Seven lecture
7- Antibiotics
Antibiotics
Drugs: any compound taken with the intent to alter some forms or
function of the body or treat disease.
Antibiotics: a natural substance produced by a micro-organismto kill
another
Antimicrobial : any agent that kills or inhibits growth of a susceptible
Organism
Chemotherapy : treatment of a disease by a chemical compound
selectively directed against invading microbes or abnormal cells
• “-static” = agents which inhibit growth (e.g., bacteriostatic,
fungistatic, and sporistatic)
• “-cidal” = agents which kill the target organism (e.g., sporicidal,
virucidal, and bactericidal).
Adverse effect: An unwanted or dangerous reactions to a drug.
Therapeutic effect: The positive or desirable effect expected to occur
when a drug is administered.
History
• 1928: Alexander Fleming, a Scottish biologist, descovered the
antibiotic effect
of Penicillum. He observed that Penicillium notatum, a common
mold, had destroyed staphylococcus bacteria in culture . Fleming
received Nobel price
• S. A. Waksman (1941): an antibiotic is a substance produced by a
micro-organisme and has the capacity to inhibit the development of other
microorganismes and even to destroy them.
• 1946: started the industrial production of antibiotics.
CLASSIFICATION OF ANTIBIOTICS CAN IN SEVERAL WAYS:
• Depending on their mechanism of action against the infecting organism
(the most
common criteria). Some antibiotics attack the cell wall, some
disrupt the cell
membrane, the majority inhibit the synthesis of nucleic acids and
proteins, etc.
1. Inhibitors of bacterial cell wall synthesis
2. Inhibitors of the function of the bacterial cell membrane.
3. Inhibitors of bacterial protein synthesis
4. Inhibitors of nucleic acid synthesis
5. Inhibitors of the synthesis of other structures bactérienes (interference
with
metabolic processes).
• According to which bacterial strains they affect: staphylococcus,
streptococcus, E.
coli, etc.
• Based on the chemical structure: penicillins, cephalosporins,
aminoglycosides,
tetracyclines, macrolides, sulfonamides, etc
Prokaryotes vs. Eukaryotes
We've talked about how Eubacteria and Eukaryotes differ. e.g. the cell
wall, ribosomes, some enzymes may differ.
Domain
ribosomes
Eubacteria
70S
cell wall
complex
peptidoglycan
RNA polymerase
present
one kind
formylmethionine
inhibited
start codon
antibiotics*
Eukaryotes
80S
if present, simple
animals w/o cell wall
absent
several kinds
methionine
uninhibited
*a number of antibiotics i.e. penicillin.
The goal of an antimicrobial drug is to harm the pathogen and not harm
the host. This is called selective toxicity.
Spectrum of Antimicrobial Activity
Broad Spectrum: Effective against many different types of bacteria
(e.g.: both gram positive and negative). Examples: Tetracyclin
Narrow Spectrum Antibiotics: Effective against a subset of bacteria
(either gram positive and negative).Examples: Penicillin, Isoniazid
(Mycobacteria only}
Steps Involved in Pharmacokinetics Study:
1. Adsorption:
Absorption is the process whereby a substance entering the body is
assimilated by it. For proper pharmacokinetics study, it is
necessary to know both the rate and the extent to which the active
substance or therapeutic moiety are absorbed. They include
substances intended to produce / not produce systematic effects.
2. Distribution:
Distribution is the dispersion or dissemination of substances
throughout the fluids and tissues of the body.
3. Metabolism:
Metabolism is the process whereby a substance is irreversibly
transformed into metabolites.
4. Excretion:
Excretion is the elimination of the substance from the body. In rare
cases, not all substances are eliminated; some drugs irreversibly
accumulate in a tissue in the body.
Pharmacokinetics is often studied in conjunction with
pharmacodynamics. While pharmacodynamics explores what a
drug does to the body, pharmacokinetics studies what the body
does to the drug.
Pharmacodynamics is the study of
the biochemical and physiological effects of drugs and the mechanisms of
drug action and the relationship between drug concentration and effect.
II. Mechanisms of Resistance
A. Mutations have provided for the following mechanisms of bacterial
drug resistance
1. Inactivation of Drug by Enzymes
2. Prevent Drug from Entering Cell
3. Ejection of Drug
4. Alter Target Site of Drug
B. Inactivation of Drug by Enzymes
1. Destruction or inactivation of drug by enzymes produced by bacteria
2. Ex) Penicillinase (ß-lactamase) breaks ß-lactam ring of penicillins &
cephalosporins
a. Not just in S. Aureus
b. Also, Penicillinase-producing Neisseria gonorrhoeae (PPNG)
3. Penicillin was modified to beat this resistance (methicillin)
a. Methicillin resistance soon appeared
4. Over 200 variations of B-lactamase enzymes are now known
a. Each effective against minor variations of ß-lactam ring
b. We alter the drug, and bacteria acquire new resistance
1) “Battle of Our Technology vs. Evolution”
5. Methicillin-Resistant Staphylococcus aureus (MRSA pronounced
“mersa”)
a. Resistant to most antibiotics (Superbug)
b. In hospitals, invasive infections have 20% mortality rate
c. Some strains resistant to vancomycin
d. Nosocomial (hospital) – health care-associated MRSA
e. Community-associated MRSA
1) Affects healthy people in the general public
2) Virulent, produce leukocidin that kills neutrophils
B. Block Entry of Drug into Cell
1. Gram- bacteria can have modified porins which restrict entry of drug
2. Porins – proteins in outer membrane of Gram- cell walls; selectively
permeability
C. Ejection of Drug
1. Pumps in plasma membrane pump drug out of cell
D. Alter Target Site of Drug
1. If the binding site of the drug is altered, the drug cannot bind
2. Ex) In order for drugs that affect translation at ribosomes to be
effective they must bind to ribosome or another structure. If the binding
site is altered, the drug cannot bind and therefore not affect translation.
Mechanisms of Action of Antimicrobial Drugs: Introduction
Antimicrobial drugs act in one of several ways: by selective toxicity , by
inhibition of cell membrane synthesis
and function, by inhibition of protein synthesis, or by inhibition of
nucleic acid synthesis.
Selective Toxicity
An ideal antimicrobial agent exhibits selective toxicity , which means
that the drug is harmful to a pathogen
without being harmful to the host. Often, selective toxicity is relative
rather than absolute; this implies that a
drug in a concentration tolerated by the host may damage an infecting
microorganism.
Selective toxicity may be a function of a specific receptor required for
drug attachment, or it may depend on
the inhibition of biochemical events essential to the pathogen but not to
the host. The mechanisms of action of
antimicrobial drugs can be discussed under four headings:
1. Inhibition of cell wall synthesis.
2. Inhibition of cell membrane function.
3. Inhibition of protein synthesis (ie, inhibition of translation and
transcription of genetic material).
4. Inhibition of nucleic acid synthesis.
Eight lecture
8- Macrolides:
1. The investigators study intensely the antibacterial products of
metabolism of various streptomycetes a high molecular weight,
Woodward (1957) gave the name of macrolides to these compounds, also
as the product of metabolism of Str. erythreus. Macrolide antibiotics are
characterized by the presence in their molecules of the macrocyclic
lactone ring connected with one or several carbohydrate residues, these
are usually amino sugars.
Chemistry:
Macrolides contain a lacton ring and one or more deoxy sugars.
The most important members of the group are erythromycin,
clarithromycin, and azithromycin .
3. Mechanism of action of Macrolides:
Macrolides inhibit bacterial protein synthesis by binding to the 50S
ribosomal subunit. Binding inhibits elongation of the protein by peptidyl
transferase or prevents translocation of the ribosome or both. Macrolides
are bacteriostatic for most bacteria but are cidal for a few Gram-positive
bacteria.
4. Pharmacokinetics:
a. All forms of erythromycin are absorbed following oral administration
and diffuse in to most body tissues and fluids except CSF fluid.
b. Macrolides are concentrated in the liver and is excreted primarily in
bile and feces.
5. Preparations and administration:
a. Oral macrolides base is supplied as enteric coated tablets.
b. Macrolides ethylsuccinate, is available as granules or powder for oral
suspension, other available oral salts are stearate, and estolate.
c. Sterile macrolides gluceptate is available for parenteral administration.
d. Macrolides base is available in topical formulations.
6. Side effects of Macrolides:
a. Cholestatic hepatitis has occurred in adults treated for a week or longer
with the estolate form. Hepatitis can also occur with the ethylsuccinate,
and possibly with the stearate. The hepatitis is uncommon and is
reversible.
b. Epigastric distress can occur.
c. A high incidence of thrombophlebitis occurs when erythromycin is
administered intravenously even when the drug is dissolved in a large
fluid volume.
d. Superinfection can occur.
e. Transient deafness has been reported, especially with higher doses.
f. Erythromycin causes nausea and vomiting after oral administration in a
significant number of patients. Jaundice is associated with some
formulations of the drug.
7. Spectrum of activity:
a. This drug is effective against G+ve organism, including some strains
of S. aureus that are penicillin G resistance.
b. Neisseria species, some strains of H. influenzae, and Bordetella,
Legionella, Treponema, Mycoplasma species are sensitive to
erythromycin.
c. In general, it is not very active against most G-ve bacilli.
d. Macrolide antibiotics can be administered
orally, making them the choice for treating children who have
streptococcal and
staphylococcal infections. The most commonly used macrolide
is Erythromycin,
which is used to treat legionellosis, mycoplasmal pneumonia, and
streptococcal
and staphylococcal infections.
e. Clarithromycin is also active against mycobacterium. In addition, both
azithromycin and clarthromycin have demonstrated efficacy
against Borrelia burgdorferi , the causal agent of lyme disease and the
protozoan parasite Toxoplasma gondii, which causes toxoplasmosis.
5. Lincosamides :
1. The antibacterial products of metabolism of various streptomycetes,
the product of metabolism of Str. lincolnesis . including clindomycin and
lincomycin.
Chemistry:
Clindomycin is the 7-deoxy,7-chloro derivative of the parent drug,
lincomycin, which it has essentially replaced.
Pharmakinetics
a. Although it is well absorbed following oral administration,
clindomycin most often is administered parenterally.
b. The drug is widely distributed in body fluids and tissues but does
not pass readily into CSF fluid.
c. Most of the drug is metabolized to the inactive sulfoxide form,
which then is excreted in the bile and urine.
2. Mode of action: Lincosamides is chemically unrelated to the
macrolides but has a similar mode of action and spectrum, are a
miscellaneous group of protein synthesis inhibitors with activity similar
to the macrolides.
3. Spectrum activity: Lincomycin has activity against Gram-positive
bacteria and some Gram-negative bacteria (Neisseria, H. influenzae).
Clindamycin is usually used to treat infections with anaerobic bacteria but
can also be used to treat some protozoal diseases, such as malaria. It is a
common topical treatment for acne, and can be useful against some
methicillin-resistant Staphylococcus aureus (MRSA) infections. The most
severe common adverse effect of clindamycin is Clostridium difficileassociated diarrhea (the most frequent cause of pseudomembranous
colitis). Although this side-effect occurs with almost all antibiotics,
including beta-lactam antibiotics, it is classically linked to clindamycin
use.
4. Side effect: Pseudomembranous colitis can occur, resulting in diarrhea,
abdominal pain, fever, and mucus and blood in the stools. At one time,
this condition was often fatal, but now that the causative organism is
known to be C. difficile, it can treated with vancomycin.
5.Resistance bacteria of Macrolides and clindamycin
a. Altered accumulation (Minimal outer membrane penetration, efflux
pump)
b. Altered target (methylation of rRNA).
c. Enzymatic inactivation (phosphotransferase, esterase).
Macrolides:
1. The investigators study intensely the antibacterial products of
metabolism of various streptomycetes a high molecular weight,
Woodward (1957) gave the name of macrolides to these compounds, also
as the product of metabolism of Str. erythreus. Macrolide antibiotics are
characterized by the presence in their molecules of the macrocyclic
lactone ring connected with one or several carbohydrate residues, these
are usually amino sugars.
Chemistry:
Macrolides contain a lacton ring and one or more deoxy sugars.
The most important members of the group are erythromycin,
clarithromycin, and azithromycin .
3. Mechanism of action of Macrolides:
Macrolides inhibit bacterial protein synthesis by binding to the 50S
ribosomal subunit. Binding inhibits elongation of the protein by peptidyl
transferase or prevents translocation of the ribosome or both. Macrolides
are bacteriostatic for most bacteria but are cidal for a few Gram-positive
bacteria.
4. Pharmacokinetics:
a. All forms of erythromycin are absorbed following oral administration
and diffuse in to most body tissues and fluids except CSF fluid.
b. Macrolides are concentrated in the liver and is excreted primarily in
bile and feces.
5. Preparations and administration:
a. Oral macrolides base is supplied as enteric coated tablets.
b. Macrolides ethylsuccinate, is available as granules or powder for oral
suspension, other available oral salts are stearate, and estolate.
c. Sterile macrolides gluceptate is available for parenteral administration.
d. Macrolides base is available in topical formulations.
6. Side effects of Macrolides:
a. Cholestatic hepatitis has occurred in adults treated for a week or longer
with the estolate form. Hepatitis can also occur with the ethylsuccinate,
and possibly with the stearate. The hepatitis is uncommon and is
reversible.
b. Epigastric distress can occur.
c. A high incidence of thrombophlebitis occurs when erythromycin is
administered intravenously even when the drug is dissolved in a large
fluid volume.
d. Superinfection can occur.
e. Transient deafness has been reported, especially with higher doses.
f. Erythromycin causes nausea and vomiting after oral administration in a
significant number of patients. Jaundice is associated with some
formulations of the drug.
7. Spectrum of activity:
a. This drug is effective against G+ve organism, including some strains
of S. aureus that are penicillin G resistance.
b. Neisseria species, some strains of H. influenzae, and Bordetella,
Legionella, Treponema, Mycoplasma species are sensitive to
erythromycin.
c. In general, it is not very active against most G-ve bacilli.
d. Macrolide antibiotics can be administered
orally, making them the choice for treating children who have
streptococcal and
staphylococcal infections. The most commonly used macrolide
is Erythromycin,
which is used to treat legionellosis, mycoplasmal pneumonia, and
streptococcal
and staphylococcal infections.
e. Clarithromycin is also active against mycobacterium. In addition, both
azithromycin and clarthromycin have demonstrated efficacy
against Borrelia burgdorferi , the causal agent of lyme disease and the
protozoan parasite Toxoplasma gondii, which causes toxoplasmosis.
5. Lincosamides :
1. The antibacterial products of metabolism of various streptomycetes,
the product of metabolism of Str. lincolnesis . including clindomycin and
lincomycin.
Chemistry:
Clindomycin is the 7-deoxy,7-chloro derivative of the parent drug,
lincomycin, which it has essentially replaced.
Pharmakinetics
a. Although it is well absorbed following oral administration,
clindomycin most often is administered parenterally.
b. The drug is widely distributed in body fluids and tissues but does
not pass readily into CSF fluid.
c. Most of the drug is metabolized to the inactive sulfoxide form,
which then is excreted in the bile and urine.
2. Mode of action: Lincosamides is chemically unrelated to the
macrolides but has a similar mode of action and spectrum, are a
miscellaneous group of protein synthesis inhibitors with activity similar
to the macrolides.
3. Spectrum activity: Lincomycin has activity against Gram-positive
bacteria and some Gram-negative bacteria (Neisseria, H. influenzae).
Clindamycin is usually used to treat infections with anaerobic bacteria but
can also be used to treat some protozoal diseases, such as malaria. It is a
common topical treatment for acne, and can be useful against some
methicillin-resistant Staphylococcus aureus (MRSA) infections. The most
severe common adverse effect of clindamycin is Clostridium difficileassociated diarrhea (the most frequent cause of pseudomembranous
colitis). Although this side-effect occurs with almost all antibiotics,
including beta-lactam antibiotics, it is classically linked to clindamycin
use.
4. Side effect: Pseudomembranous colitis can occur, resulting in diarrhea,
abdominal pain, fever, and mucus and blood in the stools. At one time,
this condition was often fatal, but now that the causative organism is
known to be C. difficile, it can treated with vancomycin.
5.Resistance bacteria of Macrolides and clindamycin
a. Altered accumulation (Minimal outer membrane penetration, efflux
pump)
b. Altered target (methylation of rRNA).
c. Enzymatic inactivation (phosphotransferase, esterase).