Chemotherapeutic Agents Antibiotics Synthetic Drugs

History Ancient remedies Ehrlich Domagk Fleming ________ in egyptian times Quinine Ehrlich Salvarsan Domagk Dyes led to discovery of sulfa drugs Fleming ________________ mold

Properties of Antimicrobial Agents Selective Toxicity

Spectrum of Activity Narrow Broad

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

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

Side Effects Toxicity Allergy Disruption of Microflora Accumulation in kidneys Liver metabolism Allergy Disruption of Microflora

Resistance to Drugs Chromosomal mutations Plasmid borne resistance genes

Mechanisms of Drug Resistance Mutations in Target molecules Ribosome alterations Alterations in membrane permeability Transport pumps exclude drugs Enzyme development Penicillinases (β lactamase)

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

Generations of Drugs First/Second/Third Line Drugs Cross Resistance 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

Limiting Drug Resistance Effective Drug Concentrations Simultaneous Drug Administration Synergism Antagonism Restricting Drug Prescriptions

Determining Microbial Sensitivities Disk Diffusion Method Dilution Method

Ideal Antimicrobial Attributes Solubility Selective toxicity Stable toxicity level Allergenicity Tissue stability Resistance Acquisition Shelf Life Cost

Antibacterials — Cell Wall Target Penicillins Natural Semisynthetic Many Gram +ve’s but Staphylococcus is mostly resistant Safe, but allergies in 1-5% of adults

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

Antibacterials — Cell Membrane Target Polymyxins Topical use only Injure bacterial plasma membrane Used for Pseudomonas dermatitis

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

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

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

Antifungals Imidazoles (Clotrimazole) Polyenes (Amphotericin B) 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

Antifungals Flucytosine Tolnaftate/ Terbinafine (Lamisil) Nucleoside analog Tolnaftate/ Terbinafine (Lamisil) Topicals, unclear mech. of action Superficial and cutaneous mycoses

Antivirals Nucleotide analogs Ribavirin anti-influenza, anti-herpes Zidovudine (AZT) anti-HIV Acyclovir anti-herpes

Antivirals Amantidine/Rimantidine Interferons Immunoenhancers Prevents Influenza A virus penetration Ataxia/insomnia in many elderly Interferons Promote release of antiviral proteins in uninfected cells Immunoenhancers T lymphocyte stimulators

Antiprotozoan Drugs Quinine/derivatives Metronidazole Pyrimethamine Malaria Metronidazole Trichomonas/Giardia Pyrimethamine Toxoplasmosis Suramin Trypanosoma

Antihelminthic Drugs Niclosamide Mebendazole Piperazine Tapeworms Affect CHO synthesis in worms Mebendazole Roundworms Blocks glucose uptake Piperazine Neurotoxin Pinworms and Ascaris Can cause convulsions in children