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DEHY3007DEHY3007 PharmacologyPharmacology

20072007--20082008

AntibioticsAntibiotics

Tue Oct 2

2.00 – 3.00

4116

Tue Oct 9

2.00 – 3.00

4116

BeforeBefore wewe startstart

Watch out for the term ‘antibiotics’.

We usually mean ‘

But it really means a chemical produced by one organism that’s harmful to another.

Some anticancer agents are ‘antibiotics’.

or

(as in your text).

2

BeforeBefore wewe startstart

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!

jonathan.blay@dal.ca

3

Bacterial infections in the oral cavity

Bacterial infections in the oral cavity Streptococcal tonsillitis caused by a group A β -haemolytic streptococcus.

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)

4

The types of bacteria in dental infections

 
The types of bacteria in dental infections   HAVELES: APPLIED PHARMACOLOGY FOR THE DENTAL HYGIENIST, 5TH

HAVELES: APPLIED PHARMACOLOGY FOR THE DENTAL HYGIENIST, 5TH EDITION

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

They are known to cause bacterial endocarditis.

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Relative Bacteremia Incidence with Dental Treatment Procedures

Dental Treatment Bacteremias

Tooth extraction:

Periodontal surgery:

Simple prophylaxis:

Buccal anesthetic injection: 16%

Intraligamentary injection:

Rubber dam/matrix/wedge: 9% to 32%

0% to 15%

Endodontic treatment:

40% to 89% 36% to 88% 0% to 40%

97%

(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-like antibiotics Penicillin V Penicillins Amoxicillin antibiotics Cephalosporins Attack the Vancomycin
Penicillin-like antibiotics
Penicillin V
Penicillins
Amoxicillin
antibiotics
Cephalosporins
Attack the
Vancomycin
Bacitracin
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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!!!!!!
12

Structure of the Bacterial Cell Wall

Structure of the Bacterial Cell Wall 13

13

Terminology

Peptidoglycan – the fibrous that we are trying to destroy.

Penicillin-binding protein (PBP) – the helps to make the scaffold.

Membranes

in the wall

that

membranes that are very

difficult for drugs to get through.

Beta lactamase – another kind of causes resistance (see later).

Porins – protein

, that

that pierce the membrane.

14

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 (‘

not made 5. The cell loses its rigidity 6. The fluid inside exerts outward pressure 7.

’)

15

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 but not Gram

bacteria

bacteria.

If a Gram negative bacterium has

not Gram bacteria bacteria. If a Gram negative bacterium has , it may be easier for

, 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.

break down many of the common penicillin-like drugs. The susceptible drugs have a beta lactam group
break down many of the common penicillin-like drugs. The susceptible drugs have a beta lactam group

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The effect of bacterial beta lactamases

 
   

Beta

lactam ring

General structure of beta lactam drug If this happens:

General

structure of

beta lactam

drug

General structure of beta lactam drug If this happens:

If this happens:

1.The drug will not work 2.The bacterium is resistant to the drug

 

18

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-resistant e.g. Nafcillin

e.g. Amoxicillin

Which differ in their

-

sensitivity to beta lactamases

-

-

 

20

Pharmacokinetics of common penicillins

Pharmacokinetics of common penicillins e.g. Penicillin G (which is why we prefer penicillin V). in acid
Pharmacokinetics of common penicillins e.g. Penicillin G (which is why we prefer penicillin V). in acid

e.g. Penicillin G

(which is why we prefer penicillin V).

in acid

Amoxicillin has a longer

No need to remember the other details here

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Spectrum of action of common penicillins

Narrow spectrum e.g. Penicillin V

Mainly active against gram-positive bacteria (Staphylococci, Streptococci)

Extended-spectrum e.g. Amoxicillin

- Wider spectrum - Better absorbed - Longer half-life
- Wider spectrum
- Better absorbed
- Longer half-life

Active against gram-positive bacteria but also some gram-negative bacteria (e.g. E Coli).

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Cephalosporins

You don’t need to remember These 4 drug names

 

1st generation

e.g. Cefazolin

 

2nd generation

e.g. Cefuroxime

 

3rd generation

e.g. Ceftriaxone

4th generation

e.g. Cefepime

 

(Generally

)

 

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(Cephalosporins)

1st generation

Better activity

 

Better ability

 

against gram-

to cross into

2nd generation

negative bacteria

tissue spaces

3rd generation

   

4th generation

 

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The drugs that attack the bacterial cell wall Vancomycin Works at an earlier stage than

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.

25

than the PBPs. Found in (surface-applied) preparations. 25 Where else can we attack the bacterium? ©

Where else can we attack the bacterium?

© Page, 2002
© Page, 2002

… by interfering with the ability of the

bacterium to make the

it needs.

26

 

A simplified view of protein synthesis

 

DNA

DNA mRNA proteins

mRNA

DNA mRNA proteins
DNA mRNA proteins
DNA mRNA proteins

proteins

 
What happens here Can be blocked by
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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Therapeutic uses of the macrolides in dentistry

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

 
 

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Tetracyclines

 

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

 
 

30

Aminoglycosides

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 (

)

31

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

32

Where else can we attack the bacterium?

Helps make new DNA © Page, 2002
Helps make
new DNA
© Page, 2002

… by interfering with the bacterium’s ability

to form

or what it needs to do so.

33

1. Drugs that inhibit DNA gyrase enzymes

1. Drugs that inhibit DNA gyrase enzymes DNA is made up of To be able to

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

able to ‘untangle’ all of the DNA in a cell you need to cut it temporarily:
able to ‘untangle’ all of the DNA in a cell you need to cut it temporarily:

34

(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.

35

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.

).

Dietary folate Humans © Rang, 2003
Dietary
folate
Humans
© Rang, 2003

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.

‘Bugs’

36

(Drugs that block the folic acid pathway) DHPS e.g. sulfamethoxazole DHFR © Rang, 2003 37
(Drugs that block the folic acid pathway)
DHPS
e.g. sulfamethoxazole
DHFR
© Rang, 2003
37
(Drugs that block the folic acid pathway)
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®
38
So, to summarize all of the drugs we’ve covered: Drugs that - penicillins, cephalosporins, vancomycin,
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…
39
Therapeutics: Keeping above the MIC
Successive doses of drug
Antibiotic
concentration
in serum
MIC: Minimal
Inhibitory
Concentration
Antibiotic level has
fallen
© Page, 2002
40

Antibiotics are generally very safe drugs

Therapeutic index (TI) = Toxic Dose ED50 Effective Dose ED50

= TD50 … is

ED50

 

Antibacterial effect

% of patients responding

100

80

60

40

20

0

Toxic effect Therapeutic window is 50% effect ED50 TD50

Toxic effect

Toxic effect Therapeutic window is 50% effect ED50 TD50
Therapeutic window is 50% effect ED50
Therapeutic window
is
50% effect
ED50
TD50
TD50
 

0.1

1

10

100

Dose of drug

 

41

 

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

 

42

 

Bactericidal versus Bacteriostatic drugs

 
 

Progressive growth

 

DRUG

 
Number of Growth is arrested bacteria e.g. sulfonamides Cells are killed

Number of

Growth is arrested

bacteria

e.g. sulfonamides

Cells are killed

 

e.g. penicillins

43

 

(Bactericidal versus bacteriostatic drugs)

 

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

 

44

Using antimicrobial drugs in combinations Advantages: Wider Reduced for mixed infections. for individual agents.
Using antimicrobial drugs in combinations
Advantages:
Wider
Reduced
for mixed infections.
for individual agents.
between antibiotics.
Risks:
Increased possibility of
between antibiotics.
Greater risk of antibiotic
45
Synergism, antagonism and indifference
A
A
B
B
A+B
B
A+B
A+B
A
© Page, 2002
46

Remember Septra®

Remember Septra® ? The combination sulfamethoxazole/trimethoprim : Sulfamethoxazole + Trimethoprim Septra® =

?

The combination sulfamethoxazole/trimethoprim:

Sulfamethoxazole

+

Trimethoprim

: Sulfamethoxazole + Trimethoprim Septra® = bacteriostatic = bacteriostatic Synergism - ‘ =

Septra®

= bacteriostatic

= bacteriostatic

Synergism - ‘

= bactericidal

47

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

3. Lower binding of drug to an

4. Enzyme

of the target protein.

of the drug.

target protein.

48

Chronic Acute Candidiasis of the buccal mucosa and tongue
Chronic
Acute
Candidiasis of
the buccal mucosa
and tongue

(Laskaris, George. Color Atlas of Oral Diseases in Children and Adolescents:. Thieme Medical Publishers).

49

Uses of antifungals in dentistry

• 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.

50

Uses of antifungals in dentistry

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.

51

Uses of antifungals in dentistry

• 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

Therapeutics for Dentistry, 5th Edition. C.V. Mosby).

Pharmacology and

52

How do these antifungals work?

• Mostly they target

, a lipid in the

fungal cell membrane that is equivalent to the cholesterol in ours.

• They may bind to ergosterol and leak out cell contents (e.g. amphotericin B)

• They may

that

that are important in

making ergosterol (e.g. ketoconazole)

53

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

For information only – not on the exam

(Yagiela, John A

Pharmacology and Therapeutics

for Dentistry, 5th Edition. C.V. Mosby).