michaelbio chapter 10

March 3rd 1990 = my new birthday

selective toxicity

a drug should harm the pathogen but not the host

• “Magic bullet”

toxic dose

concentration causing harm to the host

therapeutic dose

concentration eliminating pathogens in the host

therapeutic index

• ratio of toxic dose compared to minimum effective (therapeutic) dose

  • Smaller ratio = greater potential for toxic drug reactions

  • Higher therapeutic index = widest margin of safety

  • (toxic)/(therapeutic) = _______________________

an antimicrobial drug must be:

• Easy to administer and able to reach the infectious agent anywhere in the body

• Absolutely toxic to infectious agent and absolutely nontoxic to host

• Remain active in body as long as needed

• Safely and easily broken down and excreted

types of antimicrobial agents

• Plant extracts

• Chemicals

• Antibiotics

• Synthetic

• Semisynthetic drugs

quinine

source of plant extracts

sulfa drugs

source of chemicals

products of/derived from metabolism of living microorganisms

source of antibiotics

synthetic agents

made in pharmaceutical lab

semisynthetic drugs

new generation antimicrobials are chemically modified antibiotics

Paul Ehrlich (1907)

Salvarson 606: (compound derived from arsenic) in search of syphilis cure

Alexander Fleming (1928)

he made penicillin

Gerhard Domagk (1935)

• Sulfa drugs

• Prontosil: red dye found to inhibit Gram (+) bacterial species (animal studies)

Howard Florey and Ernst Chain (1939)

Purified penicillin; by 1943 drug was mass produced

ideal antimicrobial traits

• Toxic to the microbe but nontoxic to host cells

• Microbiocidal rather than microbiostatic

• Relatively soluble; functions even when highly diluted in body fluids

• Remains potent long enough to act and is not broken down or excreted prematurely

• Does not lead to the development of antimicrobial resistance

• Complements or assists the activities of the host’s defenses

• Remains active in tissues and body fluids

• Readily delivered to the site of infection

• Does not disrupt the host’s health by causing allergies or predisposing the host to other infections

3 factors in considering antimicrobial therapy

• The identity of the microorganism causing the infection

• The degree of the microorganism’s susceptibility (sensitivity) to various drugs

• The overall medical condition of the patient

In vitro vs in vivo complications

• Inability of drug to diffuse into that body compartment

• Resistant microbes not tested

• An infection caused by more than one pathogen (mixed), some are resistant

• Compliance

considerations for physician to prescribe a drug

• Preexisting conditions

• History of allergy

• Underlying liver or kidney disease

• Infants, the elderly, and pregnant women require special precautions

• Other drug interference or drug combinations that have synergistic effects, may allow for reduced dosages

antimicrobial drug goals

• Disrupt cell processes or structures of bacteria, fungi, or protozoa

• Inhibit virus replication

• Interfere with the function of enzymes required to synthesize or assemble

• macromolecules

• Destroy structures already formed in the cell

goals of chemotherapy

disrupt the structure or function of an organism to the point where it can no longer survive

antimicrobial drug categories

• Inhibition of cell wall synthesis

• Inhibition of nucleic acid (RNA and DNA) structure and function

• Inhibition of the ribosome in protein synthesis

• Interference with cytoplasmic membrane structure or function

• Inhibition of folic acid synthesis

narrow vs broad spectrum drugs

• Narrow: affect only a few pathogens

• Broad: affect many taxonomic groups

nomenclature

• Class name

• Chemical name

• Generic name

• Trade name

therapeutic treatment

used for confirmed infection

empiric treatment

used for presumed infection

prophylactic treatment

used for preventing possible infection

biofilm treatment strategies

• Interrupting quorum sensing pathways

• Daptomycin: shown success

• Adding DNAse to antibiotics aids penetration through extracellular debris

• Impregnating devices with antibiotics prior to insertion to prevent colonization

reasons for microbes becoming newly resistant

• Spontaneous mutations in critical chromosomal genes

• Acquisition of entire new genes or sets of genes via horizontal transfer from another species

• Slowing or stopping of metabolism so that the microbe cannot be harmed by the antibiotics (“Persister cells”)

Production of an enzyme to inactivate the microbial agent

Beta lactamase enzymes target the beta lactam rings of PCNs/cephalosporins

Alteration of target (binding) site

modifying the drug targets

alteration in permeability to agent

• Reducing membrane permeability 

• Tetracyclines: bacteria pump the tetracycline out of cell

sulfonamides

block function of enzyme but bacteria develop other pathway

persister cells

• Sleeper cells are dormant during treatment by toxin produced by bacteria

• Multidrug tolerance, biofilms

horizontal transfer

• Genotypic: mutations are spontaneous changes in genetic material

• R plasmids

• Horizontal gene transfer from donor cells

  • Transformation, transduction, conjugation

selection

• Selection of drug resistant strain

• Lots of bacteria present initially, antibiotics kill most and remaining reproduce

superinfection

• Microbes that were once small in number can begin to overgrow and cause disease

• UTIs caused by E. coli

• Antibiotic-associated colitis

probiotics

ingestion of live microorganisms to improve normal microbiota

prebiotics

nutrients that encourage growth of normal microbiota

kirby bauer testing

• Solid media- Mueller –Hinton agar

• Antimicrobials are in disc form with one concentration per drug

• Results in MM zone then sensitive or resistant

dilution susceptibility tests

• minimum inhibitory concentration (MIC)

• Liquid media- in a microtiter plate

• Antimicrobials are added to wells and several different concentrations are tested

• Results in Ug/m

minimum inhibitory concentration (MIC)

• the smallest concentration (highest dilution) of drug that visibly inhibits growth

  • More sensitive and quantitative than the Kirby-Bauer test

  • Useful in determining the smallest effective dosage and providing a comparative index against other antimicrobials

idk

ballsack microbial