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PHAY00011 > Infectious disease III > Flashcards

Infectious disease III Flashcards

Antibacterial agents

1
Q

Classification of antibacterial agents based on resources

A

Natural products

Semi-synthetic compounds - extracted agent has been altered to improve activity.

Totally synthetic compounds

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2
Q

Classification of antibacterial agents based on impact on bacteria.

A

Bactericidal

Bacteriostatic

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3
Q

Is one antibiotic always bactericidal or bacteriostatic?

A

No, dependent on the bacteria species

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4
Q

Differences between antibiotics and other drugs.

A

Not directed at human metabolic process -> selective toxicity

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5
Q

How can an antibiotic be selective to bacterial cells?

A

Structure difference of target

Different composition of cell membrane

Different drug handling mechanism

Targets might not play important roles in host cells

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6
Q

Why is it important for antibacterial agents to be able to target several body sites?

A

Microorganism can affect different body sites

Through bloodstream

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7
Q

Explain how drug resistance can be transfered?

A

Transfer vertically or horizontally (through conjugate plasmids)

Transfer to different host directly or indirectly

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8
Q

What are the desirable properties of an antimicrobial agents?

A

Useful sprectum of activity

Limited effects on host normal flora

Reach site of infection at therapeutically useful levels

Formulated in convenient mode of administration

Lack undesirable effects

Low toxicity to host and minimal adverse drug interactions

Inexpensive and easy to produce

Chemical stable + long shelf-life

No or rare resistance

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9
Q

Explain how normal flora can provide protective functions against potential pathogens

A

Block the attachment sites physically

Produce inhibitory molecules + waste products

Stimulate immune response

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10
Q

What can be the consequences of disruption of host flora caused by the use of antimicrobial agents?

A

Superinfection

Clostridium difficile -> colitis

Candida species -> thrush

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11
Q

Undesirable side effects of tetracycline.

A

Stained teeth

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12
Q

Undesirable side effects of metronidazole

A

black hairy tongue - breakdown of Hb

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13
Q

Undesirable side effects of penicillins

A

Rash => can be serious like anaphylaxis

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14
Q

Undesireable side effects of rifampicin

A

Red Man Syndrome - excretion of drugs into body fluid + elimination through sweat glands

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15
Q

Interactions: Gentamicin + Furosemide

A

Ototoxicity

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16
Q

Interactions: Metronidazole + Alcohol

A

Disulfiram reaction - inhibition of aldehyde dehydrogenase

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17
Q

Interactions: Metronidazole + Warfarin

A

Potentiation of anticoagulation

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18
Q

Interactions: Rifampicin + Oral contraceptives

A

Reduced contraceptive effects

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19
Q

Interactions: Rifampicin + Warfarin

A

Reduced effect of warfarin

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20
Q

Interactions: Tetracyclines + Antacids

A

Reduced effect of tetracyclines - chelation

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21
Q

Interactions: Tetracyclines + Warfarin

A

Potentiation of anticoagulation

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22
Q

What conditions that are commonly mistaken to require antibiotics?

A

Cold and flu, sore throat, chest infections, ear infectons and sinusitis

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23
Q

Main component of bacterial cell wall?

A

Peptidoglycan - cross linking chain -> mesh-like structure

Polymer of disaccharide of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM)

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24
Q

Describe briefly the synthesis of cell wall of bacteria

A

Step 1: NAG -> NAM in cytoplasm

Step 2: First 3 a.a of stem peptide attached to NAM

Step 3: Last 2 a.a of D-Ala-D-Ala added to stem peptide

Step 4: Park nucleotide attached to lipid carier molecule

Step 5: NAG attached to NAM to form a disaccharide unit

Step 6: A chain of 5 glycine residues attached to L-Lys of stem peptide chain

Step 7: Disaccharide precursor molecule is transported to external side of cytoplasmic membrane

Step 8: Transglycosulation by PBPs - disaccharide unit attached to growing glycan chain

Step 9: Transpeptidation by PBP - glycan chains within are crosslinked via stem peptides attached to NAM

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25
Q

What are the antibiotics that can interfere with the cell wall synthesis? What steps do they interfere?

A

Fosfomycin - interfere step 1 (NAG->NAM)

Cycloserine - Step 3 (atttachment of D-Ala-D-Ala) to form Park nucleotide

Bacitracin - Step 4 (attachment of Park nucleotide to lipid carrier molecule)

Vancomycin, Teicoplanin - Step 8 (transglycosylation)

Beta-lactams - Step 9 (transpeptidation)

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26
Q

Are beta-lactams bactericidal or bacteriostatic?

A

Bactericidal

Weakening of cell wall -> cell lysis

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26
Q

Mechanism of actions of beta-lactams

A

Similar structure to PBP substrate (beta-lactam rings)

Interfere the transpeptidation domains of PBPs -> prevent cross-linking

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26
Q

Roles of PBPs

A

Penicillin - binding proteins -> 2 domains, each for:

Transglycosylation = adding more disaccharide units to the peptidogylcan chain -> extend the chain

Transpeptidation = linking the pentaglycine bridge to the stem peptide -> cross-linking to form mesh-like

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27
Q

Requirements of beta-lactams to be effective.

A

Cells have to be actively growing and dividing

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28
Q

What are the different classes of beta-lactams?

A

Penicillins

Cephalosporins

Monobactams

Carbapenems

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29
Q

How many types of penicillins are there?

A

Four types:

1/Natural penicillin

2/Antistaphylococcal penicillins

3/Aminopenicillins

4/Antipseudomonal penicillins

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30
Q

How many generations of cephalosporins are there?

A

5 generations

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31
Q

What are the two main differences between cephalosporin structure and penicillins?

A

The rings:
+ Penicillins = beta lactam rings + thiazolidine rings
+ Cephalosporins = beta lactam ring + dihydrothiazine rings

Number of side chains
+ Penicillins = 1 side chains
+ Cephalosporins = 2 side chains -> more possible modification

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32
Q

How are the modifications at the side chains of cephalosporin different?

A

At R2 (next to the dihydrothiazine ring) -> pharmacokinetics

At R1 (near the beta-lactam rings) -> antibacterial activity

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33
Q

What are the two currently used natural penicillins?

A

Penicillin G (parenteral)

Penicillin V (Oral)

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34
Q

Spectrum of activity of natural penicillins.

A

Some species of Gram-(+), Gram-(-), anaerobics and some spirochetes

Majority are intrinsically resistance or acquired resistance

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35
Q

What conditions are natural penicillins still used for?

A

Syphilis

Pneumococcal pneumoniae

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36
Q

Why is natural penicillins not used for gnorrhoea anymore?

A

Neisseria gonorrhoea produce beta-lactamase

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37
Q

Name the drugs classifed as antistaphylococcal penicilins.

A

Flucloxacillin

Methicillin

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38
Q

Why are flucloxacillin and methicillin effective against Staphylococcus aureus?

A

Bulky side chains

Prevent binding of the staphylococcal beta-lactamases

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39
Q

Spectrum of activity of flucloxacillin and methicillin.

A

Effective agaisnt Staphylococcal aureus

NOT effective against MRSA and enterococci

NOT effective much against other bacteria

Flucloxacillin effective against streptococcus

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40
Q

Name the drugs classified as aminopenicillins

A

Ampicillins

Amoxicillin

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41
Q

Spectrum of activity of aminopenicillins.

A

Effective against selected Gram-(-) bacilli - E.coli, Shigella and Salmonella

Vulnerable to beta-lactamase -> require beta-lactamse inhibitors

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42
Q

Why are amoxicillin and ampicillins effective against some selected Gram-negative bacilli?

A

Addition amino group in side chains

Increases hydrophilicity -> entry through porins of outer membranes

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43
Q

What are the beta-lactamase inhibitors commonly used with aminopenicillins?

A

Amoxicillin + clavulanate -> oral

Ampicillin + sulbactam -> parenteral

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44
Q

Explain why Pseudomonas species are more difficult to treat compared to other Gram-negative organism.

A

Fewer porins present on outer membrane

Presence of efflux punps

Different structure of outer membranes

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45
Q

Name the drugs classified as antipseudomonal penicillins.

A

Ticarcillin

Piperacillin

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46
Q

Spectrum of activity of piperacillin.

A

Broad spectrum

Effective against Gram-negative bacteria

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47
Q

Explain why piperacillin is effective against Pseudomonas species.

A

Polar side chains

Facillitate entry through porins

Protection against beta-lactamase -> still an issue

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48
Q

What are piperacillin and ticarcillin be given with?

A

beta-lactamase inhibitors:

Piperacillin + tazobactam

Ticarcillin + clavulanic acid

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49
Q

Why are piperacillin and ticarcillin not used against Staphylococci?

A

Production of beta-lactamase that can degrade the drugs

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50
Q

Pharmacokinetics of penicillins.

<Hint: Absorption after PO, distribution, penetration into tissues, pregnancy use, renal impairment use>

A

Incompletely absorbed after PO (except amoxicillin)

Absorption decreased with food -> take before food

Extensive distribution

Insufficient penetration across BBB and bones (unless inflammation)

Safe for pregnancy

Req dose adjustment for renal dysfunction

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51
Q

What are the common adverse effects of penicillins?

A

Hypersensitivity - range from rash to anaphylaxis

N + V, diarrhoea

Neurotoxicity -> risk of seizures -> high in renal dysfunction

Nephritis

Cation toxicity

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52
Q

Explain the importance of cross-reactivity of penicillins.

A

If patients allergic to one type -> cannot use the other type

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53
Q

Why does penicillins cause diarrhoea and N+V?

A

Disruption of normal bowel flora

Severity higher with agents incompletely absorbed + wide spectrum

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54
Q

How can penicillins cause neurotoxicity?

A

Irriate neuronal tissue (if inflammed -> can cause membrane)

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55
Q

What penicillin drug is associated with nephritis?

A

Methicillin

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56
Q

Why do penicillins cause cation toxicity?

A

Normally administered as sodium and potassium salt

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57
Q

First-generation cephalosporin drugs.

A

Cefazolin

Cephalexin

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58
Q

What bacteria is intrinsically resistant to ALL cephalosporins? Why?

A

Enterococci (a Gram-positive)

Poor PBP binding

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59
Q

Spectrum of activity of first-generation of cephalosporins
<Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Active against Gram-positive cocci include Staph and Strep (except entero)

NOT MRSA and highly penicillin-resistant strep

Limited activities against aerobic and facultative Gram-negative bacteria -> due to beta-lactamase production

Poor against anaerobes and spirochetes

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60
Q

Second-generation cephalosporins drugs

A

Cefuroxime (sodium/axetil)

Cefoxitin and other cephamycins

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61
Q

Spectrum of activity of second-generation of cephalosporins
<Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Increased activity against Gram-(-), esp Haemophilus influenzae and Neisseria gonorrhoea

Reduced activity against Gram-(+)

Cefoxitin - increased against ESBL

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62
Q

Third-generations cephalosporins drugs

A

Cefotaxime

Ceftriaxone

Ceftazidime

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63
Q

Modifications of third-generations of cephalosporins.

A

An aminothiazoyl group

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64
Q

Spectrum of activity third-generation of cephalosporins
<Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Enhanced activity against Gram-(-)

Lacks activity against Pseudomonas aeruginosa (except Ceftazidime)

Lack activity against Gram-positive like Staph.

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65
Q

What third-gen cephalosporin drug effective against Pseudomonas aeruginosa?

A

Ceftazidime

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66
Q

Why ceftazidime effective against Pseudomonas aeruginosa?

A

Has carboxypropyl group modifications on aminothiazoyl side chain at R1

Prevent removal by pump + better entry

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67
Q

Fourth-generation cephalosporin drugs

A

Cefepime

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68
Q

Spectrum of activity of fourth-generation cephalosporins <Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Effective against Gram-(-) and Pseudomonas aeruginosa

Effective againstStaph, Enterobacteriacease

NOT against MRSA

Limited against anaerobes

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69
Q

How do fourth-gen cephalosporins regain activity against Staph?

A

Modification at R2, polar pyrrolidine gorup is added

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70
Q

Pharmacokinetics of cephalosporins
<Hint: distribution, adverse effects profile, renal impairments>

A

Distributed well in the body, not ALL can reach therapeutic levels in CSF even with inflammation

Good safety profile in general

Dose reduction in renal failure

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71
Q

Can patients with penicillin allergy use cephalosporins?

A

Low cross-activity -> reduce with higher generations

Must not be used if the allergies are anaphylactic, Steven Johnson Syndrome or skin necrotic response

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72
Q

What cephalosporin can be used in renal insufficiency?

A

Ceftriaxone as it is excreted through bile

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73
Q

Name a monobactam

A

Aztreonam

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74
Q

Route of administration of aztreonam.

A

Only IV or IM

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75
Q

Spectrum of activity of aztreonam.
<Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Effective against Gram-(-) - not ESBLs

NOT effective against Gram-(+)

NOT effective against anaerobic

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76
Q

Cross-activity and adverse effects of aztreonam.

A

No cross-activity with penicillins

Generally non-toxic and not associated with nephrotoxicity

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77
Q

Name drugs classified as carbapenems.

A

Imipenem

Meropenem

Ertapenem

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78
Q

What drug should carbapenem be given with and why?

A

Only imipenem be given with cilastatin

Cilastitin - inhibitor of dehydropeptidase I enzyme in kidney

Cilastitin - prevent imipenem degradation + protect kidney from toxic effects from imipenem

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79
Q

Why do other carbapenems not need cilastitin?

A

Meropenem and ertapenem

Additional methyl group -> protect against dihydropeptidase I

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80
Q

Spectrum of activity of Carbapenems <Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Suitable charge -> Effective against Gram-(-)

Effective against Gram-(+)

Effective against both anaerobes and aerobes

NOT effective against MRSA, C.difficile, Chlamydia and Legionella

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81
Q

What type of beta-lactamses are effective against carbapenem?

A

Carbapenem-hydrolysing enzymes

Metallo-beta-lactamases

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82
Q

Route of administration of carbapenems.

A

IV

IM with ertapenem

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83
Q

Distribution properties of carbapenem

A

Penetrate well into body tissue + fluid + CSF when inflammed`

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84
Q

Side effects of carbapenems

A

N + V, diarrhoea

risk of seizures

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85
Q

What patients group must not use carbapenems?

A

Renal insufifficiency

Central nervous disease

Risk of seizures

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86
Q

What are the three types of resistances developed against beta-lactams?

A

Intrinsic resistance

Mutational resistance

Acquired resistance

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87
Q

Name some examples of intrinsic resistance of beta-lactam.

A

Not produce peptidoglycan - Mycoplasma

Weird form of peptidoglycan - Chlamydia

Efflux pumps - Pseudomonas aeruginosa

Poor PBPs binding - enterococci to cephalosporin

Intracellular in human cells - beta lactams cannot reach

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88
Q

Name some examples of mutational resistance developed against beta-lactams

A

Alterations of PBPs or porins

Increased productions of efflux pumps

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89
Q

What is ESBL?

A

produced by resistant Gram-(-) bacteria

Extended-spectrum beta-lactamase -> can hydrolyse penicillins, cephalosporins and even aztreonam

Induced by gene mutations

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90
Q

What are the four types of beta-lactamses exists in Gram-negative bacteria?

A

Class A: Penicillinase, ESBL and Carbapenemase

Class B: Metallo-beta-lactamase

Class C: Cephalosporinase

Class D: Cloxacillinase and carbapenemase

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91
Q

What beta-lactams do class A and class D carbapenemase hydrolyse?

A

All current beta-lactams

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92
Q

What beta-lactams do penicillinase hydrolyse?

A

Penicillin and early gen cephalosporins

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93
Q

What beta-lactams do ESBLs can hydrolyse?

A

Penicillins, cephalosporins, monobactams, combination with beta-lactamse inhibitors

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94
Q

What beta-lactams do metallo-beta-lactamase hydrolyse?

A

All beta-lactams except monobactams

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95
Q

What beta-lactams do cephalosporinase hydrolyse?

A

Penicillins + cephalosporins

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96
Q

What beta-lactams do cloxacillinase hydrolyse?

A

Penicillins include oxacillin and cloxaciillin

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97
Q

How can MRSA be resistant to flucloxacillin?

A

Production of PBP2a (additional PBP)

PBP2a bind poorly to beta-lactam -> still able to perform transpeptidation

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98
Q

Differences between PBP2a and normal PBP.

A

1 domain

Still req normal PBP for transglycosylation

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99
Q

Treatment for MRSA.

A

Fifth generation cephalosporins

Ceftaroline

Ceftobiprole

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100
Q

Explain how Streptococcus pneumonae develop resistance to penicillin through genetic DNA transformation.

A

Induce mosaic structure of PBPs

Low affinities to beta-lactams

Still function normally.

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101
Q

Name the antibiotics class that target the bacterial cell wall.

A

Beta-lactams - Penicillins, cephalosporins, monobactams, carbapenems

Glycopeptides - vancomycin, televancin

Fosfomycin

102
Q

Name the two common glycopeptide drugs

A

Vancomycin

Televancin

103
Q

Mechanism of action of glycopeptides

A

Bind to terminal of D-Ala-D-Ala of peptidoglycan precursor - through H bonds

Block transglycosylation

104
Q

Spectrum of activity of vancomycin <Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Restricted to Gram-positive, both anaerobes and aerobes

No activity against Gram-negative

Not effective against VRE

105
Q

Importance of vancomycin in infection treatment

A

MRSA-related

Penicillin-resistant Strep.pneumoniae

Clostridium difficile (not first-line)

106
Q

Why is vancomycin ineffective against Gram-negative?

A

Large size -> canont penetrate through the membrane

107
Q

Route of administration of vancomycin

A

IV -> systemic infections

PO -> treat GI infections caused by Gram-positive

108
Q

Adverse effects of vancomycin

A

Hearing loss - if co-administer with aminoglycosides or in patients with renal failure

Red-man syndrome - associated with rapid infusion rate

Neutropenia (less common)

109
Q

What is red-man syndrome? How is it minimised when using vancomycin?

A

Flushing and possible shock

Solution:
+ Slow infusion rate over 2 hours
+ Increase dilution volume
+ Antihistamine 1 hour before infusion.

110
Q

Differences of televancin compared to vancomycin and their importances

A

Lipoglycopeptide - contain additional lipid side chain

Inhibit transglycosylation + insert into bacterial membrane

111
Q

Spectrum of activity of televancin
<Hint: Gram-(+) and Gram-(-), aerobes and anaerobes>

A

Restricted to Gram-(+), both anaerobes and aerobes

No against VRE

No against Gram-(-)

112
Q

Adverse effects of televancin

A

Taste disturbance

N+V, diarrhoea

Insomnia

Foamy urine

113
Q

Contraindications of televancin

A

Avoid in pregnancy

Avoid in certain cardiac conditions

Reduced dose in renal impairments, need monitoring functions

114
Q

What is GISA?

A

Glycopeptide-Intermediate resistant Staphyloccocus aureus

115
Q

How can Staphylococcus aureus develop intermediate resistance towards glycopeptide?

A

Produce thickened peptidoglycan layer with less cross-linked residue -> free D-Ala-D-Ala residue

Glycopeptides will bind to free residue -> not affect PBPs

116
Q

Why is GISA’s resistance intermediate?

A

Effects only reduced in moderate concentration

High concentrations, effects will not be affected

117
Q

What major microorganism can develop full resistance to vancomycin?

A

Enterococci -> VRE

118
Q

How does VRE develop full resistance to vancomycin?

A

Acquire Tn1546-like transporon

-> Alternative peptidoglycan synthesis pathway

-> Effective resistance achieved

119
Q

Explain how Tn1546-like transporons contribute to complete resistance against vancomycin.

A

Produce VanH (dehydrogenase) + VanA(ligase) -> D-Ala-D-Lac incorporate into chains -> remove H bonds -> vancomycin cannot bind

Produce VanX -> cleave D-Ala-D-Ala back to D-Ala

Produce VanY -> cleave terminal D-Ala out of tripeptide

VanX + VanY prevent normal pathways.

120
Q

Mechanism of action of Fosfomycin

A

Inhibit conversion of NAG -> NAM

Prevent peptidoglycan synthesis -> cell lysis -> death

121
Q

Spectrum of activity of fosfomycin

A

Broad spectrum against aerobes, including MRSA

Not effective against Pseudomonas aeruginosa

122
Q

Indications of fosfomycin

A

UTIs

Has immunomodulatory activity -> suppress cytokines -> effective against respiratory syncytial virus

123
Q

Resistance mechanism of fosfomycin

A

Inactivation of GlpT and UhpT - protein transport of fosfomycin into cytoplasm

Production enzymes like FosA -> open epoxide ring of fosfomycin -> inactivate the drug

124
Q

What are the antibiotics classed as antimycobacterial agents?

A

Isoniazid

Ethambutol

Pyrazinamide

Rifampicin

125
Q

Mechanism of action of isoniazid

A

Catalase-peroxidase (KatG) activate into drug

Inhibit inhA and KasA -> interfere with mycolic acid synthesis.

Mycolic acid = component of Mycobacterium cell wall

126
Q

Spectrum of activity of Isoniazid, ethambutol, pyrazinamide.

A

Only mycobacteria

Bacteriostatic at stationary phase

Bactericidal for rapidly dividing cells

127
Q

Why can’t isoniazid be used as monotherapy?

A

Rapid development of resistance

128
Q

Resistance mechanism of isoniazid

A

Mutations + inactivation of KatG

Alter the binding of drug target

Over-expression of inhA

129
Q

Distribution of isoniazid.

A

Extensive

Into CSF, necrotic tissues

Into host cells -> important against Mycobacterium tuberculosis

130
Q

Interactions of isoniazid

A

Inhibit CYP450

131
Q

Mechanism of action of ethambutol

A

Inhibit the enzyme arabinosyl transferase

Inhibit the synthesis of arabinogalactin - component of Mycobacterium cell wall

132
Q

Resistance mechanism of ethambutol

A

Mutation of gene encoding arabinosyl transferase

133
Q

Distribution of ethambutol

A

Absorbed well upon PO

Extensively distribute into CNS -> used for tuberculosis meningitis

134
Q

Toxicity and side effects of ethambutol

A

Optic neuritis -> reduced visual acuity + red-green discrimination

Reduced uric acid excretion -> gout

135
Q

Mechanism of action of pyrazinamide

A

Activated by pyrazinamidase -> pyrazinoic acid

Target intracellular pathogens within acidic phagosome

Target enzymes making mycolic acid

136
Q

Resistance mechanism of pyrazinamide.

A

Mutation -> inactivate gene encode for pyrazinamidase

137
Q

Distribution of pyrazinamide

A

Throughout the body, include CNS

138
Q

Adverse effects of pyrazinamide.

A

Hepatotoxicity

Increased level of uric acid -> gout

139
Q

Mechanism of action of rifampicin

A

Inhibit bacterial RNA polymerase -> blocking elongation of mRNA

Bactericidal

140
Q

Resistance mechanism of rifampicin

A

Mutation of gene rpoB encoding for RNA polymerase

-> change in active sites -> prevent binding

141
Q

Should rifampicin be used alone?

A

Usually used in combination with other antimicrobial agents

Alone in prophylaxis towards some selected microorganism (Neisseria meningitidis, Haemophilus influenzae)

142
Q

Spectrum of activity of rifampicin

A

In combination to treat:
Mycobacterial infections (main)

Staphylococcal infections

Alone to prevent:
Neisseria meningitidis

Haemophilus influenzae

143
Q

Interactions of rifampicin.

A

Induce CYP450

144
Q

Side effects of rifampicin.

A

GI complaints, N+V, diarrhoea

Hepatitis

Skin rashes

Haematological abnormalities.

Orange-red discolouration of body fluid

145
Q

Why does rifampicin cause discolouration of tears, staining of lens, teeth, urine..?

A

Accumulation in body fluid

146
Q

What antibiotics target protein synthesis?

A

tRNA synthetase inhibitor: Mupirocin

30S ribosomal inhibitor:
- Aminoglycosides - streptomycin, gentamicin..
- Tetracyclines - doxycycline, tetracyclines

50S ribosomal inhibitor:
- Chloramphenicol
- Clindamycin
- Macrolides - erythromycin, clarithromycin..
- Ketolides - telithromycin
- Streptogramins - quinupristin + dalfopristin
- Linezolid

147
Q

Roles of tRNA synthetases.

A

Attach appropriate amino acids to associated tRNA molecule + eliminate AMP

Form charged molecule ready for protein synthesis

148
Q

Structure of bacterial ribosomes.

A

2 subunits: 30S and 5-S

30S - ribosomal recognition process + binding of tRNA and mRNA

50S - catalysing polypeptide elongation + tRNA binding

149
Q

Describe the elongation cycle of polypeptide chain.

A

tRNA comes to + bind to A site

Transpeptidation -> amino acids of tRNA joins the existing chain

Translocation -> tRNA move to P site, previous tRNA move to E site -> leave

A site is free for new tRNA to come

Repeat until terminal codon reached

150
Q

3 sites in the ribosome-tRNA-mRNA complex.

A

A site = acceptor site

P site = formation of linkage

E site = exit site

151
Q

What is the only drug target tRNA synthetase?

A

Mupirocin

152
Q

Mechanism of action of mupirocin.

A

Binding to the tRNA synthetase

Inhibit addition of isoleucyl to relevant tRNA molecules

153
Q

Route of administration of mupirocin.

A

Only topical formulations

Cannot be used systemically due to its toxicity

154
Q

Pharmacological use of mupirocin

A

Topical -> clear staphylococcal colonisation in nose

Effective against nasal MRSA

155
Q

What are the antibiotics target 30S subunit of ribosomes?

A

Aminoglycosides - only bactericidal

Tetracyclines

156
Q

Name some aminoglycosides drugs.

A

Gentamicin

Streptomycin

Tobramycin

Kanamycin

Amikacin

157
Q

Mechanism of action of aminoglycosides.

A

Binding to 30S subunit -> distort structure

Cause misreading of mRNA -> misfolded protein or premature chain termincation

158
Q

How can aminoglycosides be bactericidal, unlike other protein synthesis inhibitors?

A

Mistranslation of mRNA and premature chain terminations -> toxic

Misfolded proteins can be inserted into cell membrane

159
Q

Spectrum of activity of aminoglycosides.

A

Due to positve charge -> effective against Gram-(-) bacteria like H.influenzae, enterobacteriaceae, Pseudomonas aeruginosa.

Some Gram-(+)

No effect against anaerobes

160
Q

Why are aminoglycosides ineffective against anaerobes?

A

Need energy-dependent bacterial transport mechanism - require oxygen -> go across the cytoplasmic membrane

161
Q

Why do enterococci have low resistance against aminoglycosides?

What is the solution?

A

The charged limit entry of this Gram-positive bacteria

Use with cell wall inhibitors such as beta-lactams (except cephalosporins) or vancomycin

162
Q

What is the only aminoglycoside drug that can not be used for enterococcus faecium?

A

Tobramycin

Presence of acetyltransferase on the surface that modify this drug

163
Q

What other Gram-positive bacteria do aminoglycosides can be used in combination with?

A

Enterococci = aminoglycosides + beta-lactams (ampicillin) or vancomycin

Pseudomonas aeruginosa = aminoglycosides + piperacillin/ticarcillin

164
Q

Toxicity of aminoglycosides

A

Nephrotoxicity -> can be reversible

Ototoxicity

Contact dermatitis (with topical neomycin)

165
Q

Resistance mechanism of aminoglycosides

A

Drug efflux

Modification (acetylation) of drug

Gene mutations -> modifcation of ribosome

166
Q

Name tetracyclines antibiotics.

A

Tetracyclines, doxycycline and minocycline

167
Q

Mechanism of action of tetracyclines.

A

Interacting with 30S subunit

Prevent binding of tRNA carrying an amino acid

168
Q

Spectrum of activity of tetracyclines.

A

Broad spectrum

Effective against some Gram-(+) like Strep.pneumoniae

Effective against some Gram-(-) like H.influenzae and N.meningitidis

Some anaerobes

Spirochetes

Atypical bacteria like Chlamydia and mycoplasmas

169
Q

Route of administration of tetracyclines.

A

Doxycycline - only parenteral

Minocycline - PO or parenteral

170
Q

What should tetracyclines not be taken with?

A

Dairy products

Antacids

Iron preparations

-> reduced absorption

171
Q

Distribution of tetracyclines

A

concentrates in liver, spleen, kidney and skin

Only minocycline provides therapeutic level in the CSF

172
Q

Contraindications of tetracyclines.
Why?

A

Children under 12 years old

Pregnant women

Breastfeeding mothers

173
Q

Why must tetracycline not used in young children or pregnant and breastfeeding patients?

A

Bind to tissue undergoing calcifications like teeth and bones

Intefered with development

174
Q

Resistance of tetracyclines.

A

Wide-spread going on

Expression of protection proteins -> alter conformations (prevent binding) + function normally

Expression of TetA efflux pump

175
Q

What is tigecycline?

A

Glycylcycline - development of tetracycylines to tackle resistance

176
Q

How can tigecycline overcome the resistance developed against tetracyclines?

A

ADditional glycyclamido group -> poor substrate to efflux pump + insensitivie to ribosomal modification

177
Q

Spectrum of activity of tigecycline.

A

Same as tetracyclines but:

Effective against MRSA, MDR Strep. pneumoniae, VRE, ESBL and many more anaerobes

NOT effective against Pseudomonas aeruginosa

178
Q

Name the antibiotics that target the 50S subunits of the ribosome.

A

Chloramphenicol

Clindamycin

Macrolides - erythromycin, clarithromycin

Ketolides - telithromycin

Streptogramins

Linezolid

179
Q

Mechanism of action of chloramphenicol.

A

Bind to 50S

Inhibit action of peptidyl transferase -> block cross-linking of amino acids

At high level: interferes with action of mitochondrial protein synthesis

180
Q

Spectrum of activity of chloramphenicol.

A

Broad spectrum:

Aerobic Gram-(-) - H.influenzae, Neisseria, Shigella, Salmonella

Aerobic Gram (+) - Streptococci

Anaerobic bacteria - Clostridium species…

Atypical - Chlamydia and mycoplasma

181
Q

Resistance mechanism of chloramphenicol

A

Enzyme-mediated drug modification

Acetylation of drug

Drug efflux pump

182
Q

Toxicity and adverse effects of chloramphenicol

A

Bone marrow suppression (dose-dependent) - associated with mitochondrial protein synthesis inhibition

Irrversible aplastic anaemia

Grey baby syndrome -> fatal -> contraindication in pregnancy

Optic neuritis

183
Q

Grey baby syndrome.

A

Collapse, hypotension and cyanosis

184
Q

Interactions of chloramphenicol

A

Inhibit CYP450

185
Q

Mechanism of clindamycin

A

Bind to 50S

Inhibit with substrate binding to A and P site

Inhibit translocation step -> chain cannot grow

186
Q

Spectrum of activity of clindamycin

A

Gram-(+) like streptococci and staphylococci (include MRSA)

Anaerobes - limited against Clostridia

No activity against Gram-(-) as no penetration properties

187
Q

Main application of clindamycin

A

Used in adjunct therapy in toxic shock syndrome caused by staphylococci and streptococci

188
Q

Route of administration of clindamycin

A

Both PO and IV

189
Q

Distribution of clindamycin

A

All body fluids except CSF

Good into bone in absence of inflamamtion -> use in osteomyelitis treatment caused by S.aureus

190
Q

Side effects of clindamycin

A

Associated with Clostridium difficile colitis

Diarrhoea

Rash

191
Q

Name some examples of macrolides.

A

Erythromycin

Clarithromycin

Azithromycin

192
Q

Mechanism of action of macrolides.

A

Bind to 50S -> block translocation

193
Q

Spectrum of activity of macrolides

A

Some Staph and Strep

NOT MRSA or penicillin-resistant Strep

Chlamydia and mycobacteria

NOT anaerobes

Gram-(+) and Gram-(-) (some) - similar to penicillins G

194
Q

What macrolides are effective and ineffective against H.influenzae?

A

Clarithromycin and Azithromycin

NOT erythromycin

195
Q

Resistance of macrolides

A

Pump action

Inhibition of drug entry

Enzyme-mediated methylation of ribosomes -> prevent drug binding

196
Q

Cross-resistance of macrolides

A

To clindamycin

To streptogramins

197
Q

Adverse effects of macrolides

A

General safe but

Erythromycin -> epigastric distress or transient deafness (high dose)

198
Q

Contraindications of macrolides.

A

In hepatic dysfunction - due to accummulation

199
Q

Ketolides example.

A

Telithromycin

200
Q

Mechanism of action of telithromycin

A

Same as macrolides

Tigher binding due to alkyl-aryl modifcation in structure

Overcome the resistance

201
Q

Spectrum of activity of telithromycin.

A

Same as macrolides and add:

Steptococcus pneumoniae

Staphylococcus aureus

Staphyloccocus pyogenes

(All are resistant to macrolides)

202
Q

Main indications of telithromycin

A

RTIs that resistant to beta lactams and macrolides

203
Q

Examples of streptogramins.

A

Quinupristin and dalfopristin (3:7) mixture

204
Q

Mechanism of streptogramins

A

Quinupristin and dalfoprisin - used together -> bactericidal

Binds to 50S both and inhibit different steps of protein elongation

Daflopristin aids binding of quinupristin to 50S

205
Q

Spectrum of activity of quinupristin and dalfopristin combination

A

Aerobic Gram-(+) like MRSA, penicillin-resistant Strep. pneumoniae and some VRE

Not effective against enterococcus faecalis

206
Q

Resistance mechanism against quinupristin and dalfopristin

A

Modification of 50S ribosomal subunit through methylation

Enzymatic inactivation

Drug efflux

207
Q

Cross-resistance of qunipristin and dalfopristin?

A

To clindamycin

To macrolides

208
Q

Adverse effects of quinupristin/dalfopristin

A

Reactions at site of infusion

Arthralgias + myalgias

Hyperbilirubinaemia

209
Q

Interaction of quinupristin/dalfopristin

A

Inhibit CYP450

210
Q

Mechanism of action of linezolid

A

Bind to 50S subunit -> prevent ribosome assembly

211
Q

Spectrum of activity of linezolid

A

Excellent against most Gram-(+) bacteria, include MRSA and VRE

No activity against E.coli (drug efflux)

Some activity against Gram-(-)

212
Q

Adverse effects of linezolid

A

Reversible thrombocytopenia

Leukopenia

-> require blood count taken

213
Q

Main interactions.

A

With serotonin inhibitors like MAOis

Increase blood pressure

214
Q

Resistance mechanism of linezolid

A

Generally low

No cross-resistance towards other 50S ribosome inhibitors.

215
Q

What is the important enzymes involved in the supercoiling of DNA in bacteria?

A

DNA topoisomerases such as DNA gyrase

216
Q

Generations of fluoroquinolones

A

2nd gen: Ciprofloxacin

3rd gen: Levofloxacin

4th gen: Moxifloxacin

217
Q

Mechanism of action of fluoroquinolones.

A

Inhibit 2 DNA topoisomerases

Stabilise the complex between topoisomerase and DNA -> alter strand cleave -> DNA break

Bactericidal

218
Q

Spectrum of activity of fluoroquinolones.

A

Broad spectum specific to each agent.

Ciprofloxacin - Gram-(-) bacteria mainly and some against mycobacteria, weak against Gram-(+)

Levofloxacin - less against Gram-(-) but enhanced against Gram-(+) like strep.pneumoniae

Moxifloxacin - enhanced against Gram-(-) and anaerobes but poor against Gram-(-)

219
Q

Adverse effects of fluoroquinolones.

A

GI symptoms

Headache and dizziness

Cartilage erosin -> cautions in children under 18

Tendonitis and tendon rupture -> CI in patients with high risk

Phototoxicity

Associated with Clostridium difficile colitis

220
Q

Cautions and CI of fluoroquinolones.

A

CI in pregnancy

CI in patients with high risk of tendonitis or tendon rupture

Cautions in children under 18 y.o

Cautions in patients with CNS disorders -> lower seizure threshold

221
Q

Resistance mechanism of fluoroquinolones.

A

Limit or prevent drug binding - through change in amino acid sequence of enzyme

Proteins bind to enzyme -> prevent interaction with drugs

Produce enzyme degrade drugs

Efflux pumps

222
Q

What are the two antibiotics used that target the folic acid synthesis pathways?

A

Trimethoprim and Sulfamethoxazole - inhibit tetrahydrofolate acid synthesis pathways

Sulfamethoxazole inhibit first step by mimic the structure of PABA -> inhibit dihydropteroate synthase

Trimethoprim inhibit the second step -> inhibit dihydrofolate reductase

223
Q

Effects of co-trimoxazole

A

Reduce tetrahydrofolate acid synthesis - important involved in generation of nucleotides -> DNA rep

Bacteriostatic

224
Q

Spectrum of activity of co-trimoxazole

A

Broad spectrum against both Gram-(+) and Gram-(-)

225
Q

Resistance mechanism of co-trimoxazole

A

Modified form of target enzymes

Overproduction of initial substrate

Changes in permeability

226
Q

Spectrum of activity of metronidazole

A

Only works against anaerobes like Clostridida

Amebic infections caused by parasites

227
Q

Mechamnism of activity of metronidazole.

A

Reduction of nitro group in structure by accepting electrons from low-redox potential electron transport protein

Produce free radicals -> break in DNA -> kill the organism

228
Q

Why is metronidazole only effective against anaerobes?

A

Aerobic bacteria lacks low-redox potential electron transport protein

No free radicals production

229
Q

Important interactions of metronidazole

A

Cause disulfram-like reaction when used with alcohol

230
Q

Adverse effects of metronidazole

A

Furring tongue

Metallic taste

Nausea and epigastric discomfort

Headaches, dizziness and peripheral neuropathy

231
Q

Mechanism of action of nitrofurantoin.

A

Reduction of 5-nitro group in structure by nitroreductase

Damage DNA -> bactericidal

232
Q

Spectrum of activity of nitrofuratoin.

A

Many Gram-(+) like staph, strep, entero, clostridia

Many species of gram-(-) of enterobact (except Proteus mirrabilis)

NOT Pseudomonas aeruginosa

233
Q

Application of nitrofuratoin.

A

Not for systemic infections (serum level and tissue concentraion is too low)

Treat UTIs is main indication as active form can be secreted into urine

234
Q

Adverse effects of nitrofuratoin

A

N+V

Anorexia

235
Q

Mechanism of action of daptomycin

A

Insert lipid portion into bacterial cytoplasmic membrane

Rapid release of ions (depolarisation) -> bactericidal effects

Req Ca2+ ions to induce insertion

236
Q

Spectrum of activity of daptomycin

A

Gram-(+), aerobic and anaerobic, include MRSA, streptococci and VRE

237
Q

Application of daptomycin

A

IV -> complicated skin infections, bacteraemia and infective endocarditis caused by susceptible organisms like MRSA

Not widely used

238
Q

Why is daptomycin not used to treat pneumonia?

A

Inactivated by pulmonary surfactants

239
Q

Name an example of polymixins antibiotics.

A

Colistins

240
Q

Mechanism of action of colistins

A

Interact with lipopolysaccharide in outer membrane of Gram-(-) -> membrane damage -> cell death.

241
Q

Spectrum of activity of colistins.

A

Only against Gram-(-) including all enterobacteria and Pseudomonas aeruginosa

242
Q

Application of colistin

A

Mainly topical use

Reversed for serioud systemic infections caused by MDR-Gram-(-)

243
Q

What compounds is colistin normally used with?

A

Hydrophilic antibiotics like sulphonamides + trimethoprim and ciprofloxacin

244
Q

Adverse effects of colistin

A

Pain at injection site

Dizziness and wekaness

Nephrotoxicity

245
Q

Resistance mechanism of colistins

A

Modification of lipid membrane

246
Q

What antibiotics are normally used as prophylaxis in patients with absent or abnormal spleen?

A

Long-term penicillin

247
Q

What antibiotics need adjustment when used in patietns with severe liver disease?

A

Clindamycin

Erythromycin

Metronidazole

Rifampicin

248
Q

What antibiotics are dangerous for breastfeeding?

A

Sulphonamides -> due to increased unbound billirubin

249
Q

What antibiotics are CI in pregnancy?

A

Chloramphenicol - Grey baby syndrome

Fluconazole - teratogenic

Quinolones - arthropathy

Tetracyclines - skeletal and dental abnormalities

Trimethoprim - teratogenic

Aminoglycosides - damage to fetal auditory

High dose metronidazole

250
Q

When are bactericidal agents absolutely prefered?

A

Patients with severely immunocompromised

Treatment of infective endocarditis - vegetation prevent phagocytic activity

251
Q

What class of antibiotics is concentration-dependent?

A

Aminoglycosides

Fluoroquinolones

252
Q

What classes of antibiotics are concentration-independent?

A

Beta-lactams

Macrolides

Glycopeptides

253
Q

What is post-antibiotic effect?

A

Continual suppression of microbial growth after reduction of levels below the MIC.

Concentration-dependet > concentration - independent

254
Q

Which case do combined antibiotic therapy needed?

A

Empirical treatment of severe infections

Minimise emergence of resistance

Provide synergistic activity

255
Q

Why do the length of treatment increase for prosthetic valve infection?

A

Lack of blood supplu to artifical device

PHAY00011 (9 decks)

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