Antibiotic Chemotherapy for Oral & Maxillofacial Surgery

History of Antibiotics-Early History

Ayurveda-Oldest medicine system (over 5000 years old) used Sesame paste, Honey, Skin from the stem of many antiseptic herbs e.g. Neem (azadirachta indica),Turmeric root etc. In 3500 BC the Sumerian doctors would give patients beer soup mixed with snakeskins and turtle shells. (yummy!!) Babylonian doctors would heal the eyes by using an ointment made of frog bile and sour milk. The Greeks used many herbs to heal ailments.

Modern History
Louis Pasteur Sir Alexander Fleming-Penicillin Domagk- discovers synthetic antimicrobial chemicals (sulfonamides). Late 1940's through the early 1950's, streptomycin, chloramphenicol, and tetracycline were discovered and introduced as antibiotics Antibiotic era

Overview
Antimicrobial compounds
Antiviral Antifungal Antibacterial

Selective Toxicity: the drug can be

administered to humans with reasonable safety while having a marked lethal or toxic effect on a specific microbe.

Decision to Use Antibiotics

Would you like to treat this patient with antibiotics

John a 30 year old patient has painful tooth #29 but no swelling , no trismus or increase in temperature. His general health is Good.
Would you administer antibiotics to him following an extraction, WHY ?

Principles of appropriate Antibiotic use

Evaluate the patient carefully and in this order:
Severity of Infection Patients host defenses Treating the infection surgically (I&D) Treating with antibiotics

Indications of Antibiotic Use

Temperature >101F with malaise Spreading cellulitis Chronic infection resistant to previous TX Anatomical space involvement Trismus Lyphadenopathy Pt with co-morbidities Acute pericornitis, osteomyelitis, ANUG, ect

Antibiotics Use Not Indicated

Minor, chronic, well localized abscess Toothache Periapical abscess Dry socket Multiple extractions in healthy patient Surgical extraction (drill and sutures) Mild pericoronitis Drained alveolar abscess

Selection of Antimicrobial Agents

Rational Antibiotic Therapy:

Is the ideal method for deciding on which antibiotic to administer, and is based on: C&S of organisms involved Site of infection Safety of agent Patients status Cost of therapy

Cost
NAME Pen VK 500mg Clindamycin 150 mg Augmentin 875mg Interval 1 tab qid 2 tabs qid Cost per week $10.99 $49.00

I tab bid

$ 100.00

Empirical Antibiotic Therapy:

Broad-spectrum antimicrobials can be administered on a educated guess basis, considering: - Site of infection - Most probable pathogens - Antibiotic sensitivity pattern - C&S is not always cost and time effective

Cidal vs. Static

Bactericidal Agents: Kills bacteria and reduces the total number of viable organisms.

Bacteriostatic Agents: Arrest the growth and replication of bacteria, thus allowing the host immune system to complete pathogen elimination.

Bactericidal vs. Bacteriostatic

Prefer Bactericidal to Bacteriostatic
Bactericidal
disrupts the cell wall synthesis-killing the bacteria Less reliance on host resistance Drug works faster than static More flexibility with dosage interval

Bacteriostatic
inhibits the RNA synthesis/reproduction Inhibit growth and reproduction of bacteria Help the host defenses to take over

Therapeutic Spectra
Refers to a particular drugs species of organisms affected. Antimicrobial agents are categorized:

-broad-spectrum: acts against both Grampositive and Gram-negative bacteria. -narrow-spectrum: effective against only specific families of bacteria.

Therapeutic Spectra Examples of Antibiotics

Narrow spectrum
Penicillin Cephalosporin (1st generation) Clindamycin Metronidazole

Broad spectrum
Amoxicillin Augmentin (Amoxicillin with clavulanic acid) Azythromycin Tetracycline Moxifloxacin

Therapeutic Spectra

Combination Therapy
The use of more that one agent is not advisable, in most dental situations because:
Risk of increased side-effects Competitive antagonism of agents Co$t

However, there are certain situations where this is appropriate:

Adding Metronidazole to Penicillin that the patient is already taking.

Clinical Scenario
Pt was I&Dd and given a Rx of Penn VK 500mg on Mon. due to significant vestibular swelling status post 5 days extraction of #19. Pt. returns to clinic today (Fri.) with diffuse indurated swelling on his left submandibular space.

What TX should be considered.

Why is TX failing
Consider if no response within 48 hours:
Inadequate I&D Inappropriate antibiotic therapy Presence of local factors Impaired host response Poor patient compliance Poor perfusion Unusual pathogen and/or no infective etiology.

Antibiotic Resistance
This is a major problem for patients and healthcare providers in the hospital setting. Resistance develops when progeny of resistant bacteria proliferate via selective advantage. As long as the antibiotic is being taken, this proliferation will continue.

Types of Antibiotic Resistance

Primary Resistance: Organism is naturally resistant to the drug. Acquired Resistance: Mutation within the same species or gene transfer between different species (plasmids).

Cross-Resistance: Resistance to one drug confers resistance to another similar drug.

Mechanism of Antibiotic Resistance

Inactivation of the Drug: very common, bacteria produces a product to inactivate. (ex. -lactamase production)

Altered Uptake: drug is not allowed to reach its target by either altered permeability or reverse pumping
Modification of the Active Site of the Drug

Complications of Antibiotic Therapy

Hypersensitivity
Anaphylactoid type reactions (IV)

Toxicity
Usually due to high serum levels

Superinfections
Most commonly due to broad-spectrum or combination therapy.

Idiosyncratic reactions
ranging from nausea to fatal aplastic anemia

Interactions

Side effects
Allergy- manifested as Hives Itching Wheezing Clindamycin
Pseudomemberanous colitis

Principles of Antibiotic Administration

Dose
Sufficient to achieve desired therapeutic effects

Time interval
Plasma Half life

Route of Administration
IV, IM, Oral

Principles of Antibiotic Administration

Use least toxic antibiotic Patients drug history
Patients drug reaction Drug/drug interactions

Effective Antibiotics for Oral Surgery

Penicillins
Pen VK Amoxicillin Augmentin

Cephalosporins Clindamycin Metronidazole (Flagyl) Azithromycin

Mechanism of Action Classification

Eight Categories:
1. Blocks cell wall synthesis (inhibition of peptidoglycan cross-linking 2. Block peptidoglycan synthesis 3. Disrupt cell membrane 4. Block nucleotide synthesis 5. Block DNA topoisomerases 6. Block mRNA synthesis 7. Block protein synthesis (50S subunit) 8. Block protein synthesis (30S subunit)

Cell wall synthesis Cycloserine Vancomycin Bacitracin Penicillins Cephalosporins Monobactams

Folic acid metabolism Trimethoprim Sulfonamides

Protein synthesis (50S inhibitors) Erythromycin Chloramphenicol Clindamycin

DNA

50S 30S

50S 30S mRNA

DNA-dependent RNA polymerase Rifampin

Cell membrane Polymyxins

Protein synthesis (30S inhibitors) Tetracycline Spectinomycin Streptomycin Gentamicin, tobramycin Amikacin

DNA replication (DNA gyrase) Nalidixic acid Quinolones

INHIBITORS OF CELL WALL SYNTHESIS

-LACTAMASE INHIBITORS
Clavulanic acid

-LACTAM ANTIBIOTICS

OTHER ANTIBIOTICS
Vancomycin
Bacitracin

Sulbactam Tazobactam

PENICILLINS
Penicillin G Penicillin V Methicillin Oxacillin Cloxacillin Ampicillin Amoxicillinn Carbenicillin

CEPHALOSPORINS

CARBAPENEMS
Imipenem/Cilastatin

MONOBACTAMS
Aztreonam

1st GENERATION
Cefazolin Cefadroxil Cephalexin Cephalothin

2nd GENERATION
Cefaclor Cefamandole Cefonicid Cefmetazole

3rd GENERATION
Cefdinir Cefixime Cefoperazone Cefotaxime

4th GENERATION
Cefepime

Cephapirin
Cephradine

Cefotetan
Cefoxitin Cefuroxime

Ceftazidime
Ceftibuten Ceftizoxime Ceftriaxone Moxalactam

Penicillins
Most commonly prescribed antibiotic in dentistry. Are extremely effective against most oral/odontogenic pathogens. Bactericidal Side effects occur frequently and range from minor rash to anaphylaxis. If allergic to one type of penicillin it will be share by all the penicillins.

Stable to acid permitting oral administration

Natural penicillins Penicillin G* Penicillin V Antistaphylococcal Cloxacillin Dicloxacillin Methicillin Nafcillin Oxacillin Extended spectrum Ampicillin Amoxicillin Amoxicillin + clavulanic acid Ampicillin + sulbactam Antipseudomonal Azlocillin Carbenicillin Mezlocillin Piperacillin Ticarcillin Ticarcillin + clavulanic acid Piperacillin + tazobactam

Stable to penicillinase

Pen V K Phenoxymethylpenicillin
Should be your first consideration for dental related infections. Inhibits cell wall synthesis via disruption of the cross-linking structure of the peptidoglycan portion of the cell wall.

Very cost effective

Pen V K Phenoxymethylpenicillin
Spectrum of activity include a majority of hemolytic streptococci and some penicilliansenegative staphylococci. Gram + sensitive include: Actinomyces, Eubacterium, Bifidobacterium and Peptostreptococcus. Gram sensitive include: Prevotella, Porphyromonas, Fusobacterium and Veillonella

Pen V K Phenoxymethylpenicillin
Resistance is common due to -lactamase production by bacteria (Staph. aureus) Penicillinase is a specific type of lactamase, showing specificity for penicillins. Dose is 500 mg for adults, qid for 7-10 days.

Amoxicillin
Is an extended spectrum, oral, agent used primarily for premedication and in situations where minor sinus pathogens are present and/or suspected. Amoxicillin > Ampicillin Spectrum of action:
Similar to pen VK Gram- (Haemophilus and Proteus)

Amoxicillin
Resistance is a drawback, via lactamase. Dosing for adult ,
premed is at 2000mg, 1 hour prior to TX Otherwise 500 mg, tid for 7-14 days

Augmentin
Potassium Clavulanate can be incorporated with amoxicillin to form Augmentin. This blocks the action of -lactamase. Dose is 500mg tid or 875mg bid, for 7-14 days.

Beta lactam ring

Cephalosporns
-lactams similar to Penicillins Relatively stable to staphylococcal penicillinase. Classified as first, second, third and fourth generation. Spectrum changes with generations. As dentist we will be concerned with a 1st generation agent Cephalexin (Keflex).

Cephalosporins
Uses in dentistry:
anti-staphylococci Orthopedic premed Second-line odontogenic

Dosing
Premed is 2000mg, 1 hour prior 500mg qid, for 7-10 days

Around 10% cross-sensitivity with penicillins.

Clindamycin
It is bacteriostatic via inhibition of protein synthesis by binding to the 50 S ribosomal protein. Spectrum favors anaerobic bacteria (Bacteroides/Prevotella), but does have some aerobic coverage. Static in low concentraations, cidal in high Metabolized in liver, excreted in urine and feces EXCELLENT abscess penetration but poor CSF penetration

Clindamycin
Uses in dentistry:
Premed (Penn allergic) Infections where significant anaerobic colonization is suspected.

Dosing:
Premed is 600 mg, 1 hour prior Infection is 150-300 mg, tid or qid for 7 days

Side effects are primarily with the GI tract

Diarrhea, Pseudomembranous Colitis (C. difficile).

Clindamycin
Contraindications
hypersensitivity to lincosamides history of inflammatory bowel disease

Metronidazole
Bactericidal Spectrum is effective against strict anaerobes (Bacteroides and Clostridia). Anaerobic bacteria convert into active metabolite, which inhibits DNA synthesis.

Metronidazole
Dental uses:
Primary agent in ANUG. Used with penicillin VK (poor-mans augmentin)

Side Effects:
Metallic taste Disulfram reaction

Dosing:
500 mg, tid for 5-7 days (caution use over 7 days at this dose).

Azithromycin
It is bacteriostatic via inhibition of protein synthesis by binding to the 50 S ribosomal protein. Spectrum:
Weak to Strep. and Staph. Active against respiratory infections.

Uses are limited to penicillin allergic sinus situations. Dosed as a Z-pack, 5 day course.

Mechanism to Reduce Antibiotic Resistance

Control and reduce use Better sterile and clean technique of treatment New antibiotics Modify existing antibiotics Agents to cure resistance plasmids Develop inhibitors of antibiotic-modifying enzymes

Current Trends
Increased incidence of Beta lactamase producing Bacteria Increase in s. aureus (Methicillinresistant Staphylococcus aureus )-MRSA

Vancomycin
Narrow spectrum bactericidal Not absorbed from GI tract Must be given iv for systemic infection Useful for treatment of C. Difficile Excreted by kidneys as active drug Use in serious penicillin allergic infections, methicillin resistant infections (mrsa)

Mechanism to Reduce Antibiotic Resistance

Control and reduce use Better sterile and clean technique of treatment New antibiotics Modify existing antibiotics Agents to cure resistance plasmids Develop inhibitors of antibiotic-modifying enzymes

References
Le, Tao, et al. First Aid for the USMLE: Step 1 2008. New York: McGraw Hill Medical, 2008. Mycek, Mary, Richard Harvey, and Pamela Champe. Illustrated Reviews: Pharmacology 2nd Edition. New York: Lippincotts, 2000. Peterson, Larry, et al. Contemporary Oral and Maxillofacial Surgery: Forth Edition. New York: Mosby, 2006. Samaranayake, L.P., Brian Jones, and Crispian Scully. Essential Microbiology for Dentistry. New York: Churchill Livingstone, 2002.