Antibiotics in periodontics

Cuurent ADA specifications and role of Antibiotics in Periodontics

1. Antibiotics In Periodontics Dr. Rinisha Sinha

2. Contents

3. Introduction Antibiotics The greatest contribution of the 20 th century to therapeutics. Inhibit / kill the infective organisms and have no / minimal effects on the recipient.

4. Antibiotics A word derived from the Ancient Greek meaning: (anti  "against“; and bios  "life") The term "antibiotic" was coined by Selman Waksman in 1942 . Antibiotics: It is a naturally occurring, semisynthetic, or synthetic substance or compound produced by the microorganisms, i.e. a type of an anti-infective agent that selectively destroys or inhibits the growth of / kill other microorganisms Generally at very low concentration.

5. Penicillin , the first natural antibiotic discovered by Alexander Fleming in 1928. Originally known as antibiosis , The term antibiosis, which means " against life ," Was introduced by the French bacteriologist Vuillemin as a descriptive name of the phenomenon exhibited by these drugs. Fleming found that a diffusible substance was elaborated by Penicillium mould which could destroy Staphylococcus on the culture plate in 1929. Chain and Florey followed up this observation in 1939 which culminated the use of Penicillin in clinical use in 1941 Antibiotics

6. Chemotherapeutic agent: G eneral term for a chemical substance that provides a clinical therapeutic benefit. Anti-infective agent is a chemotherapeutic agent that works by reducing the number of bacteria present. Antimicrobial agents: Designate synthetic as well as naturally obtained drugs that attenuate micro-organisms. 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. Disinfectants: A subcategory of antiseptics, are antimicrobial agents that are generally applied to inanimate surfaces to destroy microorganisms Terminologies

7. The value of administering antimicrobial agents as a quick and inexpensive means of augmenting mechanical periodontal debridement is worthy of consideration. Periodontitis patients may benefit from systemic antibiotics , topical antibiotics and topical antiseptics . Antibiotics in Periodontal Therapy

8. Rationale The microbial etiology of inflammatory periodontal diseases provides the rationale for use of antibiotics in periodontal therapy. The ability of the organism to cause a disease depends upon the characteristic end products of bacterial metabolism , the chemical composition of bacterial components and its ability to overwhelm host . Systemic antibiotics may be a necessary adjunct in controlling bacterial infection because bacteria can invade periodontal tissues, making mechanical therapy alone sometimes in effective .

9. Ideal Antibiotic

10. Classification Based on Chemical Structure

11. Classification Based on Mechanism of Action

12. Classification Based on Type of Organisms against which it is primarily active

13. Classification Based on Spectrum of Activity

14. Classification Based on Type of Action

15. Classification Based on where it is obtained from

16. INDICATIONS FOR ANTIBIOTICS IN PERIODONTAL THERAPY Patients who do not respond to conventional periodontal therapy, Patients with acute periodontal infections with systemic manifestations, Prophylaxis in medically compromised patients As an adjunct to surgical and non-surgical periodontal therapy. Reference: AJ Van Winkelhoff , TE Rams, J Slots. Systemic antibiotics in periodontics. Periodontol2000. 1996; 10: 45-78

17. The clinical diagnosis and situation dictate the need for possible antibiotic therapy as an adjunct in controlling active periodontal disease. Disease activity as measured by continuing attachment loss , purulent exudate , and bleeding on probing may be an indication for periodontal intervention and possible microbial analysis. Antibiotics are selected based on the patient’s medical and dental status , current medications , and results of microbial analysis , if performed. Microbial plaque samples may be obtained from individual pockets or from pooled subgingival sites . GUIDELINES FOR USE OF ANTIBIOTICS IN PERIODONTAL DISEASE

18. Studies have shown that systemic antibiotics can improve attachment levels when they are used as adjuncts to scaling and root planing. Slots et al. Not well documented Antibiotic regimen – 12 days before surgery and continuing for a total of atleast 8 days Haffajee et al. Concluded that data supports similar effects for most antibiotics Reference: Manas D et al. 2009

19. May affect pharmacokinetics of many antibiotics Eg : Tetracylines accumulate in the developing teeth and bone SELECTION OF ANTIMICROBIALS Patient factors Age of patient Renal and Hepatic functions Renal failures: aminoglycosides, vancomycin, cephalosporin, metronidazole Liver disease: erythromycin, tetracycline, nalidixicacid , chloramphenicol

20. Presence of pus and secretions decrease the efficacy of sulfonamides and aminoglycosides Presence of necrotic material and foreign body makes eradication of infection practically impossible Hematomas foster bacterial growth e.g. tetracycline , penicillin and cephalosporin get bound to degraded Hb in the hematoma Lowering of pH at site of infection reduces activity of macrolide and aminoglycosides Anaerobic environment in the center of an abscess impairs bacterial transport processes which concentrate aminoglycosides in the bacterial cell Penetration barrier may hamper the access of the antibiotics to the site of infection in sub acute bacterial endocarditis Local Factors

21. Drug Allergy Impaired Host Defense History of previous exposure Imperative in those with impaired host defense, normal host defense, a bacteriostatic antibiotics exposure Pregnancy Safety of the drug

22. Clinical diagnosis Culture and sensitivity testing When bacteriological services not available, empirical therapy to cover all likely organisms with a broad spectrum drug may be used Organism related considerations Microbial Testing Should be completed initially to determine which species are present and the most effective antibiotic for targeting them Re-testing •to ensure that the antibiotic is successful; •At an interval of 3 months Reference: Shaddox and Walker, 2009; Fine, 1994

23. Based on the specific properties Spectrum of activity — narrow spectrum drug is preferred Type of activity — bactericidal preferred over bacteriostatic Sensitivity of the organism determined on the basis of MIC values Relative toxicity — a less toxic drug is preferred. Pharmacokinetic profile — to be present at the site of infection insufficient concentration for an adequate length of time Route of administration — oral or parenteral Evidence of clinical efficacy —the drug, its optimum dosage and duration of treatment are based on comparative clinical trials Cost — less expensive drug preferred Drug factors

24. ADVERSE EFFECTS OF ANTI-MICROBIAL AGENTS

25. Employ high doses for a short duration High concentrations are more critical with aminoglycosides, metronidazole and quinolones Use an oral antibiotic loading dose Achieve blood levels of the antibiotic at 2-8 times the minimal inhibitory concentration Use frequent dosing interval so as to maintain relatively constant blood levels. Determine the duration of therapy by the remission of disease ANTIBIOTIC DOSING PRINCIPLE Reference: Pallasch TJ. Pharmacokinetic principles of antimicrobial therapy. Periodontol 2000 1996

26. ANTIBIOTIC DOSING VARIABLE Reference: Goodson JM. Antimicrobial strategies for treatment of periodontal diseasesa. Periodontol 2000 1994

27. Ideally, the duration of antibiotic therapy is the shortest that will prevent both clinical and microbiological relapse. DURATION OF ANTIBIOTIC THERAPY Slots et al. described a series of steps using anti-infective agents for enhancing regenerative healing . They recommend starting antibiotics 1-2 days before surgery and continuing for a total of at least 8 days , however, the value of this regimen has not been well documented. Acute Orofacial infections have a rapid onset & short duration of 2-7 days or less Reference: Van Winkelhoff and Winkel, 2005

28. SYSTEMIC ANTIBIOTIC THERAPY

29. Eight principle antibiotic groups have been extensively evaluated for treatment of the periodontal diseases; ANTIBIOTICS IN PERIODONTICS Reference: Goodson JM. Antimicrobial strategies for treatment of periodontal diseases. Periodontol 2000. 1994;

30. MONOTHERAPY REGIMEN DOSE/DURATION AMOXICILLIN 500 mg Thrice a day for 8 days AZITHROMYCIN 500 mg Once daily for 4 – 7 days CIPROFLOXACIN 500 mg Twice a day for 8 days CLINDAMYCIN 300 mg Thrice a day for 10 days DOXYCYCLINE / MINOCYCLINE 100 – 200 mg Once a day for 21 days METRONIDAZOLE 500 mg Thrice a day for 8 days COMBINATION THERAPY METRONIDAZOLE + AMOXICILLIN 250 mg Thrice a day for 8 days METRONIDAZOLE + CIPROFLOXACIN 500 mg Twice a day for 8 days COMMON ANTIBIOTIC REGIMENS

31. TETRACYCLINE Produced naturally from certain species of Streptomyces or derived semi-synthetically Bacteriostatic drugs, effective against rapidly multiplying bacteria and gram positive bacteria than gram negative bacteria Concentration in the gingival crevice is 2-10 times than in serum Possess unique non-antibacterial characteristics- collagenase inhibition, inhibition of neutrophil chemotaxis, anti-inflammatory effects, inhibition of microbial attachment and root surface conditioning PHARMACOLOGY

32. Act by reversal inhibition of protein synthesis by binding to 30 S ribosomes in the susceptible organism. Adjuncts in the treatment of localized juvenile Periodontitis, generalized juvenile periodontitis, early onset periodontitis, and adult periodontitis Arrest bone loss and suppress A. actinomycetemcomitans levels in conjunction with scaling and root planing. 250 mg four times daily Inexpensive; Lesser Compliance MODE OF ACTION CLINICAL USE MODE OF ACTION ADVANTAGE Reference: Patil, et al.: Systemic antimicrobial agents

33. MINOCYCLINE Effective against a broad spectrum of microorganisms Act by reversible inhibition of protein synthesis Suppresses spirochetes and motile rods as effectively as scaling and root planing, with suppression evident up to 3 months after therapy Can be given twice daily , thus facilitating compliance Although associated with less phototoxicity and renal toxicity than tetracycline, may cause reversible vertigo Yields gingival fluid levels 5 times blood levels Except for the effect of minocycline on actinomycetes, none of the tetracyclines substantially inhibit the growth of oral gram-positive organisms by systemic delivery PHARMACOLOGY DOSAGE OF ADMINISTRATION = 200 mg/day Reference: Patil, et al.: Systemic antimicrobial agents

34. DOXYCYCLINE Same spectrum of activity as Minocycline Compliance is favored since it has to be taken once daily , absorption from gastrointestinal tract is only slightly altered by calcium, metal ions, or antacids The recommended dosage is 100 mg bid the first day, then 100 mg o.d To reduce gastrointestinal upset, 50 mg can be taken bid PHARMACOLOGY

35. METRONIDAZOLE A synthetic nitroimidazole compound with bactericidal effects primarily exerted on obligate gram-positive and gram-negative anaerobes Act by inhibition of DNA synthesis Campylobacter rectus is the only facultative anaerobe and probable periodontal pathogen that is susceptible to low concentrations of metronidazole Spectrum of activity-outstanding treatment for Fusobacterium and Selenomonas infections A poor choice for A. actinomycetemcomitans and E. corrodens infections, does not substantially suppress growth beneficial species The concentrations measured in gingival fluid are generally slightly less than in plasma PHARMACOLOGY Reference: Patil, et al.: Systemic antimicrobial agents

36. Metronidazole acts by inhibiting DNA synthesis For treating gingivitis, acute necrotizing ulcerative gingivitis, chronic periodontitis, and aggressive periodontitis As monotherapy , Metronidazole is inferior , should be used in combination with root planing, surgery or with other antibiotics The most commonly prescribed regimen is 250 mg tid for 7 days; 250 mg four times daily . In a study by Haffajee et al. , sites with initial pocket depth ≥6 mm showed significantly greater pocket depth reduction and greater attachment gain in subjects receiving Metronidazole or Azithromycin than in subjects who received Doxycycline . MODE OF ACTION CLINICAL USE

37. Severe cramps Nausea Vomiting and metallic taste Avoid in patients with history of alcohol taking, patients on anticoagulant therapy SIDE-EFFECTS

38. Natural and semi synthetic derivatives of broth cultures of the Penicillium mould Narrow spectrum and bactericidal in nature Major activity in the gram positive spectrum Only the extended spectrum penicillin, such as ampicillin and amoxicillin, possess substantial antimicrobial activity for gram-negative species Interfere with the synthesis of bacterial cell wall, inhibit the transpeptidases so that cross linking does not take place PENICILLIN MODE OF ACTION Reference: Patil, et al.: Systemic antimicrobial agents

39. In the management of patients with aggressive periodontitis , in both localized and generalized forms. Recommended dosage is 500 mg tid for 8 days Exhibits high antimicrobial activity at levels that occur in GCF for all periodontal pathogens except E. corrodens , S. sputigena and Peptostreptococcus , inhibits the growth of the gram positive facultative anaerobes. Studies indicate that more than 60% of adult periodontitis patients sampled harbored periodontal plaque that exhibited β-lactamase activity. For this reason, administration of β-lactamase sensitive Penicillin, including Amoxicillin alone, is not generally recommended and, in some cases, may accelerate periodontal destruction. CLINICAL USE Amoxicillin alone is not effective for treatment of chronic and aggressive periodontitis but effective in combination with metronidazole Reference: Soaresetal.,2012; Rabeloetal.,2015

40. Amoxicillin-Clavulanate (Augmentin) The generally accepted strategy is to administer amoxicillin with an inhibitor of beta-lactamase such as Clavulanic acid Beta-lactamase producing strains are generally sensitive to this preparation Augmentin may be useful in the management of patients with refractory or localized aggressive periodontitis patients In guided tissue regeneration, systemic amoxicillin-Clavulanic acid therapy has been used to suppress periodontal pathogens and increase the gain of clinical attachment

41. Used for infections that might otherwise be treated with penicillin. Resistant to a number of β-lactamases normally active against penicillin. Interfere with the synthesis of bacterial cell wall, inhibit the transpeptidases so that cross linking does not take place . Same mode of action as penicillin, i.e., inhibition of bacterial cell wall synthesis. However, they bind to different proteins than those which bind penicillin. CEPHALOSPORIN MODE OF ACTION Reference: Patil, et al.: Systemic antimicrobial agents

42. Cephalexin is a cephalosporin available for administration in an oral dosage form. Achieves high concentrations in GCF. Effectively inhibits growth of gram-negative obligate anaerobes, fails to inhibit the gram-negative facultative anaerobes. Newer Cephalosporin with extended gram-negative effectiveness could be of value in treatment of periodontal disease conditions. CLINICAL USE

43. Effective against anaerobic bacteria , and in patients allergic to penicillin . Inhibition of protein synthesis by binding to 50 S ribosome. Clindamycin achieves higher levels of antimicrobial activity than other antibiotics. Gordon et al observed a mean gain of clinical attachment of 1.5 mm and a decrease of disease activity in patients 24 months after adjunctive Clindamycin therapy Walker et al. showed that Clindamycin assisted in stabilizing refractory patients Dosage was 150 mg qid for 10 days Jorgensen and Slots recommended a regime of 300 mg bid for 8 days CLINDAMYCIN MODE OF ACTION CLINICAL USE

44. A fluorinated 4-quinolone antibiotic available for oral administration. A potent inhibitor of gram negative bacteria (all facultative and some anaerobic putative periodontal pathogens), including Pseudomonas aeruginosa, with MIC 90 values ranging from 0.2 to 2 μ g/ml. Inhibition of bacterial DNA replication and transcription by inhibiting the enzyme DNA gyrase , an enzyme unique to prokaryotic cells. CIPROFLOXACIN MODE OF ACTION

45. Facilitates the establishment of a microflora associated with periodontal health, minimal effects on streptococcus species, which are associated with periodontal health At present, ciprofloxacin is the only antibiotic in periodontal therapy to which all strains of A. actinomycetemcomitans are susceptible Also used in combination with Nitroimidazoles (metronidazole and tinidazole) CLINICAL USE

46. Contain a poly-lactone ring to which one or more deoxy sugars are attached Can be bacteriostatic or bactericidal , depending on the concentration of the drug and the nature of micro organism The macrolide antibiotics used for periodontal treatment include erythromycin, spiramycin , and azithromycin Inhibit protein synthesis by binding to the 50 S ribosomal subunits of sensitive microorganisms interfere with translation MACROLIDES MODE OF ACTION

47. An extremely safe drug that has often been recommended as an alternative to penicillin for allergic patients Gingival fluid levels suggest that only a small portion reaches the periodontal pocket by oral route Principle limitation of erythromycin is its poor tissue absorption Preparations for systemic administration are available as pro-drugs ( erythromycin estolate , erythromycin stearate or erythromycin ethyl succinate ) to facilitate absorption The pro-drug has little antibacterial activity until hydrolyzed by serum esterases ERYTHROMYCIN MODE OF ACTION

48. It is excreted in high concentrations in saliva The results of various clinical trials have revealed good efficacy of spiramycin in the treatment of periodontitis and meta-analysis of these studies revealed high levels of evidence supporting its efficacy It has been shown to reduce gingival crevicular fluid volume, pocket depth and subgingival spirochete levels Herrera et al. in a meta analysis evaluating Spiramycin , amoxicillin plus Metronidazole, and Metronidazole showed a statistically significant additional effect of Spiramycin in comparison to other antibiotics with regard to probing pocket depth reduction for sites with initial probing depth of more than 6 mm Effective against gram positive organisms , has minimal effect on increasing attachment levels SPIRAMYCIN CLINICAL USE

49. Effective against anaerobes and gram negative bacilli After an oral dosage of 500 mg o.d for 3 days , significant levels of Azithromycin can be detected in most tissues for 7- 10 days It has been proposed that Azithromycin penetrates fibroblasts and phagocytes in concentrations 100-200 times greater than that of extracellular compartment The azithromycin is actively transported to sites of inflammation by phagocytes , then directly released into the sites of inflammation as phagocytes rupture during phagocytosis Therapeutic use requires a single dose of 250 mg/day for 5 days after initial loading dose of 500 mg AZITHROMYCIN

50. CATEGORY AGENT MAJOR FEATURES Penicillin Amoxicillin Augmentin Extended spectrum of antimicrobial activity; excellent oral absorption used systemically Extended against penicillinase producing microorganisms ; used systemically Tetracycline Minocycline Doxacycline Tetracycline Effective against broad spectrum of microorganism; used systemically, applied locally ( subgingivally ) Used systemically; applied locally. Chemotherapeutically used in subantimicrobial dose for host modulation Used in sub-antimicrobial dose for host modulation. SYSTEMIC ANTIBIOTIC used in PERIODONTAL THERAPY

51. CATEGORY AGENT MAJOR FEATURES Quinolone Ciprofloxacin Effective against gram negative rods, promotes health associated microflora. Macrolide Azithromycin Concentrate at site of inflammation; used systemically Lincomycin derivatives Clindamycin Used in penicillase -allergic patients; effective against anaerobic bacteria; used systemically Nitroimidazole Metronidazole Effective against anaerobic bacteria; used systemically and applied locally ( subgingivally ) as gel LAP, GAP, MRP, RP, AP, NUG

52. Therapeutic Uses of Systemic Antimicrobial Agents for Various Periodontal Diseases

53. There are five daunting problems that have slowed progress of antibiotic therapy are Periodontal diseases are heterogeneous Clinical diagnoses are made on the basis of clinical signs, not molecular pathology The actual causal factor(s) have not been definitively identified No microbiological sampling There are many different antibiotic protocols but few well designed, randomized controlled trials that test the efficacy of these protocols Reference: Ellen RP, Mcculloch CA. Evidence versus empiricism: Rational use of systemic antimicrobial agents for treatment of periodontitis. Periodontol 2000. 1996

54. Serial systemic therapy 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 or metronidazole) is given concurrently When both types of drug are required, they are best given serially, not in combination, to avoid unfavourable interaction yet derive the benefit of both

55. Since the subgingival microbiota in periodontal disease consists of various putative pathogens that may differ in antimicrobial susceptibility, the use of a combination of two or more antibiotics may represent a valuable approach in periodontal chemotherapy Combination therapy Reference: van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Periodontol 2000 1996 Reference: Rybak MJ, McGrath BJ. Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician. Drugs 1996

56. Clinical reasons for antibiotic failure Inappropriate choice of antibiotic Emergence of antibiotic-resistant microorganisms Too low a blood concentration of the antibiotic Slow growth rate of microorganisms Impaired host defenses Patient noncompliance Antibiotic antagonism Inability of the antibiotic to penetrate to the site of the infection Limited vascularity or decreased blood flow Unfavorable local factors (decreased tissue pH or oxygen tension) Failure to eradicate the source of the infection (lack of incision and drainage) Pallasch TJ, 1996

57. LOCAL DRUG DELIVERY Goodson et al in 1979 first proposed the concept of controlled delivery in the treatment of periodontitis. The first delivery devices involved hollow fibers of cellulose acetate filled with tetracycline. They were primarily local delivery devices with minimal control of drug release. However ,Tetracycline fibers are no longer commercially available. Provides long-term retention of a highly concentrated drug at the base of the periodontal pocket Periodontal pockets provide natural reservoir bathed by gingival crevicular fluid that is easily accessible for the insertion of a delivery device. Controlled drug delivery-more prolonged availability and sustained action.

58. CLASSSIFICATION Personally applied (in patient home self-care) Non sustained subgingival drug delivery (home oral irrigation) Sustained subgingival drug delivery (none developed to date) Professionally applied (in dental office) Non sustained subgingival drug (professional pocket irrigation) Sustained subgingival drug delivery (controlled- release device)

59. COMPARISON OF SYSTEMIC AND LOCAL ANTIBIOTIC THERAPY Mombelli,2012

60. ANTIBIOTIC PROPHYLAXIS Recommended when these patients undergo procedures that are at risk for producing bacteremia . Incidence of infections such as Infective Endocarditis ranges from 5.0 to 7.9 per 100,000 person-years with a significant increasing trend among women

61. RECENT AHA REVISION IN ANTIBIOTIC PROPHYLAXIS Only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. IE prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse out-come Reference: Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-infective periodontal therapy.A systematic review. Ann Periodontol. 2003

62. ADDITIONAL CONSIDERATIONS “If the dosage of antibiotic is inadvertently not administered before the procedure, the dosage may be administered up to 2 hours after the procedure .” Patients who require prophylaxis but are already taking antibiotics for another condition. In these cases, the guidelines for infective endocarditis recommend that the dentist select an antibiotic from a different class than the one the patient is already taking.

63. REFERENCES Jolkovsky DL, Ciancio S. Chemotherapeutic agents. In: Carranza FA, Newman MG, Takei HH, Klokkevold PR, editors. Clinical periodontology. 10th ed. Philadelphia: WB Saunders; 2006 . Tripathi KD. Antimicrobial drugs : General considerations. In: Tripathi KD, editor. Essentials of medical pharmacology. 5th ed . New Delhi: Jaypee Publishers; 2003. Systemic antibiotic therapy in periodontics , Anoop Kapoor, Ranjan Malhotra, Vishakha Grover, and Deepak Grover Dent Res J (Isfahan). 2012 Slots J, MacDonald ES, Nowzari H. Infectious aspects of periodontal regeneration. Periodontol 2000 . 1999 Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-infective periodontal therapy.A systematic review. Ann Periodontol. 2003 van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Periodontol 2000 1996 Pallasch TJ. Pharmacokinetic principles of antimicrobial therapy. Periodontol 2000 . 1996 Herrera D, Sanz M, Jepsen S, Needleman I, Roldan S. A systematic review on the effect of systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients . J Clin Periodontol. 2002 Ellen RP, Mcculloch CA . Evidence versus empiricism: Rational use of systemic antimicrobial agents for treatment of periodontitis. Periodontol 2000 . 1996 THOMAES. RAMS & JBRGEN SLOTS Local delivery of antimicrobial agents in the periodontal pocket Periodontology 2000, 1995

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