Self directed antibiotic module

Question 1

How do antibiotics that inhibit protein synthesis do so?

Answer 1

Antibiotics that inhibit protein synthesis do so by attaching to bacterial ribosomes, which are structurally different from mammalian ribosomes.

Question 2

How do we know that most antibiotics that inhibit protein synthesis are bacteriostatic?

Answer 2

Usually protein synthesis can resume when the antibiotic is removed, so most of these antibiotics (macrolides, tetracyclines) are bacteriostatic.

Question 3

What is the definition of bacteriostatic?

Answer 3

Inhibits growth but does not kill the bacteria. The bacteria are then killed by white blood cells.

Question 4

What antibiotics that inhibits protein synthesis is the exception and is not bacteriostatic?

Answer 4

THe exception to this is the aminoglycoside group, where the binding of these antibiotics to the ribosome is lethal.

Question 5

What is the role of Gentamicin (IV)?

Answer 5

It binds to ribosomes inhibiting protein synthesis, but bactericidal (kills bacteria).

Question 6

Why must Gentamicin (IV) be given intravenously?

Answer 6

Not absorbed from the gut - must be given intravenously IV (occasionally intramuscularly, IM)

Question 7

What is Gentamicin (IV) used for?

Answer 7

Active mainly against Gram negative aerobic organisms such as coliforms and Pseudomonas aeruginosa) and is used in hospital for treating serious (life-threatening) Gram negative infection.
Excreted in the urine.

Question 8

How are Erythromycin, clarithromycin and azithromycin excreted from the body?

Answer 8

This group of antibiotics is excreted via the liver, biliary tract and into the gut (not excreted in urine).

Question 9

What are Erythromycin, clarithromycin and azithromycin used for?

Answer 9

These antibiotics are lipophilic and pass through cell membranes easily. They are useful for treating certain infections where bacteria “hide” from the host’s immune system by getting into the host cells.
Erythromycin is safe in pregnancy (the others have not been trialled in pregnant women).

Question 10

What are other antibiotics that inhibit protein synthesis?

Answer 10

Clindamycin
Chloramphenicol
Tetracyclines
(all of the above antibiotics are excreted via the liver and biliary system).

Question 11

What is Clindamycin used for?

Answer 11

Used 2nd line to treat serious Staphylococcal and Streptococcal infection, particularly in penicillin-allergic patients.
Also active against the “true” anaerobes (organisms that will not grow in the presence of oxygen).

Question 12

What is Chloramphenicol used for?

Answer 12

Mainly used as topical treatment for eye infections (as eye drops)

Question 13

What is tetracyclines used for?

Answer 13

treating infections caused by bacteria that do not have a proper bacterial cell wall (atypical pneumonia organisms).
Treating some infections (chest, skin) in patients who are penicillin allergic.

Question 14

How do tetracyclines work?

Answer 14

These antibiotics also inhibit bacterial protein synthesis by attaching to ribosomes and are bacteriostatic.
Excreted mainly via the liver and biliary system into the gut.

Question 15

What type of tetracycline is used in Tayside?

Answer 15

Doxycycline (oral) is he tetracycline used in Tayside.

Question 16

How does selection pressure affect resistance of bacteria?

Answer 16

Exposure of bacteria to antibiotics in the environment encourages resistance as small numbers of “resistant mutants” will survive whilst susceptible organisms die off (“survival of the fittest”).

Question 17

When are selection pressures highest and so the most number of bacteria likely to become resistant?

Answer 17

This is particularly likely to happen in the gut of someone who is taking antibiotics, or to bacteria in the hospital environment.
This means that the antibiotics we have are becoming less effective over time and must be used with caution.

Question 18

What allows bacteria to become resistant to an antibiotic?

Answer 18

The ability to become resistant to an antibiotic is the result of a change in the bacterial DNA.

Question 19

By what 2 mechanisms does bacterial resistance occur?

Answer 19

1. Genetic mutation
   - “misreading” of the DNA
2. Transfer of DNA that codes for antibiotic resistance from one bacterium to another by:
   - Transformation
   - Conjugation
   - Transduction

Question 20

How do genetic mutations occur?

Answer 20

Bacteria can reproduce rapidly, doubling in population every 20 minutes under ideal conditions.
As a result of this there is a lot of scope for “misreading” of the genetic code.

Question 21

What is the process of transformation?

Answer 21

When bacteria die and the cells break apart, “free-floating” DNA released into the surrounding environment may be “scavenged” by other bacteria and incorporated into their DNA. This DNA may contain genes that code for antibiotic resistance and benefit the recipient cell.

Question 22

What is the process of conjugation?

Answer 22

Bacteria often contain little “extra” bits of circular DNA called plasmids.
Many plasmids carry genes that confer resistance to antibiotics.
When two bacteria are in close proximity to each other a hollow bridge-like structure, known as a pilus forms between the two cells.
The plasmid replicates and one copy is transferred via the plus to the other bacterium.
This enables a previously susceptible bacterium to acquire the antibiotic resistance.

Question 23

What is the process of transduction?

Answer 23

I this process, bacterial DNA is transferred from one bacterium to another inside a virus that infects bacteria. These viruses are called bacteriophages or phages.
When a phage infects a bacterium it takes over the bacteria’s genetic processes to produce more phage.
During this process, bacterial DNA (which may code for antibiotic resistance) may be accidentally incorporated into the new phage DNA.
When the host cell dies and the phages are released from the dead cell, they will then contain DNA from the host bacterium can be transferred to other bacterial cells.

Question 24

How do penicillins work?

Answer 24

Inhibits cell wall synthesis, bactericidal.
Safe, very few side effects.
Range from narrow spectrum to broad spectrum
- Broad spectrum = acts on a wide range of bacteria, usually both gram negative and gram positive organisms.
Excreted (rapidly) via kidneys
safe in pregnancy
Any antibiotic with “cillin” in the name is one of the penicillin group.

Question 25

How do Cephalosporins work?

Answer 25

Any antibiotic with "ceph" of "cef" in the name is a cephalosporin. Cephalosporins inhibit cell wall synthesis by preventing cross-linking of peptidoglycan in exactly the same way as penicillins and are bactericidal. Excreted via the kidneys and urine. Have few side effects. Safe in pregnancy.

Question 26

How do Glycopeptides work?

Answer 26

Examples are Vancomycin, Teicoplanin (IV). Cell-wall active antibiotics, but in a slightly different way from the penicillins and cephalosporins. Bactericidal. Vancomycin binds to the end of the growing pentapeptide chain during peptidoglycan synthesis, preventing cross-linking and weakening the bacterial wall. Not absorbed when given orally - have to be administered intravenously (IV). Glycoproteins are excreted via the kidneys and urine - toxin level of vancomycin in the blood can build up I patients who have kidney failure, causing further kidney damage. Only active against organisms with a gram positive cell wall. No activity against any gram negative organisms. Vancomycin I not absorbed from the gut, but can be given orally to treat clostridium difficile infection, where it acts topically on the gut lumen.

Question 27

How does Metronidazole (oral, IV) work?

Answer 27

Acts by causing strand breakage of bacterial DNA used for: - Infection caused by "true" anaerobes (bacteria that will only grow when there is no oxygen in the atmosphere) - Some infections caused by protozoa (organisms that are single-celled parasites).

Question 28

How does Trimethoprim (oral) (+/- sulphamethoxazole) work?

Answer 28

THe mode of action is that it inhibits bacterial folic acid synthesis. Paraminobenzoate is converted into dihydropteroate by dihydropteroate synthetase (enzyme) which in inhibited by sulphamethoxazole. This is then converted into dihydrofolate and that is ultimately converted into tetrahydrofolate by dihydrofolate reductase (enzyme) which is inhibited by trimethoprim.

Question 29

How does Fluoroquinolones work?

Answer 29

Act by interactin with topoisomerases, enzymes responsible for the supercoiling and uncoiling of bacterial DNA. This interaction means that the bacteria can no longer replicate. Fluoroquinolones are bactericidal. The use of these broad spectrum antibiotics is now severely restricted in Tayside in an attempt to reduce the risk of Clostridium difficile gut infection, especially in elderly patients. These antibiotics are the only antibiotics that can be given orally to treat Pseudomonas infection. Can get as good blood levels when given orally as when given intravenously. Excreted in urine.

Question 30

What is the role of Ciprofloxacin (IV, oral)?

Answer 30

Used for complicated urinary tract infection and sometimes for urinary tract infection in younger men (<60 years old).

Question 31

What is the role of Levofloxacin (IV only)?

Answer 31

Only used for severe community-acquired pneumonia in penicillin-allergic patients.

Question 32

What are the different types of side effects that you can get from antibiotics?

Answer 32

General side-effects Some special side-effects Penicillin hypersensitivity ("allergy")

Question 33

What are some general side effects?

Answer 33

Many antibiotics cause gastro-intestinal side effects such as nausea and diarrhoea. This may result in failure of oral contraception and another method of contraception is usually required. Antibiotics kill off the normal gut bacterial flora and allow the overgrowth in the bowel of toxin-producing strains of Clostridium difficile. This causes severe, sometimes fatal, diarrhoea especially in frail, elderly patients. Giving any antibiotic in sub-optimal doses for prolonged periods encourages bacteria to become "resistant" to the antibiotic.

Question 34

``` What are the specific side effects of: Aminoglycosides Glycopeptides Tetracyclines Metronidazole Quinolones ```

Answer 34

Aminoglycosides - Gentamicin damages kidneys and causes deafness/dizziness Glycopeptides - Vancomycin damages kidneys - Occasionally causes "red man syndrome" (allergy) Tetracyclines - Permanent staining of teeth (and bones) in children <12 years. Metronidazole - Interacts with alcohol Quinolones - Weakens tendons (tendon rupture) - May damage joints in children (did so in young animals) - May cause seizures

Question 35

In a penicillin hypersensitivity wat is the incidence and Type 1 hypersensitivity reaction?

Answer 35

Incidence - Many patients are incorrectly labelled "penicillin-allergic" - Mild rashes develop in 1-10% of the population. - True hypersensitivity (below) occurs in <0.05% of treated patients. Type 1 hypersensitivity reaction - Itchy rash - Difficulty breathing, swelling on the mouth/tongue/larynx - Low blood pressure - Swelling at the injection site Such patients must not be given any penicillin-containing antibiotic and cephalosporins should be avoided also.

Question 36

What drugs are safe to use during pregnancy and what drugs are not safe to use?

Answer 36

In genera, all the penicillins and cephalosporins are safe to use in pregnancy. Trimethoprim and metronidazole should be avoided in the first 3 months. Gentamicin, tetracyclines and fluoroquinolones are not given to pregnant women.

Question 37

What are 3 types of bacterial resistance?

Answer 37

1. Altered antibiotic target binding site 2. Destruction or inactivation of the antibiotic 3. Increased efflux

Question 38

What is an altered antibiotic target binding site?

Answer 38

A change in bacterial DNA can cuase a change to the gene product which is the target of the antibiotic. For example, in order to act on the bacterial cell penicillins (such as flucloxacillin) first have to bind to the penicillin binding proteins (PBP), which are present in the bacterial cell wall. A mutation in the bacterial DNA of Staph. aureus results in the production of an abnormal PBP which no longer binds penicillins sich as flucloxacillin, resulting in these strains becoming resistant to all peniillins and all cephalosporins. These are known as MRSA strains. Alernatively, the binding site on the bacterial ribosome may alter to prevent attachment of an antibiotic that exerts its effect there.

Question 39

What is the destruction or inactivation of an antibiotic?

Answer 39

Many bacteria possess genes which code for enzymes that chemically degrade or inactivate the antibiotic, rendering them ineffective agaist the bacterium. Some examples of these are the beta-lactamases of whch there are many different types) an cephalosporinases, which specifically target and disrupt the beta-lactam ring of these antibiotics. One particular concern just now is the production by some Gram negative bacteria of extended spectrum beta-lactamases (ESBLs), enzymes that inactivate almost all the penicillins and cephalosporins.

Question 40

What is increased efflux?

Answer 40

Antibiotics enter bacterial cells through channels in the cell wall called porins. Efflux pups are channels that actively export antibiotics (an other compound) out of the bacterial cell. Genetic change may result in an increase in the rate of efflux, such that the antibiotic is pumped straight back out of the cell before it has time to act.