ghid de antibioterapie
TRANSCRIPT
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DEHY3007 PharmacologyDEHY3007 Pharmacology20072007--20082008
AntibioticsAntibiotics
Tue Oct 2 2.00 – 3.00 4116
Tue Oct 9 2.00 – 3.00 4116
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Before we startBefore we start……
Watch out for the term ‘antibiotics’.
We usually mean ‘..........................’ or ‘...................................’ (as in your text).
But it really means a chemical produced by one organism that’s harmful to another.
Some anticancer agents are ‘antibiotics’.
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Before we startBefore we start……
There are many antibiotics.
We’ll focus on those that are used in dental practice.
I’ll only examine what we cover in class (on the completed handouts).
Help ease the pain - give me feedback!
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Streptococcal tonsillitis caused by a group A β-haemolytic streptococcus. Courtesy of Prof C. Gemmell.
(Bagg, Jeremy. Essentials of Microbiology for Dental Students, 2nd Edition. Oxford University Press)
Bacterial infections in the oral cavity
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HAVELES: APPLIED PHARMACOLOGY FOR THE
DENTAL HYGIENIST, 5TH EDITION
The types of bacteria in dental infections
The details on this slide
will not be in the exam
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Antibiotic use in dentistry
1. Treatment of ........... dental infections.
First-line antibiotics are penicillin V,
amoxicillin.
2. ..................... in patients who are .................................
- AIDS etc
- chemotherapy for cancer
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(Antibiotic use in dentistry)
3. .................... in patients at risk of ................
.....................
Dental procedures may introduce bacteria into the bloodstream.
These bacteria may lodge in susceptible areas:
- ......................... plaques
- artificial surfaces e.g. ...........
They are known to cause bacterial endocarditis.
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Relative Bacteremia Incidence with Dental
Treatment Procedures
Dental Treatment Bacteremias
Tooth extraction: 40% to 89%Periodontal surgery: 36% to 88%Simple prophylaxis: 0% to 40%Buccal anesthetic injection: 16%
Intraligamentary injection: 97%Rubber dam/matrix/wedge: 9% to 32%
Endodontic treatment: 0% to 15%
(Yagiela, John A.. Pharmacology and Therapeutics
for Dentistry, 5th Edition. C.V. Mosby).For information only
– not on the exam
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Antimicrobials that are commonly used in dentistry
• Penicillin V is the most frequently prescribed antibiotic for oral infections.
• Amoxicillin use is also common. It has better pharmacokinetics and a wider spectrum.
• Erythromycin is used against acute orofacial infections, particularly in patients who cannot tolerate penicillin-like drugs.
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Antimicrobials that are less commonly used in dentistry
• Tetracyclines are not widely used but can be
used for infections resistant to other drugs and have specific uses such as in the management of localized juvenile periodontitis (LJP).
• Many other drugs are only used for orofacial infections if they are indicated for use by sensitivity testing of the microorganism, e.g. aminoglycosides, fluoroquinolones.
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Penicillin V
Amoxicillin
Penicillins
Cephalosporins
....................
antibiotics
Vancomycin
Bacitracin
Attack the
...............
...............
Penicillin-like antibiotics
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The ‘attack strategy’ for penicillins etc
Bacteria have a ......... cell wall.
They need this to survive and grow.
It’s made up of a fibrous ..............
The scaffold is assembled using ................
So… if we can block those enzymes, the
cell wall will not be made properly and the
bacteria will not survive!!!!!!
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Structure of the Bacterial Cell Wall
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Terminology
• Peptidoglycan – the fibrous ............. in the wall that we are trying to destroy.
• Penicillin-binding protein (PBP) – the ............. that helps to make the scaffold.
• Membranes – .......... membranes that are very difficult for drugs to get through.
• Beta lactamase – another kind of ..............., that causes resistance (see later).
• Porins – protein .......... that pierce the membrane.
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What a penicillin does
1. Crosses the cell wall into the bacterium
2. Binds to the penicillin-binding protein
3. Stops the PBP enzyme working
4. The peptidoglycan is not made
5. The cell loses its rigidity
6. The fluid inside exerts outward pressure
7. The bacterium bursts (‘..........’)
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But there are potential problems
1. Getting across the outer lipid membrane
in Gram negative bacteria.
This is why many antibiotics work well against Gram ............. bacteria but not Gram ............... bacteria.
If a Gram negative bacterium has ..........., it may be easier for the drug to get through the outer membrane.
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But there are potential problems
2. Interference by beta lactamases
These enzymes break down many of the common penicillin-like drugs.
The susceptible drugs have a beta lactam group in their structure.
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If this happens:
1.The drug will not work
2.The bacterium is resistant to the drug
Beta lactam ring
.............................
The effect of bacterial beta lactamases
General structure of
beta lactam drug
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What can we do about the beta lactamases?
1. Use a beta-lactamase-............... antibiotic.
e.g. Nafcillin
(Sometimes called ‘penicillinase-resistant)
2. Combine with a beta lactamase ...............
e.g. Clavulanate(Clavulin®: amoxicillin + clavulanate)
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There are different penicillins
..............................e.g. Penicillin V
Penicillinase-resistante.g. Nafcillin
.................................e.g. Amoxicillin
Which differ in their- sensitivity to beta lactamases- ..............................- ................................
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No need to remember the other details here
Pharmacokinetics of common penicillins
e.g. Penicillin G ..................... in acid(which is why we prefer penicillin V).
Amoxicillin has a longer ................
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Spectrum of action of common penicillins
Narrow spectrume.g. Penicillin VMainly active against gram-positive bacteria
(Staphylococci, Streptococci)
Extended-spectrume.g. AmoxicillinActive against gram-positive bacteria but also
some gram-negative bacteria (e.g. E Coli).
.......................
- Wider spectrum
- Better absorbed
- Longer half-life
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Cephalosporins
1st generation e.g. Cefazolin
2nd generation e.g. Cefuroxime
3rd generation e.g. Ceftriaxone
4th generation e.g. Cefepime
You don’t need to remember These 4 drug names
(Generally ..............................................)
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(Cephalosporins)
1st generation
2nd generation
3rd generation
4th generation
Better activity Better ability
against gram- to cross into
negative bacteria tissue spaces
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The drugs that attack the bacterial cell wall
Vancomycin
Works at an earlier stage than the PBPs.Needed when many ........................................
Bacitracin
Works at an earlier stage than the PBPs.Found in ............ (surface-applied) preparations.
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Where else can we attack the bacterium?
© Page, 2002
… by interfering with the ability of the
bacterium to make the ............. it needs.
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A simplified view of protein synthesis
DNA mRNA proteins
What happens here
Can be blocked by
� Erythromycin and other macrolides
� Tetracyclines such as ... tetracycline
� Aminoglycosides such as gentamicin
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Erythromycin and the macrolide antibiotics
Erythromycin
- Somewhat ............... in acid conditions
- Food reduces ..................
Clarithromycin
- Chemically modified from erythromycin
- Improved ......................
- Improved ..........................
Azithromycin
- Further modified
- Excellent tissue penetration
- Longer ...............(about 3 d)
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Erythromycin
- used against acute orofacial infections
- particularly in ............................... infections
- works well against gram-positive organisms
- generally poor against gram-negatives
Clarithromycin
- most active against gram-positive anaerobes
Azithromycin
- has the best activity against gram-negative anaerobes
- also acts against oral spirochetes
- less likely to become involved in ..............................
Therapeutic uses of the macrolides in dentistry
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Also act on bacterial ribosomes to block protein synthesis.
Not widely used in dentistry but have some interesting
properties:
� Interact with ............................ (like calcium)
� Should not be taken alongside ......... or ..................
� Become stored in ........... and ..........................
� Should not be used in:
- second half of pregnancy
- young children
� Concentrate in ............................................
Tetracyclines
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e.g. Gentamicin
Only used for orofacial infections if they are indicated for use by sensitivity testing of the microorganism.
A few relevant points:
� used mostly against gram-negative enteric bacteria.
� oral doses are very poorly absorbed.
� usually given ......................... or ..........................
� all aminoglycosides are
- ototoxic (..........)
- nephrotoxic (.................)
Aminoglycosides
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Question:
If macrolides, tetracyclines and
aminoglycosides all block protein synthesis in bacteria, why are they different in use?
Answer:
1. They’re different chemically, which affects
things like their .............. and ...................
2. They interfere at different sites on the
bacterial ribosomes, which means they have
different .................................
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Where else can we attack the bacterium?
© Page, 2002
… by interfering with the bacterium’s ability
to form ........ or what it needs to do so.
Helps make
new DNA
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1. Drugs that inhibit DNA gyrase enzymes
DNA is made up
of ....................
To be able to
‘untangle’ all of the DNA in a cell you need to cut it
temporarily:
The protein that
does this is called a ......................
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(Drugs that inhibit DNA gyrase enzymes)
Fluoroquinolones block this DNA gyrase enzyme.
One example is ciprofloxacin
These drugs stop the bacterium from using its DNA.
But overuse has led to the widespread resistance!
Many respiratory pathogens are now resistant.
Not used in dentistry unless indicated by sensitivity testing – other drug classes have a better spectrum of activity and pharmacokinetics.
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2. Drugs that block the folic acid pathway
The story goes like this:
DNA is made of several different
kinds of molecules.
One thing that is needed for
several different purposes is
THF (..............................).
Blocking THF production
suppresses DNA synthesis.
Humans use folic acid from the
..... and can do this in one step.
Bacteria have first to ................
.........folic acid, so there are two
steps that can be blocked.
© Rang, 2003
Humans
‘Bugs’
Dietary
folate
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e.g. sulfamethoxazole
© Rang, 2003
DHPS
DHFR
(Drugs that block the folic acid pathway)
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The combination sulfamethoxazole/trimethoprim:
- More effective than either drug alone
- Still works if resistance develops to one drug
Used at a dose ratio of ..........
This gives a plasma concentration ratio of ...........
This is .............. for the drugs.
e.g. Septra®
(Drugs that block the folic acid pathway)
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So, to summarize all of the drugs we’ve covered:
Drugs that ................................................
- penicillins, cephalosporins, vancomycin, bacitracin
Drugs that ....................................................
- macrolides, tetracyclines, aminoglycosides
Drugs that ................................................
- fluoroquinolones, sulfonamides, trimethoprim
Let’s go on to a few more general things…
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Therapeutics: Keeping above the MIC
© Page, 2002
Antibiotic level has fallen ..................... ................................. ....................
Successive doses of drugAntibiotic concentration
in serum
MIC: Minimal
Inhibitory Concentration
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Antibiotics are generally very safe drugs
Therapeutic window
is .............................
Toxic effect
1 10 100
Dose of drug
0.1
0
20
40
60
80
100
% o
f patients
resp
ondin
g
Antibacterial effect
Therapeutic index (TI) = Toxic Dose ED50 = TD50 … is ................
Effective Dose ED50 ED50
TD50
50% effect
ED50
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In fact, many of the adverse effects
of antibiotics are ...............
responses, rather than toxicity at
high doses…
e.g. penicillins, sulfonamides
… or disturbances of the ..............
microbial .........., as for example in
‘antibiotic-associated diarrhea’.
e.g. erythromycin, tetracycline
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Bactericidal versus Bacteriostatic drugs
Number of
bacteria
Progressive growth
Growth is arrested
Cells are killed
e.g. sulfonamides
e.g. penicillins
DRUG
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Bactericidal drugs e.g. penicillins
• Drugs that cause the .............of the bacteria.
• Required if the patient is ....................................
Bacteriostatic drugs e.g. sulfonamides
• Drugs that .............................. of the bacteria.
• ........................... when the drug is removed.
• Success depends on there being an effective ...............................
(Bactericidal versus bacteriostatic drugs)
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Using antimicrobial drugs in combinations
Advantages:
� Wider ................. for mixed infections.
� Reduced .......... for individual agents.
� .................... between antibiotics.
Risks:
� Increased possibility of ................................
� ..................... between antibiotics.
� Greater risk of antibiotic ......................
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Synergism, antagonism and indifference
© Page, 2002
AA
A
B
BB
A+BA+B
A+B
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Remember Septra® ?
The combination sulfamethoxazole/trimethoprim:
Sulfamethoxazole = bacteriostatic
+
Trimethoprim = bacteriostatic
Synergism - ‘..............................’
Septra® = bactericidal
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The problem of antibiotic resistance
A substantial risk of antibiotics are used too freely.
Happens because bacteria are genetically ‘agile’ and can adapt to survive a toxin such as an antibiotic.
The bacteria adapt so that there is, for example:
1. Reduced ........... of the antibiotic into the bacteria.
2. Increased .............. of the target protein.
3. Lower binding of drug to an ............ target protein.
4. Enzyme ..................... of the drug.
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Candidiasis of the buccal mucosa and tongue
Acute
Chronic
(Laskaris, George. Color Atlas of Oral Diseases in Children and Adolescents:. Thieme Medical Publishers).
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• Candidiasis is the most common type of
oral fungal infection.
• Regardless of which drug is used,
therapy for at least 2 weeks is required.
• Clotrimazole, in the form of oral troches
(lozenges), is highly effective in most cases.
• On swallowing, however, clotrimazole
can cause liver problems.
Uses of antifungals in dentistry
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• Nystatin oral pastilles or rinses can be used if liver damage is a concern.
• For more extensive disease or difficult cases, such as patients with AIDS, systemic antifungal therapy may be indicated.
• Oral ketoconazole can be used; however, it is also potentially hepatotoxic.
• Oral fluconazole is an alternative to ketoconazole that is less hepatotoxic.
Uses of antifungals in dentistry
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• In extreme cases, intravenous
amphotericin B may be considered.
• This is significantly toxic and may cause renal damage.
• Surgery may be helpful to remove a
condensed lesion after medical therapy.
(Yagiela, John A.. Pharmacology and Therapeutics
for Dentistry, 5th Edition. C.V. Mosby).
Uses of antifungals in dentistry
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• Mostly they target ................., a lipid in the
fungal cell membrane that is equivalent to
the cholesterol in ours.
• They may bind to ergosterol and .................. that leak out cell contents (e.g. amphotericin B)
• They may .......................... that are important in making ergosterol (e.g. ketoconazole)
How do these antifungals work?
Common Reasons for Antibiotic Failure – In Decreasing Order of Probable Importance
1) Failure to surgically eradicate the source of the infection
2) Too low a blood antibiotic concentration
3) Inability of the antibiotic to penetrate to the site of infection
4) Impaired/inadequate host defenses
5) Patient failure to take the antibiotic
6) Inappropriate choice of antibiotic
7) Limited vascularity or blood flow
8) Decreased tissue pH or oxygen tension
9) Slow microbial growth
10) Emergence of antibiotic resistance
11) Delay in diagnosis
12) Incorrect diagnosis
13) Antibiotic antagonism
(Yagiela, John A.. Pharmacology and Therapeutics
for Dentistry, 5th Edition. C.V. Mosby).
For information only– not on the exam