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Sharma S, Kaur N, Kaur S. Anti-infective Therapy in Periodontics.J Periodontal Med Clin Pract

2015; 02:64-76

1 2 3Sharma Sahil , Kaur Navkiran , Kaur Supreet

Anti-infective Therapy In Periodontics

Review Article

Affiliation

1. MDS Student, Department of Periodontology and Oral Implantology, Sri Guru Ram Das Institute of

Dental Sciences and Research, Amritsar

2. MDS, Professor and Head, Department of Periodontology and Oral Implantology, Sri Guru Ram Das

Institute of Dental Sciences and Research, Amritsar

3. MDS, Reader, Department of Periodontology and Oral Implantology, Sri Guru Ram Das Institute of

Dental Sciences and Research, Amritsar

Corresponding Author:

Dr Sahil Sharma

Department of Periodontology and Oral Implantology, Sri Guru Ram das Institute of Dental Sciences

and Research, Amritsar

E-mail address: [email protected]

Conflict of interest declared: Nil

ABSTRACT

Periodontitis is a chronic disease characterized by INTRODUCTION

clinical attachment loss caused by intraoral biofilm Periodontitis is a chronic disease characterized by

harboring periodontal pathogenic microorganisms. clinical attachment loss caused by intraoral biofilm

The recognition that periodontal diseases are harboring periodontal pathogenic microorganisms.

associated with specific pathogens has led to The bacteria, along with calculus and other local

interest in the use of antibacterial drugs for factors, are the principal components that [1]inhibition of these microorganisms. The different perpetuate the disease process. Elevated

treatment modalities available to treat this disease proportions of some subgingival microbial species

are aimed at removal of microorganisms from both like Aggregatibacter actinomycetemcomitans,

hard and soft tissues. Systemic as well as local anti Porphyromonas gingivalis, Prevotella intermedia,

microbial agents are helpful adjuncts in reducing Tannerella forsythus etc. have been associated with [2,3] microbes especially in inaccessible areas along destructive periodontal disease activity.

with mechanical debridement therapy. Emerging evidence of bacterial specificity in

Key Words: Periodontitis , Systemic antibiotics , certain types of periodontitis has led to treatment

Locally delivered antimicrobials strategies, which are primarily aimed at

Vol-II, Issue - 2, May - Aug 2015

64

suppression or elimination of specific periodontal The microbial etiology of inflammatory [3] pathogens . Elimination or adequate suppression periodontal diseases provides the rationale for the

of putative periodontopathic microorganisms in the use of antimicrobial medication in periodontal

subgingival microbiota is essential for periodontal therapy. As evidence for bacterial specificity in [4] healing. Root deposits were considered in the periodontitis has accumulated and strengthened

etiology of periodontal disease, not because of over the past three decades, dentists have increased

mechanical irritation but rather because of their their use of systemic antibiotics in periodontal

microbial content. This observation led to therapy. This concept is based on the premise that

intensified efforts to achieve impressible oral specific microorganisms cause destructive

hygiene and to the gradual introduction of periodontal disease and that the antibiotic agent in

antimicrobial therapy, especially the systemic use vivo can exceed concentration necessary to kill or of antibiotics as an adjunct to other standard form inhibit pathogens. Prime candidates for systemic

of periodontal therapy. Adjunctive administration antibiotic therapy are patients who exhibit

of systemic antimicrobials has been useful in continuing loss of periodontal attachment despite

treating recurrent periodontal pockets. However, diligent conventional mechanical periodontal

the doses necessary to achieve sufficient local therapy .Studies demonstrated that the use of

concentrations of antimicrobials in the periodontal systemic antimicrobial agents adjunct to

environment might be associated with undesirable mechanical periodontal treatment may be an

side-effects. Therefore, local administration may important therapeutic strategy in the treatment of [6-8] [9-13]be considered as an alternative to overcome these chronic and aggressive periodontal

problems as it has lesser side effects, high potential diseases. These results were observed with the use

acceptability. o f d i f f e r e n t a n t i b i o t i c s , s u c h a s [14,15]Chemotherapeutic agents can be administered amoxicillin/metronidazole, azythromicin,

locally, orally, or parenterally. In either case, their clindamycin and clarithromycin, which showed

purpose is to reduce the number of bacteria present favourable results as adjunct to therapy for

in the diseased periodontal pocket. Systemic aggressive periodontitis and chronic periodontal

antibiotics may be a necessary adjunct in disease, when compared with the control group

controlling bacterial infection because bacteria can treated with mechanical therapy alone.

invade periodontal tissues, making mechanical CLASSIFICATION :

therapy alone sometimes ineffective. Local A. Chemical structure :

administration of antimicrobial agents, generally ? Sulfonamides and related drugs :

directly in the pocket, has the potential to provide Sulfadiazine and others Sulfones-

greater concentrations directly to the infected area Dapsone[5]and reduce possible systemic side effects. ? D i a m i n o p y r i m i d i n e s :

Trimethoprim, Pyrimethamine

S Y S T E M I C A D M I N I S T R AT I O N O F ? Quinolones : Nalidixic acid,

ANTIBIOTICS Norfloxacin, Ciprofloxacin

Background and Rationale ? B lactam antibiotics : Penicillins,



65

Cephalosporins, Monobactams Penicillins.

? Tetracycline : Oxytetracycline, Factors determining the efficacy of periodontal [16]Doxycycline antibiotic therapy

? N i t r o b e n z e n e d e r i v a t i v e : The efficacy of periodontal antibiotic therapy is

Chloramphenicol determined by the antimicrobial spectrum and the

? Aminogylcosides : Strptomycin, pharmacokinetic characteristics of the drug and by

Gentamycin the local environmental factors such as

? M a c r o l i d e a n t i b i o t i c s : 1) Drug binding to the tissues

Erythromycin, Azithromycin 2) Protection of pathogens through binding ,

? Nitroimadazole : Metronidazole, consumption, or degradation of products by

Tinidazole non target microorganisms

B. Mechanism of action : 3) Subgingival plaque biofilm protecting the

? Inhibit cell wall synthesis : pathogens

Penicil l ins, Cephalosporins, 4) Total bacterial load relative to the

Vancomycin m a x i m u m a c h i e v a b l e a n t i b i o t i c

? Caus es l e akage f rom ce l l concentration

membrane : Polymyxin, Colistins, Guidelines for use of antibiotics in periodontal [17]Bacitracin therapy include the following:

? Inhibi t protein synthesis : 1. The clinical diagnosis and situation dictate the

Tetracyclines, Chloramphenicol, need for possible antibiotic therapy as an adjunct in

erythromycin, Clindamycin controlling active periodontal disease.

? Cause misreading of m-RNA code 2. Continuing disease activity, as measured by

and affect permeability : Amino continuing attachment loss, purulent exudates,

g l y c o s i d e s , S t r e p t o m y c i n , and/or continuing periodontal pockets of ≥5 mm

Gentamycin that bleed on probing.

? I n h i b i t D N A g y r a s e : 3. Antibiotics have been shown to have value in

Fluoroquinolones – Ciprofloxacin reducing the need for periodontal surgery in

and others patients with chronic periodontitis.

? Interfere with DNA function :

Rifampicin, Metronidazole Tetracyclines (Agents that act by reversible [18]? Interfere with DNA synthesis : inhibition ofprotein synthesis)

Acyclovir, Zidovudine Tetracyclines are bacteriostatic in nature. They

C. Type of action : exert their anti-bacterial activity by inhibiting

? P r i m a r y B a c t e r i o s t a t i c : microbial protein synthesis. There is also evidence

Erythromycin, Clindamycin, that tetracycline may cause alterations in bacterial

Tetracycline, Sulfonamides cytoplasmic membrane, facilitating leakage of

? P r i m a r i l y B a c t e r i c i d a l : nucleotides and other compounds from the cell.

Cephalosporin, Metronidazole, This action would explain the rapid inhibition of



67

DNA replication that occurs when cells are Clinical Use: Systemic tetracycline can eliminate

exposed to concentrations of tetracycline in excess tissue bacteria and has been shown to arrest bone

of that needed for protein inhibition. loss and suppress A. actinomycetemcomitans levels [24]Pharmacology: in conjunction with scaling and root planing.

The tetracyclines are a group of antibiotics Tetracycline ( tetracycline-HCL, doxycycline ,

produced naturally from certain species of minocycline ) may be indicated in periodontal

Streptomyces or derived semisynthetically. They i n f e c t i o n s i n w h i c h A c t i n o b a c i l l u s

generally are more effective against gram-positive actinomycetemcomitans is the prominent pathogen [19]bacteria than gram-negative bacteria . .

Properties of Tetracycline Minocycline: Minocycline is effective against a

Apart from anti-bacterial activity, tetracycline also broad spectrum of microorganisms. In patients

exhibit additional pharmacological properties, with adult periodontitis, it suppresses spirochetes

which are of significance in management of and motile rods as effectively as scaling and root

periodontal disease. planing, with suppression remaining evident for up

They are as follows: to 3 months after therapy.[20](A) Collagenase inhibition:

Tetracycline has anti-collagenase property. Doxycycline: Doxycycline has the same spectrum

Interstitial collagenases are proteinase-type of activity as minocycline and may be equally as

enzymes, which degrade connective tissues. These effective. Doxycycline compliance is favored

enzymes are derived from a number of sources because its absorption from the gastrointestinal

including fibroblast, epithelial cells, macrophages tract is not altered by calcium, metal ions, or

(MMP-1), and neutrophils (MMP-8). antacids, as is absorption of other tetracyclines.[21](B) Anti-proteolytic property: METRONIDAZOLE

Tetracycline inhibition of neutrophil collagenase Pharmacology: Metronidazole is a nitroimidazole

may also prevent other proteolytic events . compound used to treat protozoal infections. It is [22](C) Inhibition of bone resorption: bactericidal to anaerobic organisms and is believed

Bone anti-collagenase and anti-proteolytic activity to disrupt bacterial DNA synthesis in conditions in

has been resulted in application of these drugs to which a low reduction potential is present. It is [22]inhibit bone resorption. Tetracyclines inhibit effective against A. actinomycetemcomitans when

[25-26]bone resorption induced by parathyroid hormone. used in combination with other antibiotics.

It inhibits osteoblast collagenase and may also have Metronidazole is also effective against anaerobes

a modifying effect on osteoclasts. such as Porphyromonas gingivalis and Prevotella [23] [27](D) Anti-inflammatory actions: intermedia.

Potential anti-inflammatory properties include the Nitroimidazole compounds have been used for the

ability of tetracycline to suppress PMN activity, in treatment of ANUG (metronidazole), refractory

particular, by scavenging action on reactive oxygen periodontitis (metronidazole), (ornidazole), adult

metabolites. periodontitis (metronidazole,) and early onset



68

periodontitis (ornidazole). or systemic adverse effects.

Clinical Usage: Metronidazole has been used 4. Organisms should not be resistant to the

clinically to treat gingivitis, acute necrotizing antimicrobial agents.

ulcerative gingivitis, chronic periodontitis, and 5. Antibiotic should be specific for periodontal

aggressive periodontitis. Metronidazole may arrest pathogens and not in general use for treatment of [29]disease progression in recalcitrant periodontitis other diseases and should be inexpensive.

patients with Porphyromonas gingivalis and / or

Prevotella intermedia infections with few or no IDEAL REQUISITES OF LOCAL DELIVERY

other potential pathogens. SYSTEMS

Side Effects: Metronidazole has an antabuse effect For the safe and effective administration of a drug

when alcohol is ingested. Metronidazole also into the periodontal pockets, the local drug delivery

inhibits warfarin metabolism. Patients undergoing system must possess certain basic properties.

anticoagulant therapy should avoid metronidazole Goodson (1985) suggested three important criteria

because it prolongs prothrombin time. for successful local drug delivery that includes:

L O C A L A D M I N I S T R A T I O N O F 1. Device must deliver drug to the base of the

ANTIBIOTICS pocket.

If preventive care combined with conventional 2. It must deliver drug at microbiologically

professional treatment is sufficient to control efficacious concentration.

periodontal disease progression, then no further 3. It must sustain the concentration of the drug

treatment is needed, except for maintenance care at in the pocket for sufficient length of time

an appropriate interval. When localized diseased and in sufficient concentration to be [30]sites do not respond to initial oral hygiene and clinically effective.

scaling and root planing treatments, or when L O C A L D R U G D E L I V E R Y I N

localized diseased sites are present in an otherwise PERIODONTICS

stable maintenance patient, local drug delivery The advent of local drug delivery vehicles has [28]systems may be indicated. Before any enabled local application of antimicrobials and

antimicrobial agent can be recommended for other therapeutics over a prolonged period of time.

periodontal therapy a number of basic and Locally delivered antimicrobials have been used as

important conditions have to be fulfilled: stand-alone treatment and adjunctive to scaling and

1. Drug must show in-vitro activity against the root planing. The localized or site-specific

organisms considered most important in the administration of chemotherapeutic agents may

etiology. offer the advantage of treatment of specific disease

2. It should be demonstrated that a dose sufficient sites, possible use of lower total dosage levels,

to kill the target organism can be reached within the probable avoidance of systemic complications

subgingival environment. associated with high dosage levels and the

3. At that dose the drug should not have major local possibility of controlling the release and



69

concentration of therapeutic agents if a controlled within other niches in the oral mucosa, poor plaque

release delivery vehicle or device is employed. control harbor pathogenic bacteria that recolonize

H I S T O R I C A L P E R S P E C T I V E O F the periodontal pocket and can act as sources for

L O C A L L Y - D E L I V E R E D r e i n f e c t i o n . A g g r e g a t i b a c t e r

ANTIMICROBIALS actinomycetemcomitans and other tissue-invasive

Beginning in the 1970s it became widely organisms are not easily irradicated without

recognized that the early allergic problems with concomitant antibiotic therapy. Mechanical

topical antibiotics were almost uniquely a therapy alone may not effectively control infection, [33] phenomenon of penicillin, with minimal problems particularly in deep pockets. By placing an

resulting from the topical application of other antibiotic or antiseptic in direct contact with the

antibiotics. At the same time concern emerged root surface, pathogenic organisms that were not

relative to growing problems with the use of accessible to mechanical removal by hand or

systemic antibiotics including allergies, power-driven instruments can be reduced or

gastrointestinal disorders, and the development of eliminated.

bacteria that were resistant to multiple antibiotics. Indications

The convergence of these two lines of thought 1. As an adjunct to Scaling and Root planing

suggested that locally-delivered antimicrobial 2. Periodontal maintenance therapy:

agents should not only be reinvestigated but may Recurrent periodontitis usually involves only a few

well provide advantages over systemic agents in teeth. These sites are ideal for the treatment with

selected situations. this device.

GOALS 3.Medically compromised patients for whom

The primary goal in using an intra-pocket device surgery is not an option or those who refuse

for the delivery of an antibacterial agent is the surgical treatment.

achievement and maintenance of therapeutic levels 4. During periodontal regenerative procedures

of the drug for the required period of time. This Contraindications:

inhibits or kills the pathogens, without any harm to Patients with known hypersensitivity to a drug[4]the surrounding tissues. Studies suggest that the Advantages:

critical period of exposure of the pocket to an ? Attains 100-fold higher concentrations of [31]antibacterial agent is in the range of 7 – 10 days. an antimicrobial agent in subgingival sites

RATIONALE compared with a systemic drug regimen.

Locally delivered anti-infective pharmacological For example, local placement of a tetracycline

agents, specifically antibiotics, are generally releasing ethylene vinyl acetate monolithic fiber

administered in doses much lower than that can yield tetracycline concentrations in excess of

required with systemic administration, reducing 1300 Fg /ml in gingival crevicular fluid over 10

the risk of serious systemic side-effects associated days . In comparison, repeated systemic doses of [32]with the drug. Root surface, tongue, tonsils and tetracycline- HCl can only provide tetracycline



70

[34] (controlled-release device)levels of 4-8 pg/ml in gingival crevicular fluid.

Eg: subgingival irrigation of agents intrinsically ? Employs antimicrobial agents not suitable

substantive for tooth root surfaces (aqueous for systemic administration, such as

tetracycline) or pocket placement of commercial various broad-spectrum antiseptic

antimicrobial fibers, gel or films.solutions.

? Reduces the risk of developing drug-

Intra pocket devices can be divided in two broad resistant microbial populations at nonoral

categories depending on degradability:body sites.[4] 1. Nondegradable devices (first generation) Disadvantages:

and ? diff icul ty in placing therapeut ic

2. degradable devices (second generation)concentrations of the antimicrobial agent

Non degradable devices have the advantage that into deeper parts of periodontal pockets and

the therapist controls the removal of the device and furcation lesions.

therefore has greater control over the time of ? time-consuming and labor-intensive.

exposure of the pocket environment to the drug. ? Antimicrobial agents locally applied into

The degradable device has the advantage of periodontal pockets do not markedly affect

requiring the patient pay only a single visit to periodontal pathogens residing within

therapist for the insertion of the device. This adjacent gingival connective tissues and on

minimizes the patient visits and ensures extra-pocket oral surfaces (tongue, tonsils

compliance. Patient revisit for the removal of the and buccal mucosa), which increases the

device can be avoided. Devices that have been risk of disease recurrence .

developed include fibers, films, slabs and ? Relatively costly[4] injectable systems.CLASSIFICATION:

DRUGS USED IN LOCAL DELIVERY Types of local antimicrobial agent therapy in

SYSTEMSperiodontics

This section briefly addresses the advantages and 1. Personally applied (in patient home self-care)

limitations of the 5 main antimicrobial agents a. Nonsustained subgingival drug delivery

employed in the drug delivery systems discussed in (home oral irrigation)

this text. (Table 1) b. Sustained subgingival drug delivery (none

The tetracyclines (tetracycline hydrochloride, developed to date)

doxycycline, minocycline) are broad spectrum 2. Professionally applied (in dental office)

antibiotics that affect anaerobes and facultative a. Nonsustained subgingival drug delivery

organisms. They are bacteriostatic for many (professional pocket irrigation)

pathogens at concentrations found in the gingival Eg: Subgingival irrigation with antiseptic agents

crevicular fluid after systemic administration (3 to lacking substantivity for oral tissues( povidone-

6 mg/ml). However, local delivery of these agents iodine) .

provides high concentrations that are bactericidal. b. Sustained subgingival drug delivery



71

[35](Table 2) reduced potential to induce bacterial resistance.

Metronidazole's spectrum of activity is relatively The drugs discussed above are capable of reducing

s p e c i f i c f o r o b l i g a t e a n a e r o b e s . A the subgingival flora and each has advantages.

hydroxymetabolite of metronidazole can affect Since each antimicrobial agent is associated with a

facultative organisms, however, in general, specific local delivery system (Table 1), selection

metronidazole is considered effective only against of a drug dictates utilizing that particular delivery

anaerobes. This specificity is both an advantage device.

and a liability.

Chlorhexidine is an antiseptic whose use has been CHARACTERISTICS OF LOCAL DRUG

associated with some side effects such as staining, DELIVERY SYSTEMS

increased calculus formation, and altered taste Important features of local drug delivery products [35]sensation. However, the amount of drug are compared in Tables 1 and 2. Biodegradability is

employed in a chip with chlorhexidine is small (2.5 a desirable characteristic, because it precludes the

mg) and minimal side effects appear to be need to remove the drug device. All systems listed [36]induced. Development of resistance to in Table 1 are resorbable, except the tetracycline

chlorhexidine is uncommon, and an advantage of fibers which need to be removed after 10 days. The

using an antiseptic instead of an antibiotic is time necessary for other agents to resorb are listed

System Composition Resorbable Controlled or Countries

(time) sustained release available

Tetracycline fibre Ethylene

vinylacetate ,

tetracycline

No Controlled United States,

Europe

Metronidazole

dental gel

Sesame oil ;

metronidazole

(25%)

Yes (1 day ) Sustained Europe, Israel

Chlorhexidine

chip

Hydrolysed

gelatin matrix

Yes (8 days ) Controlled Israel, England

Minocycline

dental gel

Minocycline (2%)

lipid gel

Yes ( 1day ) Sustained England

Doxycycline

polymer

Doxycycline

hyclate

Yes (27 days ) Controlled Unavailable

Table 1. Comparison of Drug Delivery System



72

Tetracycline fiber 1500µg/ml Moderate

Metronidazole

dental gel

24 hours

>1µg/ml

Easy

Chlorhexidine

chip

150µg/ml Easy

Minocycline

dental gel

Unknown Easy

Doxycycline

polymer

420µg/ml Easy

Table 2. Comparison of drug delivery devices

CONCLUSION : should be based on the clinicians consideration of

Scaling and root planing alone are effective in the clinical findings, the patient's medical and

reducing pocket depth ,gaining increase in dental history ,patient preferences and potential

periodontal attachment levels, and decreasing benefits of adjunctive therapy with these agents .

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Competing interest / Conflict of interest The author(s) have no competing interests for financial support, publication of this research, patents and royalties through this collaborative research. All authors were equally involved in discussed research work. There is no financial conflict with the subject matter discussed in the manuscript.Source of support: NIL

Copyright © 2014 JPMCP. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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stannous fluoride gel in debrided



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Vol-II, Issue - 2, May - Aug 2015jpmcp.com/vol II issue 2/64-76.pdf · mechanical irritation but...

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