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Phase 2a - ICS > Antibiotics > Flashcards

Antibiotics Flashcards

1
Q

Definition of antiobiotics

A

Agents produced by microorganisms that kill or inhibit the growth of other microorganisms in high-dilution.

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2
Q

Antibiotics today

A

Most agents are semi-synthetic derivatives - termed antimicrobials.

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3
Q

Antimicrobials include

A

Antifungal, antibacterial, antihelmeinthic, antiprotozoal and antiviral agents.

In practice; antibiotics=antibacterial.

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4
Q

Antibiotic molecules work by

A

Binding a target site on a bacteria.

Points of biochemical reactions crucial to the survival of the bacterium.

This crucial binding site varies with the antibiotic calss.

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5
Q

What are the three main groups of antibiotics classes?

A

Cell wall synthesis
Nucleic acid synthesis
Protein synthesis

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6
Q

What groups of antibiotics target cell wall synthesis?

A

Beta lactams
Vancomycin
Bacitracin
Glyopeptides (cell membrane)

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7
Q

What are the subclasses of Beta Lactams?

A

Penicillins
Cephalosporins
Carbapenems
Monobactams

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8
Q

Examples of Penicillins

A

Penicillin V
Penicillin G (Benzyl penicillin)
Flucloxacillin
Amoxicillin/Ampicillin
Pipercillin

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9
Q

Examples of Cephalosporins

A

Cefalexin
Cefuroxime
Cefotaxime
Ceftriaxone
Ceftazidime

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10
Q

Examples of Carbapenems

A

Meropenem
Ertapenem
Imipenem

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11
Q

Example of Monobactams

A

Aztreonam

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12
Q

Examples of Glyopeptides

A

Vancomycin
Teicoplanin

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13
Q

Peptidoglycan layers in Gram -ve and +ve

A

Gram -ve: thin

Gram +ve: thick

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14
Q

What do Gram -ve have?

A

LPS - Lipid A, O antigen, Terminal Sugars attached to capsule.

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15
Q

MOA of beta lactams

A
  • Disrupt peptidoglycan production
  • By binding covalently and irreversibly to the Penicillin Binding Proteins on the transpeptidase subunit)
  • Cell wall is disrupted and lysis occurs

-Results in a hypo-osmotic or iso-osmotic environment

Active only against rapidly multiplying organisms.

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16
Q

What does the block of transpeptidase activity result in?

A

Interrupts cross-linking and cell wall synthesis.

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17
Q

Which bacteria is more sensitive to beta lactams and why?

A

Gram +ve.

Gram -ve has LPS layer which decreases the penetration of the ABX.

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18
Q

What causes differences in the spectrum and activity of B-lactam ABX?

A

Their relative affinity for different PBPs.

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19
Q

Are penicillins effective in the treatment of intracellular pathogens?

A

No - they poorly penetrate mammalian cells.

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20
Q

What are the groups of ABX that inhibit nucleic acid synthesis?

A

DNA Gyrase - Quinolones

RNA polymerase - Rifampin

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21
Q

Examples of ABX that inhibits nucleic acid synthesis

A

Rifampicin (Inhibit DNA-dependent RNA polymerase)

Metronidazole (blocks nucleic acid synthesis).

Fluoroquinolones (DNA gyrase)

Ciprofloxacin
Levofloxacin
Moxifloxacin

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22
Q

ABX that inhibit protein synthesis 50S subunit

A

50S subunit
Macrolides
Clindamycin
Linezolid
Chloramphenicol
Streptogramins

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23
Q

ABX that inhibit protein synthesis 30S subunit

A

30S subunit
Tetracyclines
Aminoglycosides

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24
Q

Example of aminoglycoside

A

Gentamicin

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25
Q

Example of Tetracyclines

A

Doxycyclines

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26
Q

Example of Lincosamides

A

Clindamycin

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27
Q

Examples of Macrolides

A

Erythromycin
Clarithromycin
Ayzithromycin

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28
Q

ABX targeting folate synthesis

A

Sulphonamides (Sulphamethoxazole)
Trimethoprim
Co-Trimoxazole

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29
Q

Targeting DNA/RNA synthesis in fungal cells

A

Flucytosine

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30
Q

Targeting cell wall in fungi

A

Exhinocandins

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31
Q

Targeting plasma membrane in fungi

A

Amphotericin
Azoles
Terbinafine

32
Q

What are ABX trying to achieve?

A

Give time and support for the immune system to deal with an infection.

33
Q

Explain the bacterial agenda

A
  1. attach and enter
  2. local spread
  3. multiply
  4. evade host defences
  5. shed from body
34
Q

What are the direct consequences of bacterial infections?

A

Destroy phagocytes or cells in which bacteria replicate.

35
Q

What are the indirect consequences of bacterial infections?

A

Inflammation (necrosis).
Immune pathology (AB).

36
Q

Which bacteria has endotoxins?

A

Gram -ve

37
Q

What are exotoxins?

A

Proteins produced by the bacteria.

38
Q

How do bactericidal ABX work?

A

Kills bacteria >99.9% in 18-24 hours.

ABX that inhibit cell wall synthesis.

39
Q

In what conditions are bactericidal ABX useful?

A

Location is poorly penetrable, need eradication quickly.

Sepsis
Meningitis and encephalitis
Endocarditis
Primary and secondary immunodeficiency

40
Q

How do bacteriostatic ABX work?

A

Prevent growth of bacteria (kill >90% in 18-24 hours).

41
Q

What is the definition of bacteriostatic ABX?

A

The ratio of Minimum Bactericidal Concentration (MBC) to Minimum inhibitory Concentration (MIC) >4.

42
Q

Examples of bacteriostatic ABX

A

Inhibit protein synthesis, DNA replication or metabolism.

43
Q

What is an advantage of bacteriostatic ABX?

A

Reduce toxin production and endotoxin surge is less likely.

44
Q

What is a big red flag of bactericidal ABX?

A

Can lead to release of endotoxin and result in increase in antigenic load causing an aggressive and dangerous inflammatory response.

45
Q

Examples of dangerous inflammatory response caused by endotoxin release:

A

Gram -ve: sepsis secondary to LPS

Gram +ve: S. aureus - TSS or S. pneumoniae and pneumolysin release.

Syphilis/Leptospirosis and Jarisch-Herxheimer (JH) reaction.

46
Q

MIC is determined based on what?

A

Turbidity.

47
Q

A drug must do (in relation to how much ABX we need)

A

Attach to its binding target and occupy an adequate number of binding sites (related to its concentration within the microorganism).

48
Q

For an ABX to work effectively, it should…

A

Remain at the binding site for sufficient period of time (to inhibit metabolic processes).

49
Q

What are the two major determinants of anti-bacterial effects are

A

Concentration and time.

50
Q

Time dependent killing

A

Time that serum concentration remain above the MIC during the dosing interval.

t>MIC

51
Q

ABX with time-dependent killing

A

beta-lactams (penicillins, cephalosporins, carbapenems, monobactams),

clindamycin,

macrolides

oxazolidinones

52
Q

Concentration dependent killing

A

Key parameter is how high the concentration is above MIC

peak concentration / MIC ratio

53
Q

ABX with concentration dependent killing

A

Aminoglycosides and quinolones.

54
Q

AUC (Area under concentration)

A

The area under the concentration–time curve over 24 hours in steady-state divided by the MIC value for the same drug.

55
Q

Pharmacokinetics of ABX

A
  1. Its release from the dosage form;
  2. Its absorption from the site of administration into the bloodstream;
  3. Its distribution to various parts of the body, including the site of action and
  4. Its rate of elimination from the body via metabolism (LIVER) or excretion (KIDNEY) of unchanged drug.
56
Q

ABX can be administered via various routes…(examples)

A

Injection, oral, PR suppositories.

57
Q

ABX distribution depends on

A

Which ABX will penetrate that site.

What is the pH of the site.

Is the ABX lipid soluble.

58
Q

Dosage interval and duration depend on…

A

Half life and elimination of the drug.

59
Q

How do bacteria resits ABX?

A

Change or mask ABX target.

Destroy ABX.

Prevent ABX access.

Remove ABX from the bacteria.

60
Q

Examples of change in the ABX binding site.

A
  1. Flucloxacillin - MRSA
  2. Wall components change in enterococci - VRE (vancomycin resistant enterococci)
  3. Rifampicin - changes to RNA polymerase (MTB-MDR-TB)
61
Q

Examples of ABX destruction.

A

Beta lactam ring of Penicillins and cephalosporins hydrolysed by beta lactamase produced by bacteria thus unable to bind PBP.

Staphylococci produce penicillinase = penicillin and flucloxacillin inactivated.

GNB phosphorylate and acetylate aminoglycosides (gentamicin).

62
Q

Examples of prevention of ABX access.

A

Modification in bacterial membrane porin channel size, number and selectivity.

P. aeruginosa against imipenem

GNB againts aminoglycosides.

63
Q

Examples of removal of ABX from bacteria

A

Proteins in bacterial membranes act as efflux pumps - ABX level is reduced.

S. aureus and S. pneumoniae - fluoroquinolones.

Enterobacteriacae - tetracyclines.

64
Q

How does bacterial resistance develop?

A

Intrinsic or acquired resistance.

65
Q

Intrisic resistance

A

All subpopulations are equally resistant.

Aerobic bacteria - unable to reduce metronidazole to its active form.

Anaerobic bacteria lack oxidative metabolism required to uptake aminoglycosides.

Vancomycin cannot penetrate outer membrane of gram negative bacteria.

The PBP in enterococci are not effectively bound by the cephalosporins.

66
Q

Acquired resistance

A

A bacterium which was previously susceptible obtains the ability to resist the activity of a particular antibiotic.

Only certain strains or subpopulations of a species will be resistant.

67
Q

Acquired - spontaneous gene mutation.

A

New nucleotide base pair
change in amino acid sequence
change to enzyme or cell structure
reduced affinity or activity of antibiotic.

MTB - Point mutations in the rifampin-binding region of rpoB.

68
Q

Acquired - horizontal gene transfer

A

Transduction (bacteriophages mediate transfer of DNA between bacteria - DNA from donor bacterium is packed into a virus particle and transferred into recipient bacterium during infection).
mecA genes for MRSA

Transformation (some bacteria take up free DNA from environment and incorporate it into their genome).
foreign DNA from S. mitis to S. pneumoniae, conferring penicillin resistance.

Conjugation (most concerning aspect - sex pilus and plasmid transfer).
New Delhi metallo-_-lactamase, ES_Ls

69
Q

MRSA (Gram negative)

A

Methicillin resistant Staphylococcus aureus.

Bacteriophage mediated acquisition of Staphylococcal cassette chromosome mec (SCCmec)
contains resistance gene mecA
encodes penicillin-binding protein 2a (PBP2a) confers resistance to all β-lactam antibiotics in addition to methicillin (= flucloxacillin).

70
Q

VRE (Gram -ve)

A

Vancomycin-resistant enterococci.

Plasmid mediated acquisition of gene encoding altered amino acid on peptide chain preventing vancomycin binding.

Promoted by cephalosporin use.

71
Q

ESBL (Gram -ve)

A

ESBL
Further mutation at active site extended range of antimicrobial resistance to form extended spectrum beta lactamase (ESBL) inhibition.

These hydrolise oxyimino side chains of cephalosporins: cefotaxime,ceftriaxone, andceftazidime and monobactams: aztreonam.

TEM-1 in E. coli, H. influenzae and N. gonorrhoea.

SHV-1 in K. pneumoniae.

An even more extensive ESBL, this time plasmid mediated, is the CTX-M cephalosporinase in Enterobacteriacae.

72
Q

ESBL resistant strains

A

Such strains remain sensitive to beta-lactamase inhibitors.

Amoxicillin + Clavulanate = Co-Amoxiclav

Pipericillin + Tazobactam = ‘Tazocin’

73
Q

AmpC B-lactamase resistance (Gram -ve)

A

Broad spectrum penicillin, cephalosporin and monobactam resistance

encoded on the chromosome in bacteria such as Citrobacter spp., Serratia marcescens, Enterobacter spp.

b-lactamase inhibitor resistant!

inducible expression (gene only turned on by antibiotic)

74
Q

AmpC B-lactamase resistant bacteria is treated with

A

Carbapenems

ertapenem, imipenem, meropenem

in contrast to other b-lactams, are highly resistant to degradation by b-lactamases or cephalosporinases.

often the antimicrobials of last resort to treat infections due to ESBL or AmpC -producing organisms of the Enterobacteriacae family*.

75
Q

Carbapenem Resistant Enterobacteriaceae

A

Which produce ‘carbapenemases’ e.g.
metallo-β-lactamases
IMP or VIM – Pseudomonas aeruginosa, Acetinobacter spp.
NDM-1 - E. Coli, Klebsiella pneumoniae

OXA
(oxacillinases –Acetinobacter baumanii)

KPC
(Klebsiella pneumoniae)

Treatment options are very few
and very toxic.

76
Q

What are the options for CPEs (Carbapenemase producing enterobacteriaceae).

A

Colistin, a polymyxin

Tigecycline (but not as monotherapy for bacteremia or respiratory infection as bacterostatic)

Fosfomycin or aminoglycosides in combo with other agents

Meropenam 2g tid (high dose, prolonged 3h infusion if MIC 4-8mg/ml) with colistin/aminoglycoside

Colistin and tigecycline
Combo therapy may be better

Phase 2a - ICS (43 decks)

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