Download Chemotherapeutic Agents in the Treatment of

Chemotherapeutic Agents in the
Treatment of Periodontal Diseases
D. Logien Al Ghazal
22/12/2015
Introduction
•Periodontal diseases result from susceptible hosts having their periodontal
tissues colonized by specific oral pathogens, that they are found in high number
that overcome the host defense mechanism
•In certain types of periodontal disease including:
•Chronic advanced periodontitis.
•Refractory periodontitis.
•Aggressive periodontitis.
•Periodontitis as a manifestations of systemic diseases.
• Adjunctive chemotherapeutic agents may be necessary to control the disease
process.
Chemotherapeutic agent is a general term for a chemical substance that
provides a clinical therapeutic benefit.
Clinical benefits can be derived through:
1. antimicrobial actions.
2. increase in the host's resistance
Antimicrobial agent: is a chemotherapeutic agent that works by reducing
the number of bacteria present.
Antibiotics are a naturally occurring, semisynthetic or synthetic type of
antimicrobial agent that destroys or inhibits the growth of selective
microorganisms, generally at low concentration.
•Antiseptics are chemical antimicrobial agents that are applied topically or
subgingivally to mucous membranes, wounds, or intact dermal surfaces to
destroy microorganisms and inhibit their reproduction or metabolism.
Antiseptics examples as the active ingredient in antiplaque and antigingivitis
mouthrinses and dentifrices.
•Disinfectants a subcategory of antiseptics, are antimicrobial agents that are
generally applied to inanimate surfaces to destroy microorganism.
Chemotherapeutic agents can be administered:
•Locally
•Orally.
•Parenterally.
Rationale for the use of antibiotics for treatment of periodontal
disease:
Systemic antibiotics may be a necessary adjunct in controlling bacterial
infection because bacteria can invade periodontal tissues, making
mechanical therapy alone sometimes ineffective.
Local administration of antimicrobial agents, generally directly in the
pocket, has the potential to provide greater concentrations directly to the
infected area and reduce possible systemic effects.
The possible clinical benefits of administering antibiotics to help control
periodontal disease must be weighed against possible adverse reactions.
Some adverse reactions include:
• Allergic/anaphylactic reactions
• Superinfections of opportunistic bacteria
•Development of resistant bacteria.
•Interactions with other medications.
•Upset stomach nausea,
•Vomiting.
Misuse of antibiotics
•Common and indiscriminate use of antibiotics worldwide has contributed to
increasing numbers of resistant bacterial strains over the last 15 to 20 years.
•The overuse, misuse, and widespread prophylactic application of antimicrobial
drugs are some of the factors that have led to the emergence of resistant
microorganisms.
•Increasing levels of resistance of subgingival microflora to antibiotics has been
correlated with the increased use of antibiotics in individual countries.
NOTE
Currently, an ideal antibiotic for the treatment of periodontal diseases does
not exist.
Although oral bacteria are susceptible to many antibiotics, no single
antibiotic at concentrations achieved in body fluids inhibits all putative
periodontal pathogens.
Indeed, a combination of antibiotics may be necessary to eliminate all
putative pathogens from some periodontal pockets"
Guidelines for use of antibiotics in
periodontal therapy
1. The clinical diagnosis and situation dictate the need for possible
antibiotic therapy as an adjunct in controlling active periodontal disease.
The patient's diagnosis can change over time. Example:
Patient that presents with generalized slight chronic periodontitis can return to
a diagnosis of periodontal health after initial therapy.
However, if this patient has been treated appropriately and continues to have
active disease, the diagnosis can change to refractory periodontitis.
2. Continuing disease activity, as measured by continuing attachment loss,
purulent exudate, and/or continuing periodontal pockets of >_5 mm, that
bleed on probing, is an indication for microbial analysis and
further periodontal therapy.
3. When used to treat periodontal disease, antibiotics are selected based
on the microbial composition of the plaque, the patient's medical status
and the current medications.
4. Microbiologic sampling is performed according to the instructions of the
reference microbiologic laboratory.
5. Plaque sampling can be performed at the initial examination, root
planning, reevaluation, or supportive periodontal therapy appointment.
6. Antibiotics have been shown to have value in reducing the need for
periodontal surgery in patients with chronic periodontitis.
7. Antibiotic therapy should not be used as a monotherapy. That is, it must
be part of the comprehensive periodontal treatment plan. This therapy
should have debridement of root surfaces, optimal oral hygiene, and
frequent supportive periodontal therapy at the center of therapy.
8. Slots and co-workers have described a series of steps using antimicrobial
agents for enhancing regenerative healing. They recommend starting
antibiotics 1 to 2 days before surgery and continuing for a total of at
least 8 days.
Guidelines for use of antimicrobial therapy
Types of antibiotics
Tetracyclines
Tetracyclines have been widely used in the treatment of periodontal diseases.
They have been frequently used in treating refractory periodontitis, including
localized aggressive periodontitis.
Mechanism of action
•Tetracyclines have the ability to concentrate in the periodontal tissues and
inhibit the growth of Actinobacillus actinomycetemcomitans.
•In addition, they exert an anticollagenase effect that can inhibit tissue
destruction and may aid bone regeneration
Pharmacology
 The tetracyclines are a group of antibiotics produced naturally from certain
species of Streptomyces or derived semisynthetically.
Bacteriostatic.
More effective against gram-positive bacteria than gram-negative bacteria.
Tetracyclines are effective in treating periodontal diseases in part because
their concentration in the gingival crevice is 2 to 10 times that in serum.
 Absorption altered by calcium, metal ions, or antacids.
Members of the tetracycline group
TETRACYCLINE. Tetracycline requires administration of 250 mg qid. It is
compliance may be reduced by having to take four capsules per day.
MINOCYCLINE: can be given twice a day, thus facilitating compliance when
compared with tetracycline.
Although it is associated with less photo- and renal toxicity than tetracycline, it
may cause reversible vertigo.
Minocycline administered in a dosage of 200 mg per day for 1 week results in a
reduction in total bacterial counts.
DOXYCYCLINE. Doxycycline has the same spectrum of activity as
minocycline and may be equally as effective." Because it can be given only
once daily, patients may be more compliant.
The recommended dosage when used as an antimicrobial agent is 100 mg
twice daily the first day, then 100 mg once daily.
Metronidazole
Pharmacology:
•Metronidazole is a nitroimidazole.
It is bactericidal to anaerobic organisms and is believed to disrupt bacterial DNA
synthesis.
•It is effective against A. actinomycetemcomitans when used in combination with
other antibiotics.
•Metronidazole is also effective against anaerobes such as Porphyromonas
gingivalis and Prevotella intermedia.
Clinical Usage.
•Metronidazole has been used clinically to treat acute necrotizing ulcerative
gingivitis, chronic periodontitis, and aggressive periodontitis.
•It has been used as monotherapy and also in combination with both root
planing and surgery or with other antibiotics.
•The most commonly prescribed regimen is 250 mg tid for 7 days
•Combination therapy: amoxicillin or amoxicillin-clavulanate potassium
(Augmentin), metronidazole may be of value in the management of patients with
localized aggressive or refractory periodontitis
Side Effects.
•Metronidazole has an antabuse effect when alcohol is ingested. The
response is generally proportional to the amount ingested and can result in
severe cramps, nausea, and vomiting.
•Products containing alcohol should be avoided during therapy and for at
least 1 day after therapy is discontinued.
•Metronidazole also inhibits warfarin metabolism. Patients undergoing
anticoagulant therapy should avoid metronidazole because it prolongs
prothrombin time.
•It also should be avoided in patients who are taking lithium.
Penicillins
Pharmacology:
•Penicillins are the most widely used antibiotics.
•Penicillins are natural and semisynthetic derivatives of broth cultures of the
Penicillium mold.
•Bactericidal.
Clinical Usage. Penicillins other than amoxicillinand amoxicillin-clavulanate
potassium (Augmentin).
Side Effects. Penicillins may induce allergic reactions and bacterial resistance; up
to 10% of patients may be allergic to penicillin.
Amoxicillin
May be useful in the management of patients with aggressive periodontitis,
both in the localized and generalized forms. Recommended dosage is 500 mg
tid for 8 day.
Amoxicillin-Clavulanate (Augmentin).
The combination of amoxicillin with clavulanate potassium makes Augmentin
resistant to penicillinase enzymes produced by some bacteria.
Augmentin may be useful in the management of patients with refractory or
localized aggressive periodontitis.
Cephalosporins
Pharmacology:
The family of /3-lactams known as cephalosporins is similar in action and
structure to penicillins.
They are frequently used in medicine and are resistant to a number of ßlactamases normally active against penicillin.
Clinical Usage. Cephalosporins are generally not used to treat dental-related
infections.
Side Effects. Patients allergic to penicillins must be considered allergic to all
ß-lactam products.
Rashes, urticaria, fever, and gastrointestinal upset have been associated with
cephalosporins.
Clindamycin
Pharmacology:
Clindamycin is effective against anaerobic bacteria.
It is effective in situations in which the patient is allergic to penicillin.
Clinical Usage.
In patients with periodontitis refractory to tetracycline therapy.
150 mg qid for 10 days or 300 mg twice daily for 8 days.
Side Effects
Pseudomembranous colitis
Diarrhea or cramping.
If symptoms persist, the patient should be referred to an internist.
Ciprofloxacin
Pharmacology.
Ciprofloxacin is a quinolone active against gram-negative rods.
.
Clinical Usage.
At present, ciprofloxacin is the only antibiotic in periodontal therapy to which
all strains of A. actinomycetemcomitans are susceptible. It also has been
used in combination with metronidazole.
Side Effects.
Nausea, headache, and abdominal discomfort have been associated with
ciprofloxacin.
Quinolones inhibit the metabolism of theophylline, and caffeine and
concurrent administration can produce toxicity.
Quinolones have also been reported to enhance the effect of warfarin and
other anticoagulants.
Macrolides
Pharmacology.
•They inhibit protein synthesis.
•They can be bacteriostatic or bactericidal, depending on the concentration of
the drug and the nature of the microorganism
Clinical Usage:
1. Erythromycin
•
It is not effective against most putative periodontal pathogens.
•
It is not recommended as an adjunct to periodontal therapy.
Spiramycin:
•Is active against gram-positive organisms; it is excreted in high
concentrations in saliva.
•It is used as an adjunct to periodontal treatment in foreign countries.
•It is a safe, nontoxic drug with few and infrequent side effects and is not
in general use for medical problems.
Azithromycin (Zithromax)
•Is a member of the azalide class of macrolides.
•It is effective against anaerobes and gram-negative bacilli.
•After an oral dosage of 500 mg once daily for three consecutive days,
significant levels of azithromycin can be detected in most tissues for 7 to
10 days.
•Therapeutic use requires a single dose of 250 mg per day for 5 days after
an initial loading dose of 500.
SERIAL AND COMBINATION ANTIBIOTIC
THERAPY
General points
•No single antibiotic is effective against all putative pathogens.
•It may be necessary to use more than one antibiotic, either serially or in
combination.
•Before combinations of antibiotics are used, the periodontal pathogen(s) being
treated must be identified and antibiotic susceptibility testing performed.
Clinical usage
•Antibiotics that are bacteriostatic (e.g., tetracycline) generally require rapidly
dividing microorganisms to be effective.
•They do not function well if a bactericidal antibiotic (e.g., amoxicillin) is given
concurrently.
•When both types of drugs are required, they are best given serially, not in
combination.
Combination therapy
Metronidazole and amoxicillin are clinically effective in treating localized
aggressive periodontitis.
Metronidazole-ciprofloxacin combination is a powerful combination against
mixed infections.
Selection of specific agents should be guided by the results of
cultures and sensitivity tests for subgingival plaque microorganisms.
HOST MODULATION
1. Doxycycline Hyclate: (Periostat)
Is given as an adjunctive treatment of periodontitis.
Periostat, available as a 20-mg capsule of doxycycline hyclate, is
prescribed for use by patients twice daily.
The mechanism of action:
•Is by suppression of the activity of collagenase, particularly that produced by
polymorphonuclear leukocytes.
•A schematic diagram of the role of matrix metalloproteinases in the progression of
periodontal disease.
2. Nonsteroidal Anti inflammatory Drugs
Rationale for their use in periodontal disease
•Following activation of inflammatory cells in the periodontium by bacteria,
phospholipids in the plasma membranes of cells are acted on by
phospholipase.
•This leads to the liberation of free arachidonic acid, which then can be
metabolized into prostaglandins, thromboxanes, and prostacycline by the
enzyme cyclooxygenase.
• Strong evidence suggests that cyclooxygenase pathway products (e.g.,
prostaglandins) may be important mediators of some pathologic events
occurring in periodontal diseases.
•Nonsteroidal antiinflammatory drugs (NSAIDs) may be of therapeutic value in
treating periodontal disease because of their ability to interfere with arachidonic
acid metabolism and thereby inhibit the inflammatory process.
•Some NSAIDs have been shown to affect the response of polymorphonuclear
neutrophils (PMNs) to inflammation not related to prostaglandin inhibition.
•Beneficial effects of NSAIDs have also been found after topical application.
•Drugs such as flurbiprofen, ibuprofen, mefenamic acid, and naproxen have been
studied.
Rationale
•The limitations of mouthrinsing and irrigation have prompted research for
the development of alternative delivery systems.
•Recently, advances in delivery technology have resulted in the controlled
release of drugs.
•The requirements for treating periodontal disease include a means for
targeting an antimicrobial to infection sites and sustaining its localized
concentration at effective levels for a sufficient time while concurrently
evoking minimal or no side effects
Tetracycline-Containing Fibers (Actisite)
•The first local delivery product.
•Is an ethylene/vinyl acetate copolymer fiber, diameter 0.5 mm, containing
tetracycline, 12.7 mg/9 inches (Actisite tetracycline fiber; manufactured by
Alza Corporation, Palo Alto, CA; distributed by Procter & Gamble Co.,
Cincinnati, OH).
•When packed into a periodontal pocket, it is well tolerated
by oral tissues, and for 10 days it sustains tetracycline concentrations.
•Crevicular fluid concentrations achieved by Actisite are more than systemic
administration.
Advantages:
•Reduction in probing depth, bleeding on probing, and periodontal pathogens
•Gain in clinical attachment level.
•In a 2-month study, compared with scaling and root planing, the fibers used
alone have provided more than a 60% greater improvement in probing depth
and clinical attachment level than scaling alone.
•No change in antibiotic resistance to tetracycline has been among
the tested putative periodontal pathogens.
Disadvantages:
•The length of time required for placement (10 minutes or more per tooth).
•Placement of fibers around 12 or more teeth has resulted in oral candidiasis in
a few cases.
Tetracycline-Containing Fibers (Actisite)
Subgingival Delivery of Doxycycline (Atridox)
•Atridox® (manufactured by Atrix Laboratories, Fort Collins, CO; licensed for
marketing by Block Drug, Inc., Jersey City, NJ).
•Is a gel system that incorporates the antibiotic doxycycline (10%) in a
syringeable gel system.
•Some studies showed reduction in probing depth and gain in clinical
attachment over 9 months.
Syringeable gel system
Subgingival Delivery System for Minocycline (Dentamycin and PerioCline)
•A subgingival delivery system of 2% (w/w) minocycline hydrochloride
(Dentamycin, Cyanamid International, Lederle Division, Wayne, NJ; PerioCline,
SunStar, Osaka, Japan).
•This system is a syringeable gel suspension delivery formulation.
•Reduction of probing depth and bleeding index.
•Gaining in clinical attachment and reduction in the periodontal pathogen count.
Subgingival Delivery of Metronidazole
•A topical medication (Elyzol; Dumex, Copenhagen, Denmark) containing an oilbased metronidazole 25% dental gel (glyceryl mono-oleate and sesame oil) has
been tested in a number of studies.
•It is applied in viscous consistency to the pocket, where it is liquidized by the
body heat and then hardens again forming crystals in contact with water.
•As a precursor, the preparation contains metronidazole-benzoate, which is
converted into the active substance by esterases in the crevicular fluid.
•Studies showed reduction in all clinical parameters with application of gel in 6
months follow up study.
LOCAL DELIVERY OF AN
ANTISEPTIC AGENT
(Periochip)
•It is a small chip (4.0 x 5.0 x 0.35 mm) composed of a biodegradable
hydrolyzed gelatin matrix, cross-linked with glutaraldehyde and also containing
glycerin and water, into which 2.5 mg chlorhexidine gluconate has been
incorporated per chip.
•This delivery system releases chlorhexidine and maintains drug
concentrations in the gingival crevicular fluid greater than 100 hg/ml for at least
7 days.
•Because the chip biodegrades in 7 to 10 days, a second appointment for
removal is not needed..
•Improvements in clinical signs were limited as presented by studies.
•No signs of staining were noted in any of the above three studies as a result of
the "chlorhexidine chip“ treatment.
•Adverse effects were minimal, with a few patients who complained of
slight pain and swelling in the first 24 hours after chip placement.
Insertion of (Periochip) in furcation area