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Antibiotics
General Understanding
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Antibiotic
› The term antibiotic refers to substances produced by microorganisms that at low
concentration kill or inhibit the growth of other microorganisms but cause little or no
host damage.
Antimicrobial
› The term antimicrobial agent refers to any substance of natural, synthetic, or semi-
synthetic origin that at low concentration kills or inhibits the growth of
microorganisms but causes little or no host damage.
› The critical important element of antimicrobial therapy is the selective toxicity of a
drug for invading organisms rather than mammalian cells.
Cont. …
› The effectiveness of antimicrobial therapy depends on:
1. Bacterial susceptibility
2. Drug’s disposition in the body
3. Dosage regimen
4. Competence of host defense mechanisms.
› Applied for bacteriostatic antibiotics
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Microorganism
› The term microorganism or microbe refers to prokaryotes, which, by definition, are
single-cell organisms that do not possess a true nucleus.
Cont. …
Bacteria size and shape
› Bacteria range in size from 0.75 to 5 μm and most commonly are found in the shape
of a sphere (coccus) or a rod (bacillus).
Bacteria unique structure
› Bacteria are unique in that they possess peptidoglycan in their cell walls, which is the
site of action of antibiotics such as penicillin, bacitracin and vancomycin.
Bacteria Classification – Gram Stain
› Differences in the composition of bacterial cell walls allow bacteria to be broadly
classified using differential staining procedures.
› The Gram stain developed by Christian Gram in 1884, is the most important
differential stain used in microbiology.
Cont. …
› Using the Gram staining procedure, bacteria can be divided into two broad groups:
1. Gram-positive
2. Gram-negative
› This classification is based on the ability of cells to retain the dye methyl violet after
washing with a decolorizing agent such as absolute alcohol or acetone.
Cont. …
Examples of Gram-positive bacteria are:
› Bacillus, Clostridium, Corynebacterium, Enterococcus, Erysipelothrix,
Pneumococcus, Staphylococcus, and Streptococcus.
Examples of Gram-negative bacteria are:
› Bordetella, Brucella, Escherichia coli, Haemophilus, Leptospira, Neisseria,
Pasteurella, Proteus, Pseudomonas, Salmonella, Serpulina hyodysenteriae,
Shigella, and Vibrio.
Cont. …
Cell wall structure:
Gram +ve and Gram –ve bacteria
› The differential antibiotic sensitivity of Gram-positive and Gram negative bacteria to
many antimicrobials is due to differences in cell wall composition.
Cont. …
1. Gram-positive bacteria
› They have a thicker outer cell wall composed of a number of layers of peptidoglycan.
› Antibiotics that interfere with peptidoglycan synthesis are more easily reach their site
of action in Gram-positive bacteria.
Cont. …
2. Gram-negative bacteria
› They have a lipophilic outer membrane that protects a thin peptidoglycan layer.
› They have protein channels (porins) in their outer membranes that allow the passage
of small hydrophilic molecules.
› The outer membrane contains a lipopolysaccharide component that can be shed
from the wall on cell death.
– It contains a highly heat-resistant molecule known as endotoxin, which has a number of toxic
effects on the host animal, including fever and shock.
Bacteria Classification – Aerobes / Anaerobes
› Antibiotic sensitivity differs between aerobic and anaerobic organisms.
Cont. …
Anaerobic organisms
› They are further classified as facultative and obligate.
1. Obligate anaerobes
 They die in the presence of oxygen.
2. Facultative anaerobes
 They derive energy by aerobic respiration if oxygen is present.
 They are also capable of switching to fermentation.
 Examples of facultative anaerobic bacteria are:
1. Staphylococcus (Gram-positive)
2. Escherichia coli (Gram-negative)
3. Listeria (Gram-positive)
Cont. …
› Anaerobic organisms are resistant to antimicrobials that require oxygen-dependent
mechanisms to enter bacterial cells, such as aminoglycosides.
› Anaerobic organisms may elaborate a variety of toxins and enzymes that can:
1. Cause extensive tissue necrosis, limiting the penetration of antimicrobials into
the site of infection
2. Inactivating antimicrobials once they are present
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Pharmacokinetics
It describes;
› The time course of drug absorption, distribution, metabolism, and excretion.
› What the body does to the drug?
› The relationship between the dose of drug administered & the concentration of non-
protein-bound drug at the site of action.
Cont. …
› Pharmacokinetics PK (absorption, distribution, metabolism and excretion) of an
antimicrobial drug are governed largely by;
1. Drug’s chemical nature and physicochemical properties.
2. Drug’s concentration at the site of infection.
Cont. …
1- Drug’s Chemical Nature and Physicochemical Properties
› In regards to PK, molecular size and shape, lipid solubility and the degree of
ionization are of particular importance.
Cont. …
The degree of ionization
› The degree of ionization may not be an important consideration for amphoteric
compounds (molecule or ion that can react both as an acid as well as a base) such
as fluoroquinolones, tetracycline and rifampin.
› But, the majority of antimicrobial agents are weak acids or bases for which the
degree of ionization depends on the pKa of the drug and the pH of the biological
environment.
› Only the un-ionized form of these drugs is lipid-soluble and able to cross cell
membranes by passive diffusion.
Cont. …
Example 1
› Sodium salt of a weak acid (pKa 4.4) infused into the mammary glands of dairy
animals to treat mastitis.
› The pH of the normal mammary gland is 6.4, at this pH, the Henderson–Hasselbalch
equation predicts that the ratio of un-ionized to ionized drug is 1 : 100.
› Mastitic milk is more alkaline, pH ∼ 7.4, and the ratio of un-ionized to ionized drug is
1 : 1000. This is identical to the ratio for plasma, which also has a pH of 7.4.
› So, compared to the normal mammary gland, the mastitic gland will have more drug
“trapped” in the ionized form.
Cont. …
Example 2
› The injection of a lipid-soluble, organic base which diffuses from the systemic
circulation (with pH 7.4) into ruminal fluid (pH 5.5–6.5) during the distributive phase
of a drug.
› The ionized form becomes trapped in the acidic fluid of the rumen; the extent of
trapping will be determined by the pKa of the organic base.
Cont. …
› In summary, weakly acidic drugs are trapped in alkaline environments and, vice
versa, weakly basic drugs are trapped in acidic fluids.
Cont. …
2- Drug’s Concentration at the Site of Infection
› Drug concentration reflects the drug’s distributive behavior which is critically
important in term of efficacy.
› Dosage interval is dependent on drug concentration at the infection site.
› Usually, the infection site (the biophase) is remote from the circulating blood that is
commonly sampled to measure drug concentration.
› Several authors have reported that plasma concentration of free (non-protein
bounded) drug is generally the best predictor of the clinical success of antimicrobial
therapy.
Cont. …
› The biophase in most infections comprises extracellular fluid (plasma + interstitial
fluids).
› Most pathogens are located extracellularly and as a result, plasma concentrations of
free drug are generally representative of tissue concentrations; however, there are
some exceptions such as:
Cont. …
1. Intracellular microbes such as Lawsonia intracellularis, the causative agent of proliferative
enteropathy in pigs, are not exposed to plasma concentrations of antimicrobial drugs.
2. Anatomic barriers to the passive diffusion of antimicrobial drugs are encountered in certain
tissues, including the central nervous system, the eye, and the prostate gland.
3. Pathological barriers such as abscesses impede the passive diffusion of drugs.
4. Certain antimicrobial drugs are preferentially accumulated inside cells, macrolides are
known to accumulate within phagocytes.
5. Certain antimicrobial drugs are actively transported into infection sites. The active transport
of fluoroquinolones and tetracyclines by gingival fibroblasts into gingival fluid is an example.
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Pharmacodynamics PD
It describes;
› The relationship between the concentration of non-protein-bound drug at the site of
action and the drug response.
› The therapeutic effect.
› What the drug does to the body?
Cont. …
› The PD of antimicrobial drugs against microorganisms comprises 3 main aspects:
1. Spectrum of activity
2. Bactericidal and bacteriostatic activity
3. Type of killing action
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
MIC
Definition
› MIC is the lowest concentration of antimicrobial agent that prevents visible growth
after an 18- or 24-h incubation.
MBC
› The MBC is the minimal concentration that kills 99.9% of the microbial cells.
The Post-antibiotic Effect (PAE)
› The post-antibiotic effect (PAE) refers to a persistent antibacterial effect at
subinhibitory concentrations.
The Post-antibiotic Leukocyte Enhancement (PALE)
› The post-antibiotic leukocyte enhancement (PALE) refers to the increased
susceptibility to phagocytosis.
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Bactericidal and Bacteriostatic Activity
› The activity of antimicrobial drugs has also been described as being bacteriostatic or
bactericidal, this depends mainly on;
1. Drug concentration at the site of infection.
2. The microorganism involved.
Bacteriostatic Drugs
› They inhibit the growth of organisms at the MIC but require a significantly higher
concentration (MBC) to kill these organisms.
› Such as:
1. Tetracyclines
2. Phenicols
3. Sulfonamides
4. Lincosamides
5. Macrolides
Bactericidal Drugs
› They cause death of the organism at a concentration near the same drug
concentration that inhibits its growth.
› Such as:
1. Penicillins
2. Cephalosporins
3. Aminoglycosides
4. Fluoroquinolones
› Bactericidal drugs are required for effectively treating infections in
immunocompromised patients and in immunoincompetent environments in the body.
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Antibiotics Types of Killing Action
Antimicrobial drugs killing action may be;
1. Time dependent drugs
– It is the duration of exposure (time exceeding MIC for plasma concentration) that best correlates
with bacteriological cure.
2. Concentration dependent killing
– It is the maximum plasma concentration and/or area under the plasma concentration–time curve
that correlates with outcome.
3. Co-dependent killing effect
– Both the concentration achieved and the duration of exposure determine outcome
Cont. …
Time-dependent killing activity include:
1. β-lactams
2. Macrolides
3. Tetracyclines
4. Trimethoprim–sulfonamide combinations
5. Chloramphenicol
6. Glycopeptides
Concentration-dependent killing action includes:
1. Aminoglycosides
2. Fluoroquinolones
3. Metronidazole
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Spectrum of Activity
› Antibacterial agents may be classified in several ways;
Cont. …
Classification 1
1. Narrow – medium spectrum
– Antibacterial agents that inhibit only bacteria
2. Broad spectrum
– Antibacterial that also inhibit mycoplasma, rickettsia, and chlamydia (so-called atypical bacteria)
Cont. …
Classification 2
1. Narrow spectrum
– Antimicrobial agents that inhibit only Gram-positive or Gram-negative bacteria
2. Broad-spectrum
– Antimicrobial agents that are active against a range of both Gram-positive and Gram-negative
bacteria as.
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Antibiotics Mechanisms of Action
› Antimicrobial agents demonstrate 5 major mechanisms of action, these mechanisms,
with examples of each type, are as follows:
Cont. …
1. Inhibition of cell wall synthesis
– (β-lactam antibiotics, bacitracin, vancomycin)
2. Damage to cell membrane function
– (polymyxins)
3. Inhibition of nucleic acid synthesis or function
– (nitroimidazoles, nitrofurans, quinolones, fluoroquinolones)
4. Inhibition of protein synthesis
– (aminoglycosides, phenicols, lincosamides, macrolides, streptogramins, pleuromutilins,
tetracyclines)
5. Inhibition of folic and folinic acid synthesis
– (sulfonamides, trimethoprim)
Plan of talk
› Antibiotic - Antimicrobial definition
› Microorganism definition
› Pharmacokinetics definition
› Pharmacodynamics definition
› MIC – MBC – PAE – PALE definitions
› Bactericidal and bacteriostatic antibiotics
› Antibiotics types of killing activity
› Antibiotic spectrum of activity
› Antibiotics mechanism of action
› Antibiotic combination
Antimicrobial Drug Combinations
› The use of antimicrobial combinations is indicated in some situations such as mixed
infections.
› Such cases may respond better to the use of two or more antimicrobial agents.
Cont. …
› There are some fixed combinations such as the potentiated sulfonamides
(comprising a sulfonamide and a diaminopyrimidine such as trimethoprim) that
display synergism of antimicrobial activity.
› Other examples include;
1. The sequential inhibition of cell wall synthesis
2. Facilitation of one antibiotic’s entry to a microbe by another
3. Inhibition of inactivating enzymes
4. The prevention of emergence of resistant populations
Cont. …
Advantage of using antimicrobial drugs in combination
1. Treating mixed infections.
2. Lower dose of every antibiotics in the combination, therefore reducing the toxicity of
drugs used in combination.
Cont. …
Disadvantage of using antimicrobial drugs in combination
› To avoid disadvantages, combinations should be justified from both pharmacokinetic
and pharmacodynamic perspectives.
› In a combination of an aminoglycoside and a β-lactam
– Aminoglycosides display a concentration-dependent killing action and should be administered
once.
– β-lactam displays time-dependent killing and should be administered twice or 3 times.
Cont. …
› One way to achieve this, is to combine an aminoglycoside and the procaine salt of
benzylpenicillin.
– Aminoglycoside requires a high Cmax:MIC ratio
– Procaine salt of benzylpenicillin gives prolonged absorption to maintain plasma concentrations
above MIC for most of the inter dose interval.
› Some bacteriostatic drug may prevent some classes of bactericidal drugs from
being efficacious.
Antibiotics_Understanding_Basics

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Antibiotics_Understanding_Basics

  • 2. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 3. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 4. Antibiotic › The term antibiotic refers to substances produced by microorganisms that at low concentration kill or inhibit the growth of other microorganisms but cause little or no host damage.
  • 5. Antimicrobial › The term antimicrobial agent refers to any substance of natural, synthetic, or semi- synthetic origin that at low concentration kills or inhibits the growth of microorganisms but causes little or no host damage. › The critical important element of antimicrobial therapy is the selective toxicity of a drug for invading organisms rather than mammalian cells.
  • 6. Cont. … › The effectiveness of antimicrobial therapy depends on: 1. Bacterial susceptibility 2. Drug’s disposition in the body 3. Dosage regimen 4. Competence of host defense mechanisms. › Applied for bacteriostatic antibiotics
  • 7. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 8. Microorganism › The term microorganism or microbe refers to prokaryotes, which, by definition, are single-cell organisms that do not possess a true nucleus.
  • 9. Cont. … Bacteria size and shape › Bacteria range in size from 0.75 to 5 μm and most commonly are found in the shape of a sphere (coccus) or a rod (bacillus). Bacteria unique structure › Bacteria are unique in that they possess peptidoglycan in their cell walls, which is the site of action of antibiotics such as penicillin, bacitracin and vancomycin.
  • 10. Bacteria Classification – Gram Stain › Differences in the composition of bacterial cell walls allow bacteria to be broadly classified using differential staining procedures. › The Gram stain developed by Christian Gram in 1884, is the most important differential stain used in microbiology.
  • 11. Cont. … › Using the Gram staining procedure, bacteria can be divided into two broad groups: 1. Gram-positive 2. Gram-negative › This classification is based on the ability of cells to retain the dye methyl violet after washing with a decolorizing agent such as absolute alcohol or acetone.
  • 12. Cont. … Examples of Gram-positive bacteria are: › Bacillus, Clostridium, Corynebacterium, Enterococcus, Erysipelothrix, Pneumococcus, Staphylococcus, and Streptococcus. Examples of Gram-negative bacteria are: › Bordetella, Brucella, Escherichia coli, Haemophilus, Leptospira, Neisseria, Pasteurella, Proteus, Pseudomonas, Salmonella, Serpulina hyodysenteriae, Shigella, and Vibrio.
  • 13. Cont. … Cell wall structure: Gram +ve and Gram –ve bacteria › The differential antibiotic sensitivity of Gram-positive and Gram negative bacteria to many antimicrobials is due to differences in cell wall composition.
  • 14. Cont. … 1. Gram-positive bacteria › They have a thicker outer cell wall composed of a number of layers of peptidoglycan. › Antibiotics that interfere with peptidoglycan synthesis are more easily reach their site of action in Gram-positive bacteria.
  • 15. Cont. … 2. Gram-negative bacteria › They have a lipophilic outer membrane that protects a thin peptidoglycan layer. › They have protein channels (porins) in their outer membranes that allow the passage of small hydrophilic molecules. › The outer membrane contains a lipopolysaccharide component that can be shed from the wall on cell death. – It contains a highly heat-resistant molecule known as endotoxin, which has a number of toxic effects on the host animal, including fever and shock.
  • 16. Bacteria Classification – Aerobes / Anaerobes › Antibiotic sensitivity differs between aerobic and anaerobic organisms.
  • 17. Cont. … Anaerobic organisms › They are further classified as facultative and obligate. 1. Obligate anaerobes  They die in the presence of oxygen. 2. Facultative anaerobes  They derive energy by aerobic respiration if oxygen is present.  They are also capable of switching to fermentation.  Examples of facultative anaerobic bacteria are: 1. Staphylococcus (Gram-positive) 2. Escherichia coli (Gram-negative) 3. Listeria (Gram-positive)
  • 18. Cont. … › Anaerobic organisms are resistant to antimicrobials that require oxygen-dependent mechanisms to enter bacterial cells, such as aminoglycosides. › Anaerobic organisms may elaborate a variety of toxins and enzymes that can: 1. Cause extensive tissue necrosis, limiting the penetration of antimicrobials into the site of infection 2. Inactivating antimicrobials once they are present
  • 19. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 20. Pharmacokinetics It describes; › The time course of drug absorption, distribution, metabolism, and excretion. › What the body does to the drug? › The relationship between the dose of drug administered & the concentration of non- protein-bound drug at the site of action.
  • 21. Cont. … › Pharmacokinetics PK (absorption, distribution, metabolism and excretion) of an antimicrobial drug are governed largely by; 1. Drug’s chemical nature and physicochemical properties. 2. Drug’s concentration at the site of infection.
  • 22. Cont. … 1- Drug’s Chemical Nature and Physicochemical Properties › In regards to PK, molecular size and shape, lipid solubility and the degree of ionization are of particular importance.
  • 23. Cont. … The degree of ionization › The degree of ionization may not be an important consideration for amphoteric compounds (molecule or ion that can react both as an acid as well as a base) such as fluoroquinolones, tetracycline and rifampin. › But, the majority of antimicrobial agents are weak acids or bases for which the degree of ionization depends on the pKa of the drug and the pH of the biological environment. › Only the un-ionized form of these drugs is lipid-soluble and able to cross cell membranes by passive diffusion.
  • 24. Cont. … Example 1 › Sodium salt of a weak acid (pKa 4.4) infused into the mammary glands of dairy animals to treat mastitis. › The pH of the normal mammary gland is 6.4, at this pH, the Henderson–Hasselbalch equation predicts that the ratio of un-ionized to ionized drug is 1 : 100. › Mastitic milk is more alkaline, pH ∼ 7.4, and the ratio of un-ionized to ionized drug is 1 : 1000. This is identical to the ratio for plasma, which also has a pH of 7.4. › So, compared to the normal mammary gland, the mastitic gland will have more drug “trapped” in the ionized form.
  • 25. Cont. … Example 2 › The injection of a lipid-soluble, organic base which diffuses from the systemic circulation (with pH 7.4) into ruminal fluid (pH 5.5–6.5) during the distributive phase of a drug. › The ionized form becomes trapped in the acidic fluid of the rumen; the extent of trapping will be determined by the pKa of the organic base.
  • 26. Cont. … › In summary, weakly acidic drugs are trapped in alkaline environments and, vice versa, weakly basic drugs are trapped in acidic fluids.
  • 27. Cont. … 2- Drug’s Concentration at the Site of Infection › Drug concentration reflects the drug’s distributive behavior which is critically important in term of efficacy. › Dosage interval is dependent on drug concentration at the infection site. › Usually, the infection site (the biophase) is remote from the circulating blood that is commonly sampled to measure drug concentration. › Several authors have reported that plasma concentration of free (non-protein bounded) drug is generally the best predictor of the clinical success of antimicrobial therapy.
  • 28. Cont. … › The biophase in most infections comprises extracellular fluid (plasma + interstitial fluids). › Most pathogens are located extracellularly and as a result, plasma concentrations of free drug are generally representative of tissue concentrations; however, there are some exceptions such as:
  • 29. Cont. … 1. Intracellular microbes such as Lawsonia intracellularis, the causative agent of proliferative enteropathy in pigs, are not exposed to plasma concentrations of antimicrobial drugs. 2. Anatomic barriers to the passive diffusion of antimicrobial drugs are encountered in certain tissues, including the central nervous system, the eye, and the prostate gland. 3. Pathological barriers such as abscesses impede the passive diffusion of drugs. 4. Certain antimicrobial drugs are preferentially accumulated inside cells, macrolides are known to accumulate within phagocytes. 5. Certain antimicrobial drugs are actively transported into infection sites. The active transport of fluoroquinolones and tetracyclines by gingival fibroblasts into gingival fluid is an example.
  • 30. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 31. Pharmacodynamics PD It describes; › The relationship between the concentration of non-protein-bound drug at the site of action and the drug response. › The therapeutic effect. › What the drug does to the body?
  • 32. Cont. … › The PD of antimicrobial drugs against microorganisms comprises 3 main aspects: 1. Spectrum of activity 2. Bactericidal and bacteriostatic activity 3. Type of killing action
  • 33. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 34. MIC Definition › MIC is the lowest concentration of antimicrobial agent that prevents visible growth after an 18- or 24-h incubation.
  • 35. MBC › The MBC is the minimal concentration that kills 99.9% of the microbial cells.
  • 36. The Post-antibiotic Effect (PAE) › The post-antibiotic effect (PAE) refers to a persistent antibacterial effect at subinhibitory concentrations.
  • 37. The Post-antibiotic Leukocyte Enhancement (PALE) › The post-antibiotic leukocyte enhancement (PALE) refers to the increased susceptibility to phagocytosis.
  • 38. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 39. Bactericidal and Bacteriostatic Activity › The activity of antimicrobial drugs has also been described as being bacteriostatic or bactericidal, this depends mainly on; 1. Drug concentration at the site of infection. 2. The microorganism involved.
  • 40. Bacteriostatic Drugs › They inhibit the growth of organisms at the MIC but require a significantly higher concentration (MBC) to kill these organisms. › Such as: 1. Tetracyclines 2. Phenicols 3. Sulfonamides 4. Lincosamides 5. Macrolides
  • 41. Bactericidal Drugs › They cause death of the organism at a concentration near the same drug concentration that inhibits its growth. › Such as: 1. Penicillins 2. Cephalosporins 3. Aminoglycosides 4. Fluoroquinolones › Bactericidal drugs are required for effectively treating infections in immunocompromised patients and in immunoincompetent environments in the body.
  • 42. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 43. Antibiotics Types of Killing Action Antimicrobial drugs killing action may be; 1. Time dependent drugs – It is the duration of exposure (time exceeding MIC for plasma concentration) that best correlates with bacteriological cure. 2. Concentration dependent killing – It is the maximum plasma concentration and/or area under the plasma concentration–time curve that correlates with outcome. 3. Co-dependent killing effect – Both the concentration achieved and the duration of exposure determine outcome
  • 44. Cont. … Time-dependent killing activity include: 1. β-lactams 2. Macrolides 3. Tetracyclines 4. Trimethoprim–sulfonamide combinations 5. Chloramphenicol 6. Glycopeptides Concentration-dependent killing action includes: 1. Aminoglycosides 2. Fluoroquinolones 3. Metronidazole
  • 45. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 46. Spectrum of Activity › Antibacterial agents may be classified in several ways;
  • 47. Cont. … Classification 1 1. Narrow – medium spectrum – Antibacterial agents that inhibit only bacteria 2. Broad spectrum – Antibacterial that also inhibit mycoplasma, rickettsia, and chlamydia (so-called atypical bacteria)
  • 48. Cont. … Classification 2 1. Narrow spectrum – Antimicrobial agents that inhibit only Gram-positive or Gram-negative bacteria 2. Broad-spectrum – Antimicrobial agents that are active against a range of both Gram-positive and Gram-negative bacteria as.
  • 49. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 50. Antibiotics Mechanisms of Action › Antimicrobial agents demonstrate 5 major mechanisms of action, these mechanisms, with examples of each type, are as follows:
  • 51. Cont. … 1. Inhibition of cell wall synthesis – (β-lactam antibiotics, bacitracin, vancomycin) 2. Damage to cell membrane function – (polymyxins) 3. Inhibition of nucleic acid synthesis or function – (nitroimidazoles, nitrofurans, quinolones, fluoroquinolones) 4. Inhibition of protein synthesis – (aminoglycosides, phenicols, lincosamides, macrolides, streptogramins, pleuromutilins, tetracyclines) 5. Inhibition of folic and folinic acid synthesis – (sulfonamides, trimethoprim)
  • 52. Plan of talk › Antibiotic - Antimicrobial definition › Microorganism definition › Pharmacokinetics definition › Pharmacodynamics definition › MIC – MBC – PAE – PALE definitions › Bactericidal and bacteriostatic antibiotics › Antibiotics types of killing activity › Antibiotic spectrum of activity › Antibiotics mechanism of action › Antibiotic combination
  • 53. Antimicrobial Drug Combinations › The use of antimicrobial combinations is indicated in some situations such as mixed infections. › Such cases may respond better to the use of two or more antimicrobial agents.
  • 54. Cont. … › There are some fixed combinations such as the potentiated sulfonamides (comprising a sulfonamide and a diaminopyrimidine such as trimethoprim) that display synergism of antimicrobial activity. › Other examples include; 1. The sequential inhibition of cell wall synthesis 2. Facilitation of one antibiotic’s entry to a microbe by another 3. Inhibition of inactivating enzymes 4. The prevention of emergence of resistant populations
  • 55. Cont. … Advantage of using antimicrobial drugs in combination 1. Treating mixed infections. 2. Lower dose of every antibiotics in the combination, therefore reducing the toxicity of drugs used in combination.
  • 56. Cont. … Disadvantage of using antimicrobial drugs in combination › To avoid disadvantages, combinations should be justified from both pharmacokinetic and pharmacodynamic perspectives. › In a combination of an aminoglycoside and a β-lactam – Aminoglycosides display a concentration-dependent killing action and should be administered once. – β-lactam displays time-dependent killing and should be administered twice or 3 times.
  • 57. Cont. … › One way to achieve this, is to combine an aminoglycoside and the procaine salt of benzylpenicillin. – Aminoglycoside requires a high Cmax:MIC ratio – Procaine salt of benzylpenicillin gives prolonged absorption to maintain plasma concentrations above MIC for most of the inter dose interval. › Some bacteriostatic drug may prevent some classes of bactericidal drugs from being efficacious.

Notes de l'éditeur

  1. pKa is an index to express the acidity of weak acids. For example, the Ka constant for acetic acid (CH3C00H) is 0.0000158 (= 10-4.8), but the pKa constant is 4.8, which is a simpler expression.