ANTIMICROBIAL THERAPY CHAPTER 13 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Chemotherapy Antibiotics Synthetics Semi-synthetics Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

History Ancient remedies Molds in Egyptian times Quinine Ehrlich Salvarsan Domagk Dyes led to discovery of sulfa drugs Fleming Penicillium mold Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Antimicrobial Drug Properties Selective Toxicity Activity Spectrum – Broad vs. Narrow Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Kinds of Drug Side Effects Toxicity Renal Hepatic Allergy Microflora disruption Intestinal Vaginal Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Drug Resistance Acquisition Chromosomal resistance Plasmid resistance Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Novel Enzyme Activity Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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!! Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Combination Therapy Approaches Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Determining Microbial Drug Sensitivity Disk diffusion Drug Dilution Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Ideal Drug Attributes Solubility Selective Toxicity Stable toxicity level Non-allergenic Tissue concentration stable Resistance acquired slowly Long shelf life Reasonable cost Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Antibacterials – Cell Membrane Target Polymyxins Topical use only Injure bacterial plasma membrane Used for Pseudomonas dermatitis Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

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 Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Antiprotozoan Drugs Quinine/derivatives Malaria Metronidazole Trichomonas/Giardia Pyrimethamine Toxoplasmosis Suramin Trypanosoma Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.

Antihelminthic Drugs Niclosamide Tapeworms Affect CHO synthesis in worms Mebendazole Roundworms Blocks glucose uptake Piperazine Neurotoxin Pinworms and Ascaris Can cause convulsions in children Copyright © 2012 John Wiley & Sons, Inc. All rights reserved.