CHEMOTHERAPEUTIC AGENTS IN PERIODONTAL THERAPY

Comprehensive Point-Wise Theory Examination Notes

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SECTION 1: DEFINITIONS AND CONCEPTUAL FRAMEWORK

1.1 Definitions (Carranza's Clinical Periodontology, 10th Edition - Chapter 52; Newman & Carranza 14th Edition - Chapter 53)

• Chemotherapeutic agent: "A general term for a chemical substance that provides a clinical therapeutic benefit. This term does not specify in what way the agent aids in attaining a clinical benefit. Clinical benefits can be derived through antimicrobial actions or an increase in the host's resistance." (Carranza 10th ed, Ch. 52)
• Antiinfective agent: "A chemotherapeutic agent that works by reducing the number of bacteria present." (Carranza 10th ed, Ch. 52)
• Antibiotic: "A naturally occurring, semisynthetic, or synthetic type of antiinfective agent [or chemotherapeutic agent - Newman 14th] that destroys or inhibits the growth of selective microorganisms, generally at low concentrations." (Carranza 10th ed, Ch. 52; Newman 14th ed, Ch. 53)
• Antiseptic: "A chemical antimicrobial agent applied topically or subgingivally to mucous membranes, wounds, or intact dermal surfaces to destroy microorganisms and inhibit their reproduction or metabolism. In dentistry, antiseptics are widely used as the active ingredient in antiplaque and antigingivitis oral rinses and dentifrices." (Newman 14th ed, Ch. 53)
• Disinfectant: "A subcategory of antiseptics; antimicrobial agents that are generally applied to inanimate surfaces to destroy microorganisms." (Newman 14th ed, Ch. 53)

[Essentials - S. Reddy 5th ed, Ch. 52]:

• Chemotherapeutic agents: "They refer to the ability of an active chemical substance to provide a therapeutic clinical benefit."
• Antimicrobial agents: "They are chemotherapeutic agents that reduce the amount of bacteria present either by specifically targeting certain organisms or by nonspecifically reducing all bacteria."
• Antibiotics: "They are a form of antimicrobial agents produced by or obtained from microorganisms that have the capacity to kill other microorganisms or inhibit their growth."

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1.2 Rationale for Use of Chemotherapeutic Agents

1. Periodontal pocket as a protected environment: "Bacteria grow in an apical direction and become subgingival, and eventually, as bone is destroyed, a periodontal pocket is formed. In a periodontal pocket the bacteria form a highly structured and complex biofilm." (Carranza 10th ed, Ch. 52)
2. Biofilm resistance: "It has been suggested that an antibiotic strength 500 times greater than the usual therapeutic dose may be needed to be effective against bacteria arranged in biofilms." (Carranza 10th ed, Ch. 52; Newman 14th ed, Ch. 53)
3. Tissue invasion: "Bacteria can invade periodontal tissues, thereby making mechanical therapy alone sometimes ineffective." (Newman 14th ed, Ch. 53)
4. Direct and indirect bone loss: "Bacteria and their toxic products cause 'direct bone loss.' Ultimately, however, the host's own immunologic response to this bacterial infection can cause even more bone destruction ('indirect bone loss') than that caused by pathogenic bacteria and their byproducts." (Carranza 10th ed, Ch. 52)
5. Dual mechanism: "A single chemotherapeutic agent can have a dual mechanism of action. For example, tetracyclines (especially doxycycline) are chemotherapeutic agents that can reduce collagen and bone destruction through their ability to inhibit the enzyme collagenase. As antibiotic agents, they also can reduce periodontal pathogens in periodontal tissues." (Carranza 10th ed, Ch. 52)

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1.3 KEY FACT: Bacteriostatic vs. Bactericidal Antibiotics

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SECTION 2: CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

2.1 Based on Route of Administration (Carranza 10th ed; Essentials - S. Reddy 5th ed)

CHEMOTHERAPEUTIC AGENTS
        |
        |------ SYSTEMIC ADMINISTRATION (Oral)
        |             - Antibiotics (oral tablets/capsules)
        |             - Host Modulation Therapies (HMT)
        |
        |------ LOCAL ADMINISTRATION (Subgingival/Topical)
                      - Antiseptics (rinses, gels)
                      - Controlled/Sustained-release devices
                      - Irrigation devices

2.2 Complete Classification of Antibiotics Used to Treat Periodontal Diseases

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SECTION 3: IDEAL PROPERTIES OF AN ANTIBIOTIC FOR PERIODONTAL DISEASE

1. Specific for periodontal pathogens
2. Allogenic (non-antigenic)
3. Nontoxic, substantive
4. Not in general use for treatment of other diseases (to minimize resistance)
5. Inexpensive

"Currently, however, an ideal antibiotic for the treatment of periodontal disease does not exist. Although oral bacteria are susceptible to many antibiotics, no single antibiotic at the concentrations achieved in body fluids inhibits all putative periodontal pathogens." (Newman 14th ed, Ch. 53)

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SECTION 4: SYSTEMIC ANTIBIOTICS IN PERIODONTAL THERAPY

4.1 Background and Rationale (Newman 14th ed, Ch. 53)

• "The treatment of periodontal diseases is based on their infectious nature. Ideally, the causative microorganisms should be identified, and the most effective agent should be selected with the use of antibiotic-sensitivity testing."
• "When antibiotics are administered orally, they reach all surfaces and fluids, including the gingival crevicular fluid (GCF)."

4.2 Guidelines for Use of Systemic Antibiotics (Carranza 10th ed, Ch. 52)

1. Systemic antibiotics should be an adjunct to a comprehensive periodontal treatment plan - not as monotherapy.
2. Indications: Continuing disease activity measured by continuing attachment loss, purulent exudate, continuing periodontal pockets of 5 mm or greater that bleed on probing; refractory or aggressive periodontitis.
3. Antibiotics are selected based on patient's medical and dental status, current medications, and results of microbial analysis.
4. Microbiologic plaque sampling: Samples taken at the beginning of an appointment before instrumentation. An endodontic paper point is inserted subgingivally into the deepest pocket(s). Placed in reduced transfer fluid and sent overnight to laboratory.
5. Plaque sampling can be performed at initial examination, root planing, reevaluation, or supportive periodontal therapy appointment.
6. Clinical indications for microbial plaque testing: Aggressive forms of periodontal disease, diseases refractory to standard mechanical therapy, periodontitis associated with systemic conditions.
7. Antibiotics have been shown to have value in reducing the need for periodontal surgery in patients with chronic periodontitis.

4.3 Advantages of Systemic Medication (Essentials - S. Reddy 5th ed)

• Ensures drug penetration till the base of the pocket
• Affects tissue-invasive organisms
• Takes less time and is inexpensive
• Treats multiple sites simultaneously
• In acute conditions such as NUG, used to decrease active inflammation
• As a premedication for patients with medical problems requiring prophylactic antibiotic coverage

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SECTION 5: SPECIFIC SYSTEMIC ANTIBIOTICS

5.1 TETRACYCLINES

5.1.1 Pharmacology

• "The tetracyclines are a group of antibiotics that are produced naturally from certain species of Streptomyces or derived semisynthetically." (Newman 14th ed)
• Bacteriostatic and effective against rapidly multiplying bacteria
• Generally more effective against gram-positive bacteria than gram-negative bacteria
• "Tetracyclines are effective for the treatment of periodontal diseases in part because their concentration in the gingival crevice is 2 to 10 times that found in serum." (Newman 14th ed)
• "Several studies have demonstrated that tetracyclines at a low GCF concentration (i.e., 2 μg/mL to 4 μg/mL) are very effective against many periodontal pathogens." (Newman 14th ed)
• Tetracycline HCl is also a chelating agent - chelates Ca²⁺, Mg²⁺, Al³⁺ in the GI tract; advisable to take either half an hour before or after food (Essentials - S. Reddy)

5.1.2 Special Properties of Tetracyclines Relevant to Periodontal Management (Essentials - S. Reddy; Antibiotics & Antiseptics - Dumitrescu; Carranza 10th)

5.1.3 Clinical Use of Tetracyclines

• "Tetracyclines have been widely used for the treatment of periodontal diseases. They have been frequently used to treat refractory periodontitis, including localized aggressive periodontitis (LAP), currently termed as periodontitis with molar-incisor pattern in 2018 classification." (Newman 14th ed, Ch. 53 - RECENT TERMINOLOGY CHANGE)
• Systemic tetracycline can eliminate tissue bacteria and arrest bone loss, suppress A. actinomycetemcomitans levels in conjunction with SRP
• "As a result of increased resistance to tetracyclines, metronidazole or amoxicillin in combination with metronidazole has been found to be more effective for the treatment of aggressive periodontitis (currently classified as Generalized Stage III or IV Grade C Periodontitis or Localized Stage III/IV Grade C Periodontitis with molar-incisor pattern)." (Newman 14th ed)

5.1.4 Tetracycline Hydrochloride

• Dosage: 250 mg four times daily for 21 days (commonly cited in literature)

5.1.5 Minocycline

• Effective against a broad spectrum of microorganisms
• Used systemically and applied locally (subgingivally)
• Can result in complete elimination of spirochetes for up to 2 months, and improvement in all clinical parameters (Carranza 10th ed)

5.1.6 Doxycycline

• "Doxycycline has the same spectrum of activity as minocycline and may be equally as effective." (Carranza 10th ed)
• Compliance advantage: can be given once daily (qd); absorption only slightly altered by calcium, metal ions, or antacids
• Dosage as anti-infective agent: 100 mg bid the first day, then 100 mg qd. To reduce GI upset: 50 mg bid
• Subantimicrobial dose (for host modulation/collagenase inhibition): 20 mg twice daily (see Section 9 - Host Modulation)

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5.2 METRONIDAZOLE

5.2.1 Pharmacology

• "A nitroimidazole compound developed in France to treat protozoal infections."
• Bactericidal to anaerobic organisms
• "Believed to disrupt bacterial deoxyribonucleic acid (DNA) synthesis in conditions with a low reduction potential."
• "Not the drug of choice for treating A. actinomycetemcomitans infections, but it may be effective at therapeutic levels because of its hydroxy metabolite. However, metronidazole is effective against A. actinomycetemcomitans when used in combination with other antibiotics."
• Effective against anaerobes such as Porphyromonas gingivalis and Prevotella intermedia

5.2.2 Clinical Use

• Used clinically to treat: gingivitis, acute necrotizing ulcerative gingivitis (NUG), chronic periodontitis, and aggressive periodontitis - as monotherapy and in combination with root planing and surgery or with other antibiotics
• "A single dose of metronidazole (250 mg orally) appears in both serum and GCF in sufficient quantities to inhibit a wide range of suspected periodontal pathogens."
• Administered systemically (750-1000 mg/day for 2 weeks), reduces the growth of anaerobic flora, including spirochetes
• Most common regimen: 250 mg three times daily (tid) for 7 days
• Loesche et al.: 250 mg tid for 1 week - infection considered "anaerobic" when spirochetes composed 20% or more of the total microbial count
• "Metronidazole used as a supplement to rigorous scaling and root planing resulted in a significantly reduced need for surgery compared with root planing alone."
• As monotherapy: "metronidazole is inferior and at best only equivalent to root planing. Therefore, if used, metronidazole should [be combined with SRP]."

5.2.3 Side Effects and Contraindications

• Disulfiram-like reaction with alcohol (patients must avoid alcohol)
• Patients on anticoagulant therapy should avoid metronidazole because it prolongs prothrombin time
• Should be avoided in patients taking lithium

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5.3 PENICILLINS

5.3.1 Pharmacology

• "Natural and semisynthetic derivatives of broth cultures of the Penicillium mold."
• Bactericidal - inhibit bacterial cell wall production

5.3.2 Clinical Use

• "Penicillins other than amoxicillin and amoxicillin-clavulanate potassium (Augmentin) have not been shown to increase periodontal attachment levels, and their use in periodontal therapy does not appear to be justified."

5.3.3 Amoxicillin

• "A semisynthetic penicillin with an extended antiinfective spectrum that includes gram-positive and gram-negative bacteria."
• Demonstrates excellent absorption after oral administration
• Susceptible to penicillinase, a β-lactamase produced by certain bacteria that breaks the penicillin ring structure
• Useful in management of patients with aggressive periodontitis (both localized and generalized forms)
• Recommended dosage: 500 mg tid for 8 days

5.3.4 Amoxicillin-Clavulanate Potassium (Augmentin)

• "The combination of amoxicillin with clavulanate potassium makes this antiinfective agent resistant to penicillinase enzymes produced by some bacteria."
• Useful in management of patients with LAP or refractory periodontitis
• Bueno et al. reported that Augmentin halted/arrested alveolar bone loss in patients with periodontal disease refractory to treatment with other antibiotics (including tetracycline, metronidazole, and clindamycin)

5.3.5 Side Effects

• KEY FACT: "Up to 10% of patients may be allergic to penicillin. Reactions... can range from skin rash to life-threatening anaphylaxis." (Newman 14th ed)

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5.4 CEPHALOSPORINS

• Family of β-lactams, similar in action and structure to penicillins
• Resistant to a number of β-lactamases normally active against penicillin
• "Generally not used to treat dental-related infections." Penicillins are superior to cephalosporins in range of action against periodontal pathogenic bacteria
• Side effects: Patients allergic to penicillins must be considered allergic to all β-lactam products; rashes, urticaria, fever, and GI upset

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5.5 CLINDAMYCIN

Pharmacology

• Effective against anaerobic bacteria
• Effective in situations where patient is allergic to penicillin (lincomycin derivative)

Clinical Use

• "Has shown efficacy in patients with periodontitis refractory to tetracycline therapy."
• Walker et al.: Clindamycin assisted in stabilizing refractory patients; dosage 150 mg qid for 10 days
• Jorgensen and Slots recommend: 300 mg bid for 8 days

Side Effects

• "Associated with pseudomembranous colitis" (caused by Clostridium difficile), but incidence is higher with cephalosporins and ampicillin

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5.6 CIPROFLOXACIN (Quinolone)

• Effective against gram-negative rods (including A. actinomycetemcomitans)
• Promotes health-associated microflora
• Can be combined with metronidazole (Metronidazole + Ciprofloxacin combination)
• "The only antibiotic in use in periodontal therapy that is effective against all strains of A. actinomycetemcomitans" (Carranza 10th ed)

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5.7 MACROLIDES - AZITHROMYCIN

• Concentrates at sites of inflammation; used systemically
• "Because azithromycin concentrates in phagocytes, there is potential for it to reach tissue-invasive A. actinomycetemcomitans." (Carranza 10th ed)
• Particularly valuable because of its unique pharmacokinetics - prolonged tissue half-life

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SECTION 6: ANTIBIOTIC COMBINATIONS IN PERIODONTAL THERAPY

• "As a result of increased resistance to tetracyclines, metronidazole or amoxicillin in combination with metronidazole has been found to be more effective for the treatment of aggressive periodontitis." (Newman 14th ed)

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SECTION 7: LOCAL DRUG DELIVERY (LDD) IN PERIODONTAL THERAPY

7.1 Rationale for Local Drug Delivery (Carranza 10th ed; Essentials - S. Reddy; Periodontics: Medicine, Surgery and Implants - Rose et al.)

• "The limitations of mouth rinsing and irrigation have prompted research for the development of alternative delivery systems."
• "Local administration of antiinfective agents, generally directly in the pocket, has the potential to provide greater concentrations directly to the infected area and reduce possible systemic side effects." (Carranza 10th ed)

7.2 Advantages of Local Drug Administration (Essentials - S. Reddy)

• Greater concentrations are achieved with reduced drug doses
• Systemic side effects are reduced
• Slow-releasing devices have the advantage of releasing antibiotics gradually
• Effect can be directed to specific target area

7.3 Disadvantages

• Drug can induce superinfections or hypersensitivity reactions
• Drug cannot reach tissue-invasive bacteria

7.4 Classification of Controlled-Release Local Delivery Systems (Essentials - S. Reddy)

CONTROLLED-RELEASE LOCAL DELIVERY SYSTEMS
         |
         |---- Reservoirs WITHOUT a rate-controlling system
         |          e.g. hollow fibers, gels, dialysis tubing
         |          [Effective only for 24 hours]
         |
         |---- Reservoirs WITH a rate-controlling system
                    e.g. polymeric matrices, polymer membranes,
                    monolithic matrices, coated particles
                    [Effective for MORE THAN 24 hours]

7.5 Locally Administered Agents - Currently Available (FDA-Approved)

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7.6 Tetracycline Fiber (Actisite) - Detail

• "Consist of a woven tube made of the polymer ethylene vinyl acetate (EVA) saturated with 25% tetracycline hydrochloride."
• Marketed as a 23-cm length of 0.5 mm diameter fiber containing 12.7 mg tetracycline hydrochloride
• "The flexible fiber is placed in an overlapping pattern into the periodontal pocket until it fills the pocket 1 mm apical to the gingival margin."
• "A serrated cord packing instrument is helpful in fiber placement."
• The gingival margin is then sealed with isocyanoacrylate
• "The placement of the cord does not in itself require anesthesia, but thorough root debridement is always required before placement."
• "EVA system is based on polymer technology with tetracycline dispersed within a solid (monolithic) polymer of EVA." (Essentials)
• "Maintaining over a 7- to 10-day period an average concentration of >1,590 mg/mL crevicular fluid." (Antibiotics & Antiseptics - Dumitrescu)

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7.7 Chlorhexidine Chip (PerioChip) - Detail

• "A small chip (4.0 × 5.0 × 0.35 mm) that contains 2.5 mg of the active ingredient chlorhexidine gluconate in a resorbable, biodegradable matrix of hydrolyzed gelatin that is cross-linked with glutaraldehyde."
• Stored at 20°C to 25°C (68°F to 77°F)
• "Indicated as an adjunct to SRP procedures for the reduction of pocket depth in adults with periodontitis, and it can be used as part of a periodontal maintenance program."
• "After placement in the pocket, the chip has been reported to release chlorhexidine into the GCF over 7 to 10 days."
• Chlorhexidine disrupts the cell membrane and causes precipitation of the cytoplasm, resulting in cell death
• No significant tooth staining noted in clinical studies of chlorhexidine chip

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7.8 Methods of Delivery of Chemotherapeutic Agents (Essentials - S. Reddy)

METHODS OF DELIVERY
        |
        |---- Keyes Technique
        |       (Sodium bicarbonate + hydrogen peroxide slurry)
        |
        |---- Root Biomodification
        |       (Tetracycline, doxycycline, citric acid, fibronectin on root surfaces)
        |
        |---- Irrigation Devices
                |
                |---- Home Irrigation Devices
                |         Supragingival
                |         Subgingival
                |         Marginal
                |
                |---- Professional Subgingival Irrigation

Keyes Technique

• "Involves application, by toothbrushing, of a slurry of sodium bicarbonate and hydrogen peroxide for the control of plaque microorganisms."
• "Various studies have proved that minimal clinical benefit can be expected from this technique simply because toothbrushing offers an ineffective means of delivering medicaments into the periodontal pocket." (Essentials - S. Reddy)

Root Biomodification

• "Application of various medicaments to root surfaces during surgical therapy."
• Agents include: tetracycline, doxycycline, citric acid and fibronectin
• "Application... during surgery may enhance connective tissue attachment to the roots, although available data are inconclusive." (Essentials - S. Reddy)

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SECTION 8: ANTISEPTICS IN PERIODONTAL THERAPY

8.1 CHLORHEXIDINE

8.1.1 Chemistry

• "Chlorhexidine is the most studied and certainly the most effective antimicrobial in oral use." (Dumitrescu)
• "At physiological pH, chlorhexidine is a large dicationic molecule, (1,6-di(4-chlorophenyl-diguanido)hexane, with the positive charge distributed over the nitrogen atoms on either side of the hexamethylene bridge." (Dumitrescu)
• "Chlorhexidine has the ability to adsorb onto negatively charged surfaces, such as bacterial cell walls, where it exerts its bacteriostatic and bactericidal effects." (Dumitrescu)
• "Has a wide spectrum of activity encompassing gram-positive and gram-negative bacteria, yeasts, dermatophytes, and some lipophilic viruses." (Dumitrescu)
• Activity is greater at alkaline than at acid pH and is reduced in the presence of organic matter

8.1.2 Mechanism of Action (Dumitrescu)

1. Chlorhexidine (dicationic) adsorbs onto negatively charged surfaces (bacterial cell walls)
2. Strongly adsorbs to phosphate-containing compounds
3. Alters the integrity of the bacterial cell membrane
4. Binds to phospholipids in the inner membrane - increases permeability of inner membrane
5. Leakage of low-molecular-weight components (e.g., potassium ions)
6. "Reservoir" effect: Chlorhexidine binds to oral surfaces (teeth, mucosa), pellicle and saliva - after a single rinse, saliva exhibits antibacterial activity for up to 5 h; persistence at oral surfaces suppresses salivary bacterial counts for over 12 h

8.1.3 Clinical Use

• 0.2% concentration (Europe): Used as a preventive and therapeutic agent for years (Carranza 10th ed)
• 0.12% concentration (USA): Prescription rinse
• "Is either bacteriostatic or bactericidal, depending on the dose." (Carranza 10th ed)
• "ADA Council on Dental Therapeutics has approved chlorhexidine to help prevent and reduce supragingival plaque and gingivitis." (Carranza 10th ed)
• Prescription rinse for short-term use (<6 months); long-term use (>6 months) has not been extensively studied
• Chlorhexidine gluconate is effective as an antiplaque rinse to reduce gingivitis, but not as a subgingival irrigant to reduce periodontal pocketing. Antiinfective activity is greatly reduced in the presence of organic matter in the subgingival periodontal pocket (Carranza 10th ed)
• Uses in periodontal practice (Dumitrescu):
  • Immediate preoperative rinsing/irrigation
  • Post-oral surgery / post-root planing
  • Full-mouth SRP protocol: brushing tongue dorsum with 1% CHX gel, chairside rinsing with 0.2% CHX, spraying tonsils, subgingival irrigation with 1% CHX gel

8.1.4 Interaction with Other Oral Products

• "CHX, a cation, interacts and forms salts of low solubility and antibacterial activity with anions, such as sodium lauryl sulfate (SLS) and sodium monofluorophosphate (MFP)." (Dumitrescu)
• "To optimize the antiplaque effect of CHX, it seems best that the interval between toothbrushing and rinsing with chlorhexidine be more than 30 min, cautiously close to 2 h after brushing." (Dumitrescu)

8.1.5 Side Effects (Dumitrescu)

• Tooth staining (brown coloration)
• Poor taste / taste disturbance (dysgeusia)
• Occasionally mucosal erosion
• Rarely parotid gland enlargement
• Calculus formation increase
• Proposed mechanisms of staining:
  1. Degradation of CHX molecule to release parachloroaniline
  2. Catalysis to Maillard reactions
  3. Protein denaturation with metal sulfide formation
  4. Precipitation of anionic dietary chromogens
• Effect minimized by limiting tea, coffee intake during CHX treatment

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8.2 PHENOLIC COMPOUNDS (Listerine)

• Mechanism: Nonspecific antibacterial action - "dependent upon the ability of the drug in its nonionized form to penetrate the lipid component of the cell walls of gram-negative organisms"
• "Phenolic compounds have also been shown to exhibit anti-inflammatory properties" - inhibit neutrophil chemotaxis, generation of neutrophil superoxide ion, and production of prostaglandin synthase (Essentials)
• Listerine: "an over the counter phenol precipitate that contains thymol, eucalyptol, menthol, methyl salicylate, benzoic acid and boric acid." (Essentials)
• Active ingredients: methyl salicylate and three essential oils (eucalyptol, thymol, and menthol) (Carranza 10th ed)
• ADA Council on Dental Therapeutics approved to help prevent and reduce supragingival plaque and gingivitis
• "May exacerbate xerostomia because of its high alcohol content, ranging from 21.6% to 26.9%." (Carranza 10th ed)
• "Generally contraindicated in patients under treatment for alcoholism who take Antabuse (disulfiram)." (Carranza 10th ed)

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8.3 QUATERNARY AMMONIUM COMPOUNDS

• "Cationic antiseptics and surface-active agents"
• "Tend to be more effective against gram-positive than gram-negative organisms" - most effective against early developing plaque (predominantly gram-positive)
• Include: Benzethonium chloride, Benzalkonium chloride, Cetylpyridinium chloride (CPC - Reach), Domiphen bromide
• Mechanism: Cationic binding to phosphate groups in cell wall; disruption of membrane integrity by hydrophobic interaction; disturbance of membrane functions and leakage of cytoplasmic material (Essentials)

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8.4 TRICLOSAN

• Phenol precipitate/bisphenol - broad-spectrum antimicrobial agent
• Mechanism: Inhibits cyclooxygenase and 5-lipoxygenase in pathways of arachidonic acid metabolism - reduces formation of proinflammatory metabolites such as PGE2 and leukotriene B4
• "Inhibited IL-1-induced production of PGE2 in human gingival fibroblasts" (Dumitrescu)
• "Since it does not bind well to oral sites due to its lack of a strong positive charge, formulations have been developed to enhance its ability to bind to plaque and teeth":
  • Combinations with zinc citrate
  • Incorporation of triclosan in a copolymer of methoxyethylene and maleic acid (Gantrez copolymer) to increase retention time
  • Combination with pyrophosphates to enhance calculus-reducing properties
• "No reports of adverse effects on the oral hard or soft tissues... No shifts in the microflora... favoring the growth of either opportunistic or pathogenic bacterial or yeast species." (Dumitrescu)

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8.5 POVIDONE-IODINE (Betadine)

• "Some evidence suggests that povidone-iodine (Betadine) may be an effective antibacterial agent when used directly into the periodontal pocket, even at low concentrations, but further studies are needed to substantiate these data."
• Must be used with caution in patients sensitive to iodine
• Should be used with caution in patients who are pregnant or lactating

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SECTION 9: HOST MODULATION THERAPY (HMT)

9.1 Definition and Concept

• "Host modulation with chemotherapeutic agents or drugs is the latest adjunctive therapeutic option for the management of periodontal diseases." (Newman 14th ed)
• "The concept of host modulation was first introduced to dentistry by Williams and Golub et al. and then expanded on by many other scholars." (Newman 14th ed)
• In 1990, Williams concluded: "there are compelling data from studies in animals and human trials indicating that pharmacologic agents, that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction, may be efficacious in slowing the progression of periodontitis."
• In 1992, Golub and colleagues discussed "host modulation with tetracyclines and their chemically modified analogues."

9.2 Drug Classes Evaluated as Host Modulation Agents (Newman 14th ed)

HOST MODULATION THERAPIES (HMT)
         |
         |---- SYSTEMIC HMTs
         |         NSAIDs
         |         Bisphosphonates
         |         Sub-Antimicrobial Dose Doxycycline (SDD) [ONLY FDA-APPROVED]
         |         Tetracyclines (CMT - Chemically Modified Tetracyclines)
         |
         |---- LOCAL HMTs
                   Topical NSAIDs (Ketorolac, Ketoprofen)
                   Enamel Matrix Proteins (Emdogain)
                   Bone Morphogenetic Proteins (BMP-2, BMP-7)
                   Growth Factors (PDGF, IGF)
                   Tetracyclines
         |
         |---- EMERGING HMTs
                   Probiotics
                   Omega-3 Polyunsaturated Fatty Acids (PUFAs)
                   Resolvins

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9.3 NSAIDs as HMTs (Newman 14th ed; Carranza 10th ed)

• "NSAIDs inhibit the formation of prostaglandins, including PGE2, which are produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to the presence of LPS." (Newman 14th ed)
• "PGE2 has been extensively studied in periodontal disease because it upregulates bone resorption by osteoclasts." (Newman 14th ed)
• NSAIDs include: salicylates (aspirin), indomethacin, ibuprofen, flurbiprofen, and naproxen
• Flurbiprofen: "In a 3-year study, Williams et al. reported that flurbiprofen significantly inhibited radiographic alveolar bone loss when compared with placebo. Unfortunately, by 24 months, the difference in the rate of bone loss had disappeared." (Carranza 10th ed)
• Topical ketorolac mouthrinse: "GCF levels of PGE2 were reduced by approximately half over 6 months and... bone loss was halted." (Newman 14th ed)
• "At present, topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis." (Newman 14th ed)

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9.4 Bisphosphonates as HMTs (Newman 14th ed)

• Can inhibit osteoclast-mediated bone resorption
• "Reports of bisphosphonate-related osteonecrosis of the jaw (BRON/ONJ), although primarily associated with intravenous administration rather than oral administration, have impeded the development of bisphosphonates as an HMT to manage periodontitis."
• "At present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases."

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9.5 Sub-Antimicrobial Dose Doxycycline (SDD) - PERIOSTAT

9.5.1 Definition

• "Sub-antimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline (Periostat) that is approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis." (Newman 14th ed, Carranza 10th ed)
• Taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing
• "In 1998 the Food and Drug Administration approved Periostat® (from CollaGenex) for use in the USA." (Dumitrescu)
• "Periostat® contains 20 mg of doxycycline in tablets to be taken orally twice a day for at least 3 months as adjunctive therapy in patients with chronic periodontitis (CP) undergoing the initial phase of periodontal treatment (SRP)." (Dumitrescu)
• "SDD (Periostat) is the ONLY systemically administered HMT specifically indicated for the treatment of chronic periodontitis that is approved by the US Food and Drug Administration (FDA) and accepted by the American Dental Association (ADA)." (Newman 14th ed)

9.5.2 Mechanism of Action - NON-ANTIBIOTIC

• "The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect."
• "Research studies have found no detectable antimicrobial effect on the oral flora or the bacterial flora in other regions of the body."

9.5.3 Mechanisms by which SDD/Doxycycline Inhibits MMPs (Summary by Walker, 2008 - cited in Dumitrescu)

1. Direct inhibition of active MMPs by cation chelation (dependent on Ca²⁺ and Zn²⁺-binding properties)
2. Inhibits oxidative activation of latent MMPs (independent of cation-binding properties)
3. Downregulates expression of key inflammatory cytokines (IL-1, IL-6, TNF-α) and PGE2
4. Scavenges and inhibits production of reactive oxygen species produced by neutrophils
5. Inhibits MMPs and ROS, thereby protecting α₁-proteinase inhibitor, indirectly reducing tissue proteinase activity
6. Stimulates fibroblast collagen production
7. Reduces osteoclast activity and bone resorption
8. Inhibits osteoclast MMPs

9.5.4 Clinical Evidence

• Preshaw et al.: 266 subjects with periodontitis, modified-release SDD vs. placebo as adjunct to SRP - "significantly greater clinical benefits than SRP alone."
• "Clinical improvements with SRP alone resulted in a mean gain of 0.5 mm in CAL, while adjunctive therapy with SDD resulted in an additional 0.35-mm gain in CAL above and beyond that seen with mechanical therapy alone, representing a 70% improvement in CAL." (Newman 14th ed)
• Modified-release SDD (Oracea): more recently approved by FDA for the common skin disorder rosacea; off-label use for periodontal diseases; once-a-day administration increases compliance
• Contraindicated: allergy to tetracycline; patients with allergic to tetracycline (Periostat is contraindicated)

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9.6 Alternatives to Systemic Antibiotics (Emerging) (Newman 14th ed)

• "Several novel preventive and therapeutic strategies, such as probiotics, prebiotics, and secreted bacterial products - such as bacteriocins - are being investigated as alternatives for antibiotics."
• Ability to suppress the periodontal pathogens and/or change the environment to be unfavorable for pathogens while protecting the commensal bacterial species
• Omega-3 Polyunsaturated Fatty Acids (PUFAs) and Resolvins: being investigated as HMTs

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SECTION 10: ANTIBIOTIC RESISTANCE

• "The overuse, misuse, and widespread prophylactic application of anti-infective drugs are some of the factors that have led to the emergence of resistant microorganisms."
• "Increasing levels of resistance of subgingival microflora to antibiotics have been correlated with the increased use of antibiotics in individual countries."
• "At least one Antibiotic Resistance Gene (ARG) has been identified in a majority of the population in a cross-sectional study, and the disease sites exhibited a further increase in prevalence of these ARGs."
• However, "the subgingival microflora tends to revert to similar proportions of antibiotic-resistant isolates 3 months after therapy."
• "No consensus exists regarding the magnitude of risk for the development of bacterial resistance."

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SECTION 11: CLINICAL GUIDELINES / SEQUENCING

11.1 Sequencing of Antimicrobial Agents (Carranza 10th ed - Figure 52-2)

FLOWCHART: SEQUENCING OF ANTIMICROBIAL AGENTS

STEP 1: COMPREHENSIVE EXAMINATION
         |
         v
STEP 2: INITIAL THERAPY (Scaling and Root Planing)
         Plaque and calculus removal
         Biofilm disruption
         |
         v
STEP 3: RE-EVALUATION (4-6 weeks post-SRP)
         |
         |--- Adequate response? --> Supportive periodontal therapy
         |
         |--- Inadequate response? (Refractory/Aggressive/Tissue-invasive disease)
                   |
                   v
STEP 4: MICROBIAL ANALYSIS
         (Endodontic paper point in deepest pocket
         Placed in reduced transfer fluid
         Sent to reference laboratory)
         |
         v
STEP 5: SELECTION OF APPROPRIATE ANTIMICROBIAL
         Based on: Patient's clinical status,
                   Medical and dental history,
                   Microbial analysis results,
                   Risks vs. benefits
         |
         v
STEP 6: ADJUNCTIVE ANTIMICROBIAL THERAPY
         (Systemic OR Local OR Both)
         ALWAYS as ADJUNCT to mechanical therapy
         |
         v
STEP 7: RE-EVALUATION POST-ANTIMICROBIAL THERAPY

11.2 Conclusion from Evidence (Newman 14th ed, Ch. 53; Carranza 10th ed, Ch. 52)

• "Manual instrumentation (scaling and root planing) alone is effective for reducing pocket depths, gaining increases in periodontal attachment levels, and decreasing inflammation levels (i.e., bleeding on probing)."
• "When systemic antibiotics are used as adjuncts to root instrumentation, the evidence indicates that some systemic antibiotics (e.g., metronidazole, tetracycline) provide additional improvements in attachment levels (0.35 mm for metronidazole; 0.40 mm for tetracycline) depending on the severity and form of the disease."
• "The use of anti-infective chemotherapeutic treatment adjuncts does not result in significant adverse effects for patients." (Newman 14th ed)

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SECTION 12: COMPARISON TABLE OF VIEWPOINTS ACROSS REFERENCES

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SECTION 13: RECENT TERMINOLOGY CHANGES (Examiner Note)

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SECTION 14: IMPORTANT EXAMINER KEYWORDS (Summary)

• Biofilm - Key rationale for chemotherapy (500x resistance)
• Bacteriostatic vs. bactericidal
• GCF concentration of tetracyclines (2-10x serum)
• Anticollagenase / MMP inhibition (tetracyclines/doxycycline)
• Sub-antimicrobial-dose doxycycline (SDD) / Periostat - only FDA-approved systemic HMT
• Controlled-release / sustained-release delivery
• EVA (ethylene vinyl acetate) - Actisite fiber
• Arestin, Atridox, PerioChip - FDA-approved local delivery
• Chlorhexidine - substantivity / reservoir effect (5h saliva / 12h oral surfaces)
• Chlorhexidine chip (PerioChip) - 2.5 mg CHX gluconate, 4×5×0.35 mm, biodegradable gelatin matrix
• CHX + SLS interaction - neutralization, >30 min gap required
• Metronidazole + Amoxicillin combination - aggressive periodontitis
• Ciprofloxacin - only antibiotic effective against ALL strains of A. actinomycetemcomitans
• Azithromycin - concentrates at sites of inflammation via phagocytes
• Penicillin allergy - up to 10% of patients; β-lactam cross-reactivity
• Pseudomembranous colitis - clindamycin side effect
• Disulfiram-like reaction - metronidazole + alcohol
• Antibiotic resistance genes (ARGs) - revert to pre-treatment levels 3 months post-therapy
• BRON/ONJ - bisphosphonate-related osteonecrosis; limits use as HMT
• Host modulation therapy (HMT) - Williams (1990) and Golub et al. (1992) - introduced concept
• "No silver bullet" - no single ideal antibiotic for all periodontal pathogens (Newman 14th ed)

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SECTION 15: TABLE OF COMMONLY USED DRUG DOSAGES

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Examiner's Overview of These Notes

1. Newman & Carranza's Clinical Periodontology and Implantology, 14th ed (2023)
2. Carranza's Clinical Periodontology, 10th ed (2006)
3. Antibiotics and Antiseptics in Periodontal Therapy - Dumitrescu (Springer 2011)
4. Clinical Periodontology and Implant Dentistry, 6th ed - Lang & Lindhe (2015)
5. Periodontics: Medicine, Surgery and Implants - Rose et al. (2004)
6. Essentials of Clinical Periodontology and Periodontics, 5th ed - Shantipriya Reddy
7. Pharmacology and Therapeutics for Dentistry, 7th ed - Dowd et al. (2017)
8. Misch Implantology 4th ed (limited relevant content found for this topic)

• Definitions and conceptual framework
• Full classification with the exact Table 52-1 / Table 53.1 from Carranza
• Ideal antibiotic properties (Gibson/Slots criteria)
• Systemic antibiotics - each drug with pharmacology, clinical use, dosage, side effects
• Local drug delivery - all FDA-approved devices with dimensions, compositions and mechanisms
• Antiseptics - Chlorhexidine (detailed mechanism, CHX chip, substantivity, interactions, side effects), Phenolics, QAC, Triclosan
• Host Modulation Therapy - SDD/Periostat (Walker 2008 mechanisms), NSAIDs, Bisphosphonates, Emerging HMTs
• Antibiotic resistance
• Sequencing flowchart
• Recent terminology changes (2018 AAP/EFP classification)
• Cross-reference comparison table of viewpoints across all sources
• Drug dosage summary table