Systemic antimicrobials in periodontal therapy

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

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.

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. Inhibit DNA gyrase

• Fluoroquinolones – Ciprofloxacin

6. Interfere with DNA function

• Rifampacin

• Metronidozole

7. Interfere with DNA synthesis

• Idoxuridine

• Acyclovir

• Zidovudine

8) Interfere with intermediary metabolism

Sulfonamides

Pyrimethamine

Ethambutol

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

4. Tetracycline's

• Oxytetracycline

• Doxycycline etc

5. Nitrobenzene derivative

• Chloramphenicol

6. -lactam antibiotics

• Penicillins

• Cephalosporins

• Monobactams

• Carbapenems

7. Aminoglycosides

• Streptomycin

• Gentamicin

• Neomycin etc

8. Macrolide antibiotics

• Erythromycin

• Roxithromycin

• Azithromycin etc

9. Polypeptide antibiotics

• Polymyxin-B

• Colistin

• Bacitracin

10.Glycopeptides

• Vancomycin

• Teicoplanin

11. Oxazolidinone

• Linezolid

12.Nitrofuran derivatives

• Nitrofurantoin

• Furazolidone

13.Nitroimidozoles

• Metronidozole

• Tinidazole

14.Nicotinic acid derivatives

• Isoniazid

• Pyrazinamide

• Ethionamide

15.Polyene antibiotics

• Nystatin

• Amphotericin-B

• Hamycin

16.Azole derivatives

• Miconazole

• Clotrimazole

• Ketoconazole

C) Type of organisms against which primarily active

1. Antibacterial • Penicillins• Aminoglycosides• Erythromycin

2. Antifungal • Griseofulvin• Amphotericin B• Ketoconazole

3. Antiviral• Idoxuridine• Acyclovir• Zidovudine

4. Antiprotozoal

• Chloroquine

• Pyrimethamine

• Metronidazole

• Diloxanide etc

5. Anthelmintic

• Mebendazole

• Pyrantel

• Niclosamide

• Diethyl carbamazine

D) Spectrum of activity

1. Narrow spectrum

• Penicillin G

• Streptomycin

• Erythromycin

2. Broad spectrum

• Tetracyclines

• Chloramphenicol

E) Type of action

1. Primarily bacteriostatic

• Sulfonamides

• Tetracyclines

• Chloramphenicol

• Erythromycin

• Ethambutol

2. Primarily bactericidal

• Penicillins

• Aminoglycosides

• Rifampin

• Cotrimoxazole

• Cephalosporins

• Vancomycin

• Nalidixic acid

• Ciprofloxacin

F) Antibiotics are obtained from

1. Fungi

• Penicillin

• Cephalosporin

• Griseofulvin

2. Bacteria

• Polymyxin B

• Colistin

• Bacitracin

• Tyrothricin

3. Actinomycetes

• Aminoglycosides

• Tetracyclines

• Chloramphenicol

• Macrolides

• Polyenes

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)

Acute periodontal infections associated with systemic manifestations

Prophylaxis in medically compromised patients

Recurrent periodontitis

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)

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

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

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

COMMON ANTIBIOTICS USED FOR TREATMENT OF PERIODONTAL DISEASES

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.

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

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)

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

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

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.

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)

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.

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)

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. 

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%)

Metronidazole

Pharmacology: Metronidazole is a Nitroimidazole compound

developed in France to treat protozoal infec tions

bactericidal to obligate anaerobic organisms

disrupt bacterial DNA synthesis in conditions in which a low

reduction potential is present.

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.

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.

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.

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

Cephalosporins:

Pharmacology:

similar in action and structure to peni cillins. 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.

Side Effects: Patients allergic to penicillins must be considered

allergic to all beta-lactam products

Rashes, ur ticaria, fever, and gastrointestinal upset

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.

Side Effects:

pseudomembranous colitis

Diarrhea or cramping that develops during the use of

clindamycin may be indicative of colitis --should be

discontinued.

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)

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

 

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 concen trate 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 peri odontal therapy

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

--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.

Drug interactions

Methylprednisolone ---Increased steroid concentration

Nonsedating antihistamines (terfenadine, astemizole)

Increased antihistamine concentration--with the risk of life-

threatening arrhythmia

Theophylline---- Increased serum levels

Metronidazole ---P.g, P.i

Clindamycin ---peptostreptococcus,ß-hemolytic

streptococcus,gram –ve anaerobic rods

Eikenella corrodens

Tetracyclines ---A.a

Selection of antibiotics

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.)

 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

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.

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.

Metronidazole + amoxicillin 250 mg/t.i.d./8 days of each drug

Metronidazole + ciprofloxacin 500 mg/b.i.d./8 days of each

drug

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)

The growth rates of these deeper cells decreased allowing

them to survive better

the slower-growing bacteria often over express ‘‘nonspecific

defense mechanisms’’

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

Conclusion

Position Paper:Systemic Antibiotics in Periodontics. J Periodontol

2004;75:1553-1565.

Systemic antibiotics in the treatment of periodontal diseaseJørgen 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

References

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

Thank you!