CPTP 3.10 Pharmacology of Antimicrobials 1 Flashcards
What does antimicrobial chemotherapy include?
- Synthetic chemicals to destroy pathogens
* Naturally-occuring antibiotics
What is selective toxicity?
When one kind of cell is influenced strongly without any effect on other cells.
What two things must be considered when choosing an antimicrobial agent?
- The patient (pharmacokinetics, allergies, pregnancy, other medications)
- The pathogen (antimicrobial sensitivities)
What are broad spectrum and narrow spectrum antibiotics? What are the main differences between them and their use?
Broad spectrum:
• Target both gram positive and gram negative antibiotics
• More likely to cause resistance due to lack of specificity
• Prescribed if you don’t know the identity of the pathogen
Narrow spectrum:
• Targets either gram negative or gram positive bacteria
• Less likely to cause resistance due to increased specificity
• Prescribed if the causative agent is known
What is the main disadvantage of narrow spectrum antibiotics?
• If the causative agent is misidentified, the treatment may be completely ineffective
How are broad and narrow spectrum antibiotics used in practise?
Broad spectrum antibiotic is used until the causative agent is known, then the patient is switched to a narrow spectrum antibiotic
In what ways can antibiotics be classified?
Broad and narrow spectrum
Bacteriostatic & bacteriocidal:
• Bacteriostatic - Inhibits bacteria from reproducing but doesn’t kill them
• Bacteriocidal - Actively kills bacteria
How are antibiotics placed into bacteriostatic and bacteriocidal categories?
Categorisation is not distinct, it depends not only on the identity of the antibiotic, but also:
• Bacterial species targeted
• The concentration of the drug used
What are the ‘classes’ of targets for antimicrobial action in the bacterial cell?
Class I:
• Utilisation of carbon sources (e.g. glucose) to generate ATP
• Synthesis of carbon compounds used in Class II reactions
Class II:
• Utilisation of precursors to create:
> Amino acids
> Phospholipids
> Nucleotides
> Carbohydrates (from Class I precursors)
Class III:
• Assembly of small molecules into macromolecules:
> RNA
> DNA
> Proteins
> Polysaccharides
What are the limitations of using Class I targets?
- Bacteria often use similar mechanisms to humans to acquire and internalise sugars
- Bacteria are very good at switching to different substrates
Generally not effective
What is the best type of selective toxicity against bacteria?
Class III targeting - there are distinct differences between the pathogen and the host, therefore the toxicity is selective
What are the three major targets of antibiotics?
- Cell wall
- Nucleic acid synthesis
- Protein synthesis
What antibiotics does beta-lactam form the core structure of?
- Penicillins
* Cephalosporins
Name the penicillins in the formulary and their route of administration
Oral
• Amoxicillin
• Flucloxicillin
Parenteral
• Benzylpenicillin
What is the mechanism of action of the penicillins?
- Bacteriocidal
- Binds to penicillin binding proteins on susceptible microorganisms
- This inhibits peptide cross-linking within the cell wall
Describe the pharmacokinetics of penicillins, with regard to distribution and excretion.
Distribution
• Diffuse into all tissues but not CSF
• 60% is plasma protein bound
Excretion
• Excreted in the urine
In what case might a penicillin cross the blood brain barrier into the CSF?
If the meninges are inflamed
What can penicillins become metabolised into?
Penicilloic acid
In what population in clearance of penicillins reduced?
Neonates
Penicillin prevents peptide cross-linking between which proteins in the cell wall?
- N-acetyl glucosamine (NAG)
* N-acetyl muramic acid (NAM)
What are the penicillin binding proteins? What do they do?
Transpeptidase enzymes
These form the cross links between NAG and NAM using 4 amino acids
What are the components of penicillins? What does the active component do do?
(IMG 4)
• A carboxylic acid side chain
- An acylamino side chain
- Thiozidine ring
• Beta-lactam ring
>Forms a covalent bond with transpeptidase enzymes (penicillin binding protein)
>This blocks the active site and prevents the cross linking
What is the R (variable) group between the different penicillins?
The acylamino side chain
What are the adverse drug reactions of penicillins?
- GI disturbances
* Hypersensitivity and anaphylaxis
What causes GI disturbances when penicillins are given?
Altered gut flora
D&V, nausea
What are the components of cephalosporins?
(IMG 5)
• Dihydrothiazine ring
• Beta-lactam ring (works in the same way as penicillins)
What is the benefit of the dihydrothiazine ring on cephalosporins?
Makes the beta-lactam more resistant to beta-lactamases
What happens when antibiotics successfully prevent cross links to form in the cell wall?
The bacteria cell explodes out through the weakened cell wall, killing it
What type of antibiotics are cephalosporins?
- Broad spectrum
* Bacteriocidal
Name the formulary cephalosporins and their route of administration.
Cefalexin - oral
Cefotaxime - parenteral
How are the cephalosporins used?
As a second choice agent for many infections
Describe the pharmacokinetics of cephalosporins, with regard to distribution and excretion.
Distribution
• Diffuse into all tissues but not CSF (unless inflamed like with penicillins)
What can be used to treat bacterial meningitis?
Cefotaxime
What must be considered for patients with renal disease?
Penicillin clearance is reduced in people with renal disease, so it may be better to use cephalosporins for these patients (still mostly excreted through kidney tho)
What are the adverse effects of cephalosporins?
- Shares sensitivity with penicillin
- Antibiotic associated colitis
- Hepatitis and jaundice
- Blood disorders (aplastic ones like with chemotherapy)
How is folate acquired by humans and bacteria?
Humans
• Absorbed
• No pathways for synthesis
Bacteria
• Synthesised
• No pathways for absorption
How do bacteria synthesise DNA? (Pathway)
(IMG 6) By biosynthesising folate:
PABA • Dihydropteroate synthase FOLATE • Dihydrofolate reductase TETRAHYDROFOLATE THYMIDYLATE THYMIDINE (pyramidine) DNA
What class of antibiotics inhibits the metabolic pathways involving folate? What enzyme does this class act on? It it bacteriostatic or bacteriocidal?
Sulphonamides (act on Dihydropteroate synthase)
Bacteriostatic, as it prevents DNA replication
What is PABA? What is it used for by bacteria?
p-aminobenzoic acid
Essential in bacterial folate synthesis and subsequent production of pyrimidines and purines for DNA synthesis
Name an analogue of folate. What enzyme is it used to antagonise
Trimethoprim (note, this does act on the folate pathway but is not a sulphonamide because it does not act on Dihydropteroate synthase)
BACTERIAL Dihydrofolate reductase (but not human)
What gives trimethoprim its selective toxicity? (i.e. acts on bacteria but not humans) What other drug works on the same enzyme and what is it used for?
Bacterial dihydrofolate reductase has a higher affinity for trimethoprim than for folate
Human dihydrofolate reductase has a higher affinity for folate than for trimethoprim
Methotrexate is also DHFR inhibitor, used in chemotherapy. In this case, HUMAN pyrimidine and purine synthesis is inhibited, to prevent mitosis of cancer cells (form of chemo)
What are the routes of administration of the antibiotics affecting folate pathways? What type of antibiotic are each of these?
Trimethoprim - oral
Co-trimoxazole - Parenteral
Both bacteriostatic:
What is co-trimoxazole a combination of?
Trimethoprim (not a sulfonamide, DHPR)
Sulfamethoxazole (sulphonamide, DHFR)
What is the distribution and excretion of the drugs affecting folate pathways?
Distribution
• Good diffusion and passes the blood-brain barrier
Excretion
• Renal
How could sulphonamides be used for burns victims?
Topical application
What are the contraindications of sulphonamides (and similar folate-affecting compounds i.e. trimethoprim)?
Pregnancy, because these drugs can cross the placenta (NTDs from no folate)
Neonates (as it causes bilirubin displacement causing brain damage)
So whats the deal with trimethoprim, it’s kind of confusing?
It can be considered a sulphonamide because it affects the same pathway, but it technically isn’t one because it affects a different enzyme.
What are sulphonamides (and trimethoprim) typically used to treat?
• Simple UTIs
• Respiratory tract infections
• Immunocompromised patients:
> T. gondii
> P. jirovecilWhat are the unique side effects of sulphonamide?
- Bone marrow
- Crystalluria (causing renal failure)
- Hepatitis
