Antiinfective host modulation dr alaa

صدق هللا العظيم ،،

(32)رة آيه ــورة البقــــس

Anti-infective therapy and

host modulating agents

By

Associate Professor

Dr. Alaa M Attia

Introduction • The basic treatment of periodontitis is the

mechanical debridement of periodontal pockets by scaling and root planing in combination with effective plaque control.

• Certain periodontal pathogens can invade the connective tissue e.g. Aa making it unreliably removed with mechanical debridement alone.

• Systemic and local antimicrobial therapies aim to help the mechanical and surgical periodontal treatment by killing susceptible periodontal pathogens that remain after conventional mechanical treatment.

Systemic Antimicrobial Therapy

General Guidelines for Antimicrobial Use • Used as “adjunctive therapy”, never a substitute to

mechanical therapy.

• They enhance the effect of debridement.

Indications • Patients not responding to conventional mechanical therapy.

• Aggressive periodontitis.

• Refractory periodontitis (not respond to conventional ttt).

• Acute periodontal infections e.g. (abscesses and NPD).

• As an adjunct to surgical and non-surgical periodontal therapy.

Systemic Antibiotics

Antibiotics

Penicillins

- Amoxicillin

- Amox./Clav.

Tetracycline

- Minocycline

- Doxcycline

Macrolides

- Spiramycin

- Azithromycin

Quinolone

- Ciprofloxacin

Lincomycin

- Clyndamycin

Nitromidazole

- Mitronidazole

A- Systemic Antimicrobial Therapy

Disadvantages

• Allergic reactions

• Super infection, e.g. fungal infections, on prolonged use

• Toxicity

• Drug interactions

• Patient compliance is extremely important

• Bacterial resistance

1- Penicillins

Amoxicillin: Used for all aggressive

periodontitis cases 500mg/3/8.

Amoxicillin-Clavulnate (Augmentin):

Can be used for refractory and localized

aggressive periodontitis cases; 625

mg/3/8.

ttt : Localized aggressive P.

- Refractory periodontitis – P Abscess

2- Tetracycline

Properties

• Broad spectrum antibiotic

• 4-8 µg/ml in the GCF (2-10 times more

than serum concentration)

• Bacteriostatic, Bactericidal (at high doses)

• Tetracycline, Doxycycline, and

Minocycline are the tetracyclines used for

periodontal therapy

• Dose: 250 mg, 4 times daily

2- Tetracycline

Side Effects

• Photosensitivity

• Stains teeth in children

• Absorption is impaired by antacids, milk &

calcium rich foods

• oral contraceptive effect

2- Tetracycline

Indications

• Refractory cases

• Localized aggressive periodontitis

Contraindications

• Pregnancy

• Children

• Renal insufficiency (can use doxycycline)

• Liver dysfunction (can use minocycline)

Minocycline

• It suppresses the spirochetes

• Less photosensitivity and renal toxicity than tetracycline

• May cause reversible vertigo

• Administered in a dose of 200 mg per day for one week

Doxycycline

• Has the same spectrum as minocycline

• Its absorption is not affected by calcium, metal ions or antacids.

• Given 100 mg once daily or 50 mg twice daily.

3- Metronidazole

Mechanism of Action

• Bactericidal antimicrobial.

• Disrupts DNA synthesis

• Susceptible bacteria include Bacteroides, P. gingivalis, Treponema, Campylobacter and Veillonellae.

Indications

• Necrotizing ulcerative gingivitis

• Refractory periodontitis (Combined with Amoxicillin or Augmentin)

• Localized aggressive cases (combined with amoxicillin or Augmentin).

• Ineffective against Aa except when combined with other drugs.

• Dose: 250 mg tid for 7-10 days or 500 mg bid for 1-2 weeks.

4- Ciprofloxacin

Action: active against gram-negative rods,

including all facultative and some anaerobic

putative periodontal pathogens.

• Indicated for use in refractory periodontitis

• May facilitate repopulation of pocket with

organisms associated with periodontal health

• Not for use in children as it disrupts the growth

pattern

• Side effect: Nausea, headache, metallic taste

in the mouth, and abdominal discomfort,

enhance anticoagulant.

5- Clindamycin

Action: against anaerobic bacteria and has a strong affinity for osseous tissue

• Indicated: for refractory periodontitis especially in cases that are non-responsive to tetracycline.

• Side Effects

- Diarrhea

- Pseudomembranous colitis- caused by clostridium difficile

- Super infections

- Fungal overgrowth in oral cavity, intestine and vagina

• Dose: 250-500 mg, tid, for 8 days

6- Azithromycin

Azithromycin is a member of the azalide class of

macrolides.

Action: against anaerobes and gram-negative bacilli.

For treatment of Aggressive periodontitis.

After an oral dosage of 500 mg qd for 3 days, significant levels of azithromycin can be detected in most tissues for 7 to 10 days.

Dose: 250 mg/day for 5 days after an initial loading dose of 500 mg.

Combination Therapies

• Augmentin & Metronidazole - 250 mg of each 3 times daily - 8 days

• Ciprofloxacin & Metronidazole - 500 mg of each twice daily

- 8 days

• Clindamycin & Ciprofloxacin - 300 mg clindamycin - 500 mg ciprofloxacin - twice daily 8 days

Important notice

Antibiotic treatment should be reserved for specific subsets of periodontal patients who do not respond to conventional therapy.

Selection of specific agents should be guided by the results of cultures and sensitivity tests for subgingival plaque microorganisms.

At this time, systemic antibiotics for the treatment of periodontal diseases have been indicated primarily for adjunctive use in the treatment of aggressive periodontal diseases

Decision tree for selection of Antibiotics in PDs

Local Delivery

Antimicrobials

B- Local Delivery Antimicrobials

Advantages

• Facilitates prolonged drug delivery.

• GCF concentration greater than serum

levels.

• Reduces systemic effects.

• Enhances treatment results at specific

locations (i.e. acts on treated sites only).

• Improves clinical signs of periodontitis.

1- Tetracycline (Actisite)

How Supplied

• Fiber of 23 cm in length that has 12.7 mg tetracycline hydrochloride

Indications:

• Pockets measuring 5 mm that bleed on probing.

• Localized treatment of sites not responding to mechanical therapy.

Application

• Fiber is inserted into the pocket.

• Some control of saliva is needed.

• Should contact the pocket base.

• Surgical dressing is not necessary.

• Removed 7-10 days after placement.

2- Minocycline (Arestin)

How Supplied

sustained-release form of minocycline microspheres (Arestin) is available for subgingival placement as an adjunct to scaling and root planing. The 2% minocycline is encapsulated into bioresorbable microspheres in a gel carrier.

Patient Instructions

• Do not eat hard or sticky foods for 1 week.

• Avoid of brushing for 12 hours.

• Do not use interproximal cleaning aids for 10 days

Arestin It is minocycline microencapsulated in in gel carrier.

Placement of minocycline

microspheres (Arestin).

3- Doxycycline hyclate (Atridox)

It is an 10 % Doxycycline hyclate

• Bioresorbable.

• Released at minimal inhibitory

concentration levels for most

periodontal pathogens over a period of 7-8 days.

How Supplied

• A liquid polymer in one syringe and powdered doxycycline hyclate in a second syringe, the two syringes are mixed together just before use.

• The mixture is injected into the pocket using a blunt needle and solidifies in contact with crevicular fluid and saliva.

Placement of 10% doxycycline

(Atridox) gel.

4- Metronidazole (Elyzol)

• Metronidazole. (Elyzol)

Is A topical medication containing an oil-

based metronidazole 25% dental gel

5- Chlorhexidine gluconate (Periochip)

• 34 % chlorhexidine gluconate in a cross-linked gelatin matrix.

• Each chip contains 2.5mg of chlorhexidine gluconate.

• Chip is gently pushed into the pocket and it biodegrades over 7-10 days.

• Chlorhexidine has been detected in gingival fluid for one week following a single application.

• Absence of any bacterial resistance with repeated use.

• Good substantively.

Chlorhexidine chip: (Periochip)

Placement of chlorhexidine gluconate chip

(PerioChip).

Conclusions

Mechanical plaque removal remains the

cornerstone of preventive and therapeutic

regimens in the management of gingivitis and periodontitis.

Specific subgroups of patients can significantly benefit from an adjunctive antimicrobial agents.

Host Modulating

Drugs

Host Modulation: is the process that uses drugs

or chemicals, other than antimicrobials, to reduce

periodontal breakdown and enhance the immune

response of the host.

A- Systemically Administered Agents

B- Locally Administrating Agents

Host Modulations

A- SYSTEMICALLY ADMINISTERED

AGENTS

1- Nonsteroidal Antiinflammatory Drugs (NSAID)

2- Bisphosphonates

3- Sub-Antimicrobial-Dose Doxycycline

Potential roles of Host modulating agents

1- Subantimicrobial dose doxycycline

Periostat

• Periostat is the first therapeutic agent designed to modulate the host response and helps to slow the progression of periodontal disease.

• It is a doxycycline hyclate that is not used as an antibiotic and has no detectable effect on bacteria.

• Inhibits collagenase activity in gingival crevicular fluid of patients with periodontitis.

Available as a 20 mg tablet to be taken orally two times a day (about an hour before, or two hours after meals). It should be taken with plenty of fluids.

Typical treatments range from 3 months to 12 months.

Should not be used for children, pregnant and nursing women or anyone with tetracycline hypersensitivity.

Subantimicrobial dose doxycycline

(Periostat)

2– NSAID NSAIDs inhibit the formation of

prostaglandins, including PGE2, which is produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to the presence of LPS, a component of the cell wall of gram-negative bacteria.

They are used to treat pain, acute inflammation, and a variety of chronic inflammatory conditions.

NSAIDs inhibit prostaglandins and therefore reduce tissue inflammation.

NSAID

Anti Cox 1 - 2

Salicylates

Indomethacin

Propionic acid derivatives (ibuprofen, flurbiprofen,

and naproxen)

Ketoprofen

Diclofenics

Paracetamol

Selective Cox 2 Meloxicam

Celecoxib Celebrix

Cyclooxygenase Lipooxygenase

PGE2

Thromboxanes

Leukotrines

Hydroxyeicosatetraaeonic

acid

Lipoxins (antiinflammatory)

Arachidonic acid

Phospholipase

Prostacycline

Protect the

stomach mucosa

Cox-1 Cox-2

Phospholipids

Present in plasma membrane in inflammatory cells

COX-1 is constitutively expressed and has

antithrombogenic and cytoprotective functions.

Therefore, inhibition of COX-1 by nonselective NSAIDs

causes side effects such as gastrointestinal ulceration

and impaired hemostasis.

COX-2 is induced after stimulation by various

cytokines, growth factors, and LPS and results in the

production of elevated quantities of prostaglandins.

Inhibition of COX-2 by selective COX-2 inhibitors results

in reduction of inflammation.

Research shows that the periodontal benefits of taking

long-term NSAIDs are lost when patients stop taking the

drugs, with a return to or even an acceleration of the rate

of bone loss seen before NSAID therapy, often referred to

as a (rebound effect).

For these reasons, the long-term use of NSAIDs as an

adjunctive treatment for periodontitis has never really

developed beyond research studies.

NSAIDs (including the selective COX-2 specific inhibitors)

are presently not indicated as adjunctive human

modulators (HMTs) in the treatment of periodontal

disease.

3- Bisphosphonates

The bisphosphonates are bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity.

Bisphosphonates interfere with osteoblast metabolism and secretion of lysosomal enzymes.

Recent evidence has suggested that bisphosphonates also possess anticollagenase properties.

In animal models of experimentally induced periodontitis, bisphosphonates reduced alveolar bone resorption.

In human studies, these agents resulted in enhanced alveolar bone status and density.

Side effect: ostenecrosis , oral ulcers , altered WBCs count

Dose: very small dose in comparison to anti-malignant dose about (0.2 to 1 mg/kg/d).

B- Locally Administered Agents

1- NASID e.g. topical ketorolac mouthrinse

2- Periodontal bone regenerative agents:

A- Enamel Matrix Proteins

B- Growth Factors e.g.

(Platelet-derived growth factor, insulinlike g. factor).

C- Bone morphogenetic proteins (BMP-2, BMP-7).