PHARM - 5. Antibiotics (6p)

Week 12
Clinical Pharmacology & Toxicology Notes

Antimicrobial Therapy: Selective Toxicity
Review of Microbial Cell Biology:

- Host:
o Eukaryotes
- Bacteria:
o Prokaryotes (Very different from Eukaryotic Host Cells Therefore Selective Toxicity is easy)
o (Therefore, Antibacterials are safer (Have less side effects) than Antifungals)
o NB: Gram Positive & Gram Negative Bacteria Differ by their Cell Wall Structures:
Gram Positive:
Thick Peptidoglycan Layer
Gram Negative:
Primarily Lipid-Based (Including Lipopolysaccharide LPS)
(Negligible Peptidoglycan Layer)
- Fungi/Parasites:
o Eukaryotes (Very similar to Eukaryotic Host-Cells Therefore Selective Toxicity is Difficult)
o (Therefore, Antibacterials are safer (Have less side effects) than Antifungals)
- Viruses:
o Encapsulated DNA/RNA (Very different from Eukaryotic Host Cells)
o However the are Obligate Intracellular Pathogens Ie. Hijack Host-Cell Machinery to Replicate.
Therefore, Selective Toxicity is Difficult, because you have to inhibit Host-Cell machinery in
order to stop the virus.
www.MedStudentNotes.com
Principle of Antimicrobial Therapy:
- Origins of Antimicrobial Therapy:
o NB: Most Anti-Microbials are derived from other Organisms.
o Eg. Penecillin s Anti-Bacterial property was discovered by Alexander Fleming as it was killing his
Bacterial Cultures.
- Selective Toxicity:
o Critical to Efficacy & Safety of Anti-Microbials
o Exploits Differences in Cell Biology between Host & Pathogen Cells.
o Aim Kill only the Pathogen Cells
- Scope of Activity:
o Specific to Class of Microbe:
Ie Antibacterials aren t effective against Viruses
o The Effect on the Microbes:
Eg. Bacterio-Cidal Kills Bacteria (Eg. Penecillin)
Eg. Bacterio-Static Slows Bacterial Growth (Eg. Tetracycline)
(FYI: Bacteriostatic drugs are more useful than Bacteriocidal drugs for Sepsis Because
bacteriocidal drugs ill liberate the bacteria s Endotoxins Further Sepsis)
o Synergy:
Some antibacterial agents can amplify each-other s mechanism of action
Eg Aminoglycosides β-Lactams:
Aminoglycosides Inhibit Protein Synthesis, but need to gain access into cell.
-Lactams inhibit Cell Wall Synthesis Cell all Integrit Access into cell
o Broad Spectrum Antibiotics Empirical Therapy :
Compounds active against a wide range of bacteria.
Eg. Gram + & Gram Bacteria.
o Narrow Spectrum Directed Therapy :
Compounds active against a specific class/type of bacteria.
Eg. Gram + only.
- Antimicrobial Therapy Should be EVIDENCE BASED:
o Ie. KNOW what organism you are dealing with before treatment (Unless Emergency):
Allows treatment to be Direc ed rather than Empirical .
Maximises Efficacy
Minimises Antibiotic Resistance.
- Antimicrobial Resistance:
o NB: Bacteria employ An ibiosis of their own to potentiate their Own Survival.
They also develop Resistance to Antibiosis from other bacteria to potentiate survival.
- THIS CAN WORK AGAINST US As Bacteria develop Resistance to Our Drugs!
o NB Also Bacterial Resistance Genes exist and Mutation Potential is HIGH!
(Due to huge numbers of rapidly proliferating bacteria)
o Antibiotic Usage Preferentially Selects these resistant strains, giving them a Competitive
Advantage over the rest Transmission of Resistance Genes to offspring
o THEREFORE Restraint of antimicrobial use is the best way to ensure their efficacy
Sites for Selective Toxicity:
Antibacterial Drugs:
NB The Suffi -M cin simpl means an antibiotic derived from the fungus Er hrom cin
It is irrelevant to classes of antibiotics.
- 1. Anti Cell-Wall Synthesis Antibiotics (Bacteriocidal):

o Target Peptidoglycan Synthesis on Gram-Positive Bacteria.
Classical Agents: Common Uses: Mechanism of Action: Side Effects:

β-Lactam Antibiotics:
Penicillins: Gram Positive Bacteria Block Penicillin-Binding Proteins GI Upset & Diarrhoea
Penicillins G & V (NB: Bacteria Producing (Enzymes) Inhibit Synthesis of the Allergic Rash
Amoxicillin & Ampicillin -Lactamase are Peptidoglycan Layer of the Bacterial Anaphylaxis (Need
Flucloxacillin resistant) Cell Wall. Adrenaline Handy)
Methocillin
Ticarcillin (NB: Fluclox for -
Suffix -Cillin Lactamase Resistant)
Cephalosporins: (NB: Cephalosporins (As above)
(Ceftriaxone) for Non- -Lactamase + Mild Renal Toxicity
Risistant)
β-Lactamase Inhibitors: (In Combination with Inhibits -Lactamase Allo s -
Augmentin Penicillins) for Penicillin- Lactams to work on Penicillin-
Resistant Gram Positive Resistant Bacteria.
Bacterial Infections
Glycopeptide Antibiotics:
Vancomycin Gram Positive Bacteria Prevents incorporation of specific Local Pain
Teicoplanin (As a LAST RESORT for Peptide Subunits into the Phlebitis (Vein Inflam)
Telavancin MRSA) Peptidoglycan Layer of the Bacterial Kidney Damage
(Also if Pt. is allergic to Cell Wall. Hearing Loss
-Lactams)
- 2. Anti Protein-Synthesis Antibiotics (Bacteriostatic):

o Exploits differences between Eukaryotic (Human) Ribosomes & Prokaryotic Ribosomes.
o Selective Toxicity Due to specific binding to Prokaryotic Ribosomes.
o NB: Aminoglycosides are Solely eliminated by the Kidneys & Are Nephrotoxic. (Need to assess renal
function first, then Dose Accordingly)

Aminoglycoside Antibiotics:
Gentamicin Gram Negative Bacteria Bind Specifically to Prokaryotic Ototoxic (Hearing Loss
Streptomycin (Used Synergistically Ribosomal Subunits Causes & Vertigo)
Tobramycin with -Lactams to Misreading of mRNA Inhibits Nephrotoxic (Kidney
drug entry into Bacteria) Synthesis of Proteins vital to Bacteria. Damage)
Tetracycline Antibiotics:
Doxycycline Gram Negative Bacteria Bind Specifically to Prokaryotic Nausea/Vom/Diarr.
Tetracycline Syphilis (G-), Chlamydia Ribosomal Subunits Inhibits Binding Photosensitivity
- -
(Suffix = Cycline (G ), Lyme Disease (G ) of tRNA to mRNA Inhibits Synthesis Staining of Teeth
(And Malaria -Protazoa) of Proteins vital to Bacteria. Renal/Liver Toxicity.
Macrolides:
Erythromycin, Gram Negative Bacteria Bind Specifically to Prokaryotic Nausea/Vom/Diarr.
Azithromycin Syphilis, Lyme Disease. Ribosomal Subunits Inhibits release Jaundice
of tRNA Inhibits Synthesis of
Proteins vital to Bacteria.
- 3. Anti Nucleic-Acid Synthesis Antibiotics (Bacteriostatic):
o Exploits differences in the Metabolic Pathways of DNA Synthesis (Humans rely solely on Dietary
Folate, while Bacteria have to make their own):
Eg. Competitive Inhibition of Dihydropteroate-Synthase, a key Enzyme involved in Folate
Synthesis in Bacteria.
Eg. Competitive Inhibition of Dihydrofolate-Reductase, a key Enzyme involved in Folate
Synthesis in Bacteria. (NB: Humans share this pathway, but bacteria require it 100x more
than humans)
Eg. Inhibition of Bacterial DNA Gyrase/Topoisomerase Stops DNA Replication/Transcrib.

Sulphonamides:
Sulfasalazine Urinary Tract Infections Competitive inhibition of Nausea/Vom/Diarr
Prefix Sulfa Dihydropteroate-Synthase, a key Allergy
Enzyme involved in Folate Synthesis. Precipitation in Urine
(Folate is necessary for Nucleic Acid Kidney Failure
Synthesis & Hence DNA Synthesis. Leukopaenia
Photosensitivity
Trimethoprim:
Trimethoprim Urinary Tract Infections Competitive inhibition of Nausea/Vom/Diarr
Dihydrofolate-Reductase, a key Allergy
Enzyme involved in Folate Synthesis. Precipitation in Urine
(Folate is necessary for Nucleic Acid Kidney Failure
Synthesis & Hence DNA Synthesis. Leukopaenia
Photosensitivity
(BIRTH DEFECTS)
Quinolones:
Ciprofloxacin Urinary Tract Infections Inhibits bacterial DNA Gyrase or
Norfloxacin Comm.Acq. Pneumonia Topoisomerase Inhibits DNA
Suffix Floxacin Bacterial Diarrhoea Replication & Transcription.
Gonorrhea
Antimycobacterial Drugs:
- Mycobacterial Infections in Humans:

o 2 Main Types:
Tuberculosis
Leprosy
o Why are they a Problem?
Because Mycobacteria can live inside Macrophages following Phagocytosis.
Also, Multi-Drug-Resistant strains are on the rise.
o Compound Drug Therapy:
A frequent strategy to decrease the probability of the emergence of resistant organisms.
Also requires Long-Term Therapy.

Isoniazid:
Isoniazid Combination Treatment MOA unknown. Allergic Skin Eruptions
of M. Tuberculosis (Bacteriostatic & Bacteriocidal) Fever
Hepatotoxicity
Haemolysis (in G6PD
Deficiency)
Rifampicin:
Rifampicin Combination Treatment Binds to & Inhibits DNA-Dependent Allergic Skin Eruptions
of M. Tuberculosis Prokaryotic RNA-Polymerase Fever
Inhibits DNA Transcription & therefore Hepatotoxicity
Inhibits Protein Synthesis.
(Bacteriostatic & Bacteriocidal)
Ethambutol:
Ethambutol Combination Treatment MOA Unknown. Optic Neuritis
of M. Tuberculosis (Bacteriostatic) Visual Disturbances
Colour Blindness.
Pyrazinamide:
Pyrazinamide Combination Treatment Active in Low pH (In Phagolysosomes) Gout
of M. Tuberculosis (Bacteriostatic) GI Upset
Hepatotoxicity
Antifungal Drugs:
- NB: Fungi are Eukaryotic:
o Therefore Selective Toxicity is Difficult.
- Drug Targets:
o 1. Difference in Lipid Composition of Cell Membrane:
Fungi Ergosterol
Humans Cholesterol.
o 2. Inhibition of Ergosterol Synthesis:
Fungal Cell Cytochrome Enzymes
o 3. Inhibition of DNA & RNA Synthesis:
Intracellular Conversion to Inhibition Substances.
- Routes of Administration:
o Systemic (Oral/Parenteral) For Systemic Fungal Infections
o Oral For Mucocutaneous Infections.
o Topical For Mucocutaneous Infections. (Selective Toxicity is less important)
Antiviral Drugs:
- Viruses are Obligate Intracellular Pathogens Ie. Hijack Host-Cell Machinery to Replicate:
o Therefore, Selective Toxicity is Difficult, because you have to inhibit Host-Cell machinery in order to
stop the virus.
- Mechanisms of Antiviral Selective Toxicity:
o Nucleoside Reverse Transcriptase Inhibitors.
o Non- Nucleoside Reverse Transcriptase Inhibitors.
o Protease Inhibitors
o Viral DNA Polymerase Inhibitors
o Inhibitors of Fusion with Host Cells
o Inhibitors of Viral Coat Disassembly
o Biologics & Immunomodulators (Eg. Interferon)
Antiparasitic Drugs:
- NB: Parasites are Eukaryotic:
o Therefore Selective Toxicity is Difficult.
- Drug Targets:
o 1. Unique Enzymes
o 2. Shared Enzymes but those Indispensable for Parasite.
o 3. Common Pathways with Different Properties.
- NB: Antimalarial Drugs & G6P-Dehydrogenase Deficiency:

o Eg. Chloroquine/Primaquine/Pamaquine:
Must NOT be given to Pts with Glucose-6-Phosphate Dehydrogenase Deficiency, as they can
cause Fatal Haemolysis.
(NB: G6PD is an essential enzyme in RBC Metabolism)

PHARM - 5. Antibiotics (6p)

Uploaded by

Copyright:

Available Formats

PHARM - 5. Antibiotics (6p)

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

PHARM - 5. Antibiotics (6p)

Uploaded by

Copyright:

Available Formats

Week 12

Clinical Pharmacology & Toxicology Notes

Review of Microbial Cell Biology:

Sites for Selective Toxicity:

- 1. Anti Cell-Wall Synthesis Antibiotics (Bacteriocidal):

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

- 2. Anti Protein-Synthesis Antibiotics (Bacteriostatic):

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

- Mycobacterial Infections in Humans:

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

- NB: Antimalarial Drugs & G6P-Dehydrogenase Deficiency:

You might also like