College aantekeningen
MG: infectious diseases and oncology
- Instelling
- Rijksuniversiteit Groningen (RuG)
alle college aantekeningen van het vak MG: infectious diseases and oncology van de Bachelor pharmacy op de RUG.
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MG: infectious diseases and oncologyLecture 1 – introductory lecture
Chemotherapy:
- Selective toxicity
- Based on effect
◼ Bactericide (in cancer: cytotoxic) → kill bacteria at safe plasma conc. levels (used in:
endocarditis, meningitis, infections of immunocompromised patients)
◼ Bacteriostatic (in cancer: cytostatic) → inhibit bacterial growth, immune mechanisms
eliminate the bacteria
Antimicrobial therapy targets:
- Cell wall synthesis inhibition (ß-lactams), folic acid synth. Inhibition, ergosterol synth.
Inhibition, HIV protease inhibition, neuraminidase inhibition (influenza)
Similar pathway/target:
- Dihydrofolate reductase inhibition
- Topoisomerase inhibition
- Protein synthesis inhibition
Same (co-existent) pathways/targets: MIC = minimal inhibitory concentration
- Dihydrofolate reductase inhibition
- Anti-metabolite inhibition
Empiric antibacterial therapy
Empiric = based on clinical cases and studies
- Indicated in: serious mortality/morbidity if therapy is withheld
- Also indicated in: serious public health reasons
Proper treatment regimens:
1. Effectiveness:
◼ Time-dependent ABs: efficacy relates to the time of drug conc. above MIC (T > MIC)
◼ Conc. dependent ABs: efficacy relates to peak conc./MIC ratio (Cmax/MIC)
--- AUC/MIC for fluoroquinolones (both time and conc. are crucial)
➢ Post-antibiotic effect (PAE): suppression of bacterial growth after brief antimicrobial
exposure to microorganisms
- PAE = T – C
- Where: T = time required for viable count for test culture to increase 10-fold above count
immediately before drug removal
- Where: C = time required for the count in untreated culture to increase 10-fold above the
count observed after completion of the same procedure used on test culture
Generally longer PAE in vivo than PAE in vitro due to post-antibiotic leukocyte enhancement (PALE)
➢ Pharmacokinetic considerations:
o IV administration: more costly, more possible complications (but required for some
patients)
o therapeutic drug monitoring (TDM)
o most antimicrobial agents are distributed well, except in cerebrospinal fluid (CSF)
, ➢ Combination of drugs: most infections should be treated with single antimicrobial agent
◼ combining when: serious illness, polymicrobial infections, to decrease resistant strains,
to decrease dose-related toxicity, enhanced inhibition or killing
◼ general: bactericide & bacteriostatic should not be combined
2. Tolerance development:
➢ Misuse of AB therapy leading to tolerance development
• only use when needed, so not in common cold or sore throat
• patient compliance
➢ obtained resistance:
• enzyme production
• change in the target’s binding spot
• decreased accumulation
• correction of damage, decrease in apoptosis (mostly cancerous)
• transfer: between humans, between bacteria
--- slide 33 ---
Superbugs: pathogens resistant to many antibiotics (slide 36/37)
- MRSA,
Gram-negative bacteria: cytoplasmic (inner) membrane + outer membrane → thin peptidoglycan
layer
Gram-positive bacteria: outer membrane only → thick peptidoglycan layer
Gram-positive cocci:
- Staphylococcus
- Streptococcus
- Enterococcus
Gram-positive bacillus:
- Diptheria, bacillus anthracis know bacteria list from slides
Gram-negative cocci:
- Meningococcus – meningitis
- Gonococcus – gonorrhea
Other gram-negatives
- Haemophilus influenzae
- H. pylori
Anaerobe bacteria are deep within tissue → difficult to get the antibiotics to that place
Mycobacteria: have cell walls with waxi lipid-rich outer layer
- Acid-fast staining 9
,Lecture 2 – Antibiotics I: Cell wall and -membrane as a target
Penicillin is comprised from 3 amino acids
kind of penicillin (A,R,V) dependent of the type of substrate is used
penicillin G acylase = main penicillin structure
Penicillin mainly acts on bacterial cell wall
- Gram + : inner membrane + thick peptidoglycan + (high internal osmotic pressure)
- Gram - : inner & outer membrane + thin peptidoglycan + LPS
Peptidoglycan: repeating disaccharides → important for the structure
Peptidoglycan crosslinking → both Gram + & Gram – contain D-alanine in their crosslinks
- Crosslinks are made by transpeptidase (=PBP) – penicillin binding proteins
ß-lactam antibiotics inhibit PBP’s → cell dies due to the lack of a proper cell wall
Penicillin interferes mainly with transpeptidase
Contains beta-lactam ring and a lactamase
Contains beta-lactam ring and a 6-ring
Only contains beta-lactam ring
Contains beta-lactam ring but lacks a Sulfur in the 5-ring
, Penicillin G
• excellent distribution
• active against Gram + and Gram –
• fast kidney excretion and non-toxic
• only active against fast dividing bacteria
Problems with penicillin G
- unstable at acidic conditions → degraded in
stomach
- sensitive to all ß-lactamases
- less active against Gram – bacilli
- frequently allergic reactions
Low acid stability of Penicillin G due to
1. ß-lactam ring is sensitive to nucleophilic attack
2. Resonance of the amide is not possible in the ring
3. Influence of acyl side-chain
ß-lactamases catalyze the opening of the ring
- Requires design of lactamase-resistant penicillin
- Destroy ß-lactam antibiotics
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