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1
Chemotherapeutic Agents
Antibiotics
Synthetic Drugs
2
History
Ancient remedies– ________ in egyptian times– Quinine
Ehrlich– Salvarsan
Domagk– Dyes led to discovery of sulfa drugs
Fleming– ________________ mold
3
Properties of Antimicrobial Agents
Selective Toxicity
4
Spectrum of Activity
Narrow Broad
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Drug Mechanisms of Action
Inhibition of Cell Wall Synthesis– Bacterial peptidoglycan
– Bacterial mycolic acid
– Fungal β-glucans
Disruption of Cell Membrane Function– Bacterial membrane proteins - polymyxins
– Fungal ergosterol
6
Drug Mechanisms of Action
Inhibition of Protein Synthesis– 70S vs 80S protein synthesis (bacteria)
Inhibition of Nucleic Acid Synthesis– Unique bacterial or viral enzymes may be
affected
Antimetabolites– Essential biochemical pathways are blocked,
mostly bacteria, e.g. Folate synthesis inhibition by sulfa drugs
7
Side Effects
Toxicity– Accumulation in kidneys – Liver metabolism
Allergy
Disruption of Microflora
8
Resistance to Drugs
Chromosomal mutations
Plasmid borne resistance genes
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Mechanisms of Drug Resistance
Mutations in Target molecules– Ribosome alterations
Alterations in membrane permeability– Transport pumps exclude drugs
Enzyme development– Penicillinases (β lactamase)
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Mechanisms of Drug Resistance
Enzyme Activity Changes– PABA binding much greater than sulfa drug
binding
Alterations in Anabolic Pathways– Uptake of folic acid rather than synthesis
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Generations of Drugs
First/Second/Third Line Drugs– Used as evolving resistances limit the
usefulness of original drugs
Cross Resistance– Similar drugs are all broken down by the
resistant microbe, e.g. β lactamase effects
12
Limiting Drug Resistance
Effective Drug Concentrations
Simultaneous Drug Administration• Synergism• Antagonism
Restricting Drug Prescriptions
13
Determining Microbial Sensitivities
Disk Diffusion Method
Dilution Method
14
Ideal Antimicrobial Attributes
Solubility
Selective toxicity
Stable toxicity level
Allergenicity
Tissue stability
Resistance Acquisition
Shelf Life
Cost
15
Antibacterials — Cell Wall Target
Penicillins
– Natural
– Semisynthetic
– Many Gram +ve’s but Staphylococcus is mostly resistant
– Safe, but allergies in 1-5% of adults
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Antibacterials — Cell Wall Target
Cephalosporins– Work similarly to penicillins– Safe but more expensive
Carbapenems– Work like penicillins, more stable– Broader spectrum– Still effective against Staphylococcus
17
Antibacterials — Cell Membrane Target
Polymyxins– Topical use only– Injure bacterial plasma membrane– Used for Pseudomonas dermatitis
18
Antibacterials — Protein Synthesis Inhibition
Aminoglycosides (*mycin)– Streptomycin original
• Toxicity, deafness• Chromosomal mutation causing resistance
Tetracyclines (Aureomycin)– Soluble– Good for obligate intracellulars– Cause tooth discoloration in children / fetal bone malformations
Chloramphenicol– Tocicity makes it a drug of last choice in U.S.A.
Macrolides (Erythromycin)– Legionnaire’s disease– Bacteriostatic, may be used with other drugs– Low toxicity
19
Antibacterials — Nucleic Acid Synthesis Inhibition
Rifampin– Blocks RNA transcription– Red colored, v. soluble– Used against M. tuberculosis, N.
meningitidis– Many negative interactions with
other meds.
Quinolones– Inhibit DNA gyrase– Used in traveller’s diarrhea,
anthrax
20
Antibacterials — Antimetabolites
Sulfonamides– Block folate synthesis
Isoniazid– Interferes with vitamin B
conversions Ethambutol
– Similar to Isoniazid, often used together
Nitrofurans– Interfere with KREbs cycle/ETC– Used in UTIs– Veterinary topical agent
21
Antifungals
Imidazoles (Clotrimazole)– Disrupt ergosterol synthesis– Some cross-reactivity with cholesterols– Mostly for cutaneous and superficial conditions– Ketoconazole – safe for oral administration
Polyenes (Amphotericin B)– Ergosterol targeted– Systemic infections only, severe side effects
Griseofulvin– Impairs mitotic spindle formation– Oral admin, for cutaneous and superficial mycoses
22
Antifungals
Flucytosine– Nucleoside analog
Tolnaftate/ Terbinafine (Lamisil)– Topicals, unclear mech. of action– Superficial and cutaneous mycoses
23
Antivirals
Nucleotide analogs– Ribavirin anti-influenza, anti-herpes– Zidovudine (AZT) anti-HIV– Acyclovir anti-herpes
24
Antivirals
Amantidine/Rimantidine– Prevents Influenza A virus penetration– Ataxia/insomnia in many elderly
Interferons – Promote release of antiviral proteins in
uninfected cells
Immunoenhancers– T lymphocyte stimulators
25
Antiprotozoan Drugs
Quinine/derivatives– Malaria
Metronidazole– Trichomonas/Giardia
Pyrimethamine– Toxoplasmosis
Suramin– Trypanosoma
26
Antihelminthic Drugs
Niclosamide– Tapeworms– Affect CHO synthesis in worms
Mebendazole– Roundworms– Blocks glucose uptake
Piperazine – Neurotoxin– Pinworms and Ascaris– Can cause convulsions in children