DEHY3007 Pharmacology 2007-2008

Antibiotics
Tue Oct 2 Tue Oct 9 2.00 3.00 2.00 3.00 4116 4116

Before 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 thats harmful to another. Some anticancer agents are antibiotics.
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Before we start
There are many antibiotics. Well focus on those that are used in dental practice. Ill only examine what we cover in class (on the completed handouts). Help ease the pain - give me feedback! jonathan.blay@dal.ca
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Bacterial infections in the oral cavity

Streptococcal tonsillitis caused by a group A -haemolytic streptococcus. Courtesy of Prof C. Gemmell.

(Bagg, Jeremy. Essentials of Microbiology for Dental Students, 2nd Edition. Oxford University Press)
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The types of bacteria in dental infections

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

The details on this slide will not be in the exam

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.

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.

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 Cephalosporins .................... antibiotics 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. Its 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. 2. 3. 4. 5. 6. 7. Crosses the cell wall into the bacterium Binds to the penicillin-binding protein Stops the PBP enzyme working The peptidoglycan is not made The cell loses its rigidity The fluid inside exerts outward pressure 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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The effect of bacterial beta lactamases

Beta lactam ring

General structure of beta lactam drug

If this happens:

.............................

1.The drug will not work 2.The bacterium is resistant to the 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-resistant e.g. Nafcillin ................................. e.g. Amoxicillin Which differ in their - sensitivity to beta lactamases - .............................. - ................................
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Pharmacokinetics of common penicillins

e.g. Penicillin G ..................... in acid (which is why we prefer penicillin V). 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) ....................... - Wider spectrum - Better absorbed - Longer half-life

Extended-spectrum e.g. Amoxicillin

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

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Cephalosporins 1st generation 2nd generation 3rd generation 4th generation

You dont need to remember These 4 drug names

e.g. Cefazolin e.g. Cefuroxime e.g. Ceftriaxone e.g. Cefepime

(Generally ..............................................)
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(Cephalosporins) 1st generation 2nd generation 3rd generation 4th generation

Better activity against gramnegative bacteria Better ability to cross into 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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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 ............................................
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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 (.................)
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Question: If macrolides, tetracyclines and aminoglycosides all block protein synthesis in bacteria, why are they different in use? Answer: 1. Theyre 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?

Helps make new DNA

Page, 2002

by interfering with the bacteriums ability to form ........ or what it needs to do so.
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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 Dietary kinds of molecules. folate One thing that is needed for several different purposes is THF (..............................). Humans Blocking THF production suppresses DNA synthesis.
Rang, 2003

Bugs

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.
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(Drugs that block the folic acid pathway)

DHPS
e.g. sulfamethoxazole

DHFR

Rang, 2003

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(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

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So, to summarize all of the drugs weve covered:

Drugs that ................................................

- penicillins, cephalosporins, vancomycin, bacitracin

Drugs that ....................................................

- macrolides, tetracyclines, aminoglycosides

Drugs that ................................................

- fluoroquinolones, sulfonamides, trimethoprim

Lets go on to a few more general things

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Therapeutics: Keeping above the MIC

Successive doses of drug
Antibiotic concentration in serum

MIC: Minimal Inhibitory Concentration

Antibiotic level has fallen ..................... ................................. ....................

Page, 2002

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Antibiotics are generally very safe drugs

Therapeutic index (TI) = Toxic Dose ED50 = TD50 Effective Dose ED50 ED50
Antibacterial effect Toxic effect
100

is ................

% of patients responding

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Therapeutic window
50% effect

is

.............................

60

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ED50
0 0.1 1 Dose of drug 10

TD50
100

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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

Progressive growth
DRUG

Number of bacteria

Growth is arrested
e.g. sulfonamides

Cells are killed

e.g. penicillins

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(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 ...............................
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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

A B B A+B

B A+B

A+B

Page, 2002

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Remember Septra
Sulfamethoxazole + Trimethoprim = bacteriostatic = bacteriostatic

The combination sulfamethoxazole/trimethoprim:

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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Chronic Acute

Candidiasis of the buccal mucosa and tongue

(Laskaris, George. Color Atlas of Oral Diseases in Children and Adolescents:. Thieme Medical Publishers).
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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.
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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.
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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.. Pharmacology and Therapeutics for Dentistry, 5th Edition. C.V. Mosby).

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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 .................. that leak out cell contents (e.g. amphotericin B) They may .......................... that are important in making ergosterol (e.g. ketoconazole)

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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 For information only 12) Incorrect diagnosis not on the exam 13) Antibiotic antagonism
(Yagiela, John A.. Pharmacology and Therapeutics for Dentistry, 5th Edition. C.V. Mosby).

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