ (has no antibacterial qualities, but inhibits beta lactamase) along with antibiotic to inhibit beta lactamase

Potassium clavulanate

not inhibited by lactamase inhibitors; many enteric bacteria carry this genes that is usually turned off, but turned on when the bacteria encounter b-lactam ring in antibiotics, creating B lactamase that inactivates the antibiotic

AmpC Beta-lactamase

What can AmpC do with its genes?

Confer them to other bacteria, creating a major resistance to which the only medical option is to treat with carbapenems

more common form of resistance to aminoglycoside antibiotics; enzymes that modify the antibiotic molecule and render it inactive; genes encoding these enzymes often found on plasmids and transposons, so resistance is easily passed to other bacteria

Aminoglycoside-inactivating enzymes

Active transport mechanism that requires ATP (or proton pumps)

Efflux pumping