Antibiotics used in periodonticsSHASHI KANT CHAUDHARY JR I DEPT OF PERIODONTOLOGY AND ORAL IMPLANTOLOGY

2Contents

Introduction Rationale Systemic antibiotics used in

periodontics Local drug delivery Conclusion References

3Introduction

An antibiotic is a word derived from the

Ancient Greek meaning:

(anti, i.e., "against", and bios, i.e., "life") It is a substance or compound that kills bacteria or inhibits its

growth

The term "antibiotic" was coined by Selman Waksman in 1942

4

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

5

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

7Terminologies

Chemotherapeutic agent is a general 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.

8

Antibiotics: A naturally occurring , semisynthetic, or synthetic type of anti-infective agent that destroys or inhibits the growth of selective microorganisms, generally at low concentrations.

9

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

10ANTIBIOTICS IN PERIODONTAL THERAPY

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.

11

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.

Rationale

12Ideal antibiotics

Toxic to microbes and not to humans Bactericidal rather than bacteriostatic Specific for periodontal pathogens Should not be allergic and hypersensitive reactions Should be active in plasma, and other body fluids Desired levels should be reached rapidly and maintained

for adequate period of time. Should not cause drug resistance, long shelf life, Inexpensive

13Classification

1. On the basis of chemical structure: Sulphonamides and related drugs: Sulphadiazene Quinolones: Nalidixic acid, Norfloxacin β-lactam antibiotics: penicillins Tetracyclines Aminoglycosides Macrolides Glycopeptide antibiotics: Vancomycin Nitroimidazole: Metronidazole, Tinidazole

14

2. Mechanism of action Inhibit cell wall synthesis

–penicillins, cephalosporins, vancomycin Cause leakage from cell membranes

–polymyxins, bacitracin, nystatin Inhibit protein synthesis

–tetracyclines, chloramphenicol, erythromycin Cause misreading of m-RNA code and affect

permeability –aminoglycosides

15

Inhibit DNA gyrase

–fluoroquinolones Interfere with DNA function

–metronidazole, rifampicin Interfere with DNA synthesis

–idoxuridine, acyclovir Interfere with intermediary metabolism

–sulfonamides, trimethoprim

16

17

3. Group of organisms against which primarily active

•Antibacterial—penicillins, aminoglycosides

•Antifungal---griseofulvin, amphotericin-B

•Antiviral—idoxuridine, acyclovir

•Antiprotozoal—chloroquine, pyrimethamine

•Antihelmintic---mebendazole, pyrantel

18

On the basis of Spectrum of activity

Narrow spectrum- penicillin G, erythromycin

Broad spectrum- tetracyclines, chloramphenicol

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Type of action Bacteriostatic---sulfonamides, tetracyclines, erythromycin Bactericidal---penicillins, aminoglycosides, cephalosporins

Bacteriostatic Antimicrobial agents that reversibly inhibit growth of bacteria

are called as bacteriostatic

Bactericidal Those with an irreversible lethal action on bacteria are known

as bactericidal

20

On the basis of Source of antibiotics Fungi—penicillin, griseofulvin, cephalosporin Bacteria—polymyxinB, bacitracin Actinomycetes—aminoglycosides, macrolides,

tetracyclines, chloramphenicol

21INDICATIONS 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.

AJ Van Winkelhoff, TE Rams, J Slots. Systemic antibiotics in periodontics. Periodontol2000. 1996; 10: 45-78

22GUIDELINES FOR USE OF ANTIBIOTICS IN PERIODONTAL DISEASE The clinical diagnosis and situation dictate the need for possible

antibiotic therapy

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 through plaque sampling.

Antibiotics are selected based on the patient's medical and dental status, current medications, and results of microbial analysis, if performed

23

Microbial plaque samples may be obtained from individual pockets with recent disease activity or from pooled subgingival sites.

Studies have shown that systemic antibiotics can improve attachment levels when they are used as adjuncts to scaling and root planing.

24

systemic antibiotics were used as adjuncts to scaling and root planing, improvements were observed in the attachment levels of patients with chronic and aggressive periodontitis, although patients with aggressive periodontitis experienced greater benefits

25

The identification of which antibiotics were most effective for the treatment of destructive periodontal diseases (only tetracycline and metronidazole were shown to significantly improve attachment levels)

Debridement of root surfaces, optimal oral hygiene, and frequent periodontal maintenance therapy are important parts of comprehensive periodontal therapy

27Guidelines for use of antimicrobial therapy

28

29ADVERSE EFFECTS OF ANTI MICROBIAL AGENTS:

Allergic/anaphylactic Superinfection of opportunistic Development of resistant Interaction with other drugs Stomach upset, nausea, vomiting Most common GIT upset

30CHOICE OF AN ANTIMICROBIAL AGENT

1. PATIENT FACTORS Age

May affect kinetics of many AMAs. Eg: tetracycline accumulate in developing teeth and bones. Hence are

contraindicated < 8 yrs Renal and hepatic function

•Renal failures: aminoglycosides, vancomycin, cephalosporin, metronidazole

•Liver disease: erythromycin, tetracycline, nalidixicacid, chloramphenicol

31

LocalFactors

•Presence of pus and secretions decrease the efficacy of most AMAs esp. sulfonamides and

aminoglycosides

•Presence of necrotic material and foreign body makes eradication of infection practically

impossible

•Hematomas foster bacterial growth eg: tetracycline, penicillin and cephalosporin get bound to degraded Hb in the hematoma

32

•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 AMA to the site of infection in sub acute bacterial

endocarditis

33

Drug allergy: History of previous exposure to an AMA

Impaired host defense : Cidal drugs is imperative in those with impaired host defense, normal host defense, a bacteriostatic antibiotic

Pregnancy: safety of the drug

34

2. ORGANISM RELATED CONSIDERATIONS Clinical diagnosis Culture and sensitivity testing

When bacteriological services not available, empirical therapy to cover all likely organisms with abroad spectrum drug may be used

35MICROBIAL TESTING

Should be completed initially to determine which species are present and the most effective antibiotic for targeting them

(Shaddox and Walker, 2009; Fine, 1994)

Re-testing

•to ensure that the antibiotic is successful;

•At an interval of 3months

36

3. DRUG FACTORS

Based on the specific properties of the AMAs— 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

37DRUG FACTORS

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

38FACTORS THAT PLAY A ROLE IN THE EFFICACY IN THE PERIODONTAL AREA

Drug binding to tissues Protection of key organisms thru binding and/or

consumption of the drug by non-target microorganisms Microbial invasion of periodontal tissues and root

surfaces Total bacterial load in the periodontal pocket in relation

to maximum achievable antibiotic concentration

39 Periodontal pathogens may reside on buccal surfaces, tongue

tonsils and gingiva Microorganisms in biofilms are more resistant to bactericidal

actions of antibiotics in comparison to planktonic cells Bacteriostatic tetracycline can suppress susceptible

pathogens but are notable to completely eradicate some key subginigval pathogens

Penicillin and other B –lactam antibiotics may be inactivated by bacterial derived B-lactamases especially inpatients with recent penicillin exposure

Arie jan van winkelhoff, Thomas e. rams & Jorgen slots. Systemic antibiotic therapy in periodontics. Periodontology 2000, 1996 ; 10: 45-78

40ANTIBIOTIC DOSING PRINCIPLES

1) Employ high doses for a short duration: High concentrations are more critical with aminoglycosides, metronidazole and quinolones

2) Use an oral antibiotic loading dose

3) Achieve blood levels of the antibiotic at 2-8 times the minimal inhibitory concentration

4) Use frequent dosing intervals: so as to maintain relatively constant blood levels.

5) Determine the duration of therapy by the remission of disease

Pallasch TJ. Pharmacokinetic principles of antimicrobial therapy.Periodontol 2000 1996;10:5-11

41ANTIBIOTIC DOSING VARIABLES

Diffusion to site of infection, lipid solubility, Plasma protein binding, Inoculum effect, Surface area to volume ratio Altered patient physiology (pregnancy, age, kidney

and liver function).

42

Two critical factors should be specifically considered in selecting a systemic antibiotic in periodontal therapy

1. Gingival fluid concentration

2. Minimum inhibitory concentrationGoodson JM. Antimicrobial strategies for treatment ofperiodontal diseasesa. Periodontol 2000 1994;5:142-68

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The gingival fluid concentration (CGCF) provides information on the peak levels achieved by systemic delivery at the primary ecological niche for periodontal pathogens, the periodontal pocket.

44

The 90% minimum inhibitory concentration (MIC90) is an in vitro determination of the concentration that will inhibit growth of 90% of the bacterial strains of a species that are tested.

Antimicrobial activity can be defined as a relationship between CGCF and MIC90

45

POST-ANTIBIOTIC EFFECT

Short dosing intervals to maximize the time of exposure of microorganism are preferred for time dependent antibiotics with no significant post-antibiotic effects.

46DURATION OF ANTIBIOTIC THERAPY

The ideal duration of antibiotic therapy is the shortest that will prevent both clinical and microbiological relapse

47

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.

48

Acute orofacial infections have a rapid onset and relatively short duration of 2-7days or less

(Van Winkelhoff and Winkel, 2005)

49Administration

Systemic administration

Local administration

50ADVANTAGES OF SYSTEMIC ANTIBIOTIC THERAPY

Simple, easy administration of drug to multiple sites of disease activity

Eliminate or reduce pathogens on oral mucosa and extra-dental sites

51DISADVANTAGES OFSYSTEMIC ANTIBIOTIC THERAPY

In ability to achieve high GCF concentration

Increased risk of adverse drug reactions

Increased selection of multiple antibiotic resistant

micro-organisms

Uncertain patient compliance

52ANTIBIOTICS IN PERIODONTICS

Eight principle antibiotic groups have been extensively evaluated for treatment of the periodontal diseases;

1.Tetracycline 2.Minocycline

3.Doxycycline 4.Erythromycin

5.Clindamycin 6.Ampicillin

7.Amoxicillin 8.Metronidazole

Goodson JM. Antimicrobial strategies for treatment of periodontal diseases. Periodontol 2000. 1994;5:142–68

54Tetracycline

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

55 Mode of action Act by inhibition of protein synthesis by binding to 30 S

ribosomes in the susceptible organism

Clinical use Adjuncts in the treatment of localized aggressive

periodontitis (LAP) Arrest bone loss and suppress A. actinomycetemcomitans

levels in conjunction with scaling and root planing

Dosage regimen 250 mg four times daily, inexpensive, lesser compliance

56

Minocycline and Doxycycline are semisynthetic members of the tetracycline group that have been used in periodontal therapy

57Minocycline

Effective against a broad spectrum of microorganisms

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

58

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

Dosage of administration: 200 mg/day

59Doxycycline

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

60Metronidazole

A synthetic nitroimidazole compound with bactericidal effects primarily exerted on obligate gram-positive and gram-negative anaerobes

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

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The best candidate for Peptostreptococcus infections, a reasonable candidate for P. gingivalis, P. intermedia and C. rectus 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

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Mode of action Metronidazole acts by inhibiting DNA synthesis

63Clinical use

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

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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

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Side effects Severe cramps Nausea Vomiting and metallic taste

Avoid in patients with history of alcohol taking, patients on anticoagulant therapy

66Penicillin

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

67Mode of action Interfere with the synthesis of bacterial cell wall, inhibit the

transpeptidases so that cross linking does not take place

Clinical use 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

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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

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Amoxicillin alone is not effective for treatment of chronic and aggressive periodontitis but effective in combination with metronidazole

(Soaresetal.,2012; Rabeloetal.,2015)

70Amoxicillin-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

71Cephalosporin

Used for infections that might otherwise be treated with penicillin

Resistant to a number of β-lactamases normally active against penicillin

Mode of action 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

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Clinical use 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

73Clindamycin

Effective against anaerobic bacteria, and in patients allergic to penicillin

Mode of action Inhibition of protein synthesis by binding to 50 S

ribosome

Clinical use Clindamycin achieves higher levels of

antimicrobial activity than other antibiotics

74 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

75Ciprofloxacin

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 MIC90 values ranging from 0.2 to 2 μg/ml

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Mode of action Inhibition of bacterial DNA replication and

transcription by inhibiting the enzyme DNA gyrase, an enzyme unique to prokaryotic cells

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Clinical use 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)

78Macrolides

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

79

Mode of action Inhibit protein synthesis by binding to the 50

S ribosomal subunits of sensitive microorganisms and interfere with translation

80Erythromycin

Clinical use

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

81

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

82Spiramycin

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

83

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

Clinical use Effective against gram positive organisms, has minimal effect

on increasing attachment levels

84Azithromycin

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

85

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

86Aminoglycosides

Inhibit protein synthesis by binding irreversible to a particular protein or proteins of the 30 S ribosomal subunit

Are inactive under anaerobic conditions because intracellular transport is severely impaired in the absence of oxygen

Therefore, all anaerobic bacteria are markedly resistant even though they contain ribosomes that are sensitive to these antibiotics

87Therapeutic Uses of Systemic Antimicrobial Agents for Various Periodontal Diseases

88There 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

Ellen RP, Mcculloch CA. Evidence versus empiricism: Rational use of systemic antimicrobial agents for treatment of periodontitis. Periodontol 2000. 1996;10:29–44

89Serial 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

90Combination therapy

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

van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapyin periodontics. Period ontol 2000 1996;10:45-78

91Advantage

(i) empirical treatment of severe infections

(ii) treatment of polymicrobial infections

(iii) prevention of the emergence of bacterial resistance

(iv) increased effectiveness from antibiotic synergism (more than

additive)

92Disadvantages

increased adverse reactions

antagonistic drug interactions with improperly selected antibiotics

Superinfections with Candida or other microbes owing to major suppression of the indigenous microbiota

Rybak MJ, McGrath BJ. Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician. Drugs 1996: 52: 390–405.

93Amoxicillin-metronidazole

most common antibiotic combination in periodontics

Amoxicillin exerts antimicrobial synergy with metronidazole against periodontal pathogens

250 mg of amoxicillin and 250 mg of metronidazole, three times daily for 8 days

A-M is particularly effective against A.a infections (Slots et al.2002)

94

A-M combination therapy used as the sole periodontal treatment has yielded a clinical outcome similar to that of scaling and root planing

Lo´pez NJ, Socransky SS, Da Silva I, Japlit MR, Haffajee AD Effects of metronidazole plus amoxicillin as the only therapy on the microbiological and clinical parameters of untreated chronic periodontitis. J Clin Periodontol 2006: 33: 648–660

95

the most promising drugs for the treatment of periodontal diseases are metronidazole or the combination of metronidazole + amoxicillin

96Ciprofloxacin - metronidazole

500 mg of each drug, twice daily for 8 days valuable alternative for penicillin-allergic periodontitis patients Unique antimicrobial benefit Non periodontopathic viridans streptococci exhibit resistance to

both and dominate the periodontal micro-biota post-treatment delay pocket colonization by pathogenic species

97Clinical 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

Pallasch TJ, 1996

98 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)

99LOCAL 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

100LOCAL DRUG DELIVERY

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.

101

For local chemotherapy (drug delivery) to be effective, it must meet 3 requirements: Reach the site of disease activity namely the base of

the pocket, Be delivered at a bacteriostatic or bactericidal

concentration, Remain in place long enough to be effective

102INDICATIONS FOR LDD

As an adjunct to Scaling and Root planing Periodontal maintenance therapy: Recurrent periodontitis

usually involves only a few teeth. These sites are ideal for the treatment with this device.

Medically compromised patients for whom surgery is not an option or those who refuse surgical treatment.

To halt the progression of periodontal disease in patients with moderate periodontitis.

103Classification

1. Personally applied (in patient home self-care)

A. Nonsustained subgingival drug delivery(home oral irrigation)

B. Sustained subgingival drug delivery(none developed to date)

2. Professionally applied (in dental office)

A. Nonsustained subgingival drug (professional pocket irrigation)

B. Sustained subgingival drug delivery (controlled-release device)

104ADVANTAGES OF LOCAL

DRUG DELIVERY

Can attain 100-fold higher concentrations of an antimicrobial agent in sub gingival sites

No potential danger of resistant strains and super imposed infections

No risk of adverse drug reactions and dependence of patient compliance

May employ antimicrobial agents not suitable for systemic administration.

105DISADVANTAGES

Difficulty in placing into deeper parts of periodontal pockets and furcation lesions.

Lack of adequate manual dexterity limited understanding of periodontal anatomy, & poor compliance limits the use as home self-care procedures

Time-consuming and labor-intensive. Do not markedly affect periodontal pathogens residing within

adjacent gingival connective tissues and on extra pocket oral surfaces, which increases the risk of reinfection.

106LOCAL DELIVERY AGENTS

•Tetracycline •Doxycycline•Minocycline•Metronidazole•Moxifloxacin•Azithromycin•Chlorhexidine

107TETRACYCLINE CONTAINING

FIBER The first local delivery product Tetracycline fibers with 12.7mg per 9 inches, an

ethylene/vinyl acetate copolymer fiber 0.5mm diameter and 23 cm long

It was well tolerated in oral tissues and concentration reach 1300μg/ml for 10 days

No change in antibiotic resistance to tetracycline was found

ACTISITE, PERIODONTAL PLUS AB These fibers are no longer commercially available

109DOXYCYCLINE

A gel system using a syringe with 10% doxycycline (Atridox).

only local delivery system accepted by the American Dental Association

1500mcg/ml in 2 hrs and remains >1000mcg/ml through18 hrs

110

The combined use of systemically delivered doxycycline hyclate (20 mg twice daily) plus locally delivered doxycycline hyclate gel (10%) in combination with scaling and root planning provided statistically significantly greater clinical benefits

Novak MJ, Dawson DR, 3rd, Magnusson I, et al: Combining host modulation and topical antimicrobial therapy in the Management of moderate to severe periodontitis: a randomized multicenter trial. J Periodontal 79(1):33, 2008.

112MINOCYCLINE

A locally delivered sustained release form of minocycline microspheres (arestin).

The 2% minocycline is encapsulated into bioresorbable microspheres in gel carrier.

113

Grace et al evaluated topical locally delivered minocycline as an adjunctive to non-surgical periodontal treatment and found advantageous outcome for nonsurgical periodontal treatment in terms of probing attachment level and bleeding on deep probing.

115METRONIDAZOLE

A topical medication containing an oil based metronidazole 25% dental gel. (glyceryl monooleate and sesame oil)

Two 25% gel application at a 1- week interval have been used.

116

Studies have shown that metronidazole gel is equivalent to scaling and root planing, but they have not shown adjunctive benefits with scaling and root planing

Bleeding on probing was reduced by 88% of cases.

118Moxifloxacin

fourth-generation synthetic fluoroquinolone with broad-spectrum antibacterial Antimicrobial activity against aerobic and anaerobic bacteria,

including a number of periodontal pathogens the local delivery of 0.4% moxifloxacin may be of benefit as

an adjunct to scaling and root planning for the treatment of periodontitis

119AZITHROMYCIN

Has a wide antimicrobial spectrum of action towards an aerobic bacteria & Gram-negative bacilli. It is effective against periodontal pathogens such a s A.a & P.g

120

Tyagi et al investigated the clinical effectiveness of AZM at a concentration of 0.5%In an indigenously prepared bioabsorbable controlled release gel as an adjunct to non surgical mechanical therapy in the treatment of chronic periodontitis. Although both treatment strategies seem to benefit patients, the adjunctive use of 0.5%ofAZM showed better results.

121Choice of LDD

Several local anti-infective agents combined with SRP appear to provide additional benefits in PD reduction and CAL gain compared to SRP alone. The decision to use local anti-infective adjunctive therapy remains a matter of individual clinical judgment, the phase of treatment, and the patient's status and preferences

Hanes PJ, Purvis JP. Local anti-infective therapy: pharmacological agents. A systematic review. Ann Periodontol. 2003 Dec;8(1):79-98.

122Comparative study

In a study, attempted to compare LDD devices doxycycline polymer, metronidazole gel, and PerioChip were compared in 47 periodontal patients. The study found that all controlled-release polymer devices increased gingival attachment levels but there was a slightly greater improvement with the doxycycline polymer

Salvi GE, Mombelli A, Mayfield L, et al: Local antimicrobial therapy after initial periodontal treatment. J Clin Periodontol 29:540, 2002

123CHLORHEXIDINE

A resorbable delivery system resorbs in 7-10 days.

No signs of staining were noted in any of the studies!!

PERIOCHIP, PERIOCOL-CG

124

Studies have shown suppression of pocket flora for upto11 weeks following treatment with periochip

Paquette DW, Ryan ME, Wilder RS 2008

Largest effect on PPD reduction—tetracycline fibres, doxycycline, minocycline

Highest effect for CAL gain—CHX xanthan gel

Matesanz-Pe´rezP 2013

125

COMPARISON OF SYSTEMIC AND LOCAL ANTIBIOTIC THERAPY-Issue Systemic

administration Local delivery

Drug distribution Wide distribution Narrow effective range

Drug concentration Variable levels in different body compartments

High dose at treated site low levels else where

Therapeutic potential May reach widely distributed micro-organisms

may act locally on biofilm associated bacteria better

Problems Systemic side effect Re-infection from non-treated sites

Clinical limitation s Requires good patient compliance

infection limited to the treated site

Mombelli,2012

126Antibiotic prophylaxis

Recommended when these patients undergo procedures that are at risk for producing bacteremia.

incidence of infections such as IE ranges from 5.0 to 7.9 per 100,000 person-years with a significant increasing trend among women

127RECENT 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

129CARDIAC CONDITIONS

WITH HIGH RISK

Prosthetic cardiac valve or prosthetic material used for cardiac valve repair

Previous infective endocarditis Cardiac transplantation recipients who develop cardiac

valvulopathy

130

Congenital heart disease(present from birth) unrepaired cyanotic congenital heart disease, including palliative

shunts and conduits a completely repaired congenital heart defect with prosthetic

material or device, whether placed by surgery or by catheter intervention, during the first six months after the procedure

any repaired congenital heart defect with residual defect at the site or adjacent to the site of a prosthetic patch or a prosthetic device (that inhibit endothelialization)

Except for the conditions listed above, antibiotic prophylaxis is no longer recommended for any other form of congenital heart disease.

132

American Heart Association guidelines for dental procedures for which endocarditis prophylaxis is recommended All dental procedures that involve

manipulation of gingival tissue on the periapical region of teeth or perforation of the oral mucosa

135Procedures do not need prophylaxis

Routine anesthetic injections through non-infected tissue Taking dental radiographs Placement of removable prosthodontic or orthodontic appliances Adjustment of orthodontic appliances Placement of orthodontic brackets Shedding of deciduous teeth Bleeding from trauma to the lips or oral mucosa

136Antibiotic prophylaxis for

infective endocarditis Standard general prophylaxis Amoxicillin Adult dose: 2 g PO Pediatric dose: 50 mg/kg PO; not to exceed 2 g/dose

Unable to take oral medication Ampicillin Adult dose: 2 g IV/IM Pediatric dose: 50 mg/kg IV/IM; not to exceed 2 g/dose Antibiotic Prophylactic Regimens for Endocarditis , Mary L Windle, PharmD; Karlheinz Peter, MD, PhD (13 jan 2015)

137

Allergic to penicillin

Clindamycin Adult dose: 600 mg PO Pediatric dose: 20 mg/kg PO; not to exceed 600 mg/dose

Cephalexin or other first- or second-generation oral cephalosporin in equivalent dose

Pediatric dose: 50 mg/kg PO; not to exceed 2 g/dose

Azithromycin or Clarithromycin Adult dose: 500 mg PO Pediatric dose: 15 mg/kg PO; not to exceed 500 mg/dose

138

Allergic to penicillin and unable to take oral medication

Clindamycin Adult dose: 600 mg IV Pediatric dose: 20 mg/kg IV; not to exceed 600 mg/dose

Cefazolin or ceftriaxone Adult dose: 1 g IV/IM Pediatric dose: 50 mg/kg IV/IM; not to exceed 1 g/dose

139Additional 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

140Concluding with few queries

What is the significance of the periodontal biofilm when prescribing systemic antibiotics? Periodontitis is an infection caused by bacteria residing

in biofilms within a mature biofilm structure they have a reduced

susceptibility to antimicrobials compared to planktonic or free floating bacteria concentration of 500 time more is needed

mechanical debridement - critical to disrupt the biofilm

141

Should antibiotics be used as a monotherapy in the treatment of periodontitis? Haffajee et al the effect of the antibiotic alone was minimal

and short term. Lopez et al showed similar clinical results for scaling and root

planing as for antibiotics (amoxicillin plus metronidazole) prescribed as a monotherapy

But the majority of studies do not support the concept of monotherapy with inferior results

142

Do adjunctive systemic antibiotics offer an advantage over non-surgical mechanical therapy alone for the treatment of chronic periodontitis? The majority of case can be successfully treated following

mechanical debridement, adequate oral hygiene and regular maintenance care

Hererra et al. concluded that systemic antibiotics used in conjunction with SRP can offer an additional benefit over SRP alone

Haffajee et al.also reported similar finding

143

Choice of systemic antibiotic – which antibiotic is the best to use? Periodontitis is a mixed microbial infection making the

choice of antibiotic regimen difficult the literature does not provide a clear indication of the

superiority of one antibiotic regimen over another and the choice of antibiotic should be made on an individual basis

144

What is the ideal duration and dosage of the antibiotic? there is no consensus on the ideal regimen In principle important to prescribe in sufficient dose

for adequate duration.

145

Common Antibiotic Regimens Used to TreatPeriodontal Diseases

146

In which phase of the mechanical treatment should the antibiotic be prescribed? Two different questions (i) should the antibiotic(s) be administered during the

active phase of therapy or on re-evaluation (i.e. 3 or 6 months after active treatment);

(ii) should the antibiotic(s) be administered on the first or last day of the scaling and root planing procedure

147

Indirect evidence suggests that antibiotic intake should start on the day of debridement completion and debridement should be completed within a short period of time (< 1 week)

148

How critical is patient compliance when using adjunctive antibiotics? studies have shown that as little as 20 per cent of

patients comply with antibiotic regimens prescribed If a patient is non-compliant with oral hygiene measures

and maintenance protocols Prescription of antibiotics is no substitute for adequate

debridement, good oral hygiene and regular maintenance care

149

Are adjunctive systemic antibiotics useful for the treatment of aggressive periodontitis? Frequently associated with A.a and P.g which have

potential to invade the periodontal tissue adjunctive antibiotics may be required to eradicate or

suppress these pathogens In the systematic review by Hererra et al. it was

concluded that adjunctive systemic antibiotics should be considered in cases of aggressive periodontitis

150

Should antibiotics be used when regenerative periodontal therapy is attempted? limited evidence for the additional benefit of systemic

antibiotics for the regenerative outcome The rationale for use of the antibiotics is to prevent

postsurgical infection, particularly if membrane exposure occurs and to optimize the potential for regeneration.

151

Periodontal abscess – should systemic antibiotics be prescribed? The role of systemic antibiotics is controversial. Some authors advocate use of systemic antibiotics as

adjunct Others recommend only if a clear systemic involvement is

present ( lymphadenopathy, fever or malaise or when the infection is not well localized)

Mechanical debridement and drainage through the periodontal pocket usually effective

152

most prevalent bacterial species is Porphyromonas gingivalis, with a range in prevalence of 50–100%

The drug with the most appropriate profile is metronidazole (250 mg, three times daily).

Azithromycin (500 mg, once per day) Amoxicillin plus clavulanate (500 + 125 mg, three

times daily) The duration, restricted to the duration of the

acute lesion, which is normally 2–3 days.

154References

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Tripathi KD. Antimicrobial drugs: General considerations. In: Tripathi KD, editor. Essentials of medical pharmacology. 5th ed. New Delhi: Jaypee Publishers; 2003. pp. 627–40

Systemic antibiotic therapy in periodontics, Anoop Kapoor, Ranjan Malhotra, Vishakha Grover, and Deepak Grover Dent Res J (Isfahan). 2012 Sep-Oct; 9(5): 505–515.

Slots J, MacDonald ES, Nowzari H. Infectious aspects of periodontal regeneration. Periodontol 2000. 1999;19:164–72

Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-infective periodontal therapy.A systematic review. Ann Periodontol. 2003;8:115–81

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van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Period ontol 2000 1996;10:45-78

Pallasch TJ. Pharmacokinetic principles of antimicrobial therapy. Periodontol 2000. 1996;10:5–11

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;29:136–59

Ellen RP, Mcculloch CA. Evidence versus empiricism: Rational use of systemic antimicrobial agents for treatment of periodontitis. Periodontol 2000. 1996;10:29–44.

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Thank you