1. ANTIMICROBIAL THERAPY
CHAPTER 13
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2. Chemotherapy Antibiotics Synthetics Semi-synthetics
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3. History Ancient remedies Molds in Egyptian times Quinine Ehrlich
Salvarsan
Domagk
Dyes led to discovery of sulfa drugs
Fleming
Penicillium mold
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4. Antimicrobial Drug Properties
Selective Toxicity
Activity Spectrum – Broad vs. Narrow
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5. Drug Target Sites Cell wall Peptidoglycan Mycolic acid
Fungal beta glucans
Cell membrane
Some bacterial proteins
Ergosterol
Protein synthesis
70S ribosomes
Nucleic acid synthesis
DNA gyrase
RNA - viral enzymes
Antimetabolite
Bacterial folic acid
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6. Kinds of Drug Side Effects
Toxicity
Renal
Hepatic
Allergy
Microflora disruption
Intestinal
Vaginal
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7. Drug Resistance Acquisition Chromosomal resistance Plasmid resistance
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8. Mechanisms of Resistance
Altered target
70S Ribosomal alterations
Streptomycin resistance
Altered membrane permeability
New transport pumps
Tetracycline resistance
Novel enzyme activity
Beta lactamases
Enzyme affinity alteration
PABA versus sulfa drug affinities
New metabolic capabilities
Folic acid uptake ability
Sulfa drug resistance
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9. Novel Enzyme Activity
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10. Resistance Considerations
Drug generations
Cross resistance
Limiting drug resistance
Effective Drug Concentrations
Higher doses, short duration
Simultaneous Drug Administration
Synergism
Antagonism
Restricting Drug Prescriptions
Viruses don’t respond!!
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11. Combination Therapy Approaches
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12. Quorum Sensing Over 20 drugs inhibit quorum sensing inducer enzymes
Enzyme is not found in mammals
Toxin production (endo/exotoxins) never occurs
Current research – Vibrio cholerae
Likely to work for other common pathogens
E. coli O157:H7
Staphylococcus aureus
Streptococcus pneumoniae
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13. Determining Microbial Drug Sensitivity
Disk diffusion
Drug Dilution
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14. Ideal Drug Attributes Solubility Selective Toxicity
Stable toxicity level
Non-allergenic
Tissue concentration stable
Resistance acquired slowly
Long shelf life
Reasonable cost
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15. Antibacterials - Cell Wall Target
Penicillins
Natural
Penicillin V, G
Semi synthetic
Methicillin
Amoxicillin
Many Gram +ve’s
Staphylococcus is mostly resistant
Safe, but allergies in 1-5% of adults
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16. Peptidoglycan Target Cephalosporins Work similarly to penicillins
Safe but more expensive
Carbapenems
Work like penicillins, more stable
Broader spectrum
Still effective against Staphylococcus
Bacitracin
Topical use, poor absorption, some toxicity
Vancomycin
Non β-lactam inhibition of peptidoglycan synthesis
Highly toxic
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17. Antibacterials – Cell Membrane Target
Polymyxins
Topical use only
Injure bacterial plasma membrane
Used for Pseudomonas dermatitis
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18. Antibacterials – 70S 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
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19. 70S Ribosome Inhibition Chloramphenicol Macrolides (Erythromycin)
Toxicity makes it a drug of least choice in U.S.A.
Macrolides (Erythromycin)
Legionnaire’s disease
Bacteriostatic, may be used with other drugs
Low toxicity
Lincosamides
Lincomycin
Clindamycin (semisynthetic)
Rapid resistance acquisition
C. difficile application
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20. Antibacterials – Nucleic Acid Synthesis Inhibition
Rifampin
Blocks RNA transcription
Red colored, very soluble
Used against M. tuberculosis, N. meningitidis
Many negative interactions with other meds.
Quinolones
Inhibit DNA gyrase
Used in traveler's diarrhea, anthrax
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21. 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
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22. Antifungals – Cell Membrane Target
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
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23. Other Antifungals Griseofulvin* Impairs mitotic spindle formation
Oral admin, for cutaneous and superficial mycoses
Flucytosine
Nucleoside analog
Tolnaftate (Tinactin) / Terbinafine (Lamisil)
Topical administration
Used for superficial and cutaneous mycoses
Mechanism of action unclear
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24. Antivirals Purine/Pyrimidine analogs
Ribavirin anti-influenza, anti-herpes
Zidovudine (AZT) anti-HIV
Acyclovir anti-herpes
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
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25. Antiprotozoan Drugs Quinine/derivatives Malaria Metronidazole
Trichomonas/Giardia
Pyrimethamine
Toxoplasmosis
Suramin
Trypanosoma
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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
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