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4.2 Medical Microbiology > Antimicrobials > Flashcards

Antimicrobials Flashcards

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1
Q

Talk a little on the history of antibiotics

A

Greatest medical breakthrough of the 20th century

First antibiotic salvarson deployed in 1910

Penicillin in 1928 - golde age of natural produce antibiotic discovery

Over 100 years theyve drastically changed medicine

Extended human life span by 23 years

Invasive procedures now possible e.g. open heart surgery and infections now survivable

However no new antibiotics in recent years - were now in the postantibiotic era

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2
Q

Why are no new antibiotics being made?

A

theres no money in antibiotics

Any new drugs will eventually incur resistance - companies wont make money from them

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3
Q

Talk about the UK O’Neill report, what are some of the findings

A

A report on resistance comissioned by the UK government

Determined that 700,000 deaths occur due to resistant bacteria at the moment

Predict that 10 million deaths will occur due to resistant bacteria by 2050

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4
Q

How was Penicillin discovered

A

S. aureus plates were left in an incubater over the weekend

Fungus grew on plates

Observed antimicrobial affect of fungus on the S. aureus

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5
Q

What has been our most recent large discovery in antibiotics

A

Macrolides

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6
Q

Define antimicrobials, what are the three types?

A

Agents used to kill or inhibit the growth of microorganisms such as bacteria, fungi, viruses or pasites

Antibiotics are used to control bacterial growth
Annifungals are used to control fungal growth
Anivirals used to control viral growth

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7
Q

What three things must be balanced when selecting an antibiotic to use

A

Effective treatment
Minimisation of toxicity
Prevention of resistance

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8
Q

What are the different properties of an antibiotic, what properties of a drug should be considered

A

Spectrum of activity: broad or narrow
Mechanism of action: bacteriostatic vs bactericidal
Pharmacokinetic properties: absorption, distribution, metabolism, excretion
Pharmacodynamic properties: time-dependent killing, concentration-dependent killing
Toxicity and safety profile: organ toxicity, allergic reactions, side effects
Interactions with other drugs
Stability and formulation
Impact on normal flora
Cost and availability

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9
Q

Talk about broad spectrum antibiotics

A

Effective against both gram positive and negative organisms
Most commonly used is Norfloxacin
They are used in empirical treatment where we dont have time to ID the causative organism
They attack every bacteria and thus disrupt microbiome
Cause side effects such as GI distress and yeast infections in women

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10
Q

Talk about narrow spectrum antibiotics

A

Act against a limited number of bacteria
e.g. penicillin targetting peptidoglycan and thus only being affective against gram +/ves
We often switch to narrow spectrum to target therapy when we have ID’d the organism
More targetted therapy means more effective treatment - means patient needs to be treated for less time
Often has fewer side effects and little impact on normal flora

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11
Q

Compare baceriostatic vs bactericidal antibiotics

A

Bacteriostatic only inhibit bacteria from reproducing but doesnt actively kill them

Bactericidal actively kills bacteria - kills at least 99% in the first 4-8 hours

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12
Q

What is the most commonly used antibiotic in empirical treatment?

A

Norfloxacin

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13
Q

Some antibiotics can have both bacteriocidal and bacteriostatic affects, comment on this and give an example

A

Different affects on different organisms e.g.
Linezolid is bacteriostatic against staph and enterococcus but bactericidal against strep

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14
Q

What is pharmacokinetics

A

The study of how the body interacts wih administered substanced for the entire duration of exposure

Defined as the kinetics of drug absorption, distribution, metabolism and excretion (KADME)

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15
Q

Talk about the absorption PK property of antibiotics

A

How well the antibiotic is absorbed into the bloodstream when taken orally or through other routes

IV or oral etc

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16
Q

Talk about the distribution PK property of antibiotics

A

How the drug spreads throughout the body’s tissues and fluids

Some antimicorobials will penetrate well into specifric tissues e.g. CNS while others will not

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17
Q

Talk about the metabolism PK property of antibiotics

A

The process by which the drug is broken down
Some antimicrobials are metabolised in the liver, and understandin this helps avoid drug-drug interactions

Chronic illness e.g. those affecting liver and kidney can affect the metabolism of antimicrobials
The same can happen with other medications- they can interfere with metabolisation of antibiotics

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18
Q

Talk about the excretion PK property of antibiotics

A

How the drug is removed from the body, primarily through the kidneys or liver

Patients with renal or hepatic impairment may need dosage adjustments to compensate for this - might need lower dosage etc

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19
Q

What are pharmacodynamic properties

A

The effects of drugs in the body and the mechanism of their action

Time-dependent killing and conentration-dependent killing

Monitoring concentration of antibiotics done in bio lab to balance conc above MIC

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20
Q

Talk about time-dependent killing PD property of antimicrobials

A

The effectiveness of some antimicorbials such as B-lactams is dependent on how long the drug concentration remains above the minimum inhibitory concentration of the pathogen

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21
Q

Talk about concentration -dependent killing PD property of antimicrobials

A

Some antimicrobials such as aminoglycosides and fluoroquinolone effectiveness increases with higher concentration

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22
Q

What are the differences between pharmacokinetics and pharmacodynamics

A

PK is the study of what the body does to the drug
- absorption, metabolism etc etc

PD is the study of what the drug does to the body
- in tems of antimicrobials this is the effect of concentrations and time of drug on body

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23
Q

Talk about the organ toxicity property of antimicrobials, give examples

A

Some can be toxic to specific organs e.g. aminoglycosides are nephrotoxic and isoniazid is hepatotoxic

Monitoring is necessary for high-risk patients

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24
Q

Talk about allergic reactions in antimicrobials

A

Some such as penicillins can cause severe allergic reactions

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25
Q

Talk about the side effects of antimicrobials

A

Can range from mild e.g. GI upset to severe eg. anaphylaxis or C. diff associated diarrhea

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26
Q

What are the properties of a good antibiotics

A

Selective toxicity ie. the ability to kill or inhibit growth of an organism without harming the cells of the host

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27
Q

Talk about the ability of antimicrobials to inteact with other drugs

A

Can inteact with others to either affect their own activity of the acivity of the othe drug

Can reduce efficacy or increase toxicity

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28
Q

Talk about stability and formulation of antimicrobials

A

Stability: what tempeature does it have to be stored at, does it work best at certain pHs etc

Formulation: does it have to be made up, oral, intravenous, topical etc

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29
Q

Talk about the impact of antimicrobials on normal flora

A

Broad spectrum disrupt normal flora
Can potentially cause secondary infections usch as yeast
Can cause superinfections such as C. diff

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30
Q

Talk about superinfections

A

Infections which follow treatment
Either opportunistic e.g. C, diff or resistant following antimicobirl resistance

31
Q

Talk about the cost and availability of antimicrobials

A

The expense and availability can impact their use especially in low-resource settings

Generic formulations are often preferred to reduce costs

32
Q

What are the four ideal properties of an antimicrobial

A

Selective toxicity
Bactericidal activity
Narrow spectrum of activity (if appropriate)
Slow emergency of resistance

33
Q

What does the duration of treatment depend on?

Give examples of reflections of this

A

Nature of infection
Site of infection
Growth rate of pathogen

3-5days reatment for UTIs (updated guidelines, used to be 5-7)
2-3 weeks for BSIs
6 wekks for IEs
9 weeks for TB

34
Q

What are the three main mechanisms of antibiotics

A

Disrupt cell structures or processes
- by interfering with cell wall synthesis or maintenance

Interfere with the function of enzymes required to synthesise or assemble macromolecules
- by targetting nucleic acid replication or
- by targetig protein synthesis

Destroy structures already formed in the cell

35
Q

Talk about cell wall inhibitors, give examples

A

These are bacteriocidal and are selectively toxic for bacterial cell walls

Include B-lactams, bacitracin, vancomycin and isoniazid

36
Q

Talk about protein synthesis antimicrobials, give examples

A

Bacteriostatic but selective
Attack 30S and 50S ribosomoal subunits of bacteria that humans dont have

e.g. azithromycin, clindamycin, aminoglycosides such as gentamycin, tetracyclines and linezolid

37
Q

Talk about antimicrobials against cytoplasmic membrane, give examples

A

Bacteriocidal but not selective
Targets both human and bacterial cells
hence used with caution
e.g. polymixin or daptomycin

38
Q

How do cell wall antibiotics work, give examples

A

Target peptidoglycan - blcoking synthesis - cells lyse and die

Beta-lactams:
- Penicilins, cephalosporens, carbapenems, monobactams

Glycopeptides:
- Vancomycin and teicoplanin

Polypeptides:
- Bacitracin (strep)

39
Q

What is peptidoglycan, describe its structure

A

A strong, mesh-like polymer that forms a protective layer around bacterial cells giving structural integrity and shape

It is made up of glycan chains (sugars) that are cross-linked by peptide chains (amino acids)

Its glycan backone consisits of alternating units of NAG and NAM

Short peptide chain attached to NAM unit
- D-alanine-D-alanine

Traspeptidase facilitates cross linkage between peptides by acting on D-ala D-ala

40
Q

What does NAM and NAG stand for?

A

NAM = N-acetylglucosamine
NAG = N-acetylmuramic acid

41
Q

How do Beta lactams work?

A

They mimic D-ala D-ala and thus confuse transpeptidase - thus blocking cross linkage of PG

42
Q

What are the four major classes of beta lactams, ive examples

A

Penicillins: narro spectrum
- augmentin
- methicillin

Cephalosporins: extended spectrum
- cefotaxime

Carbapenems: reserve
- meropenem

Monobactams: newest

43
Q

Comment on the use and side effects of beta lactams

A

Most commonly used antimicrobials

Rearded as safe but can be associated with diarrhoea and allergy

Usage can range from superficial infections to bloodstream infections

44
Q

What is the main strucutral component of beta lactam antibiotics how does this differ between classes?

A

The beta-lactam ring
- a four-membered ring structure essential for action

Classes are defined by the structure of the ring or attachments e.g.
- five-membered ring in penicillins
- six-membered ring in cephalosporins
- side chains attached

45
Q

Why do we make new classes of B-lactams and new generations

A

We develop new classes to increase the spectrum of activity and to address specific resistance mechanisms

Within each class there are generational hierarchy e.g. 1st, second, thrid and fourth generation cephalosporins to target specific resistance

46
Q

List the penicillins

A

Penicillin
Methicillin
Amoxicillin
Ampicillin
Ticarcillin
Piperacillin

47
Q

List the cephalosporins

A

Cefuroxime
Cefotoxime
Ceftazidime
Cefepime
Cefaroline

48
Q

List the carbapenems

A

Imipenem
Meropenem
Ertapenem

49
Q

Give an example of a monobactam

A

Aztreonam

50
Q

Talk about the formation of peptidoglycan

A

Precursor of NAG and NAM are synthesised in cytoplasm
NAM is attached to a short peptide chain (D-ala D-ala) used later in cross-linking
NAG an NAM units are transported across the cell membrane by bactoprenol
Bactoprenol delivers these units to the growing PG layer outside the cell membrane
Once outside the NAG and NAM units link together to form a glycan chain which provid the backbone of PG layer which supports bacteial cell wall
Penicillin-binding proteins such as transpptidases link the peptide side chains of NAM to form cross-links and thus a strong, mesh-like structure

51
Q

What is bactoprenol and what does it do?

A

Bactoprenol is a lipid carrier molecule
It helps deliver NaG and NAM units across the cell membrane to outside the cell membrane

52
Q

What is transpeptidase, what does it do?

A

An example of a penicillin-binding protein
Which cross links the D-ala D-ala s of NAM molecules to form cross linked PG

53
Q

How exactly do B-lactams work?

A

They resemble D-ala-D-ala
Thus they act as a flas substrate in PG synthesis
They bind to transpeptidase enzymes (hence penicllin binding protein) responsible for final stages of cell wall cross-linkage
Thus inhibit transpeptidation in PG synthesis

This results in accumulation of precursors of cell wall units and activation of cells autolytic system and thus cell lysis

54
Q

How do B-lactams affect gram positives?

A

Gram positive cell walls are rich in Peptidoglycan and thus the Penicillin binding proteins/transpeptidase are easily accessible

Following exposure to B-lactams GPs release lipoteichoic acid fom the cell wall

This lipoteichoic acid triggers a generalised autolytic dismantling of the PG i.e. suicidal activation of wall autolysins

55
Q

What are released from GPs following exposure to Beta lactams?

A

Lipoteichoic acid

56
Q

What does Leipoteichoic acid trigger

A

Activation of wall autolysins thus incurring cell suicide

57
Q

How do B-lactams affect gram negatives?

A

In gram negatives the PBP/transpeptidase are not as easily accessed - they are inside the periplasmic space

B-lactams need to cross the oute membrane through passive diffusion or pass through porin chanels to access the target PBPs

58
Q

Talk about the Penicillin class, how do they work

A

Contain a B-lactam ring
- this is the target for resistance (penicillinase)

Work by inhibiting PG cross-linking

They naturally target Gram positives and thus have a narow spectrum of activity

Synthetic penicllins can have broader spectrum

59
Q

Talk about synthetic penicillins, how do they work

A

New generations to extend the spectrum of activity and reduce vulnerability to evolving resistance mechanisms

We now have beta lactamase producers so to combat this we made B-lactamase inhibitors such as clavulanate and tazobactam which have weak antibacterial activity but act false/suicide substrate for analogue for penicillin i.e. distract the Beta lactamase enzymes so that penicillins can work

60
Q

Give three examples of synthetic penicillins

A

Augmentin: amoxicillin + clavulanate
Timentin:: Ticarcillin + clavulanate
Tazocin: Piperacillin + tazobactam

61
Q

Talk about cephalosporins

A

They have an extended spectrum of activity compared to penicillins

They have activity against gram -/ves

3rd and 4th generation have an extended spectrum of activity and are less susceptible to inactivation by beta-lactamases

Theres a need for further generations to reduce vulnerability to ESBL and CPOs

62
Q

Give some examples of cephalosporins and their usage

A

Ceftazidime/avibactam -> beta-lactamase gram -ves
Ceftolozane/tazobactam -> beta-lactamase gram-ves

Cefidirocol -> new drug throught to be useful against resistance without moving up a class to carbapenems

63
Q

How do cephalosporins affect gram negative bacteria

A

They can penetrate the outer membrane through the porin channels

64
Q

Talk about Carbapenems

A

Of all B-lactams, carbapenems posses the broadest spectrum of activity and greatest potency against gram-positive and gram negative bacteria

They were meant to be our reserve but usage is now widespread

Less susceptible than pen and ceph to B-lactamase activity but we now have CPEs

65
Q

Talk about some of the different carbapenems and their uses

A

Imipenem was the first clinically used

Meropenem provides the highest bacterial response

Ertapenem can be given as a once a day therapy but lacks activity against P. aeruginosa and Acientobacter

66
Q

Talk about the redesign of ertapenem

A

Redesigned in 2017 so that it could be used as a once a day treatment

67
Q

Talk about monobactams

A

Mode of action similar to penicillins
Newest form of B-lactam drugs
Some capability in inhibiting B-lactamase but not ESBLs or carbapenemases
Limited for gram-negative bacteria

68
Q

Give some examples of monobactams

A

Aztreonam - primary monobactam used in gram-negative infections particularly in patients with penicillin allergies

Aztreonam and avibactam combination is under development for resistant strains
- avibactam is a beta lactamase inhibitor -> this combo is currently in phase 3 trials

69
Q

What are the three main glycopeptides

A

Vancomycin
Teicoplanin
Dalbavancin and Oritavancin

70
Q

Talk about Vancomycin Glycopeptide and its use

A

The most well known glycopeptide

We tend to limit its use due to high nephrotoxic effect

We tend to limit it to MRSA, endocarditis (and other severe GP infections) and C. diff infections

71
Q

Talk about Teicoplanin Glycopeptide and its use

A

Tend to prescribe teicoplanin over vancomycin in Europe

It has a longer half life then vancomycin -> hence have to dose less frequently than vancomycin

Used for gram positive infections

72
Q

Talk about Dalbavancin and Oritavancin

A

Newer glycopeptide with a longer half life

Used for skin and soft tissue infections caused by resistant gram positive organisms

These drugs allow for one-weekly dosing

73
Q

List the modes of action of glycopeptides

A

Binding to Peptidoglycan Precursors:
- bind directly to D-ala-D-ala portion of the peptidoglycan precursor

Prevents Cross-linking:
- binding to the D-ala-D-ala part of the precursor, glycopeptides block the cross-linking of peptidoglycan strands - cross-linking is essential for cell wall strength and integrity

Prevents Incorporation of Subunits:
-prevents transport of the subunit through the cytoplasmic membrane, stopping the insertion of new peptidoglycan units into the cell wall - inhibiting the transglycosylation and transpeptidation reactions, critical for peptidoglycan chain assembly and maturation

NB: prevents cross linking and prevenys transport of precurosors across cytoplasm to PG chain

*different glycopeptides have slight differences in binding profiles but we dont need to know these

4.2 Medical Microbiology (6 decks)

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