Systemic antibiotics used in periodontics

systemic antibiotics in periodontics

1. SYSTEMIC ANTIBIOTICS

2. Contents INTRODUCTION DEFINITIONS HISTORY CLASSIFICATION SYSTEMIC ADMINISTRATION OF ANTIBIOTICS Background And Rationale Biologic Implications Commonly used antibiotics SERIAL AND COMBINATION ANTIBIOTIC THERAPY Rationale Clinical Use CONCLUSION REFERENCES

3. INTRODUCTION Antibiotics typically used in medicine - eliminate infections. Caused by invasion of host by foreign, pathogenic microorganism. Microbial etiology established inflammatory periodontal disease. Provides basis for introduction of antibiotics in overall management.

4. TERMINOLOGY Antimicrobial agent : designate synthetic as well as naturally obtained drugs that attenuate microorganisms. Antibiotics: Substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentrations.

5. Chemotherapeutic agent :: general term ability of an active chemical substance to provide therapeutic clinical benefits. Antiseptics : chemical antimicrobial agents that applied topically or subgingivally to destroy microorganisms and inhibit their reproduction or metabolism. Disinfectants: subcategory generally applied to inanimate surfaces to destroy microorganisms .

6. HISTORY Ehrlich’s Magic Bullets

7. Fleming and Penicillin

8. CLASSIFICATION Inhibit cell wall synthesis Protein Synthesis Inhibitors Penicillins Cephalosporins Vancomycin Bacitracin Inhibit 30s Subunit Aminoglycosides (gentamicin) Tetracyclines Inhibit 50s Subunit Macrolides Chloramphenicol Clindamycin Linezolid  Streptogramins MECHANISM OF ACTION

9. DNA Synthesis Inhibitors Fluoroquinolones   Metronidazole RNA synthesis Inhibitors Rifampin Mycolic Acid synthesis inhibitors Isoniazid Folic Acid synthesis inhibitors Sulfonamides Trimethoprim

10. Bacteriostatic Bactericidal Erythromycin Penicillin Tetracycline Cephalosporin Clindamycin Vancomycin Metronidazole Bactericidal : Works by killing the bacteria , inhibiting cellwall synthesis, interfering with bacterial DNA. Bacteriostatic : Weakens , disables and reversibily inhibits the growth and replication of bacteria. Giving the body’s natural defence mechanism time to become effective in overcoming an infection .

11. RATIONALE Microbial etiology provides the rationale for use of antimicrobial medication in periodontal therapy. Invading ability major periodontal pathogens to tissues outside the reach of periodontal instruments. Poor host defense mechanisms.

12. patients attachment loss after conventional therapy, patients with aggressive forms . predisposing medical conditions Refractory periodontitis. Patients with acute / severe periodontal infections. Patients with gingivitis or stable adult periodontitis responds well to mechanical periodontal therapy. Prime candidates – systemic therapy;

13. Reinforce mechanical periodontal treatment. Support host defense system in overcoming infection. by killing subgingival pathogens remain after conventional mechanical periodontal therapy. Efficacy lies in susceptibility of bacteria to antibiotics. AIMS

14. GUIDELINES

15. When used, selected based on patient's medical and dental status, current medications, and results of microbial analysis, if performed. An antibiotic strength 500 times greater than the systemic therapeutic dose be required . Systemic antibiotic therapy adjunct to comprehensive periodontal treatment plan.

16. Slots et al . Recommend starting antibiotics 1-2 days before surgery and continuing for a total of atleast 8 days. The value of this regimen has not been well documented. (Infectious aspects of periodontal regeneration. Periodo ntol 2000 :1999) Haffajee et al . concluded that data support similar effects for most antibiotics. Risks and benefits must be discussed with patient before using as adjuncts. (Systemic anti-infective periodontal therapy. A systematic review. Ann P eriodontol 2003)

17. SELECTION

18. Gingival fluid concentration Peak levels achieved at the primary ecological niche. Minimum inhibitory concentration (MIC90). Concentration that will inhibit growth of 90% of the bacterial strains. 100 (C GCF /MIC 90 ) = antimicrobial activity expressed as a percentage for each antibiotic and each organism. Two critical factors

19. PERIODONTAL DISEASES Chronic periodontitis Tetracycline, Doxycycline, Metronidazole, Clindamycin, Amoxicillin + Clavulinic acid (Augmentin), Azithromycin, Metronidazole + Amoxicillin, Spiramycin . Aggressive periodontitis systemic metronidazole-amoxicillin combination therapy. Tetracycline, Doxycycline, Minocycline, Metronidazole, Amoxicillin + Clavulinic acid (Augmentin), Metronidazole + Amoxicillin.

20. Necrotizing periodontal diseases: Periodontal abscess: Antibiotics recommended are amoxicillin, metronidazole and combination of amoxicillin+metronidazole . with systemic manifestations (fever, malaise, lymphadenopathy). In conjunction with surgical incision and drainage.

21. Antibiotic regimens for adult patients Amoxicillin: Loading dose of 1.0 g, maintenance dose of 500 mg/ t.i.d . for 3 days. With allergy to ß-lactam drugs: Azithromycin: Loading dose of 1.0 g on day 1, followed by 500 mg/ q.d . for days 2 and 3; Clindamycin: Loading dose of 600 mg on day 1, followed by 300 mg/ q.i.d . for 3 days.

22. PRINCIPLES OF ANTIBIOTIC DOSING Use an oral antibiotic loading dose: Achieve blood levels of the antibiotic at 2-8 times the minimal inhibitory concentration: Use frequent dosing intervals: Determine the duration of therapy by the remission of disease:

23. COMMONLY USED ANTIBIOTICS IN PERIODONTICS Tetracycline Pharmacology Produced Streptomyces or derived semisynthetically . Bacteriostatic drug Rapidly multiplying bacteria and gram positive bacteria than gram negative bacteria. Concentration in the gingival crevice is 2-10 times that in serum.

24. collagenase inhibition, inhibition of neutrophil chemotaxis , anti-inflammatory effects, inhibition of microbial attachment and root surface conditioning. Mode of action protein synthesis inhibition by binding to 30 S ribosomes. Non-antibacterial characteristics-

25. Clinical use Adjuncts in treatment of (LAP). Arrest bone loss and suppress A. actinomycetemcomitans levels. Tetracycline Dosage regimen-250 mg four times daily, Inexpensive lesser compliance.

26. Minocycline broad spectrum Suppresses spirochetes and motile rods. Suppression evident up to 3 months after therapy. Given twice daily. May cause reversible vertigo. Yields gingival fluid levels 5 times blood levels. Inhibit growth of gram-positive organisms .

27. Doxycycline Spectrum of activity as minocycline. Compliance favoured - once daily. Absorption slightly altered by calcium, metal ions, or antacids. R.D- 100 mg bid the first day, then 100 mg o.d . Reduce GI upset, 50 mg can be taken bid.

28. Doxycycline 20 mg – Sub antimicrobial dose. Indicated for management of chronic periodontitis. Trade name; Periostat – Doxycycline hyclate . Primarily; anti- collagenolytic . R.D- taken twice daily upto 9 months.

29. METRONIDAZOLE Pharmacology Synthetic nitroimidazole compound bactericidal effects - obligate gram-positive and gram-negative anaerobes. Campylobacterrectus - only facultative anaerobe susceptible to low concentrations.

30. Spectrum of activity- Fusobacterium and Selenomonas infections, Peptostreptococcus infections, P. gingivalis , P.intermedia and C. rectus infection, A. actinomycetemcomitans and E. corrodens infections. Mode of action Metronidazole acts by inhibiting DNA synthesis.

31. Clinical use Gingivitis, acute necrotizing ulcerative gingivitis, chronic periodontitis, and aggressive periodontitis. Used in combination with root planing , surgery or with other antibiotics. commonly 250 mg tid for 7 days

32. 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. (Clinical changes following four different periodontal therapies for the treatment of chronic periodontitis: 1 year results. J Clin Per iodontol 2007)

33. PENICILLIN Pharmacology Natural and semi synthetic derivatives. Broth cultures of the penicillium mould. Narrow spectrum and bactericidal in nature. Major activity : gram positive spectrum. Extended spectrum penicillins , ampicillin and amoxicillin, possess substantial antibacterial antimicrobial activity for gram-negative species.

34. Mode of action Interfere with the synthesis of bacterial cell wall, inhibit the transpeptidases so that cross linking does not take place.

35. Clinical use Management in aggressive periodontitis, both localized and generalized forms. Recommended dosage 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.

36. STUDIES More than 60% of adult periodontitis patients sampled harboured periodontal plaque that exhibited β-lactamase activity. Administration of β-lactamase sensitive penicillins , including amoxicillin alone, is not generally recommended. Some cases, may accelerate periodontal destruction.

37. Amoxicillin- Clavulanate (Augmentin) – Accepted strategy to administer amoxicillin with an inhibitor of beta-lactamase clavulanic acid . Augmentin management in refractory or localized aggressive periodontitis patients. Guided tissue regeneration, used to suppress periodontal pathogens and increase the gain of clinical attachment.

38. CEPHALOSPORINS Pharmacology Used for infections that might otherwise be treated with penicillin. Resistant to a number of β-lactamases normally active against penicillin. Mode of action Inhibition of bacterial cell wall synthesis.

39. CLINICAL USE Cephalexin - oral dosage form. Achieves high concentrations in GCF Inhibits gram-negative obligate anaerobes. Fails gram-negative facultative anaerobes. Newer cephalosporins extended gram-negative effectiveness Value in treatment of periodontal disease conditions.

40. CLINDAMYCIN Pharmacology Effective against anaerobic bacteria, and in patients allergic to penicillin. Mode of action Inhibits protein synthesis 50 S ribosome. Clinical use Achieves higher levels of antimicrobial activity. Gordon et al . observed mean gain of clinical attachment of 1.5 mm .

41. 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.

42. CIPROFLOXACIN Pharmacology Fluorinated 4-quinolone antibiotic-oral administration. Inhibits - gram negative bacteria, all facultative and some anaerobic putative periodontal pathogens including Pseudomonas aeruginosa , MIC 90 values ranging from 0.2 to 2 μg /ml. Mode of action Inhibits bacterial DNA replication. Transcription by inhibiting the enzyme DNA gyrase .

43. Clinical use Facilitates the establishment of a microflora associated with periodontal health. Only antibiotic in periodontal therapy to which all strains of A. actinomycetemcomitans are susceptible. Also used in combination with Nitroimidazoles .

44. MACROLIDES Pharmacology A poly-lactone ring to which one or more deoxy sugars are attached. Bacteriostatic or bactericidal, depending on the concentration of the drug and the nature of micro organism. Include erythromycin, spiramycin , and azithromycin. Mode of action Inhibit protein synthesis by binding to the 50 S ribosomal subunits.

45. ERYTHROMYCIN Principle limitation- poor tissue absorption. Preparations - as pro-drugs (erythromycin estolate , erythromycin stearate or erythromycin ethylsuccinate ). Clinical use Alternative to penicillin for allergic patients. GCF levels- small portion reaches the periodontal pocket by oral route.

46. Spiramycin Excreted high concentrations in saliva. Shown to reduce GCF volume, pocket depth and subgingival spirochete levels. Clinical use Effective against gram positive organisms, has minimal effect on increasing attachment levels.

47. 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. (A systematic review on the effect of systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients. J Clin Periodontol 2002)

48. AZITHROMYCIN Clinical use Effective - anaerobes and gram negative bacilli. Oral dosage of 500 mg o.d for 3 days, Significant levels detected in most tissues for 7-10 days. Proposed , penetrates fibroblasts and phagocytes in concentrations 100-200 times greater than that of extracellular compartment .

49. Actively transported to sites of inflammation by phagocytes 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.

50. AMINOGLYCOSIDES M.O.A-Inhibit protein synthesis binding irreversible 30 S ribosomal subunit. Inactive, anaerobic conditions- impaired intracellular transport in the absence of oxygen. All anaerobic bacteria are markedly resistant.

51. Adverse Effects

52. CHRONIC PERIODONTITIS Adjunctive antibiotic therapy Reduction in need for periodontal surgery. Adjunctive metrondazole 250 mg ., tid *7 days . Effective reduction in PPD, subgingival bacteria & gain in attatchment . ( Loesche et al.,1984.1991, 1992 & 1996) Amoxicillin + metrondazole as adjunctive therapy-effective reduction in Aa & P.gingivalis . ( van Winkelhoff et al.,1992 )

53. No additional treatment outcome benefits when antibiotics are used as adjuncts to scaling and root planning and periodontal pocket elimination surgery. ( Slots & Rams, 1990),( Listgarten et al.,1978). Currently systemic antibiotics are not an indication for chronic periodontitis.

54. REFRACTORY PERIODONTITIS Antibiotic sensitivity testing from subgingival microbial samples. Selection and testing of appropriate antibiotics Conventional periodontal therapy used in conjunction. Reevaluation with microbiological testing. Decision of choice of antibiotic depends on the pathogens present. Determined from DNA testing. Antibiotic therapy , reduce bacterial load when used in conjunction with scaling and root planning.

55. Clindamycin( gram negative) 150 mg q6h for 10 days. ( Walker et al) Metronidazole + Amoxicillin (Gram negative obligate/ facultative): 500mg amoxicillin+250 mg metronidazole: initially take 2 tabs of each, then 1 tab each q8h for 7 days. Amoxicillin.Clavulanate (Gram-positive): 250mg tid for 10 days. Metronidazole (Gram negative obligate): 250-500mg tid for 10 days. ( Loesche et al 1996, Winkel et al..2001).

56. AGGRESSIVE PERIODONTITIS Antibiotics immediately after scaling and root planing provide more probing depth reduction and gain of attatchment with healing improved upto 6 months. ( Dogan et al.,2007; Soder et al 1989 1. Penicillin VK ( 250-500 mg qid ) + metronidazole (250-500 mg tid )for 8-10 days. ( Yek et al,2010; Warker & Karpania 2002) 2. Other antibiotics recommended Tetracycline, Doxycycline, Minocycline, Metronidazole, Amoxicillin + Clavulinic acid (Augmentin), Metronidazole + Amoxicillin.

57. Guerreo et al . used a comparable treatment protocol in patients with aggressive periodontitis ,showed significantly better improvement of all periodontal parameters in the antibiotic treated patients compared to placebo treated subjects 6 months post-treatment. In chronic as well as in aggressive periodontitis, the antibiotics result in better resolution of the periodontal inflammation, better probing depths, and attachment loss reduction. (Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: A randomized placebo controlled clinical trial. J Clin Perio dontol 2005)

58. PERIODONTAL ABSCESS Indicated when accompanied with systemic manifestations (fever, malaise, lymphadenopathy). In conjunction with surgical incision and drainage.

59. Antibiotic regimens for adult patients with acute periodontal abscesses Amoxicillin : Loading dose of 1.0 g maintenance dose of 500 mg/ t.i.d . for 3 days, followed by a patient evaluation. Allergy to ß-lactam drugs: Azithromycin: Loading dose of 1.0 g on day 1, followed by 500 mg/ q.d . for days 2 and 3; Clindamycin: Loading dose of 600 mg on day 1, followed by 300 mg/ q.i.d . for 3 days. Slots et al, Science and Therapy Committee. Systemic Antibiotics in Periodontics. J Pe riodontol 2004

60. PROBLEMS IN THERAPY Periodontal disease is heterogeneous; Clinical diagnoses-based on clinical signs, not molecular pathology; Actual causal factor not been definitively identified. No microbiological sampling. Many different antibiotic protocols but - few RCT’s test efficacy of these protocols.

61. COMBINATIONS Broaden antimicrobial range of the therapeutic regimen. Prevent emergence of resistance - overlapping antimicrobial spectra. Lower dose of individual antibiotics - exploiting synergy between two drugs. Disadvantages Increased adverse reactions Antagonistic drug interactions with improperly selected antibiotics.

62. Six patients with recurrent progressive periodontitis were given the usual adult dosage of doxycycline for 4 days followed by amoxicillin with clavulanate for 5 days. Five similar patients were given doxycycline alone for 10 days. After 25 weeks, patients receiving the sequential combination had significantly greater pocket depth reduction than those receiving doxycycline alone.

63. In another study, all patients with recurrent periodontitis received regular bimonthly scaling and sequential dose of doxycycline and metronidazole. In the combined antibiotic group, 9% were observed to have recurrent periodontitis, whereas 42% of the placebo group showed signs of recurrent disease. Although these differences appear statistically significant, by 7 months after metronidazole, no difference in microbiota between groups could be detected.

64. Metronidazole and amoxicillin (MA) effective to combat Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis -associated periodontal infections. Winkel et al ., observed patients with subgingival P. gingivalis at baseline who were treated with metronidazole+amoxicillin showed approximately half the number of >5 mm pockets after therapy compared with P. gingivalis positive patients treated with placebo.

65. Metronidazole and clindamycin more efficient in eradicating anaerobic periodontopathic bacteria than doxycycline or mechanical therapy alone. Effective against A. actinomycetemcomitans . Metronidazole targets obligate anaerobes, and ciprofloxacin targets facultative anaerobes. Powerful combination against mixed infections . Studies of this drug combination in the treatment of refractory periodontitis have documented marked clinical improvement.

66. ANTIBIOTIC PROPHYLAXIS At greater risk of developing infection after dental procedures. Due to immunosuppression or decreased number of immune cells. Uncontrolled diabetes, organ transplantation, bone marrow transplantation, prosthetic joint replacement, leukemia , neutropenia, thrombocytopenia. To prevent infective endocarditis.

67. INFECTIVE ENDOCARDITIS HIGH RISK Prosthetic cardiac valves Previous bacterial endocarditis Complex cyanotic congenital heart disease (e.g. single ventricle states, transposition of the great arteries, tetralogy of Fallot ) Surgically constructed systemic pulmonary shunts or conduits A cardiac transplant that develops a problem in a heart valve. Mitral valve prolapse Rheumatic heart disease Bicuspid valve disease Calcified aortic stenosis Congenital heart conditions like VSD,ASD & hypertrophic cardiomyopathy. Those who no longer need prophylaxis

68. Endocarditis prophylaxis recommended (Walter et al 2007) Dental extractions Periodontal procedures including surgery, scaling and root planning, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips Initial placement of orthodontic bands but not brackets Intraligamentary local anaesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated

69. Indications for systemic use of antibiotics in periodontal therapy ( Beikler et al, 2003). antibiotic prophylaxis (e.g. with increased risk of endocarditis) NUG/NUP (American Academy of Periodontology, 2001) adjunctive antibiotic therapy in presence of specific periodontal pathogens in – aggressive periodontitis (American Academy of Periodontology, 2000b) – generalised severe chronic periodontitis – refractory periodontitis (American Academy of Periodontology, 2001) – moderate to severe periodontitis with systemic diseases or immune deficiencies (American Academy of Periodontology, 2000b) periodontal abscess spreading into adjacent tissue, with fever and/or severe lymphadenopathia (American Academy of Periodontology, 2001)

70. Antibiotic prophylaxis for oral procedure( 2007 Guidelines) Situation Drug Regimen( 30 min- 60 min before dental procedure) Oral Amoxicillin Adults: 2.0 g/ children: 50 mg/kg. Unable to take oral medications Ampicillin Or Cefazolin , or Ceftriaxone Adults: 2.0 g IM /IV/ children: 50 mg/kg IM/IV. Adults: 1.0 g IM /IV/ children: 50 mg/kg . Allergic to penicillins or ampicillin- oral Cephalexin Or Clindamycin Or Azithromycin Adults: 2.0 g / children: 50 mg/kg. Adults: 600mg / children: 20 mg/kg . Adults: 500 mg / children: 15 mg/kg . Allergic to penicillins & unable to take oral medications. Cefazolin or Ceftriaxone Or Clindamycin Adults: 1.0 g IM /IV/ children: 50 mg/kg IM/IV. Adults: 600 mg IM /IV/ children: 20 mg/kg IM/IV.

71. ANTIBIOTIC FAILURE Inappropriate choice of antibiotic. Emergence of antibiotic-resistant microorganisms. Too low blood concentration of the antibiotic. Slow growth rate of microorganisms. Impaired host defenses . Patient noncompliance Antibiotic antagonism

72. 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)

73. MECHANISMS OF RESISTANCE ANTIBIOTIC BACTERIAL RESPONSE Penicillins and cephalosporins • Destruction of the β-lactam ring by β-lactamases • Conformational modification of the target • Reduction in autolysis Erythromycin • Immediate excretion by intramembranal pumps • Conformational modification of the antibiotic target Tetracycline and derivatives • Immediate excretion by intramembranal pumps • Conformational modification of the antibiotic target • Enzymatic modification of the antibiotic Metronidazole • Lack of metronidazole activation through modification of bacterial nitroreductases • Reduction in uptake

74. Journal Reviews Systemic antimicrobial therapy using a combination of amoxicillin and metronidazole as an adjunct to SRP can enhance the clinical benefits of non-surgical periodontal therapy in adults who are otherwise healthy. ( Zandbergen et al ; . J Periodontol 2013) Systemic antibiotics combined with SRP offer additional clinical improvements compared to SRP alone. There were no statistically significant differences. A trend that for initially moderate and deep pockets, metronidazole or metronidazole combined with amoxicillin, resulted in clinical improvements that were more pronounced over doxycycline or azithromycin. A trend that the magnitude of the clinical benefit became smaller over time (1 year). ( Keestra et al, J Periodont Res 2015)

75. MONOTHERAPY ? From results of four studies evaluating metronidazole alone, or metronidazole combined with amoxicillin as monotherapy , it was concluded that the effect of the antibiotic alone was minimal and short term. ( Haffajee et al, systematic review. Ann Periodontol 2003) In patients with advanced periodontal disease, systemic antibiotic therapy without subgingival debridement might change the composition of the subgingival microbiota , resulting in multiple periodontal abscesses. ( Topoll et al.. Multiple periodontal abscesses after systemic antibiotic therapy. J Clin Periodontol 1990;)

76. Antibiotic regimens documented for treatment of periodontitis

77. CONCLUSION Systemic antibiotic therapy in Periodontics aims to reinforce mechanical treatment and to support host defences in overcoming periodontal infections by killing subgingival pathogens that remain after periodontal instrumentation.

78. References Carranza’s Clinical Periodontology 10 th ediion . Haffajee et al,Clinical changes following four different periodontal therapies for the treatment of chronic periodontitis: 1-year results. J Clin Periodontol 2007; 34:243–253. Pradeep et al, Clarithromycin, as an adjunct to non surgica periodontal therapy for chronic periodontitis: a double blinded, placebo controlled, randomized clinical trial. Arch Oral Biol 2011;56:1112–1119.

79. Newman et al, The use of the evidence based approach in periodontal therapy contemporary clinical workshop.Ann Periodontol 2003: 8,1-11. Slots et al, Infectious aspects of periodontal regeneration. Periodo ntol 2000 1999;19:164-72. Haffajee et al, Systemic anti-infective periodontal therapy. A systematic review. Ann P eriodontol 2003;8:115-81.

80. Guerrero et al . Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: A randomized placebo controlled clinical trial. J Clin Perio dontol 2005;32:1096-107.