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M201 > W7 Antibiotics- drug classes and mechanisms > Flashcards

W7 Antibiotics- drug classes and mechanisms Flashcards

1
Q

Microorganisms – brief recap:
Examples of prokaryotic, eukaryotic cells and acellular microorganisms

A

Bacteria

Fungi (yeasts/moulds)
Parasites (protozoa)

Viruses
Prions

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2
Q

What are the differences between prokaryotic and human/eukaryotic cells?

A
  • Without a nucleus (different DNA arrangements)
  • Without membrane-bound organelles
  • Simple organisation and smaller
  • Different components (cell walls, glycocalyx, sex pili, fimbriae, flagella
  • Different compositions of ribosomes (70s vs 80s)
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3
Q

What is Antimicrobial chemotherapy?

A

Drugs to treat infectious diseases, having selective toxicity against the pathogens involved, while damaging the host as little as possible

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4
Q

Terminology:

A

Antibiotics/antibacterial drugs bacterial infections
Antiviral drugs = virus infections
Antifungal drugs= fungal infections Antiprotozoal drugs = protozoan infections (parasites)

Each group has different classes of drugs (different mechanisms of actions/targets)
Prescribed only for patients with evidence of (or a reasonable suspicion of) BACTERIAL infection (along with all the other ANTIMICROBIAL STEWARDSHIP principles

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5
Q

What is Selective toxicity?

A
  • Ability of drug to kill or inhibit pathogen while damaging host as little as possible
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6
Q

What is therapeutic index?
How can you calculate it?
What does a high index indicate?

A

Selective toxicity
TI= toxic dose/ therapeutic dose
The larger the index, the safer/better the agent

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7
Q

What is a toxic dose?

A

Drug level that is toxic for the host

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8
Q

What is a therapeutic dose?

A

Drug level to treat/resolve an infection

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9
Q

Effect on bacteria of antibiotics:

What are the properties of Broad-spectrum drugs?

A
  • Target and inhibit many kinds of
    bacteria (e.g. Gram +ve & Gram -ve)
  • Serious bacterial infections by an
    unidentified organism
  • Infection with multiple bacteria
    Spectrum of activity
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10
Q

What are the properties of Narrow-spectrum drugs?

A
  • effective only against a limited
    variety of bacteria
  • When the microorganism is identified
  • Minimise the disruption of normal
    flora
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11
Q

What is meant by Bacteriostatic?
What is meant by Bacteriocidal?

A
  • Prevent bacterial growth (no killing)
  • Reversible effect
  • Bacterial clearance depends on the immune system

*Kill the target bacteria
*Irreversible effect
*Appropriate in poor immunity

Often, the distinction of the effect depends upon drug concentration and bacterial species

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12
Q

How can you measure the effectiveness of antimicrobial drugs? (2)

A
  1. Minimal inhibitory concentration (MIC)
    - lowest concentration of drug that
    prevents the visible growth of the pathogen (bacteriostatic)
    * It varies against different bacterial species (spectrum of activity)
    * Indicator for assessing bacterial drug resistance
  2. Minimum bactericidal concentration (MBC) - lowest concentration of drug
    that kills the pathogen

Both expressed as concentrations (usually, mg/mL or μg/mL)

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13
Q

From calculating MBC and MIC, when is a drug considered
bacteriostatic?
bacteriocidal

A

Bacteriostatic
* When MBC is significantly higher than the MIC
* MBC/MIC ratio is > 4

Bactericidal
* When is MBC ≈ MIC or
* MBC/MIC ratio is < 4

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14
Q

Antimicrobial Activity Can Be Measured by which Specific Tests? (3)

A
  • Dilution Susceptibility Tests
  • Disk Diffusion Tests (Kirby-Bauer Method)
  • The Etest®
  • When the isolated bacteria from biological samples can be cultivated in laboratory settings
  • Some bacterial species, cannot be cultivated in the laboratory
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15
Q

What are Dilution Susceptibility Tests?

A
  • Used to determine MIC and MBC values.
  • Inoculating media with different concentrations of a drug and a fixed number of bacteria.
  • Broth or agar with the lowest concentration showing no growth is MIC.
  • Liquid media from tubes that showed no
    growth are then cultured into agar plates
  • The lowest antibiotic concentration from the tubes that fails to support the microbe’s growth is the MBC.
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16
Q

What are Disk Diffusion Tests? (Kirby-Bauer test)

A

=Used to determine susceptibility or resistance

  • Disks impregnated with different antibiotics are placed on agar plates inoculated with a microbe.
  • Antibiotic diffuses from disk into agar, establishing concentration gradient.
    -Higher concentrations near the disk.
  1. Innoculated agar plate
  2. Addition of antibiotic discs
  3. Measurement of zone of inhibition
  • Measurement of the clear zones diameter
    (no growth) around disks compared to a
    standardized chart, determining
    susceptibility or resistance
  • Diameter correlates with MIC (empirically)
     Wider clear zone indicates that a microbe
    is more susceptible to that antibiotic.
     Narrower clear zone indicates drug
    resistance
  • Cannot distinguish bacteriostatic and bactericidal effects
  • Cannot compare efficacies between drugs
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17
Q

What is The Etest?

A
  • Bacterial is inoculated on agar,
    then Etest® strips are placed on
    the surface.
  • Etest® strips contain a gradient of
    an antibiotic.
  • Intersection of elliptical zone of inhibition with strip indicates MIC
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18
Q

Mechanism of action: different classes of antibiotics
What are the different mechanisms of action?

A
  1. Inhibition of cell wall synthesis (bactericidal)
  2. Inhibition of protein synthesis
  3. Acting as antimetabolites
  4. Inhibition of nucleic acids synthesis
  5. Alternative mechanisms
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19
Q

What are examples of inhibitors of cell wall synthesis?

A
  • B-lactams
  • Penicillins
  • Cephalosporins
  • Monobactams
  • Carbapanems
  • Glycopeptides
  • Vancomycin
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20
Q

(RECAP – PMP101)
What are the Differences of cell wall in Gram+ and Gram?

A
  • Cell wall confers protection, gives the cell shape and prevents the cell from burIf damaged or inhibited, bacteria burst by osmosis
  • Sting by osmosis

Gram-Positive Cell Walls
* Thick peptidoglycan (including teichoic acids

Gram-Negative Cell Walls
Thin peptidoglycan
* Outer membrane (LPS, porins)

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21
Q

Peptidoglycan formation: What 2 subunits are they formed from?

A
  1. N-acetylglucosamine (NAG)
  2. N-acetylmuramic acid (NAM)

Bacterial transpeptidase (or penicillin-binding proteins) form peptide cross-link bridges between tetrapeptide of NAMs of peptidoglycan strands

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22
Q

What are β-Lactam mechanisms of action?

A
  • Block NEW cell wall formation
  • Bacterial lysis
  • β-Lactams bind to and block transpeptidases (PBP)
  • β-Lactams block the transpeptidation of peptidoglycan strands
  • Prevent the synthesis of complete cell walls, leading to lysis of bacteria
    -Only effective against bacteria reproducing
  • Activates enzymes to break down peptidoglycan
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23
Q

1) Inhibitors of Cell Wall Synthesis: β-Lactam antibiotics

Important Structure they have?
MoA?

A
  • Containing a β-lactam ring — core structure
  • Essential for bioactivity

Same mechanism of action:
- Blocking the formation of peptide bridges between peptidoglycan chains
- Bactericidal effect and high therapeutic index
- Some resistant bacteria produce β -lactamase (penicillinase, more common
in Gram-negative bacteria) which hydrolyses and inactivate the ring

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24
Q

What are the subclasses of β-lactam antibiotics?

A

Penicillins
Cephalosporins
Carbapenems
Monobactams

(They all have a β-lactam ring)
Same mechanism of action, but distinct related features

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25
Q

What are the Natural Penicillins? (2)
– the first antibiotics

A

Penicillin G (Benzylpenicillin)
Penicillin V (Phenoxymethylpenicillin)

Bacterial β-lactamases cut the β-lactam ring to inactivate antibiotics of this class

Development of semisynthetic penicillins to overcome this limitation

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26
Q

Semisynthetic Penicillins
What are the 3 major groups?

A
  1. Antistaphylococcal penicillins
  2. Aminopenicillins (Broad-spectrum penicillins)
  3. Antipseudomonal penicillins (Extended broad-spectrum)

-cillin: a suffix for penicillin antibiotics

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27
Q

Semisynthetic penicillins 1/3
Antistaphylococcal penicillins - Penicillinase-resistant penicillins

Example?
Features?
Used for?

A

Flucloxacillin – acid-stable (oral and iv)
* Bulkier side chains – Resistant to β-lactamase of Staphylococci
( Retain a narrow-spectrum activity (not active against Gram-

Skin/wounds infections
Ear infections
Osteomyelitis
Pneumonia

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28
Q

Semisynthetic penicillins 2/3
Aminopenicillins/Broad-spectrum penicillins:

Examples?
Features?

A

Ampicillin (oral)
Amoxicillin (oral)

Active against Gram-negative (e.g. E. coli, Salmonella spp)
o Hydrophilicity allows passage through porins of outer membrane in Gram-negative only) combined with beta-lactamase/penicillinase inhibitors (e.g. clavulanic acid)
o inactivating bacteria producing β-lactamases
o do not have anti-bacterial activity

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29
Q

Amoxicillin combinations:

A
  1. Augmentin (Co-amoxiclav) = Amoxicillin+Clavulanic acid
  2. Co-fluampicil = Amoxicillin + Flucloxacillin
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30
Q

Semisynthetic penicillins 3/3
Antipseudomonal penicillins – extended broad-spectrum
Examples?
Used to treat?

A

Piperacillin, Ticarcillin
- But only available in combination with the beta-lactamase inhibitors

e.g. Zosyn- Pipericillin + Tazobactam
Timentin- Ticarcillinn + Clavulanic acid

Coverage: Extended broad-spectrum
-wider range against Gram- (e.g. Pseudomonas aeruginosa) and anaerobes
-not active against MRSA (resistant to several widely used antibiotics)

  • Uses: treat sepsis, hospital-acquired pneumonia and complicated infections like UTIs
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31
Q

Adverse effects of Penicillins:
Penicillin hypersensitivity:

A
  • Penicillin hypersensitivity – 0.4% to 10 %
    Patients must be questioned about penicillin allergies before treatment starts!!
  • Mild: Rash - Hives (raised, itchy, red or white swellings). It disappears within hours.
    Breathing and swallowing difficulties
  • Severe: anaphylaxis (0.05%) & death
  • Cross-reactivity across all Penicillins. Avoid other β-lactams
    ~5-15% cross-reactivity with other β-lactams (e.g. cephalosporins and carbapenems)
  • Amoxicillin and ampicillin can give Maculopapular rashes (non-allergic)
     Smaller pink (non-itchy) spots in the chest, abdomen (can last 1-6 days)
     Increased risk with viral infections
  • In both cases, the drug must be discontinued.
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32
Q

Penicillin adverse effects:
What effects are common for penicillin oral antibiotics?

What are the contraindications?

A

GI distress
Diarrhoea and nausea
- disturbing gut flora, rarely leading to pseudomembranous colitis
- Clostridium difficile infections may occur
- Consider probiotics (a few hours later)

CNS toxicity
Flucloxacillin is rarely associated woth hepatic disorders

  • Penicillin resistance
    -Mainly due to the production of β-lactamases to cleave the β-lactam ring
    -Mutations changing the transpeptidase conformational structure
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33
Q

Which enzymes inactivate the activity of penicillins?
a) β-lactamases
b) Transpeptidases
c) Nucleases
d) Lysozymes
e) Kinases

A

=A

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34
Q

Which of the following antibiotic is less likely to disrupt the normal flora when administered orally?

A

Narrow spectrum antibiotic

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35
Q

Which of the following penicillins have the broadest spectrum of antibacterial activity?
a) Penicillin G
b) Amoxicillin
c) Flucloxacillin
d) Piperacillin + Tazobactam

A

=D

36
Q

What are Cephalosporins (2nd β-lactam subgroup)?
Used for treatment of?

A

Cell wall inhibitors

  • Originally isolated from the fungus Cephalosporium
  • Structurally and functionally similar to penicillins
  • 5 cephalosporin generations (different coverage)
  • Earlier-generation drugs have better Gram+ coverage than later
    generations (more effective against
    Gram-)
  • 1st -2nd generations (mainly oral), while the 3rd/4th (mainly IV)
  • Same mechanism as all the β-lactams and Bactericidal

Cef- suffix (eg Cefotaxime)

Used for the treatment of sepsis, pneumonia, meningitis, biliary-tract infections, peritonitis, and urinary-tract
infections

37
Q

What are the adverse effects of Cephalosporins?
C/I?

A
  • Overall, low toxicity and they are generally safe
  • Oral cephalosporins may disturb the gut flora and give rise to diarrhoea
  • Antibiotic-associated colitis (2nd/3rd generation – e.g. cefradine)
  • Patients allergic to penicillins may also be allergic to cephalosporins of the1st and 2nd generations (10% of cases). Reduced risk for the other generations (2-3%)
  • Disulfiram-like reactions with alcohol
  • Nephrotoxicity (kidney damage) rare
  • Drug resistance mechanism similar to penicillins (cross-resistance)

Contraindications: patients with hypersensitivity (or suspected) reactions to cephalosporins, penicillins and other β-lactams

38
Q

Carbapenem- drug class
What dosage form are they used in?
What are some examples?
Broad/narrow spectrum?
SE?
C/I?

A
  • β-lactams –same mechanism of penicillins (β-lactam ring)
  • Only in IV form and used to treat complex infections of resistant bacteria

Imipenem, ertapenem, meropenem.
-broad spectrum activity (Gram+, Gram-, anaerobes), expect for meropenem
(only against Gram-). No MRSA or Enterococcus activity.

SE: ( similar to those of penicillins)
* Neurotoxicity (seizures, confusion) with high dose (imipenem, ertapenem)
* Skin reactions-rash
C/I= pt with severe penicillin allergy

39
Q

Monobactams:
Example?
What spectrum?

A

Aztreonam (IV)
Spectrum limited to aerobic Gram- (including Pseudomonas)

40
Q

Glycopeptides e.g. Vancomycin
What is the mechanism of action? (3)
What are they effective against?
What is it used to treat? (2)

A
  • Non β-lactam antibiotics – (Vancomycin and teicoplanin)
  • Vancomycin is a glycopeptide produced by Streptomyces spp.

Mechanism:
* Inhibit cell wall synthesis - bactericidal effect
* Binds to terminal amino acids linked to NAM of peptidoglycan (the substrate of the transpeptidase)
* Prevents the transpeptidation, without targeting the enzyme (difference with β-lactams)

  • Coverage: only effective against Gram+
  • Uses – Drug of last resort for the treatment of multi-resistant staphylococcal (MRSA) and enterococcal infections. To treat C. difficile infections
  • Vancomycin-resistance strains (VRE) are a serious health threat
41
Q

Glycopeptides e.g. Vancomycin
Side effects? (4)
What should be monitored?
C/I? (2)

A

Hydrophilic molecule – Reduced intestinal absorption – Administered by IV
Renally excreted

  • Dose-related ototoxicity (ears): high-tone deafness, can progress to total deafness
  • Nephrotoxicity (kidney damage)
  • “Red man” syndrome (allergic reaction with rash on the face/neck, hands, feet)
  • Agranulocytosis/neutropenia. (reduced levels of white blood cells

Recommended to monitor the drug level in serum
* 10-20 mg drug/L (through level) should be maintained to reduce toxicities

C/I= patients with history of deafness and elderly

42
Q

What are examples of drug classes that inhibit protein synthesis?
Ribosome 30S (2) 50S (4)

A

30S subunit:
1. Aminoglycosides
2. Tetracyclines

50S:
1. Macrolides
2. Lincosamides
3. Chloramphenicol
4. Oxazolidinones

43
Q

Protein Synthesis Inhibitor classes:

A
  • Many antibiotics bind to the bacterial ribosome
  • Ribosomes: machinery to synthesise proteins
  • Inhibition of protein synthesis leads to
    cessation of bacterial growth or cell death
  • Bacterial ribosome 70S differ sufficiently from the eukaryotic ones (80S) to allow selective toxicity
  • Bacterial 70S are smaller, consisting of a small (30S) and a large subunit (50S), if compared to the eukaryotic ones 80S (formed by 40S and 60S)
44
Q

What are the 3 phases of translation in bacteria?

A
  1. Initiation: ribosome assemble with the mRNA and the first tRNA
  2. Elongation: amino acids are brought to the ribosome by tRNAs and linked together to form a chain
  3. Termination : the finished polypeptide is released and the ribosome is disassembled
45
Q

Protein Synthesis Inhibitor classes:
What do they target?
examples of these steps? (4)

A

Target different ribosomal subunits components and steps in protein synthesis
* Translation assembly/initiation
* Aminoacyl-tRNA binding to site A
* mRNA reading
* Translocation step

Examples:
* Macrolides & Lincosamines -Prevent the translocation step
* Oxazolidinones- Interfere with the
translation initiation
*Chloramphenicol- Block the attachment of tRNA to the ribosome site A
* Aminoglycosides- cause mRNA misreading (faulty/premature protein).
Also, they may block the translation initiation
Tetracyclines- Block the attachment of
tRNA to the ribosome site A

46
Q

Aminoglycosides
What are some examples?
What is the mechanism of action?

A

Structure - a cyclohexane ring and amino sugars
Streptomycin,gentamycin,neomycin,amikacin, tobramycin

  • Mechanism: Disrupt protein elongation in translation - Bactericidal effect
  • Target: Irreversible binding to 30S,
    -interfere with mRNA reading by tRNAs  causing early termination of protein synthesis or aberrant proteins
  • Additional: Some also block the ribosome assembly, preventing initiation

Coverage - Mainly used for aerobic Gram- (serious infections)
Streptomycin can be used with other drugs for tuberculosis (by IM)
Low/fair activity against few Gram+ (e.g. staphylococci).
Inactive against anaerobes (Cell penetration is O2-dep. transport)

47
Q

Aminoglycosides:
What are the pharmacokinetics?
What are the adverse effects?

A

IV infusion or applied locally (neomycin)
* Highly polar drugs – Poor oral bioavailability. Not absorbed from the gut
* Drugs excreted unchanged in the urine by glomerular filtration (dose adjustment in renal insufficiency)

Adverse effects - Used sparingly!! Narrow therapeutic range!
* Serum concentration must be monitored (reduce toxicity and avoid subtherapeutic dose)
* Ototoxicity: Loss of hearing (cochlear damage; amikacin) and balance (vestibular damage;gentamycin)
* Nephrotoxicity - killing of proximal tubular cells
* Neuromuscular toxicity -blockage of presynaptic ACh release= respiratory suppression

48
Q

Tetracyclines
What are some examples?
What is the mechanism of action?
What do they target?
What are their uses?

A

4-cyclohexane core structure
Tetracycline HCl, Minocycline, Doxycycline

Mechanism:
* inhibition of the protein synthesis elongation - Bacteriostatic effect
-Target 30S ribosomal subunit
-by blocking the binding of aminoacyl tRNA on the mRNA-ribosome (to the A site

Tetracyclines- Block the access of tRNA to the ribosome site A
Coverage – Broad spectrum
* Uses - Susceptible infections (chlamydia, rickettsia, mycoplasma), acne and in resp. tract. May be used to treat MRSA infections (with other antibiotics)

49
Q

Tetracyclines
What are the pharmacokinetics?
What are the adverse effects?
C/I?

A

Pharmacokinetics – Usually, via the oral route. Topical, IM, IV administration also possible.
-Oral absorption impaired by food (Multivalent cations reduces their absorption in the gut)

  • Adverse effects – tetracyclines chelate large cations (Ca2+, Fe2+)
  • GI distress, including antibiotic-associated colitis
  • Oesophageal irritation
  • Photosensitivity, (Sunlight can trigger immune system reactions) which can manifest as a red rash or skin blistering. avoid exposure to sunlight
  • Incorporation into teeth and bone = staining of teeth; retardation of bone growth
  • Rare risk of hepatotoxicity
  • Headache and visual disturbances (due to intracranial hypertension)

Contraindications: in children (<12 years old ) and during pregnancy
-Caution in Myasthenia gravis (it may increase muscle weakness); systemic lupus erythematosus

50
Q

Macrolides
What are examples?
What is the MoA?

What do they target?
What are they used for?

A

Erythromycin, Azithromycin,
Clarithromycin

-Prevent the translocation step
* Inhibition of protein elongation –
Bacteriostatic effect (may become bactericidal at high dose)
-Target reversibly 50S ribosomal subunit
-Block the translocation step (ribosome cannot shift along the mRNA)

-Broad spectrum (mostly against Gram+ & some Gram-). Similar to penicillins

Used for patients allergic to penicillin, various respiratory infections (CAP) andskin/cellulitis infections (β-haemolytic streptococci and Staphylococcus aureus), GI infection (H. pylori eradication - Clarithromycin) sexually transmitted infections of Chlamydia and Gonococcus- STIs (Azithromycin)

51
Q

Macrolides
What are the Pharmacokinetics?
What are the adverse effects? (5)
Contraindications?

A

Usually oral route. Excellent tissue and cellular penetration
* Oral absorption impaired by food (better without food, if no GI upset)
-ALL hepatic elimination

  • GI disturbance (nausea, vomiting, abdominal pain, and diarrhoea)
  • Hepatotoxicity and Ototoxicity
  • Prolongated QT intervals  cardiac arrhythmia (used with antiarrhythmic drugs)
  • Dry mouth
  • Drug resistance – readily acquired (cross-resistance across all macrolides

Contraindications: patients with predisposition to QT internal prolongation
-in Myasthenia gravis (it may aggravate the conditions);
-Patients taking Rivaroxaban – interaction (increased risk of bleeding)

52
Q

Lincosamines (Clindamycin)
What is the MoA?
What does it target?
What is it used to treat?

Side effects?
Contraindications?

A

Clindamycin (IM or IV)

Inhibition of protein elongation- Bacteriostatic effect
* Target 50S ribosomal subunit and interfere with the translocation step

  • Contraindications: in neonates (Clindamycin Injection contains benzyl alcohol)
  • Cautions: Monitor liver and renal function if treatment exceeds 10 days
53
Q

Oxazolidinones (Linezolid)
What is the mechanism of action?
What does it target?
What is it used to treat?
Side effects?
Contraindications?

A

Linezolid (available in tablets, suspension, and injection

MoA= inhibition of protein elongation- Bacteriostatic effect
* Target the 50S ribosomal subunit and prevent the assembly of the 70S initiation complex

Active against Gram+ (including MRSA & vancomycin-resistant enterococci). Not active against Gram-infections of the skin/soft tissue and pneumonia

Side effects
* Thrombocytopenia (decreased platelets) or other blood disorders (anaemia, eosinophilia). Full blood
counts should be monitored weekly
* Severe optic neuropathy (visual impairment) may occur rarely (if >28 days). Visual functions should be
monitored and referred to an ophthalmologist

Oxazolidinones- Interfere with the
translation initiation/assembly

54
Q

Chloramphenicol
What is the Mechanism of action?
What does it target?
What is it used to treat?
Side effects?
Contraindications?

A

Chloramphenicol (available in eye/ear drops, tablets, and injection

Mechanism: inhibition of protein elongation - Bacteriostatic effect
-Target 50S subunit and prevent the access aminocyl-tRNA to the A site

Coverage- Broad spectrum - Active against Gram+, Gram- and Mycoplasma spp.
* Side effects – dose-related (considered quite toxic for systematic use)
- Aplastic anaemia, risk of Leukaemia
- Blood disorder; bone marrow depression (even when used by ear)
- Hypersensitivity reactions
* Uses- eyes/ears infections or life-threatening infections (because of side effect
Contraindications: patients predisposed to blood Acute porphyrias

55
Q

What are examples of antimetabolites?

A

Folic acid synthesis:
Sulfonamides

  • Trimethoprim
  • Mycolic acid synthesis
    -Izoniazid
56
Q

What are the functions of antimetabolites?

A
  • Antagonize, or block, functioning of bacterial metabolic pathways (different to eukaryotic ones – selective toxicity).
  • Compete with metabolites for binding sites.
  • Stop the progression of the metabolic pathway
57
Q

What is the coverage and effect of antimetabolites?

A

Coverage&effect:
*Bacteriostatic (if removed, the metabolic activity can be restored),
*Broad-spectrum activity

58
Q

What is the mechanism of sulphonamides?

A
  • Folic acid is essential to produce purines (DNA)
  • Folic acid cannot cross the bacterial cell wall
  • Bacteria synthesise folic acid, starting from a precursor p-aminobenzoic acid (PABA)
  • Sulfonamides act by competing with PABA as a substrate for the enzyme dihydropteroate synthase
  • Bacteriostatic effect

Selective toxicity- In Human body,Folic acid (Vitamin B9) obtained in the diet

59
Q

What is the mechanism of Trimethoprim?

A
  • Dihydrofolate reductase (DHFR) targeted by Trimethoprim
  • DHFR is also present in human cells, as folic acid needs to be reduced to be active
  • Trimethoprim has 100.000 higher affinity to the bacterial enzyme rather the human DHFR (selective toxicity)
  • Bacteriostatic effect
60
Q

Which ONE of the following classes of antibiotics is NOT a cell wall
inhibitor?
a) Vancomycin
b) Cephalosporins
c) Penicillins
d) Tetracyclines
e) Monopenemens

A

D= Tetracyclines

61
Q

What are the two drugs in co-trimoxazole?
What is the MoA?

A

Sulfonamides and Trimethoprim

Sequential blocking mechanism:

  • Both drugs block the folic acid synthesis at two distinct steps of = potential synergistic effect
  • Both substrate analogues inhibiting two different enzymes:
    -Dihydropteroate synthase by Sulphonamides
    -Dihydrofolate reductase (DHFR) by Trimethoprim
  • Bacteriostatic effect
62
Q

Sulfonamides + trimethoprim (co-trimoxazole)
When is it used?
What are the SE?
C/I?
Cautions?

A

Uses combination or Trimethoprim - UTIs, prostatitis and Pneumocystis
jirovecii pneumonia (PCP treatment and prevention) in immunocompromised patients

  • Contraindications: blood dyscrasias and in first-trimester of pregnancy
  • Cautions: in acute porphyria, elderly, neonates, predisposition to folate deficiency

Side effects
-Risk of folate deficiency (during pregnancy is associated with neural tube defects- contraindicated)
-Hyperkalaemia (high levels of potassium - monitor renal function)
-Hypersensitivity; rash and anaphylaxis

  • Contraindications: blood dyscrasias and in first-trimester of pregnancy
  • Cautions: in acute porphyria, elderly, neonates, predisposition to folate deficiency
63
Q

What are examples of drug classes that are inhibitors for nucleic acid synthesis?

A

(DNA Synthesis)
* Fluoroquinolones
-ciprofloxacin, levofloxacin, moxifloxacin

(RNA Synthesis)
* Rifamycins
-rifampin

64
Q

Inhibitors of nucleic acid synthesis:

A
  • Anti-bacterial drugs that inhibit nucleic acid (DNA/RNA) synthesis function by inhibiting:
    -Topoisomerases (by fluoroquinolones)
    essential for DNA replication
    -RNA polymerase (by rifamycins) catalysing the step of DNA transcription into mRNA

-Drugs not as selectively toxic as other antibiotics

65
Q

Fluoroquinolones
What is the -ending?
What are some examples?
Coverage? What do they target?
What are they used to treat?

A

‘floxacin’
Ciprofloxacin, levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

  • Coverage & effect - Broad spectrum Wide range of activity against Gram positive and
    negative bacteria (e.g. H. influenzae, Pseudomonas aeruginosa). Bactericidal effect
  • Uses – Serious RTIs (CAP), skin and soft tissue infections- and UTI (E. coli)
66
Q

What is the Mechanism of action of Fluoroquinolones?

A
  • Inhibit DNA replication by interfering with the bacterial topoisomerases (2 types)
  • DNA gyrase (not present in human)= target in Gram-
  • Topoisomerase IV (the human enzyme is inhibited at high dose) =target in Gram+
67
Q

Nucleic Acid Synthesis Inhibition:
What 2 enzymes are involved in nucleic acid synthesis?
What are their roles?

A

DNA Gyrase and DNA topoisomerase IV

DNA gyrase unravels (relaxes) supercoiled DNA
*It is required for bacterial DNA replication.Without this step, helicase cannot unwind DNA

DNA topoisomerase IV
* DNA topoisomerase IV removes “DNA knots” generated behind the replication fork
*To keep the two duplicated DNA molecules separated

Fluoroquinolones inhibit DNA gyrase and topoisomerases IV= making DNA inaccessible
–blocking bacterial DNA replication= leading to cell death

68
Q

Fluoroquinolones
WHat are the SE?
C/I?
Cautions?

A
  • All orally active, and several are available as intravenous injections

Side effects (generally, well tolerated)
* GI distress (antibiotic-induced diarrhoea due to C.difficile overgrowth)
* tendonitis, tendon rupture – 2% cases (discontinue the treatment at the first sign of tendinitis, painful swelling, inflammation)
* Prolongs QT interval (very rare) and cardiac arrhythmia
* Seizures (rare, but taking NSAIDs may also induce them)
* Risk of aortic aneurysm (very rare and conflicting)
* Overuse is leading to rapid development of resistance
* Contraindications: patients with history of tendon damage or taking corticosteroids
* Cautions: Patients with QT prolongation risk factors, in epilepsy, psychiatric disorders, patients with renal impairment, exposure to sunlight.

69
Q

Rifamycins:
What is the mechanism of Rifampicin?

A
  • Inhibit the initiation of bacterial DNA transcription
  • By blocking the activity of the β-subunit of the bacterial RNA polymerase (enzymatic complex)
  • Bactericidal effect
70
Q

Rifamycins
Coverage?
Uses?
SE?
C/I?

A
  • Coverage- Broad spectrum INCLUDING Mycobacterium tuberculosis, but also
    against Gram-positive and negative bacteria.
  • Uses – Used to treat tuberculosis with other antitubercular drugs. Enters the
    cerebrospinal fluid  treatment of some meningitis (N. meningitidis or H. influenzae
  • Side effects
     GI distress
     Minor hepatotoxicity
     Discoloration of body fluids (urine and sweat turn orange - harmless)
     Many interactions (by inducing cytochrome P450)
  • Contraindications: patients with acute porphyrias
  • rapid development of resistance

Contraindications: patients with acute porphyria

71
Q

Alternative mechanisms: antibacterials:
e.g. Nitroimidazoles- Metronidazole, Nitrofurantoin
How do they work?

A

Generating free radicals

72
Q

Alternative mechanisms (free radicals) - Nitroimidazole
What is the MoA of Metronidazole?
What is the coverage?
What are the uses?

A
  • Mechanism – Generating free radicals in bacteria
    -It is activated by reduction in pathways, generating unstable nitroso radical metabolites (ROS)
    -ROS leads to DNA fragmentation (DNA strand breakage)
    -Bactericidal effect
  • Coverage – Only anaerobes (including protozoa – other class of microbes)
    -Reduction to the free radicals requires low redox potential within cells
    -NOT active against aerobic bacteria (high redox potential due to O2)
  • Uses – Used to treat infections of anaerobic bacteria, Helicobacter pylori eradication
73
Q

Alternative mechanisms (free radicals) -
Metronidazole:
SE?
Caution?

A
  • Rapid and effective absorption (Oral and IV)
  • Penetrate well all tissues

Side effects
-GI distress
-Skin reaction (topic use only)
-Taste disturbances (metallic taste), furred tongue
-Peripheral neuropathy (rare)
-Disulfiram-like adverse reactions when alcohol is consumed

  • Caution. Avoid exposure to sunlight with topical use.
    Avoid intravaginal preparations in young girls. Avoid alcohol (disulfiram-like reaction)
74
Q

Alternative mechanisms - Nitrofurantoin
What is the mechanism?
Coverage?
Uses?

A

Mechanism –
* Generating reactive free radicals in bacteria
* Activate pathways in bacteria to generate instable metabolites that interfere with RNA, DNA and other components synthesis.
-Bactericidal effect

  • Coverage is active against most Gram+ cocci and some Gram- (E. coli)
  • Uses – Used to treat and prevent uncomplicated acute UTIs
75
Q

Alternative mechanisms - Nitrofurantoin
SE? (4)
C/I?
Caution?

A

SE
1. Discoloration of body fluids (urine and sweat turn orange/brown - harmless)
2. Pulmonary toxicity (fever, chills, cough, myalgia, and dyspnea)
3. Peripheral neuropathy (rare)
4. blood disorders (rare, hemolytic anemia)

Contraindications: in patients with decreased renal function (if eGFR <45
mL/min), G6PD deficiency; infants less than 3 months old
* Caution in anaemia, diabetes, electrolyte imbalances and folate deficiency

76
Q

What is TB?

A

Tuberculosis
* Infection in the lungs (pulmonary), or spread to other organs (extrapulmonary)
* Latent (asymptomatic) and active tuberculosis (symptomatic)

77
Q

Features of the bacteria- Mycobacterium tuberculosis?

A
  1. Gram+ and aerobe (requires oxygen - lungs)
  2. Complex and unique cell wall
    * Virulence factors – allowing the bacteria to survive after the phagocytosis of macrophages. Mycobacteria can
    even replicate inside a macrophage and kill it
  • Marker for the microbiological diagnosis
    -Acid-fast staining (lipid-rich cell wall)
    -Auramine fluorescent staining (mycolic acids of the cell wall)
    *Therapeutic target
78
Q

What is the structure of the cell wall of Mycobacteria?

A

Mycobacterium cell wall – thick, hydrophobic, robust and waxy (variety of lipids)
*Hydrophobic barrier to antibiotics –difficult to treat Mycobacteria

79
Q

Principles of the therapy for tuberculosis? (4)

A
  • Multidrug-resistant TB (MDR-TB) is a public health threat

Principles of the therapy:
* Prompt and effective treatment of identified cases
* Combination of drugs and long therapy to prevent the emergence of MDR-TB
* Therapy adherence is vital to avoid resistance and be effective
* Rifampicin and erythromycin (less used), are the only antibiotics used to treat
tuberculosis and also other bacterial infections
* The other antitubercular drugs are only used to treat tuberculosis

80
Q

What is the Treatment for TB in newly diagnosed patients?

A
  • NEWLY DIAGNOSED (6-months therapy)
    -initial phase (RIPE):Rifampicin+ Isoniazid + Pyrazinamide + Ethambutol (2 months)
    -continuation phase (RI): Rifampicin+ Isoniazid (4 months)
81
Q

What is the Treatment for TB in retreat patients?

A

Re-treatment
(7-months therapy)
* initial phase: RIPE + Streptomycin (2 months)
* continuation: RI + Ethambutol (5 months)

  • Treatment needs to be supervised (Directly Observed Therapy) in patients at risk of non-compliance
82
Q

What are some drug-resistant strains of TB?

A
  • Multidrug-resistant TB (MDR-TB), TB resistant to Rifampicin AND Isoniazid
  • Extensively drug-resistant TB (XDR-TB), TB resistant to Rifampicin, Isoniazid, AND at least two types of drugs of the second line
83
Q

Treatment for tuberculosis (TB)
What 4 drugs are used?
What are their moA?

A
  • R- Rifampicin
    (RNA polymerase inhibitor)
    *I- Isoniazid
    (Prodrug) - Inhibitor of mycolic acids
    synthesis
    *P- Pyrazinamide
    (Prodrug) - interferes with fatty acid
    synthesis
    *E- Ethambutol interferes with synthesis of arabinogalactans
84
Q

Which of the following is the target of the antibiotic trimethoprim?
a) Cell wall synthesis
b) Protein synthesis
c) Folic acid synthesis
d) RNA polymerase

A

=C

85
Q

Which of the following is NOT a first line drug in the treatment of
tuberculosis?)
a) Rifampicin
b) Isoniazid
c) Pyrazinamide
d) Amoxicillin
e) Ethambutol

A

=D

M201 (81 decks)

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