Antibiotics

Question 1

What are Diesinfectants, Antiseptics and Antibiotics?

Answer 1

Disinfectants - applied to inanimate objects
Antispetics - sufficiently non-toxic to be applied to living tissue (hand sanatizer)
Antibiotics - produced by bacteria and fungi, exploited by humans

Question 2

Who discovered penicillin

Answer 2

Alexander Flemming in 1928

• discovered it by accident from leaving staph plates out and observing that the staph could not grow around a contaminating mold
• won nobel prize in physiology and medicine (1945)

Question 3

Antibiotics are…

Answer 3

• The most effective therapeutic treatment against bacterial infections
• enables chemotherapy, organ transplantation and all invasive surgeries

Question 4

What are 2 major problems posed by antibiotics?

Answer 4

1. Diminished interest from pharmaceutical companies to develop new antibiotics
2. Bacterial resistance to antibiotics always happens
   - because of resistance no guarentee that a drug made will be used for a long time
   - not many make it to the last stage of testing

Question 5

When was the golden age of antibiotics?

Answer 5

1940-1960 = 11 discovered

1960 - present = 4 discovered

Question 6

How old is antibiotic resistance?

Answer 6

Ancient…DNA from frozen permafrost (~30,000 years old) found antibiotic resistance genes (still able to work)

Question 7

What are the 2 ways antibiotics work?

Answer 7

Kill bacteria (bactericidal)
Stop them from gowing (bacteriostatic)

Question 8

How does one measure antibiotic activity?

Answer 8

Minimum Inhibitory Concentration (MIC)
- Series of culture tubes with varying [agent]
- check for visible growth
- MIC = lowest [agent] that inhibits growth
Zone of Inhibition
- Antibiotic strips on a plate of bacteria
- most effective antibiotic will have largest zone of inhibition where the bacteria was not able to grow

Question 9

How do antibiotics work?

Answer 9

Target essential bacterial components not present (or different) in eukaryotic cells

• cell wall synthesis
• protein synthesis
• DNA/RNA synthesis
• Folate Synthesis
• Cell membrane alteration

Question 10

Describe Beta-Lactam Antibiotics

Answer 10

e. g. Penicilin
- contains a Beta lactam ring
- Binds to bacterial penicillin binding proteins
- Stops peptide cross-links = weak cell wall = cell death

Question 11

How can bacteria be resistant to penicillin, how can this be countered?

Answer 11

Resistance: Beta-lactamase produced by some bacteria can destroy the ring

Response to resistance: Chemically modified penicillin can’t be cleaved by beta-lactamases

• Some bacteria produce a different penicillin binding protein encoded by ‘mec’ (PBP2a)
• This doesn’t bind methicillin and is therefore resistant to it

Question 12

What does Vancomycin do?

Answer 12

Inhibits cell wall synthesis in Gram+ bacteria

• glycopeptide antibiotic
• last resort drug
• Binds to peptide linkage at terminal D-Ala-D-Ala inhibiting transpeptidation

Resistance: Bacteria can change to D-Ala-D-Lac and vancomycin can no longer bind
- encoded by van genes

Question 13

What do Protein synthesis inhibitors do?

Answer 13

Protein synthesis inhbitors:

• Bacteria contain 70S (30S + 50S)ribosomes
• Eukaryotes contain 80S (40S + 60S)
• Many antibiotics target bacterial ribosomes and block translation

Question 14

What do Folic acid (vitamin B9 for humans) inhibitors do?

Answer 14

Trimethoprim and Sulfonamides

• Folic acid = thymidine synthesis in bacteria
• Must synthesize their own
• Inhibition of folic acid synthesis blocks DNA replication

Question 15

What do DNA/RNA synthesis inhibitors do?

Answer 15

e. g. Flouroquinolones
- interfere with DNA gyrase needed for supercoiling of DNA
e. g. Rifampicin
- Inhibits bacterial RNA polymerase

Question 16

What is Cell membrane alteration?

Answer 16

Polymyxin B

• Used on Gram-
• Bind to LPS
• Hydrophobic tail inserts and disrupts outer and inner membranes

Question 17

What are some stratagies for antibiotic resistance?

Answer 17

Prevention of antibiotic entry
antibiotic modification
Efflux of antibiotic (pump out)
Alteration of antibiotic target (prevents binding)
Bypassing the antibiotic action (use environmnetal folic acid)

Question 18

What are antibiotic resistance genes?

Answer 18

called R genes

- often encoded on mobile genetic elements (e.g. plasmids) leading to horizontal gene transfer -> superbugs

Question 19

What are 3 ways to horizotally transfer genes?

Answer 19

Transformation: Uptake of short fragments of naked DNA by naturally transformable bacteria
Transduction: transfer of DNA from one bacterium into another via bacteriophages (viruses that infect bacteria)
Conjugation: Transfer of DNA via sexual pilus (cell-cell contact)
- very efficient

Question 20

Paradoxically, the use of antibiotics…

Answer 20

actively selects for resistant bacteria

Question 21

What are overuses/misuse of antibiotics?

Answer 21

Empiric use (blinded use)

• acceptable for septic shock
• Increase use of broad spectrum agents (kills more than necessary)
• Pediatric use for viral infections
• Patients who do not complete the course (surviving bacteria will be resistant)
• Antibiotics in animal feed

Question 22

What are the ESKAPE bacteria?

Answer 22

Enterococcus faecium
Staphylococcus aureus
Klebsiella species
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter species
- Cause 2/3 of all health care associated pathogens

Question 23

Describe Enterococci

Answer 23

Species: faecalis, faecium(less virulent, more drug resistant)
- Gram+, non-motile, grows in chains
- Normal colonizers of intestinal tracts in mammals
Causes: UTIs, endocarditis, surgical infections

Question 24

What is VRE?

Answer 24

Vancomycin resistant enterococci

• first reported in 1989, now globablly disseminated
• has can genes which give resistance
• nosocomial (hospital aquired infection)

Question 25

Describe Acinetobacter baumannii

Answer 25

• Gram- aerobe, Iraqibacter, nosocomial (hospital aquired infection)
• found on the skin of healthy people
• Causes: UTI ventilator pneumonia, bacteremia and spesis
• can be resistant to virtually all antibiotics

Question 26

Describe Klebsiella pneumoniae

Answer 26

Gram-, facultative anaerobe, important cause of noscomial pneumonia
- produces a capsule which is resistant to multiple antibiotics

Question 27

What is NDM-1

Answer 27

• New delhi Metallo-beta-lactamase-1(carbapenems)
• Beta-lactamase resistant with broad spectrum activiy (lots of resistance)
• NDM-1 is now widespread in other Gram- bacteria

Question 28

How long does antibiotic resistnace take to evolve?

Answer 28

If widely used, 1-2 years

Penicillin
- introduced in 1941, resistant S. aureus in 1942
Methicillin
- introduced 1959, resistant S. aureus in 1961
Vanomycin
- introduced 1950s, reintroduced in `1960s, resistance in enterococci in 1989
- emergance of Multi-resistant S. aureus (MRSA) - 1999
- linezolid introduced to treat pneumococci (2000)
- Linezolid resistnace reported in S. aureus and VRE(2001)
- Vanomycin resistant S. aureus (VRSA)