Antimicrobial Drugs

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Goal of Antimicrobial Therapy

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- not distinguishing a specific pathogen- umbrella (ANTI)

- administer a drug to an infected individual that destroys the infectious agent without harming the host cell

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Goal of Antimicrobial Therapy

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Achieved by disrupting the cellular processes or structures of bacteria, fungi and protozoa or to inhibit the virus multiplication cycle

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Characteristics of the Ideal Drug

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Selective toxicity

- doesnt harm the host

Microbicidal

- kill microbe

Relatively Soluble

- functions even when diluted by bodily fluids

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Characteristics of the Ideal Drug

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- can maintain potency

- not degraded or excreted prematurely (typically liver and kidneys that secrete)

- does not contribute to antimicrobial resistance

- compliments/assists the host's defenses

- can be quickly delivered to the site of infection

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Characteristics of the Ideal Drug

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- remains active in tissues and body fluids

- reasonable pried, readily available

- does not negatively affect the host's health

- does not cause allergies

- does not predispose the host to other infections

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Terminology

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Antimicrobials: an all-inclusive term for any antimicrobial drug, regardless of its origin

Prophylaxis: use of a drug to prevent the potential for infection of a person at risk

- ex: patients with chronic illess, burn patients, immunocompromised (HIV), cancer, transplant recipient, extreme ages, surgery patients

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Terminology

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Chemotherapeutic drug: any chemical used in the treatment, relief, or prophylaxis of a disease

Antimicrobial chemotherapy: the use of chemotherapeutic drugs to control infection

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Terminology

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Microbial antagonism: microbes compete for survival in a common environment by taking actions that inhibitdistroy another organism

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Terminology

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Synergism: the coordinated/correlated action by two or more drugs or microbes that result in a heightened response/greater activity

- usually combine two drugs at lower dose than one drug on its own; one drug at higher dose would cause worse side effects than combo

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Drug Classifications

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Natural Antibiotics: metabolic products of aerobic spore-forming bacteria and fungi that can inhibit or destroy other microorganisms

- by inhibiting other microbes in the same habitat, antibiotic producers have less competition for nutrients and space

- most common: bacteria (staph, bacillus)

: molds (penicillin, cephalospore)

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Drug Classification

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Synthetic drugs: chemical reactions used to synthesize antimicrobial compounds in the lab

Semisynthetic drugs: drugs which are chemically modified in the lab after being isolated from natural sources

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Drug-Microbe Interactions

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Antimicrobial drugs should be selectively toxic
- drugs should kill or inhibit microbial cells without simultaneously damaging host tissues

As the characteristics of the infectious agent become more similar to the host cell, complete selective toxicity becomes more difficult to achieve (result = more side effects)

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Side Effects of Antimicrobial Drugs

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- liver, GI tract

- kidneys

- CV system/red bone marrow

- nervous system

- resp system

- skin- boens/teeth

EVERYTHING pretty much - anything can be damamaged by antibiotic therapy

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Range of Activity

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Narrow-spectrum: effective on a small range of specific cell types (ex: only gram positive)

- most precise treatment - know exactly what tx

Medium-spectrum: effective on wider range of cell types (ex: some gram positives, some negatives but not all)

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Range of Activity

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Broad-spectrum: greatest range of activity

- exert their effects on cellular components which are found in most pathogens

**try to avoid this type of therapy

basically shooting out antibiotic and hoping it treats whatever underlying issue

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Drug Therapy

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Aim of drug development is to target the structural or functional characteristics unique to microbes that are integral to their survival

Many antimicrobial drugs target virulence factors (cell wall/membrane/proteins/DNA)

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Mechanisms of Antimicrobial Action

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Goal: disruption of metabolism or structure of organism so it cannot survive or reproduce

Microbicidal drugs kill microbes

- can kill normal flora: superinfection potential

Microbistatic drugs reversibly inhibit growth (slow down but can be overcome)

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Mechanisms of Drug Action

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1. inhibition of cell wall synthesis

2. breakdown of the cell membrane strucutre/function(selective permeability)

3. inhibition of structures and functions of DNA/RNA

4. inhibition of protein synthesis

5. blocking key metabolic pathways

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Drugs that Affect the Cell Wall

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Some drugs interfere with enzymes (peptidases) that aid in the production of peptidoglycan (PG), essential to cell wall formation

This causes weak points in the cell wall making the cell osmotically fragile
- Drugs exhibiting this effect are considered bactericidal

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Drugs that Affect the Cell Wall

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NB: these drugs are active ONLY in young, growing cells

- old, inactive or dormant cells do not produce PG

- not effective against endospores

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Drugs that Affect the Cell Membrane Function

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A damaged membrane results in the disruption of metabolic functions or cell lysis
- Membrane loses its selective permeability

Antibiotic classes exhibit specificity for particular microbial groups based on differences in composition (types of lipids)

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Drugs that Affect the Nucleic Acid Synthesis

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Drugs block the synthesis of the basic structural units of DNA and RNA (nucleotides) at different stages

- inhibition of replication

- inhibition of helicases (unwinding enzymes)

- stopping transcription

Far-reaching effects on protein metabolism

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Drugs that Block Protein Synthesis

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Most drugs react with the ribosome-mRNA complex

While human cells have ribosomes, they are different in size from those of prokaryotes

- selective action against bacteria

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Drugs that Block Protein Synthesis

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Can cause damage to eukaryotic mitochondria

- mitochondria contain a prokaryotic type of ribosome

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Drugs that Block Protein Synthesis

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Targets large and small protein subunits:
- Prevents the initiation of synthesis
- Blocks the formation of peptide bonds between amino acids on transfer RNAs
- Prevents ribosomal translocation along mRNA strand by altering ribosomal shape

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Drugs that Affect Metabolic Pathways

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Competitive inhibition: (imposter) drugs mimick the normal substrate of an enzyme

- High concentrations of the drug ensure that the enzyme needed in a metabolic pathway is constantly occupied by the metabolic analog
rather than the true substrate
- As a result, cellular metabolism is slowed or stopped

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Drug Resistance

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An adaptive response in which microbes begin to tolerate an amount of drug that would ordinarily be inhibitory or harmful

Due to the genetic versatility and adaptability of the microbial world

Drug resistance can be intrinsic or acquired

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Drug Resistance

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Intrinsic drug resistance: bacteria must be resistant to any antibiotic that they produce

- we dont have much control over this

Acquired drug resistance: the adaptive response by a microbe that was previously sensitive to a drug

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Events Leading to Resistance

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1. spontaneous mutation in critical chromosomal genes

2. acquisition of entirely new genes or sets of genes via transfer from another species

Resistance varies from slight changes in microbial sensitivity (overcome by larger drug dosages) to complete loss of sensitivity

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Resistance (R) Factors

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Plasmids, typically shared among bacteria by conjugation, that provide resistance to the effects of antibiotics

Traits wait for an opportunity to be expressed and confer adaptability

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Resistance (R) Factors

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Transposable drug resistance sequences
(transposons) are duplicated and passed from:

- one plasmid to another

- a plasmid into a chromosome

Chromosome and plasmids are then replicated

Drug resistance inherited by future progeny

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Mechanisms of Drug Resistance

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1. Drug is inactivated by acquired defensive enzymes
- enzyme cleaves a portion of the drug molecule, rendering it inactive

2. Change in permeability
- receptor that transports the drug is altered ∴ the drug cannot enter the cell

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Mechanisms of Drug Resistance

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3. Activation of drug pumps
- membrane proteins are activated, continually pumping the drug out

4. Change in drug’s target binding site

- drug has no effect

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Mechanisms of Drug Resistance

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5. Use of an alternate metabolic pathway

- normal pathway is blocked

6. Change in previously inhibited enzyme

- activate a previously inhibited enzyme

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Resistance

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Cross resistance: tolerance to a usually toxic substance as a result of exposure to a similarly acting substance
- Arises b/c the mechanism of resistance to several drugs is the same

Multiple resistance: microbes that become resistant to more than one drug therapy

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Multiple Resistances

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- global problem

- improper use of prescribed antibiotics

- primarily developin healthcare facilities

- "superbugs"

- ex: C. diff

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Natural Selection

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Benefit of mutations not exhibited until microbe is exposed to the antimicrobial drug
- Mutations confer resistance

Eventually mutants become the dominant members of the microbial population, as drug-sensitive cells are eliminated

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Natural Selection

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****Worldwide indiscriminate use of antimicrobials has led to explosion of drug resistant microorganisms****

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Resistant Microorganisms

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MRSA: methacillin resistant staphylococcus aureus

VISA: vancomycin intermediate staphylococcus aureus

VRSA: vancomycin resistant staphylococcus aureus

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Resistant Microorganisms

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VRE: vancomycin resistant enterococcus

MDR-TB: multiple drug resistant tuberculosis

C-diff: clostridium difficile (superinfection)

Also emerging strains of resistant pseudomonas

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Preventing Resistance

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***Hand washing

Eliminate unwarranted use of antibiotics

Target a narrow range of microbes

Use drug combinations (synergism)

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Preventing Resistance

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Isolation of facilities with ongoing infections

Remain current with emerging resistance

Antibiotics must be taken as prescribed

Leftover medications should be discarded

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Preventing Resistance

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Do NOT take anyone else’s prescription

Judicious use of antimicrobial soaps and lotions
- Prevent disruption of normal flora

Avoid selecting for resistance

- dont pick drug to treat if have resistance to it