Chemotheoropathic Agents Used in Periodontal Theraphy PDF

NEAR EAST UNİVERSİTY FACULTY OF DEPARTMENT OF PERIODONTOLOGY CHEMOTHEOROPATHİC AGENTS USED İN PERİODONTAL THERAPY Learning Outcomes: 1-Will be able to list the chemotherapeutic agents used for plaque control according to their indications. 2-Will be able to to differentiat...

NEAR EAST UNİVERSİTY FACULTY OF DEPARTMENT OF PERIODONTOLOGY CHEMOTHEOROPATHİC AGENTS USED İN PERİODONTAL THERAPY Learning Outcomes: 1-Will be able to list the chemotherapeutic agents used for plaque control according to their indications. 2-Will be able to to differentiate indications for the use of local and systemic antibiotics in periodontal diseases. 3- Will be able to select the drug dosages and administration timings for systemic antibiotics used in the treatment of periodontal diseases. 4-Will be able to differentiate indications for combined antibiotic therapy and distinguish between drug combinations, dosages, and administration timings. 5- Will be able to list antimicrobial agents used in local antibiotic therapy. In periodontal pockets, more than 500 bacterial species have been isolated. However, only a few of these species are responsible for causing periodontal lesions. The most pathogenic bacteria in terms of periodontal health are Gram-negative anaerobic rods. Additionally, there are pathogenic Gram-positive facultative and anaerobic cocci and rods, as well as Gram- negative facultative rods. Many antibiotics affect all these pathogens in different ways and to varying degrees. While mechanical periodontal treatment can remove the entire supra and subgingival bacterial mass, some of the pathogens may remain unaffected by treatment due to their ability to penetrate into periodontal tissues or their presence in areas where periodontal instruments cannot reach, posing a risk for disease recurrence. In fact, the presence of small amounts of potential periopathogens can be tolerated by the tissues. However, inadequacy in eliminating microorganisms should be considered as a biological factor that can lead to treatment failure and recurrence. Therefore, the use of antimicrobial agents as a support for periodontal treatment can enhance the effects of mechanical procedures or reduce the need for surgical intervention in cases where systemic or local antibiotic applications are considered to provide support to current mechanical treatment. A chemotherapeutic agent is defined as an active chemical substance that has the ability to provide benefit in clinical treatment. Clinical benefits may be in terms of antimicrobial function or strengthening host resistance. CHEMOTHERAPEUTIC AGENTS USED FOR PLAQUE CONTROL The data from epidemiological studies indicate that adherence to mechanical oral hygiene procedures is generally low, and the inability of mentally and physically disabled individuals to perform mechanical cleaning, along with the global increase in antibiotic resistance and costs, have brought the use of antiseptic agents into consideration in periodontal treatment 1 as an adjunct to mechanical therapy. Antiseptic agents are chemical products applied to living surfaces (e.g., mucous membranes, intact skin, wound surfaces) that inhibit or destroy the growth of microorganisms. The antiseptics used topically or subgingivally in dentistry act against infectious agents without posing a risk of developing resistance or interacting with prescribed medications. Additionally, these agents have a minimal risk of penetrating gingival tissues and causing systemic damage, making them highly reliable. However, their limitations include insufficient effectiveness in eliminating microorganisms, and the risks of cytotoxicity and hypersensitivity. 1. Bisguanidine Antiseptics: Chlorhexidine, which belongs to this group, is the most commonly used and most effective antiseptic. The positively charged chlorhexidine molecule attaches to negatively charged areas like the bacterial cell wall, exhibiting bacteriostatic and bactericidal effects. Its spectrum of activity covers a wide range, including Gram-positive and Gram- negative bacteria, yeasts, dermatophytes, and some lipophilic viruses. Chlorhexidine's ability to bind to the dental pellicle and oral mucosa enhances its anti-plaque effect. It also has an anti-gingivitis effect. Chlorhexidine is available in various forms, including mouthwash, gel, tablet, varnish, toothpaste, spray, and slow-release tablets. As a mouthwash, it is used at a concentration of 0.12% or 0.2%, twice daily after brushing and interdental cleaning, by rinsing the mouth for 30 seconds. The spray form is more localized and provides similar plaque inhibition as the mouthwash form. Despite its many beneficial effects, several side effects have been reported. These include tooth staining, unpleasant taste, alteration in taste perception, and less frequently, mucosal erosion, allergic reactions, and, very rarely, enlargement of the parotid gland. It is also important to note that the chlorhexidine molecule acts antagonistically with the anionic sodium lauryl sulfate found in toothpaste. Therefore, it is recommended to wait at least 30 minutes, preferably 2 hours, after brushing before using chlorhexidine. 2. Quaternary Ammonium Compounds: The cationic surfactants in this group interact with the bacterial cell wall, affecting permeability and leading to the loss of cell contents, thus exerting their effect. At a concentration of 0.1-2%, ammonium compounds exhibit bactericidal activity. They are generally used in mouthwash form and can be classified into two groups: those containing domiphen bromide and those containing benzethonium chloride or cetylpyridinium chloride (CPC). Although there are few studies on these agents, they have been found to reduce plaque formation and improve gingivitis parameters. 3. Detergents: Sodium lauryl sulfate (SLS) is an anionic detergent derivative commonly used in toothpaste and has a high affinity for protein molecules. It has been reported to exhibit anti-plaque effects similar to those of triclosan. 4. Phenols and Essential Oils: The American Dental Association (ADA) recommends two primary antiseptic agents for the treatment of gingivitis: prescription chlorhexidine mouthwash and over-the-counter essential oil-containing mouthwashes. Essential oils destroy the cell wall and inhibit bacterial enzymes. They contain thymol, eucalyptol, menthol, and methyl salicylate. Listerine is a combination of essential oils related to phenols, consisting of thymol and eucalyptol combined with menthol, methyl salicylate, and alcohol. The main 2 antimicrobial mechanism is based on disrupting the bacterial cell wall, inhibiting enzyme activities, slowing down plaque maturation, and reducing bacterial load, plaque quantity, and pathogenicity. Side effects of essential oil-containing mouthwashes include a bitter or sharp taste and a burning sensation. Long-term use has not been associated with the development of opportunistic infections, pathogenic bacteria, or resistant strains. An advantage is that there is no interaction with toothpaste. Today, alcohol-free options are available in addition to those containing up to 24% alcohol. 5. Triclosan: Triclosan is a bisphenol and a nonionic germicide used in toothpastes and mouthwashes. It is an agent with a broad spectrum of antibacterial activity and low toxicity. Although the exact mechanism of its antimicrobial action is not fully understood, it is thought to exert its effect by adsorbing to the lipid layer of the bacterial cell wall and interacting with transport system mechanisms. In addition to its antibacterial effects, triclosan has also been shown to have anti-inflammatory properties. At bacteriostatic concentrations, it inhibits the uptake of essential amino acids, while at bactericidal concentrations, it damages the bacterial cell wall. 6. Metal Salts: Various heavy metal salts can prevent dental plaque and calculus formation. The metal ions that have been proven to show plaque inhibition activity include zinc, copper, and tin. Zinc salts inhibit plaque formation by reducing plaque acidity, inhibiting glycolytic enzymes, and preventing bacteria from adhering to tooth surfaces. Stannous fluoride (SnF2), combined with a compound like Amine Fluoride (AmF), has been shown in studies to have plaque-inhibitory properties and is available in toothpaste, gel, controlled-release varnishes, dental floss, and mouthwash forms. 7. Oxidizing Agents: These are particularly effective in cases of necrotizing ulcerative gingivitis (NUG) where anaerobic bacteria play a significant role. There are limited studies in the literature on the effectiveness of oxidizing agents in supragingival plaque control. It has been shown that the use of these mouthwashes can lead to a reduction in plaque accumulation. However, it has also been reported that these agents can cause oral ulcerations, so they should be used with caution. 8. Halogen-Containing Antiseptics: Among the most potent microbicidal agents used for both antiseptic and disinfectant purposes, iodine is the most common and has the broadest spectrum in this group. It exerts its effect by penetrating the cell walls of microorganisms, disrupting the structure and synthesis of proteins and nucleic acids. Povidone-iodine is formed by combining iodine with the organic carrier polyvinylpyrrolidone (Povidone) and acts as an iodine-releasing agent. ANTİBİOTİCS: Antibiotics are substances that have the capacity to kill or inhibit the growth of microorganisms, and they can be either naturally produced by microorganisms or obtained from them. In periodontal treatment, the ideal antibiotic to be used should be: Allogenic and non-toxic 3 Specific Low in side effects Cost-effective Chemotherapeutic agents can be used locally or systemically. In local application, a high concentration can be directly achieved within the periodontal pocket. This reduces the bacterial population without causing systemic side effects. Systemic antibiotics can be given in cases where the desired outcome cannot be achieved with mechanical treatment alone. Bacteriostatic Versus Bactericidal Antibiotics Pharmacologic agents that prevent the growth of bacteria are bacteriostatic antibiotics, whereas pharmacologic agents that actually kill the bacteria are bactericidal antibiotics. Examples of bacteriostatic antibiotics include tetracycline and clindamycin, whereas penicillin and metronidazole are good examples of bactericidal antibiotics. In periodontics, antibiotics are used systemically in three situations: -Acute periodontal diseases -Periodontal diseases that do not respond to traditional mechanical therapy alone -Prophylaxis in individuals with systemic diseases -Systemic antibiotics have various advantages compared to topically used antimicrobial agents. They enter the bloodstream, allowing them to reach deep pocket bases, furcation areas, gingival epithelium, and connective tissue. Additionally, systemic antibiotics have the capacity to affect periodontal pathogens in oral mucosa and other tissues. This means that while eliminating and suppressing pathogens in the mouth, they can prevent them from recolonizing in periodontal pockets in the future. Moreover, systemic antibiotic treatment is a more cost-effective method for patients. The disadvantages include the potential for unwanted side effects and the development of antibiotic resistance. TETRACYCLİNES Tetracyclines are a group of antibiotics produced by the bacterium Streptomyces rimosus. They inhibit protein synthesis by binding to the 30S subunit of bacterial ribosomes and blocking the binding of aminoacyl-tRNA, making them bacteriostatic. They are among the least selective and have the broadest spectrum of antibiotics. In addition to their antimicrobial properties, tetracyclines have been found to have effects on collagen production, increasing it, and inhibiting the collagenase enzyme, which reduces collagen degradation. They have been frequently used to treat refractory periodontitis, including localized aggressive periodontitis (LAP), currently termed as periodontitis with molar-incisor pattern in 2018 classiffication. Since the late 1980s, they have gained prominence in the non-surgical treatment of chronic periodontitis due to their positive effects on collagen. Research has also shown their ability to detoxify diseased root surfaces. Subsequently, special tetracycline preparations with modified chemical structures have been developed. To summarize their other characteristics: 4 -Effective against Aa. -Anticollagenolytic, prevents tissue breakdown. -Bacteriostatic, effective against Gram-positive bacteria. -More effective against fast-growing bacteria. -Found in 2-10 times higher concentrations in gingival crevicular fluid compared to serum (2- 4μg/ml). -Has a slow-release feature. -Increases fibroblast and connective tissue attachment, contributing to periodontal regeneration. I-nhibits phospholipase A2 activity. -Neutralizes the effectiveness of reactive oxygen species produced by PMNs (polymorphonuclear leukocytes). -Inhibits the function of osteoclasts. -Other long-acting members of the semisynthetic tetracycline group antibiotics used in periodontology are minocycline and doxycycline. Points to consider during their use: They form chelates with metals like Ca, Fe, Zn, Al, Mg with +2 and +3 valences, reducing their absorption when taken with foods like milk and yogurt or with antacids and anti-anemic drugs. Tetracycline and oxytetracycline are excreted by the kidneys, while minocycline and doxycycline are metabolized in the liver. Clinical Use Tetracyclines have been investigated as adjuncts for the treatment of LAP.A. actinomycetemcomitans is a microorganism that is frequently associated with LAP, and it invades tissue. Therefore, the mechanical removal of calculus and plaque from root surfaces may not eliminate this bacterium from the periodontal tissues. Systemic tetracycline can eliminate tissue bacteria and has been shown to arrest bone loss and suppress A. actinomycetemcomitans levels in conjunction with scaling and root planing.This combination therapy allows for the mechanical removal of root surface deposits and the elimination of pathogenic bacteria from within the tissues. Increased posttreatment bone levels have been noted with the use of this method. As a result of increased resistance to tetracyclines, metronida zole or amoxicillin in combination with metronidazole has been found to be more effective for the treatment of aggressive periodontitis (currently classiffed as Generalized Stage III or IV Grade C Periodontitis or Localized Stage III/IV Grade C Periodontitis with molar- incisor pattern) in children and young adults. Some investiga tors think that metronidazole in combination with amoxicillin–clavulanic acid is the preferable antibiotic. SPECİFİC AGENTS Tetracycline, minocycline, and doxycycline are semisynthetic members of the tetracycline group that have been used in periodontal therapy. TETRACYCLİNE Treatment with tetracycline hydrochloride requires the administration of 250 mg four times daily. It is inexpensive, but compliance may be reduced by the need to take the medication so frequently. Side effects include gastrointestinal disturbances, photosensitivity, hypersensitivity, increased blood urea nitrogen levels, blood dyscrasias, dizziness, and 5 headache. In addition, tooth discoloration occurs when this drug is administered to children who are 12 years old or younger. MİNOCYCLİNE Minocycline is effective against a broad spectrum of microorganisms.In patients with adult periodontitis, it suppresses spirochetes and motile rods as effectively as scaling and root planing, with suppressionevident up to 3 months after therapy. Minocycline can be given twice daily, thereby facilitating compliance as compared with tetracycline. Although it is associated with less phototoxicity and renal toxicity than tetracycline, minocycline may cause reversible vertigo. Minocycline administered at a dose of 200 mg/day for 1 week results in a reduction of total bacterial counts, complete elimination of spirochetes for up to 2 months, and improvement of all clinical parameters. Side effects are similar to those of tetracycline; however, there is an increased incidence of vertigo. DOXYCYCLİNE Doxycycline has the same spectrum of activity as minocycline and can be equally effective. Because doxycycline can be given only once daily, patients may be more compliant. Compliance is also improved because its absorption from the gastrointestinal tract is only slightly altered by calcium, metal ions, or antacids, as is absorption of other tetracyclines. Side effects are similar to those oftetracycline hydrochloride; however, it is the most photosensitizing agent in the tetracycline category. The recommended dosage when doxycycline is used as an antiinfective agent is 100 mg twice daily the first day, which is then reduced to 100 mg daily. To reduce gastrointestinal upset, 50 mg can be taken twice daily after the initial dose. When given as a subantimicrobial dose (to inhibit collagenase), 20 mg of doxycycline twice daily is recommended. Side Effects Gastrointestinal system: nausea, vomiting, anorexia, enterocolitis Fanconi syndrome (similar to cystinosis) with expired preparations Tooth and bone discoloration and developmental abnormalities; not recommended for use in pregnant women and children under 8 years of age Pseudotumor cerebri syndrome in infants Vestibular disorders with minocycline Not recommended for individuals with renal dysfunction (azotemia) except for doxycycline Fatal hepatorenal syndrome Ketoacidosis in pregnant women Photosensitivity with demeclocycline Disturbance of intestinal flora leading to enterocolitis and stomatitis. Drug Interactions: -They reduce the effectiveness of penicillins. -Drugs that induce liver enzymes especially shorten the elimination (half-life) of doxycycline. -They increase the nephrotoxicity of potent diuretics. -They reduce the effects of oral contraceptives. -They potentiate the effects of oral anticoagulants. 6 METRONİDAZOLE: It is a nitroimidazole derivative. It exerts bactericidal effects on bacterial DNA synthesis. It is effective against protozoa, P. intermedia, and P. gingivalis infections. It is not effective against Aa if not used in combination with other antibiotics. It is used in the treatment of NG, chronic and aggressive periodontitis. When taken orally at 250 mg, it reaches effective concentrations in the serum and gingival crevicular fluid. Clinical Use Metronidazole has been used clinically to treat acute necrotizing gingivitis, chronic periodontitis, and aggressive periodontitis. It has been used as monotherapy and also in combination with root planing and surgery or with other antibiotics. Metronidazole has been used successfully to treat necrotizing gingivitis. Studies have suggested that when it is combined with amoxicillinor amoxicillin–clavulanate potassium (Augmentin), metronidazole may be of value for the management of patients with LAP or refractory periodontitis. Side Effects Metronidazole has an Antabuse effect when alcohol is ingested. Theresponse is generally roportional to the amount ingested and canresult in severe cramps, nausea, and vomiting. Products that contain alcohol should be avoided during therapy and for at least 1 day after therapy is discontinued. etronidazole also inhibits warfarin metabolism. Patients who are undergoing anticoagulant therapy shouldavoid metronidazole because it prolongs proth rombin time. It also should be avoided in patients who are taking lithium. This drug produces a metallic taste in the mouth, which may affect compliance PENİCİLLİN It is the most common group of antibiotics used in many serious infections. It can be obtained naturally or semi-synthetically. They have bactericidal effects. Approximately 10% of patients are allergic to penicillins. They are ineffective against microorganisms producing β-lactamase. Therefore, preparations of amoxicillin + clavulanic acid combination have been developed. Metronidazole + amoxicillin + clavulanic acid are used together in the treatment of aggressive periodontitis. AMOXİCİLLİN Amoxicillin is a semisynthetic penicillin with an extended antiinfective spectrum that includes gram-positive and gram-negative bacteria. It demonstrates excellent absorption after oral administration. Amoxicillin is susceptible to penicillinase, which is a β-lactamase produced by certain bacteria that breaks the penicillin ring structure and thus renders penicillins ineffective. Amoxicillin may be useful for the management of patients with severe form of periodontitis (1999 classified as localized/ generalized aggressive periodontitis). The recommended dosage is 500 mg 3 times daily for 8 days. AMOXİCİLLİN–CLAVULANATE POTASSİUM The combination of amoxicillin with clavulanate potassium makes this anti-infective agent resistant to penicillinase enzymes produced by some bacteria. Amoxicillin with clavulanate 7 (Augmentin) may be useful for the management of patients with LAP or refractory periodontitis. CLİNDAMYCİN Clindamycin is effective against anaerobic bacteria and has a strong affnity for osseous tissue. It is effective for situations in which thepatient is allergic to penicillin. Clindamycin has demonstrated effcacy in patients with periodontitisthat are refractory to tetracycline therapy. Walker and colleagues showed that clindamycin helped stabilize refractory patients; the dosage used was 150 mg 4 times daily for 10 days. CİPROFLOXACİN: It is effective against Gram-negative facultative and some anaerobic bacteria. It is sensitive to Aa and can be used in combination with metronidazole. Used in periodontitis where anaerobic microorganisms dominate and are resistant to tetracyclines. It can cause colitis, so caution should be exercised. MACROLİDES Macrolide antibiotics can be bacteriostatic or bactericidal depending on the concentration of the drug and the nature of the microorganism. The macrolide antibiotics used for periodontal treatment include erythromycin, spiramycin, and azithromycin. Erythromycin does not concentrate in GCF and is not effective against most putative periodontal pathogens. For these reasons, erythromycin is not recommended as an adjunct to periodontal therapy. Spiramycin is active against gram-positive organisms; it is excreted in high concentrations in saliva. Spiramycin has a minimal effect on attachment levels. Azithromycin 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 4 times daily for 3 days, significant levels of azithromycin can be detected in most tissues for 7 to 10 days. The concentration of azithromycin in tissue specimens from periodontal lesions is significantly higher than that of normal gingiva. To ascertain the effcacy of azithromycin for the management of periodontal diseases, future studies will need to increase the number of subjects, improve diagnostic methods and tools, and determine the appropriate dose, duration, and frequency of azithromycin therapy. CEPHALOSPORİNS The family of β-lactams known as cephalosporins is similar in action and structure to penicillins. These drugs are frequently used in medicine, and they are resistant to a number of β-lactamases that are normally active against penicillin. Cephalosporins are generally not used to treat dental-related infections. Penicillins are superior to cephalosporins with regard to their range of action against periodontal pathogenic bacteria. 8 COMBİNATİON ANTİBİOTİC THERAPY Periodontal infections are caused by a group of microorganisms that have not yet been fully elucidated. These can include various species of anaerobic, microaerophilic, Gram-negative, and Gram-positive bacteria. Therefore, there is no single antibiotic that is effective against all periodontal diseases. Sequential or combination antibiotic use may be beneficial. The most important thing to note is that bacteriostatic antibiotics should not be used together with bactericidal antibiotics. Combinations such as Metronidazole + Amoxicillin, Metronidazole + Augmentin, and Metronidazole + Ciprofloxacin are used in the treatment of periodontal infections. Conclusion Manual instrumentation (scaling and root planing) alone is effctive 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 signi¿cant adverse effects for patients. The decision regarding when to use systemic antimicrobials should be made on the basis of the clinician’s consideration of the clinical findings, the patient’s medical and dental history the patient’s preferences, and the potential bene¿ts of adjunctive therpy with these agents. Common Antibiotic Regimens Used to Treat Periodontal Diseases 9 Therapeutic Uses of Systemic Antimicrobial Agents for Various Periodontal Diseases As an adjunct when necessary” refers to presence of associated systemic conditions/complications. LOCAL DELİVERY AGENTS Systemic antibiotics have been considered insufficient to eliminate bacteria embedded within microbial biofilm layers, leading to the idea of directly applying antimicrobial agents to pockets to achieve high local concentrations. To ensure the long-term effectiveness of local applications, slow-release systems have been developed. These devices release antimicrobial agents over a specified period of time, potentially eliminating bacteria that are protected within the incompletely eradicated biofilm layer. Moreover, direct application of the active agent allows for the use of antibiotics that cannot be administered systemically. Controlled release systems consist of the active drug and an element that controls its release. Various local release devices have been developed for use in periodontal pockets. Some of these devices are biologically erodible, even though they do not absorb in the conventional sense. In some, flow rate can be controlled, such as polymer matrices, polymer membranes, monolithic matrices, coated particles, dialysis tubes, fiber and gel-based carrier systems. Control of flow rate is not possible in acrylic and cellulose strips, where chlorhexidine and metronidazole have been used. There are gels on the market that contain two percent minocycline (Dentomycine-Periocline) and 25 percent metronidazole (Elyzol). 10 Adjunctive Therapy Delivered, Controlled-Release Antimicrobials Locally delivered, controlled-release antimicrobial products are available for dental use in the United States : -Chlorhexidine-containing chip (PerioChip) -Doxycycline gel (Atridox -Minocycline microspheres (Arestin -Ethylene or vinyl acetate copolymer fiber containing the antibiotic tetracycline (Actisite as a 12.7-mg, 9-inch filament), was the firrst product introduced into the U.S. market in the early 1990s and was the prototypic system. -The tetracycline fiber is no longer commercially available in the United States, and its clinical use is not further considered, but it is included because data generated from clinical studies of the product are pertinent to a discussion of the general effects of locally delivered, controlled-release antimicrobials. Non-U.S. Locally Delivered, Controlled-Release Antimicrobials -Chlorhexidine-Based Products (PerioCol-CG, Chlo-Site) -Tetracycline-Based Products (PerioCol-TC, Periodontal Plus AB) -Doxycycline-Based Products (Ligosan Slow Release) Advantages of local (site-specific) antibiotic application: -Reduces the dosage of the drug. -Remains at a sufficient concentration in the desired area without distributing throughout the entire body. -Reduces systemic side effects (such as gastric problems). -Does not alter the normal flora in areas distant from the affected ones. -Makes it harder for antibiotic resistance to develop. -Easily usable by the patient. -Provides easy and convenient use in patients with mental and physical disabilities who cannot achieve proper oral hygiene and those using orthodontic appliances. Disadvantages of local antibiotic application: -Risk of developing hypersensitivity reactions in the patient. -Time-consuming process. 11 -Costliness. -Possibility of causing tissue damage if the carrier system is not used correctly. -Difficulty in completely removing the carrier system from the site after treatment (risk of creating a post-treatment infection focus). A decision tree for the selection of antibiotic therap. SRP, Scaling and root planing. REFERENCE: 1- Newman M, Klokkevold P, Carranza F et al. Newman and Carranza’s Clinical Periodontology And İmplant Dentistry, 14th Ed.Elsevier, 2023 12