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

5

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

9

Mechanisms of Drug Resistance

Mutations in Target molecules– Ribosome alterations

Alterations in membrane permeability– Transport pumps exclude drugs

Enzyme development– Penicillinases (β lactamase)

10

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

11

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

16

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