Q1

Describe the mechanism of action of gentamicin?

  • Irreversible inhibitor of protein synthesis-possible mechanism:
  • Passive diffusion via porin channels across outer memb, then active transport into cytoplasm by an O2 dependant process.
  • Inside the cell, binds 30S ribosome & inhibits protein synthesis by 1) Inducing misreading of mRNA thus producing toxic or nonfunctional protein; 2) interfere with initiation complex of peptide formation; 3) cause break up of polysomes into non-functional monosomes.


Pass Criteria: Irreversible protein synth inhibitor; Binds ribosomes

What are the benefits of once daily dosing?
Prompt: How does this improve clinical effectiveness?

Concentration- dependant killing (at increased conc kill increased no of bacteria at a more rapid rate;

  • Postantiobiotic effect- activity lasts longer than detectable serum levels;
  • Reduced toxicity ( toxicity is time & conc dependant) – time above critical level will be longer with multi dose than single dose schedule);
  • Less nursing time; OPD therapy possible;
  • Drug level not required unless >3 day therapy. Dosage still needs to be adjusted according to renal function.

Pass: Concentration- dependant killing – PLUS 2 others

How do penicillins enhance the efficacy of gentamicin?

Low ECF pH & anaerobic conditions inhibits transport Transport enhanced by cell wall active drugs eg. Penicillin


Q2

How are cephalosporins classified?
Prompt: What are the differences between the classes?

  • 1. GPs
  • 2. Haemophilus & kleb
  • 3. GP + GN
  • 4. Pseudomonnas

Pass: Protein synthesis inhibitor; Bacteriostatic

Why are 3rd generation cephalosporins used in CNS infection?

  • Expanded GN activity
  • Cross the BBB
  • Penetrate body fluids well
  • Good toxicity profile

Pass: Spectrum activity & penetration CNS

Are there any bacteria responsible for CNS infection that cephalosporins do not cover?

  • Listeria
  • Resistant pneumococci may need vancomycin
  • Resistant E Coli; use with aminoglycoside to cover Pseudomonas

Pass: One example


Q3

Describe the pharmacokinetics of metronidazole?

  • Class: Nitroimidazole antiprotozoal drug.
  • Pharmacokinetics:
    • Well absorbed orally;
    • Oral/IV/suppository (99% oral bio-availability);
    • Metabolised in liver (can accumulate in hepatic insufficiency) and excreted in kidney;
    • Low protein binding (10-20%);
    • Dosage: 500mg tds or single dose of 2g for vaginitis;
    • Half life 7.5 hours

Pass: 3 out of 6

What are the adverse effects of metronidazole?

  • Nausea, diarrhoea, dry mouth, hairy black tongue
  • Headache, paraesthesia, dizziness, insomnia
  • Dysuria, dark urine,
  • Disulfiram-like effect, hence avoid alcohol
  • Potentiate the effect of coumarin anticoagulants, Lithium
  • Teratogenic effect on mice, but not proven in human


Pass: 3 out of 6


Q4

How are the cephalosporins classified and give examples?
Prompt: What are the different antimicrobial spectrums of the generations?

  • 1st generation:
    • Cephalexin, cephazolin, cephalothin
    • Very active against GPC (pneumococci, strep, and staph).
    • GN org (E coli, K pneumoniae, & Proteus mirabilis) often sensitive, but not against GN aerobes ( P aeruginosa, indole-positive proteus, enterobacter,Serratia marcescens, citrobacter), & acinetobacter.
  • 2nd generation:
    • Cefaclor, cefamandole, cefuroxime
    • Active against organisms inhibited by 1st-gen drugs, but have extended GN coverage. Klebsiellae are usually sensitive.
    • Some anaerobic
  • 3rd generation agents
    • Cefotaxime, ceftazidime, ceftriaxone
    • Have expanded GN coverage & X BBB.
    • Less active against staphyl than earlier cephalosporins but are active against citrobacter, S marcescens, & providencia.
    • Also effective against -lactamase-producing strains of haemophilus & neisseria. Some anaerobic
  • None above active against MRSA, enterococci or P aeruginosa.
  • 4th generation:
    • Cefepime
    • Extended spectrum of activity covering the majority of the enteric GNRs, including Pseudomonas and Enterobacter.
    • Also active against S aureus, &S pneumoniae.
    • More resistant to hydrolysis by chromosomal -lactamases (eg, those produced by enterobacter).

Pass: Know there are 4 generations, and understand principles of 3 of these.

What are the adverse effects of the Cephalosporins?

  • Hypersens reactions identical to penicillins:
    • Anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, & hemolytic anemia.
    • Some individuals with a history of penicillin allergy may tolerate cephalosporins.
    • Frequency of cross-allergenicity uncertain, probably around 5–10%.
  • Severe pain IMI.
  • Thrombophlebitis IVI.
  • Renal toxicity: interstitial nephritis & ATN.
  • Cephalosporins with a methylthiotetrazole group (eg, cefamandole, cefotetan) may cause: hypoprothrombinemia, bleeding (preventable with Vit K1 10 mg twice weekly)
  • Severe disulfiram-like reactions with alcohol


Pass: Essential penicillin cross reactivity – PLUS 2 others


Q5

Describe the mechanism of action of gentamicin?

  • Irreversible inhibitor of protein synthesis.
  • Passive diffusion via porin channels across outer memb, then active transport into cytoplasm by O2 dependant process; transmemebrane electrochem gradient supplies the E, transport coupled ti proton pump.
  • Low ECF pH & anaerobic conditions inhibits transport as reduces gradient; transport enhanced by cell wall active drugs eg penicillin.
  • Binds 30S ribosome & inhibits protein synthesis by simultaneously:
    • 1). Inducing misreading of mRNA thus producing non toxic protein;
    • 2) interfere with initiation complex of peptide formation;
    • 3) cause break up of polysomes into non-functional monosomes


Pass: Irreversible protein synth inhibitor, A ribosome inhibitor

What are the benefits of once daily dosing?

  • Concentration dependant killing (at increased conc kill increased no of bacteria at a more rapid rate)
  • Post antibiotic effect (effect lasts longer than detectable serum levels);
  • Reduced toxicity (as toxicity is time & conc dependant –time above critical level will be longer with multi dose than single dose schedule);
  • Less nursing time;
  • OPD therapy possible;
  • Convenience

Pass: Conc dependent kill, PLUS 1 other


Q6

Regarding gentamicin, outline its pharmacokinetic properties?

  • Poor oral absorption
  • Well absorbed IM and usually given IV
  • Highly polar and thus does not enter cells well; Water soluble
  • CSF –20% plasma levels
  • Bile –30% plasma level
  • Pleural/synovial 50-90%
  • Most tissues low except renal cortex
  • Not metabolised
  • May be inactivated by bacteria
  • Cleared by the kidney
  • Half life –2-3 hours
  • 40-60% removed by HD
  • Dosage adjustment needed for renal impairment

Pass: Very high renal excretion, No metabolism, Poor oral absorption

What are the reasons for once daily dosing of gentamicin?

  • Concentration dependent killing
  • Post antibiotic killing effect
  • Toxicity is both time and concentration dependent.
  • Numerous clinical studies suggest once daily dosing is just as effective and no more [possibly less] toxic.
  • More convenient.
  • Outpatient administration possible
  • No need to obtain serum levels unless > 4-5 days

Pass: 2/3 BOLD items


Q7

How do tetracyclines exert their antimicrobial activity?

  • Bacteriostatic.
  • Enter cells by diffusion and active transport.
  • Bind irreversibly to 30S sub-unit of the ribosome.
  • Block binding of tRNA to mRNA – ribosome complex. Stop addition of amino-acids to peptide

Pass: Bind to ribosome and stop protein synthesis

Describe the pharmacokinetics of the tetracyclines?

  • Variable oral absorption depending on which drug. Generally greater than 60% absorbed.
  • Absorption occurs mainly in upper small intestine.
  • Food, calcium, dairy products and alkaline pH impair absorption.
  • 40-80% protein bound.
  • Distributed widely to tissues except CSF.
  • Cross placenta.
  • Chelate to Ca and are bound to growing teeth and bones.
  • Excreted in bile and in urine.
  • Concentrated in bile (up to 10x serum conc.)
  • Undergo enterohepatic circulation.
  • Depending on drug 10-50% urine or biliary excretion.
  • Doxycycline is the exception. No renal elimination

Are there any group of patients where tetracyclines are contraindicated and who?

  • Pregnancy
  • Children < 8 yrs
  • Breast feeding

Q8

Regarding penicillins, what is their mechanism of action?

  • Interfere with bacterial wall synthesis
  • High intracellular osmotic pressure bursts weakened cell wall
  • Inhibits transpeptidase reaction –thus inhibits cross linkage

Pass: 2 of 3

How do bacteria become resistant to penicillins?

  • Beta lactamase
  • Modification of PBPs
  • Impaired penetration
  • Efflux pump

Pass: Beta lactamase AND 1 other

How are penicillins eliminated?

  • Renal excretion and secretion
  • Biliary secretion

Pass: Renal

How does probenicid alter the elimination of some penicillins?

  • Inhibits secretion of weak acids from the proximal tubule

Q9

What is the mechanism of action of erythromycin?

  • Inhibits RNA-dependent protein synthesis by binding to the 50S ribosomal subunit.
  • Bacteriostatic (at high conc with selected organisms can be bactericidal)

Pass Criteria:

  • Protein synthesis inhibitor
  • Bacteriostatic

What is the mechanism for the drug interactions associated with erythromycin. Give some examples?

  • Inhibits hepatic CYP3A4.
    • Usually inhibits metabolism of other drugs metabolism causing increased activity.
  • Examples:
    • benzodiazepines, carbamazepine, cisapride (cardiotoxicity), digoxin, warfarin, theophylline, cyclosporine, tacrolimus


Pass: Inhibit hepatic metabolism, One example

What are the adverse effects of erythromycin?

  • Common: GIT: abdo cramp, diarrhoea, N&V, candida (oral,vag)
  • Rare:  hypersensitivity, hearing loss, pancreatitis, hepatotoxicity
  • Rapid iv may cause ventric arrhythmias


Pass: GIT plus one other


Q10

What is the mechanism of action of cephalosporins?

  • Inhibit bacterial cell wall synthesis, cell division and growth (similar to penicillins)
  • Bactericidal
  • Most effective in rapidly dividing cells.

Pass: Bolded material

How does the spectrum of microbiological activity for the 4th generation cephalosporins compare to that of earlier generations?

  • Gram negative as for 3rd generation e.g. E Coli, H Influenza, Klebsiella
  • Some gm positive (S Pneumonia) but less than 1st generation
  • More resistant to B Lactamases than earlier generations


Pass: Bold

What is the relationship between penicillin allergy and cephalosporin allergy?

  • 5-15% possibility of cross-reaction with penicillin allergy

Pass: Aware of cross-reactivity


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