Antimicrobial Therapies

Question 1

Pronto I’ll and penicillin were the first antibiotics, what happened befor the discovery of these?

Answer 1

Minor infections were potentially fatal. Surgery was a major risk

Question 2

What are the origins of penicillin and prontosil?

Answer 2

Prontosil, took years for its potential to be realised and was never patented

Penicillin, discovered by chance by SAF. Other scientists then figured out ways to mass produce and administer it

Question 3

What is an antibiotic?

Answer 3

An anti microbial agent produced by a microorganism that kills it inhibits other microorganisms

Question 4

Where do antibiotics come from?

Answer 4

Produced by soil dwelling fungi (penicillum and cephalosporium) or bacteria (streptomyces or bacillus)

However they encompass a range of natural, semi synthetic and synthetic chemicals with anti microbial activity

Question 5

What is an anti microbial?

Answer 5

A chemical that selectively kills or inhibits bacteria, fungi or viruses

Question 6

What do bactericidal and bacteriostatic mean?

Answer 6

Bactericidal- kills them

Bacteriostatic - stops them growing

Question 7

What is an antiseptic?

Answer 7

Chemical that kills or inhibits microbes. Usually used topically to prevent infection

Question 8

Production of new antibiotics has slowed, why?

Answer 8

Most antibiotics in use today were developed in the 1940s and 50s

However many microorganisms are developing resistance to our usual drugs
Eg MRSA

Question 9

Why does antibiotic resistance lead to increased mortality, morbidity and cost?

Answer 9

Increased time to effective therapy

Requirement for additional approaches eg surgery

Use of expensive therapy (newer drugs)

Use of more toxic drugs that have to be administered in hospital (in patient)

Use of less effective second choice antibiotics

Question 10

What are aminoglycosides?

Answer 10

Eg gentamicin and streptomycin

Bactericidal

They target protein synthesis, RNA proofreading and cause damage to the cell membrane

It’s toxicity (eg hearing loss) has limited use but resistance to other antibiotics has lead to its increased use

Question 11

What is rifampicin?

Answer 11

Bactericidal

Targets RpoB subunits of RNA polymerase

Spontaneous resistance to it is frequent

It makes secretions go orange/red which can affect compliance to long courses of it

Question 12

What is vancomycin?

Answer 12

Bactericidal

Targets lipid II component of cell wall biosynthesis, as well as wall cross linking via D-ala residues

Its toxicity means it has limited use, however due it AB resistance to other antibiotics it’s use is increasing (especially in treatment of MRSA)

Question 13

What is linezolid?

Answer 13

Becteriostatic

Inhibits the initiation of protein synthesis by binding to the 50S rRNA subunit

Only has a Gram positive spectrum of activity

Question 14

What is daptomycin?

Answer 14

Bactericidal

Targets bacterial cell membrane

Only gram positive spectrum of activity

Higher toxicity

Question 15

What are beta lactams?

Answer 15

Most commonly prescribed class of antibiotics (eg penicillin and methicillin)

These interfere with the synthesis of the peptidoglycan component of the bacterial cell wall

They have bactericidal activity

They bind to penicillin-binding proteins that help manufacture the cell wall, inhibiting cell wall biosynthesis

They have a characteristic beta lactam ring (square)

Question 16

Antibiotics exhibit selective toxicity, how?

Answer 16

They target cellular processes that, in bacteria, invoke such different mechanisms and molecules than in humans

They also effect some pathways in bacteria that are unique to them (eg production of peptidoglycans)

Question 17

What are macrolides?

Answer 17

Eg. Erythromycin and azithromycin

Effect gram positive AND some gram negative infections

Target the 50S ribosomal subunit preventing amino Acyl transfer and truncating polypeptides

Question 18

What are quinolones?

Answer 18

Bactericidal

Synthetic

Broad spectrum

In gram negative, they target DNA gyrase

In gram positive they target topoisomerase IV

Question 19

What are broad and narrow spectrum antibiotics?

Answer 19

Broad spectrum - effect a wide range of bacteria

Narrow - only affect a small range

Question 20

What is meant by resistance?

Answer 20

Antibiotics act at diffferent doses.

The MIC (minimal inhibitory conc) is the lowest concentration of antibiotic required to inhibit growth

There is a scale, from sensitive to intermediate to resistant

At the sensitive end the bacteria is holy succeptible to the AB however past a break point concentration, the AB is no longer effective so the bacteria is resistant

Question 21

How does resistance come about?

Answer 21

The use of antibiotics selects for resistant strains

Population diversity —> application of a selection pressure —> becomes an advantage so the drug resistant bacteria survive

Question 22

What are the 4 mechanisms by which antibiotic resistance occurs?

Answer 22

Altered target site

In activation of antibiotic

Altered metabolism

Decreased drug accumulation

Question 23

How do alterations in antibiotic target site arise?

Answer 23

Via aquisition of an alternative gene or a gene that encodes a target modifying enzyme changing the shape of the protein the AB targets

MRSA encodes an alternative PBP (penicillin binding protein) with low affinity for beta lactams

Bacteria can use chemical processes to modify the target site

Question 24

How does the inactivation of antibiotic arise?

Answer 24

Enzymatic degradation or alteration, rendering antibiotic ineffective

ESBL and NDM-1 are examples of broad spectrum beta lactamases (these degrade a wide range of beta lactams, includibb the newest ones)

Question 25

How does the alteration of metabolism arise?

Answer 25

Increased production of enzyme substrate can out compete antibiotic inhibitor (so the AB binds to these instead of the bacteria)

Question 26

How does decreased drug accumulation occur?

Answer 26

Reduced penetration of AB into bacterial cell (either by reduced permeability, or increased efflux of the AB out of the cell)

So the drug doesn’t reach the concentrations required to be effective

Question 27

How do bacteria become resistant through the changing of DNA?

Answer 27

Plasmids - extra chromasal DNA is plasmids can contain AB resistant genes transposing swap genes from plasmid to chromosomal DNA and vice versa

Naked DNA - some bacteria can take up DNA from dead bacteria released into the environment

Question 28

What are the three ways bacteria can share DNA?

Answer 28

Transformation - uptake of extracellular DNA (chromosomal or plasmid)

Transduction - phages (viruses) infect bacteria, take uo DNA, spread this when they infect other bacteria

Conjugation - pilus are used to transfer dna between bacterial cells

Question 29

What are some examples of hospital acquired infections?

Answer 29

MRSA, VISA, C. Diff, E. coli, p. Aeruginosa

Question 30

What are some risk factors for hospital acquired infections?

Answer 30

Lots of immunosuppressed and I’ll people

Crowding

Presence of pathogens

Broken skin (wounds and iv)

Intubation

AB therapy (can alter the usual microbiota)

Transmission by staff

Question 31

What are some ways we can address AB resistance?

Answer 31

Prescribing strategies - controls, temporary withdrawal of certain classes

Reduce use of broad spectrum ABs

Quicker identification of infections caused by resistant strains

Combination therapy (use of Two ABs together to overcome resistance)

Knowledge of local strains and resistance

There are also some reactive approaches that we can take after resistance