1. Systemic antimicrobials in
periodontal therapy

2. CONTENTS
 Introduction
 Rationale for use of antibiotics in periodontal therapy
 Commonly prescribed antibiotics in periodontal therapy
 Penicillins (Amoxicillin)
 Nitroimadazole (Metronidazole)
 Tetracyclines
 Macrolides (Azithromycin,Clarithromycin)
 Lincomycin derivatives(Clindamycin)
 Fluoroquinolones (Ciprofloxacin)
 Antibiotic resistance
 Conclusion
 References

3. INTRODUCTION
Definition :
Antibiotics may be defined as the substances produced by
the microorganisms, which suppresses the growth of or
kill other microorganisms at very low concentrations.

4. CLASSIFICATION
A) Mechanism of action :
1. Inhibit cell wall synthesis
• Penicillins
• Cephalosporins
• Vancomycin
• Bacitracin
2. Cause leakage from cell membranes
• Polypeptides – Polymycins, colistin, Bacitracin
• Polyenes – Amphotericin B, Nystatin

5. 5. Inhibit DNA gyrase
• Fluoroquinolones – Ciprofloxacin
6. Interfere with DNA function
• Rifampacin
• Metronidozole
7. Interfere with DNA synthesis
• Idoxuridine
• Acyclovir
• Zidovudine

6. 8) Interfere with intermediary metabolism
Sulfonamides
Pyrimethamine
Ethambutol

7. B) Chemical structure
1. Sulfonamides and related drugs
• Sulfadiazine and others
• Sulfones – Dapsone (DDS), Paraaminosalicylic acid
(PAS).
2. Diaminopyrimidines
• Trimethoprim
• Pyrimethamine
3. Quinolones
• Nalidixic acid
• Ciprofloxacin
• Norfloxacin

8. 4. Tetracycline's
• Oxytetracycline
• Doxycycline etc
5. Nitrobenzene derivative
• Chloramphenicol
6. -lactam antibiotics
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems

9. 7. Aminoglycosides
• Streptomycin
• Gentamicin
• Neomycin etc
8. Macrolide antibiotics
• Erythromycin
• Roxithromycin
• Azithromycin etc
9. Polypeptide antibiotics
• Polymyxin-B
• Colistin
• Bacitracin

10. 10.Glycopeptides
• Vancomycin
• Teicoplanin
11.Oxazolidinone
• Linezolid
12.Nitrofuran derivatives
• Nitrofurantoin
• Furazolidone
13.Nitroimidozoles
• Metronidozole
• Tinidazole

11. 14.Nicotinic acid derivatives
• Isoniazid
• Pyrazinamide
• Ethionamide
15.Polyene antibiotics
• Nystatin
• Amphotericin-B
• Hamycin
16.Azole derivatives
• Miconazole
• Clotrimazole
• Ketoconazole

12. C) Type of organisms against which primarily active
1. Antibacterial
• Penicillins
• Aminoglycosides
• Erythromycin
2. Antifungal
• Griseofulvin
• Amphotericin B
• Ketoconazole
3. Antiviral
• Idoxuridine
• Acyclovir
• Zidovudine

13. 4. Antiprotozoal
• Chloroquine
• Pyrimethamine
• Metronidazole
• Diloxanide etc
5. Anthelmintic
• Mebendazole
• Pyrantel
• Niclosamide
• Diethyl carbamazine

14. D) Spectrum of activity
1. Narrow spectrum
• Penicillin G
• Streptomycin
• Erythromycin
2. Broad spectrum
• Tetracyclines
• Chloramphenicol

15. E) Type of action
1. Primarily
bacteriostatic
• Sulfonamides
• Tetracyclines
• Chloramphenicol
• Erythromycin
• Ethambutol
2. Primarily bactericidal
• Penicillins
• Aminoglycosides
• Rifampin
• Cotrimoxazole
• Cephalosporins
• Vancomycin
• Nalidixic acid
• Ciprofloxacin

16. F) Antibiotics are obtained from
1. Fungi
• Penicillin
• Cephalosporin
• Griseofulvin
2. Bacteria
• Polymyxin B
• Colistin
• Bacitracin
• Tyrothricin
3. Actinomycetes
• Aminoglycosides
• Tetracyclines
• Chloramphenicol
• Macrolides
• Polyenes

17. RATIONALE
 Bacterial deposits periodontal infections
 Mechanical treatment
Inability to eliminate pathogens like A. actinomycetemcomitans
Recolonization by pathogens residing in non – dental sites (Dorsum of
Tongue, Tonsils)
Adjunctive systemic antibiotics
(Van winkelhoff AJ,Rams TE, Slots J.Periodontol 2000 1996;10:45-78)

18.  Acute periodontal infections associated with systemic
manifestations
 Prophylaxis in medically compromised patients
 Recurrent periodontitis

19.  Ideal antibiotic for use in periodontal disease should be:
1. Specific for periodontal pathogen
2. Non-toxic
3. Substantive
4. Not in general use for treatment of other diseases
5. Inexpensive
(Gibson W,1982)

20.  GUIDELINES
1. Clinical diagnosis—patients diagnosis can change over time
2. Continuing disease activity
3. Selection based on patients medical, dental status, current
medications and microbial analysis
4. Microbiologic plaque sampling
--method
--indications: aggressive forms of disease, disease refractory to
standard mechanical therapy, periodontitis with systemic condition

21. 5. Reduce need for periodontal surgery in chronic
periodontitis patients
(Loesche 1992)
6. Antibiotics as monotherapy not recommended
--disruption of biofilm physically
(Greenstein 2005)
7. Slots et al 2000-- regenerative healing
--start antibiotics 1-2 days prior to surgery continue for 8
days
--not well documented

22. 8. Meta-analysis( Haffajee and Socransky 2003)
--similar effects for all antibiotics
--aggressive periodontitis patients benefited more
--overall factors

24. COMMON ANTIBIOTICS
USED FOR TREATMENT OF
PERIODONTAL DISEASES

25. Tetracyclines
 widely used in the treatment of periodontal diseases.
--used in treating refractory periodontitis; including localized aggressive
periodontitis.
 ability to concentrate in the periodontal tissues and inhibit the growth of
A. actinomycetemcomitans.
---anticollagenase effect that can inhibit tissue destruction and may aid bone
regeneration.

26.  Pharmacology: produced naturally from certain species of Streptomyces or
derived semisynthetically.
--bacteriostatic and are effective against rapidly multiplying bacteria.
--more effective against gram-positive bacteria than gram-negative bacteria.
 insoluble complexes by chelation

27.  concentration in the gingival crevice is 2 to 10 times that in serum
(Bader and Goldhaber 1968.)
 low gingival crevicular fluid concentration (2 to 4 µg/ml) are very
effective against many periodontal pathogens.
(Gordon et al and Pascale et al)

28. Side effects
 contraindicated during pregnancy
 cross the placenta and form a stable calcium complex in bone forming
tissue which can result in retardation of skeletal development
 not given to nursing mothers

29.  Clinical Use:
localized aggressive periodontitis (LAP).
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 (Slots et al 1983)
Increased post treatment bone levels

30.  Specific agents
 Tetracyclines:
--administration of 250 mg qid.
 Minocycline:
-- suppresses spirochetes and motile rods as effectively as scaling and root
planing, up to 3 months after therapy.
-- twice a day
--less photo and renal toxicity
-may cause reversible vertigo.

31. Minocycline --200 mg per day for I week
•reduction in total bacterial counts,
•complete elimination of spirochetes for periods of up to 2 months
•improvement in all clinical parameters.
(Ciancio 2000)

32.  Doxycycline
-- same spectrum of activity as minocycline
-once daily,
Compliance --its absorption from the gastrointestinal tract is not
altered by calcium, metal ions, or antacids, as is absorption of other
tetracyclines.
--100 mg twice daily the first day, then 100 mg once daily
--subantimicrobial dose to inhibit collagenase, it is recommended in a
20mg dose twice daily.

33. Penicillins
 Pharmacology : natural and semi-synthetic derivatives of broth cultures
of penicillium mold
 basic structure-- thiazolidine ring fused with a beta lactam ring
 inhibit bacterial cell wall production-- bactericidal.
 Substitutions and modifications on the acyl side chain ---semi synthetic
penicillins-- enhanced antimicrobial properties such stability to gastric
acids, resistance to hydrolytic enzymes
 The side chain also determines the stability of the penicillin against
degradation by gastric acid and by enzyme penicillinase (beta
lactamase)

34. Amoxicillin: semisynthetic penicillin
extended antimicrobial spectrum --gram-positive and gram-negative
bacteria.
excellent absorption after oral administration
susceptible to penicillinase,.
 Amoxicillin may be useful in the management of patients with
aggressive periodontitis, both in the localized and generalized forms.
 Jorgensen slots (2000) Recommended dosage is 500 mg tid for 8 days.

35. Amoxicillin-Clavulanate :
 management of patients with refractory or localized aggressive periodontitis.
 Bueno and co-workers arrested alveolar bone loss in patients with
periodontal disease that was refractory to treatment with other antibiotics
including tetracycline, metronidazole, and clindamycin.
Side effects
Allergic reactions(10%)

36. Metronidazole
 Pharmacology: Metronidazole is a Nitroimidazole compound developed
in France to treat protozoal infections
 bactericidal to obligate anaerobic organisms
 disrupt bacterial DNA synthesis in conditions in which a low reduction
potential is present.

37. Absorption, fate and excretion:
•rapidly and almost completely (80%) absorbed from the small bowel
•Food does not affect its bioavailability.
•The drug is metabolized mainly in liver
•The drug crosses the placental barrier and is present in the milk.

38.  Metronidazole is not the drug of choice for treating A.
actinomycetemcotnitans infections
 Rams and Slots 1992 showed, it is effective against A.
actinomycetemcomitans when used in combination with other
antibiotics.
 Greenstein in 1993 showed that Metronidazole is also effective against
anaerobes such as P. gingivalis and P. intermedia.

39.  Clinical Usage: Metronidazole has been used clinically to treat, acute
necrotizing ulcerative gingivitis, chronic periodontitis, and aggressive
periodontitis.
 Studies have suggested that when combined with amoxicillin or
amoxicillin -clavulanate potassium ---localized aggressive or refractory
periodontitis.

40.  Dosage :500mg tds for 8 days
Loesche 1992---> 20% spirochetes anaerobic infection
reduced need for surgery
 Side Effects:
 antabuse effect when alcohol is ingested
 inhibits warfarin metabolism---inc prothrombin time

41. Cephalosporins:
 Pharmacology:
similar in action and structure to penicillins. They are frequently used in
medicine and are resistant to a number of beta-lactamases
 Clinical Usage: not generally used to treat dental-related infections
 penicillins are superior to Cephalosporins in their range of action
against periodontopathic bacteria.

42. Side Effects: Patients allergic to penicillins must be considered allergic to all
beta-lactam products
Rashes, urticaria, fever, and gastrointestinal upset

43. Clindamycin
 Pharmacology: effective against anaerobic bacteria.
--patient is allergic to penicillin.
 Clinical Usage: Clindamycin has shown efficacy in patients with
periodontitis refractory to tetracycline therapy. Walker and co-workers
have shown aid in stabilizing refractory patients.(150 mg qid for 10 days.)
 Jorgensen and Slots have recommended a regimen of 300 mg twice daily
for 8 days.

44. Side Effects:
 pseudomembranous colitis
 Diarrhea or cramping that develops during the use of clindamycin may
be indicative of colitis --should be discontinued.

45. Ciprofloxacin
 Pharmacology: Ciprofloxacin is a quinolone active against gram-
negative rods, including all facultative and some anaerobic putative
periodontal pathogens.
 Chelation –cations --Decreased absorption
Clinical Usage:
 minimal effect on Streptococcus species---facilitate the establishment
of a microflora associated with periodontal health.
 only antibiotic in periodontal therapy to which all strains of A.
actinomycetemcomitans are susceptible.
 used in combination with metronidazole. (Slots et al 1992)

46. Side Effects: Nausea, headache, and abdominal discomfort have been associated
with ciprofloxacin.
-inhibit the metabolism of theophylline, and caffeine and concurrent
administration can produce toxicity.
---enhance the effect of warfarin
---NSAIDS--- Increased risk of central nervous system stimulation

47. Macrolides
 Pharmacology: Macrolide antibiotics contain a many-membered
lactone ring to which one or more deoxy sugars are attached.
 inhibit protein synthesis
 bacteriostatic or bactericidal, depending on the concentration of the
drug and the nature of the microorganism.
Clinical Usage:
 Erythromycin does not concentrate in gingival crevicular fluid, and it
is not effective against most putative periodontal pathogens. For these
reasons, it is not recommended as an adjunct to periodontal therapy

48. Azithromycin
 member of the azalide class of macrolides.
 effective against anaerobes and gram-negative bacilli
 500 mg once daily for three consecutive days.
 Concentration in tissue specimens from periodontal lesions is
significantly higher than that of normal gingiva

49. --penetrates fibroblasts and phagocytes in concentrations 100 to 200
times greater than that of the extracellular compartment.
 actively transported to sites of inflammation by phagocytes and then
released directly into the sites of inflammation as the phagocytes
rupture during phagocytosis.

50. Drug interactions
 Methylprednisolone ---Increased steroid concentration
 Nonsedating antihistamines (terfenadine, astemizole)
Increased antihistamine concentration--with the risk of life-threatening
arrhythmia
 Theophylline---- Increased serum levels

54.  Metronidazole ---P.g, P.i
 Clindamycin ---peptostreptococcus,ß-hemolytic streptococcus,gram
–ve anaerobic rods
Eikenella corrodens
 Tetracyclines ---A.a
Selection of antibiotics

55.  Fluoroquinolones(ciprofloxacin)--- enteric rods,pseudomonas,
Staphylococcus,A.a
 Azithromycin ---
Enterococcus, Staphylococcus,Eikenella corrodens, Fusobacterium
nucleatum,Peptostreptococcus
 Metronidazole +Amoxicillin---A.a,P.g
 Metronidazole +Ciprofloxacin---substitute
(Position Paper:Systemic Antibiotics in Periodontics; J Periodontol
2004;75:1553-1565.)

56. SERIAL AND COMBINATION
ANTIBIOTIC THERAPY
 why combination?
1)Synergism
2)Reduction in severity/incidence of adverse effects
3) Prevent emergence of resistance
4)Broaden spectrum of activity

57.  Rams and Slots metronidazole along with amoxicillin and
ciprofloxacin.
 metronidazole-amoxicillin combinations provided excellent elimination
of many organisms in adult and localized aggressive periodontitis that
had been treated unsuccessfully with tetracyclines and mechanical
debridement.

58. Metronidazole-ciprofloxacin
 effective against A. actinomycetemcomitans. Metronidazole targets
obligate anaerobes, and ciprofloxacin targets facultative anaerobes.
 This is a powerful combination against mixed infections. Studies of this
drug combination in the treatment of refractory periodontitis have
documented marked clinical improvement.
 therapeutic benefit --reducing or eliminating pathogenic organisms
prophylactic benefit --predominantly streptococcal microflora.

59.  Metronidazole + amoxicillin 250 mg/t.i.d./8 days of each drug
 Metronidazole + ciprofloxacin 500 mg/b.i.d./8 days of each drug

60. Antibiotic resistance
 indiscriminate use
Cross Resistance: Microorganism are resistance to particular drug frequently are
resistance to other chemically related antimicrobial agent
 organisms growing in biofilms are more resistant to antibiotics than the
same species growing in a planktonic (unattached) state
 slower rate of growth of bacterial species in biofilms
(Ashby et al 1994)

61.  The growth rates of these deeper cells decreased allowing them to
survive better
 the slower-growing bacteria often over express ‘‘nonspecific
defense mechanisms’’

62.  ion-exchange resin
 extracellular enzymes such as b-lactamases, formaldehyde lyase and
formaldehyde dehydrogenase may become trapped and concentrated in
the extracellular matrix, thus inactivating susceptible, typically
positively charged-- hydrophilic antibiotics.
 Super-resistant bacteria
 Quorum sensing

63. Conclusion

64.  Position Paper:Systemic Antibiotics in Periodontics. J Periodontol
2004;75:1553-1565.
 Systemic antibiotics in the treatment of periodontal disease
Jørgen slots& Miriam ting,
Periodontology 2000, Vol. 28, 2002, 106–176
 Clinical periodontology: Carranza 10th edition
 Dental biofilms:difficult therapeutic targets
Periodontology 2000, Vol. 28, 2002, 12–55
References

65. References
 Essentials of medical pharmacology: K.D Tripathi,5th edition

66. Thank you!