periodontal antimicrobial therapy... both systemic and local

1. Antimicrobial agent in periodontics

2. CONTENTS
 Introduction
 Principles of antimicrobial agent used in periodontics
 Systemic antimicrobial therapy
 Local antimicrobial therapy
 Conclusion

3. The recognition of periodontitis as an infection caused or sustained by living bacteria that
are present at diseased sites is fundamental for any antimicrobial treatment concept.
Antibiotics can kill or suppress living bacteria but they cannot remove calculus and
bacterial residues, which is traditionally perceived to be an essential part of periodontal
therapy.
.
.
So, the gold standard in the treatment of periodontitis is mechanical debridement of the
pockets by scaling and root planing (SRP) (Hung & Douglass 2002).
introduction

4. To overcome these limitations, different adjunctive therapies have been proposed,
mainly the use of systemic or local antimicrobial agents (Quirynen et al. 2002,
Bonito et al. 2005, Cosyn & Wyn 2006).
Adjunctive systemic antimicrobials may improve clinical outcomes (Herrera
et al. 2002, 2008, Haffajee et al. 2003), especially in particular disease conditions
(Sanz & Teughels 2008).
However, their use is not free of risks, and hence, they should be indicated for
certain situations under optimal conditions (Herrera et al. 2002, 2008).
But It would be irrational to believe that mechanical instruments alone are able to
completely remove periodontal pathogens from all infected sites (Mombelli et al.
2000). As beacause of Bacteria may be inaccessible to mechanical instruments in
concavities, lacunae, and dentin tubules, as well as invaded soft tissues.

5. Antibiotics --These are substances produced by microorganisms, which selectively
suppress the growth of or kill other microorganisms at very low concentrations.
Chemotherapeutic agent -- Initially this term was restricted to synthetic compounds,
but now since many antibiotics and their analogues have been synthesized, this
criterion has become irrelevant; both synthetic and microbiologically produced drugs
need to be included together.
It would be more meaningful to use the term Antimicrobial agent (AMA) to
designate synthetic as well as naturally obtained drugs that attenuate microorganisms.
Definition
Essentials of Medical Pharmacology ,Seventh Edition, KD TRIPATHI

6. Rationale for adjunctive systemic or topical antimicrobial agents
 Mechanical therapy alone may not effectively control infection, particularly in deep
pockets (Kerry G. 1994)
 Poor plaque control increases the rate of reinfection of the pocket (Listgarten MA,.et
al.1985, Ryder MI ,et al, 1999)
 Root surface, tongue, tonsils and within other niches in the oral mucosa harbor
pathogenic bacteria that recolonize the periodontal pocket and can act as sources for
reinfection (Bollen CML,et al, 1998)
 Actinobacillus actinomycetemcomitans and other tissue-invasive organisms are not
easily irradicated without concomitant antibiotic therapy (Mattout P. et al,1990)

7. The Council for Appropriate and Rational Antibiotic Therapy (CARAT) have
developed five criteria to guide the selection of an appropriate antibiotic
regimen:-
Evidence based results, Therapeutic benefits, Safety, Optimal drug for
optimal duration, and Cost effectiveness (Slama et al., 2005).
When applying these criteria to systemic antimicrobial use in periodontitis, there
is reasonable evidence to suggest that the use of antibiotics as an adjunct to non-
surgical therapy (NST) may provide modest improvements in clinical attachment
gain (Haffajee et al., 2003, Herrera et al., 2002, Sgolastra et al., 2012a) and that
this benefit is greater in deeper pockets and in patients suffering from aggressive
forms of periodontitis (Herrera et al., 2002, Sgolastra et al., 2012a, Zandbergen et
al., 2013).
The selection of antimicrobials for the treatment of periodontitis is generally done
empirically, due to the complex microbial aetiology of periodontal infections and a
lack of evidence to suggest that patients testing negative to certain periodontal
pathogens do not benefit from antibiotic treatment (Rooney et al., 2002).

8. Specific characteristics of the
periodontal infection
 The uniqueness of biofilm‐associated dental diseases as infections (tissue invasion and
multiplication of pathogenic microorganisms in tissues. ),lacking of massive bacterial
tissues invasion.
 Although there is confirmation of bacterial penetration in periodontal abscesses and
necrotizing periodontal diseases (Listgarten 1965; Saglie et al. 1982a, b;
Allenspach‐Petrzilka & Guggenheim 1983; Carranza et al. 1983).
 Invasion and multiplication of bacteria within periodontal tissues is not considered to be
crucial for developing disease, rather microorganisms present in subgingival deposits
can harm these tissues without penetrating them.

9.  To be effective, antimicrobial agents used in the context of periodontal therapy
need to be available at a sufficiently high concentration not only inside but also
outside of the affected tissues.
 In the periodontal pocket environment these agents may be inhibited, inactivated
or degraded by the large masses of microorganisms present.
 Therapeutic concentrations may be difficult to achieve everywhere, and antibiotic
resistance is bound to occur first where the penetration of the agent is
restricted.

10. Dental biofilm can causes antimicrobial resistance by various methods(Marsh 2004; Marsh
et al. 2011).
 Periodontal pathogens such as Aggregatibacter actinomycetemcomitans
(Norskov‐Lauritsen & Kilian 2006) and Porphyromonas gingivalis show higher levels of
tolerance to several antimicrobial agents when embedded in biofilms than as
planktonic cells (Larsen 2002; Noiri et al. 2003; Eick et al. 2004; Takahashi et al. 2007).
 Within biofilms resistant microorganisms of low intrinsic virulence can protect
antibiotic‐sensitive pathogens (O’Connell et al. 2006).
 Within biofilm efficient horizontal transfer of resistance and virulence genes takes
place(Roberts et al. 1999, Roberts & Stewart 2004)
From above statements it can be stated that periodontal diseases should not be treated
with antimicrobial agents alone (Herrera et al. 2008; Sanz & Teughels 2008), rather
thorough mechanical debridement must always be performed to disrupt the structured
aggregates ,protecting embedded bacteria and to markedly reduce the microbial mass
(that may inhibit or degrade the antimicrobial agent).

11. Should antimicrobial therapy be aimed at specific pathogens?
Periodontal treatment is targeted at a variable mixture of different bacteria (Kroes
et al. 1999; Paster et al. 2001) as it is a poly microbial disease.
On the basis of their pathogenicity, demonstrated in animal experiments, and the
identification of virulence factors, a limited number of organisms have been
suggested as specific periodontal pathogens.
A. actinomycetemcomitans and P. gingivalis have attracted particular attention because
longitudinal and retrospective studies indicated an increased risk for periodontal
breakdown in positive sites and because results of treatment were better if these
organisms could no longer be detected at follow-up (Haffajee et al. 1991; Grossi et al.
1994; Haffajee & Socransky 1994; Dahlén et al. 1996; Rams et al. 1996; Bragd et al.
1987; Wennström et al. 1987; Carlos et al. 1988; Chaves et al. 2000).

12. In one large prospective study (Haubek et al. 2008), only one subpopulation of A.
actinomycetemcomitans, the “JP2 clone” (Tsai et al. 1984), showed the properties of a
true pathogen.
There is an ongoing debate on the utility of microbiologic tests to identify such
organisms in order to optimize periodontal therapy.
Given the large diversity of the microbiota associated with all forms of periodontitis, and
the complex synergistic and antagonistic interactions between the members of this flora, the
concept of specifically identifying and eradicating a particular pathogen may be illusionary
(Cionca et al. 2010).
In most trials showing beneficial effects of antimicrobials, neither the agents nor the
subjects have in fact been selected based on microbiologic testing. Though there is
possibility that in some cases virulent organisms may be present that are resistant to a
tested drug

13. Drug delivery routes
Systemic administration of antibiotics advantage--
Systemic administration of antibiotics may be better if the target bacteria are distributed
more widely. Studies have shown that periodontal bacteria may in fact be distributed
throughout the whole mouth in some patients (Mombelli et al. 1991a, 1994), including
in non‐dental sites such as the dorsum of the tongue or tonsillary crypts (Zambon et al.
1981; Müller et al. 1993; Pavicic et al. 1994; Müller et al. 1995; van Winkelhoff et al.
1988).
Disadvantages of systemic antibiotic therapy ---
• The drug is diluted by dispersal through the whole body, and only a small portion of
the total dose actually reaches the subgingival microbiota in the periodontal pocket
• Adverse drug reactions are a greater concern and more likely to occur if drugs are
distributed via the systemic route. Even mild forms of unwanted effects may severely
decrease patient compliance (Loesche et al. 1993).

14. Local drug delivery
Independent of patient compliance.
Methods suggested for local drug application in periodontal pockets range from simple
irrigation or placement of drug‐containing ointments and gels, to sophisticated
techniques involving devices for sustained release of antibacterial agents.
In order to be effective, the drug should reach the entire area affected by the
disease, especially the base of the pocket, and should remain there at a sufficiently
high concentration for a specific period of time.
To maintain a high concentration over a prolonged period, the flushing action
of the GCF flow has to be counteracted by a steady release of the drug from a larger
reservoir
In order to have sustained control over drug release, it is necessary to have a matrix that is
stable for longer than the drug load.
Andrea Mombelli and David Herrera, 2015

15. Local therapy may allow the application of antimicrobial agents at levels that
cannot be reached by the systemic route and may be suitable for agents, for
example antiseptics, that are too toxic to be delivered by the systemic route.

16. Systemic antibiotics
A number of publications have studied dental biofilms in vitro, showing an increase in resistance against
amoxicillin, metronidazole and doxycycline (Larsen 2002), in Porphyromonas gingivalis biofilms, and also for
Streptococcus constellatus, Aggregatibacter actinomycetemcomitans and
P. gingivalis, always as single-species biofilms, for antibiotics such as clindamycin, doxycycline, metronidazole
and moxifloxacin (Noiri et al. 2003). Because of this, different authors have suggested that minimum inhibitory
concentration (MIC) profiles should be determined for bacteria as part of a biofilm and not in the planktonic
state.

21. Azithromycin is effective against anaerobes and gram-negative bacilli. After an oral
dosage of 500 mg 4 times daily for 3 days, significant levels of azithromycin can be
detected in most tissues for 7 to 10 days.(Hoepelman IM, Schneider MM., 1995)
The concentration of azithromycin in tissue specimens from periodontal lesions is
significantly higher than that of normal gingiva.(Malizia T, et al, 1997).
It has been proposed that azithromycin penetrates fibroblasts and phagocytes in
concentrations that are 100 to 200 times greater than that of the extracellular
compartment
Therapeutic use requires a single dose of 250 mg/day for 5 days after an initial loading
dose of 500 mg. (Walker CB,1996)

22. Data have suggested that azithromycin may be an effective adjunctive therapy for
increasing attachment levels in patients with aggressive periodontitis(Haas AN,et al,
2008) as well as for reducing the degree of gingival enlargement.(Clementini M,et al,
2015) .These data must be carefully considered, because they were derived from small
subject populations.
One study concluded that adjunctive azithromycin provides no additional benefit
over nonsurgical periodontal treatment for the parameters investigated in patients
with severe generalized chronic periodontitis.
Furthermore, an additional study reported that there was an increase in cardiovascular
deaths among patients who received azithromycin; this increase was most pronounced
among patients with a high baseline risk of cardiovascular disease.
As a result of this study, the US Food and Drug Administration issued a warning that
the drug can alter the electrical activity of the heart, which may lead to a potentially
fatal heart rhythm known as prolonged QT interval.(Sebastian G. Ciancio, Angelo J.
Mariotti, 2017)

23. Metronidazole targets the gram-negative strict anaerobes from the red and orange
Socransky complexes (Socransky SS , et al 1998) such as Fusobacterium
nucleatum, Tanerella forsythia, Porphyromonas gingivalis and Treponema denticola,
while members of the genera Actinomyces, Streptococcus and Capnocytophaga are
minimally affected by metronidazole.
Metronidazole also has a limited effect on the species Aggregatibacter
actinomycetemcomitans, which is a facultative anaerobe rather than a strict
anaerobe.
Metronidazole

24. Amoxicillin–Clavulanate Potassium
The combination of amoxicillin with clavulanate potassium makes this anti-infective
agent resistant to penicillinase enzymes produced by some bacteria
Amoxicillin with clavulanate (Augmentin) may be useful for the management of
patients with LAP or refractory periodontitis.(Offenbacher S, Braswell L, Loos A, et al.,
1987)
Bueno and colleagues(1988) reported that Augmentin arrested alveolar bone loss in
patients with periodontal disease that was refractory to treatment with other
antibiotics, including tetracycline, metronidazole, and clindamycin.

25. Combination antimicrobial drug therapy
Since the subgingival microbiota in periodontitis often harbors several putative
periodontopathic species with different antimicrobial susceptibility, combination
antimicrobial drug therapy with a wider spectrum of activity than a single agent may be
useful.
Overlaps in the antimicrobial spectrums of different agents may reduce the
possible development of bacterial resistance.
Some combinations of drugs have a synergistic action against target organisms,
allowing lower doses of the single agents to be used
A synergistic effect against A. actinomycetemcomitans has been noted in vitro between
metronidazole and its hydroxy metabolite (Jousimies‐Somer et al. 1988; Pavicic et al.
1991) and between these two compounds and amoxicillin (Pavicic et al. 1992)

26. The use of amoxicillin-plus metronidazole features prominently in the literature
(Heitz‐Mayfield, 2009), and it has been reported that these two agents in combination can
provide a synergistic increase in activity against gram negative anaerobes in particular (van
Winkelhoff et al., 1992, Pavicić et al., 1991).
Systematic reviews of amoxicillin-plus-metronidazole as an adjunct to NST in aggressive
and chronic periodontitis found that the antibiotic groups reported greater improvements in
clinical attachment levels (CAL) and periodontal pocket depth (PPD) reduction, with no
significant risk difference in the occurrence of adverse events (Sgolastra et al., 2012a,
Sgolastra et al., 2012b).
A subsequent review and meta-analysis assessing the effectiveness of different
systemic antimicrobials for the treatment of chronic periodontitis found that while no
antibiotic performed superiorly overall, adjunctive metronidazole-plus-amoxicillin was
more effective than metronidazole alone, azithromycin or doxycycline in moderate
and deep pockets (4-6mm and >6mm respectively) (Keestra et al., 2015).
According to Matarazzo F,et al, 2008 better clinical outcomes were reported if patients
were treated with amoxicillin and metronidazole than if metronidazole alone was
administered

27. The adjunctive benefits of using systemic antimicrobials in the treatment of
periodontitis have been reported in two systematic reviews presented
at European (Herrera et al. 2002) and World (Haffajee et al. 2003) Workshops.
Herrera et al. (2002) concluded that in specific clinical situations, such as patients
with deep pockets, patients with progressive or ‘‘active’’ disease, or with specific
microbiological profiles, antimicrobial therapy adjunctive to scaling and root planing
(SRP) could be clinically relevant.
However, Haffajee et al. (2003) concluded that, although there are sufficient data to
suggest that antibiotics might help in the treatment of periodontitis, the optimum
protocol of use has not been clearly defined.

28. Systemic antimicrobials in periodontics: current concepts
Herrera et al (2002) included 25 clinical trials comparing scaling and root planing (SRP)
alone or with placebo versus SRP with systemic antimicrobials, both randomized (RCT)
and controlled (CCT), with 6 months or more of duration.
The scientific evidence that supports the use of systemic antimicrobials in periodontitis
has been systematically evaluated in different reviews presented at European(Herrera et
al,2002,Herrera et al , 2008) and North American Workshops.(Haffajee, 2003)

29. Periodontal conditions included aggressive and chronic periodontitis, and the evaluation
of the clinical outcome variables using meta-analyses (5 analyses, Lindhe et al;,
2002)concluded that---
 Differences in study methodology and lack of data made an adequate and
complete pooling of results for more comprehensive analyses difficult.
 The best available evidence indicated that systemic antimicrobials in conjunction with
SRP, can offer an additional benefit over SRP alone, in terms of CAL and PPD
change, especially in deep pockets (CAL range 0.2–0.6mm; PPD range 0.2–0.8 mm).

30.  Systemic antimicrobial treatment in conjunction with SRP reduced the
risk of further CAL lossover a 7–24-month periodin studies including patients selected
on the basis of ‘active’ disease (three studies).
 Based on the meta-analyses, spiramycin and amoxicillin plus metronidazole in
conjunction with SRP in deep pockets, demonstrated a statistically significant added
benefit with regard to PPD reduction(mwd0.40mm,95%CI: 0.1–0.7) and CAL gain
(mwd 0.45mm, 95%CI: 0.2–0.7), respectively.
 The limited information available (two studies) showed that the adjunctive
effect of some antimicrobials might be greater in some forms of periodontitis
(‘LJP’ and ‘generalized RPP’). However, additional RCTs are needed to establish this
adjunctive benefit.
 Adverse effects were monitored in 11 out of the 25 studies. The reported
adverse effects were mild and frequently related to the GI tract. Microbiological adverse
effects have not been tested for most drugs in the studies evaluated.

31. Haffajee et al (2003) included 26 RCTs and 3 quasi-experimental and cohort studies of
more than 1 month of duration (totaling 36 comparisons). Periodontal conditions
included aggressive, chronic, and recurrent periodontitis and periodontal abscess,
and the evaluation of the clinical outcome variables using meta-analyses (22 RCTs with
27 comparisons) concluded that---
• CAL gains should be expected if systemic antimicrobials are used, both in patients
with chronic and aggressive periodontitis, after 6 months, regardless of initial pocket
depths. These results are, however, more significant in patients with aggressive
periodontitis and in deeper pockets
• Metronidazole, tetracycline, and the combination of metronidazole and amoxicillin
offered the best results, but there is not enough evidence to support a drug regimen,
including appropriate dosage and duration.
• There is not enough evidence to support the use of systemic antimicrobials as the
sole therapy.

32. Herrera et al(2008) reported 3 different reviews, 2 of them narrative and a third systematic
enlarging the data inclusion from the previous systematic review to 32 publications and
45 comparisons. Based on these reviews, the consensus concluded that(Sanz M,et al;
2008)---
• If systemic antimicrobials are indicated as part of periodontal therapy, they should be
adjunctive to mechanical debridement, preferably as part of nonsurgical periodontal therapy.
• Indirect evidence suggests that antibiotic intake should start on the day of debridement
completion; it should be completed within a short time and with an adequate quality.
• Because of the problems related to the indiscriminate use of antimicrobials
(especially systemic side effects, microbiological adverse effects, and the increase in
bacterial resistances), the use of systemic antimicrobials in periodontitis should be
restricted to certain patients and certain periodontal conditions (eg, aggressive
periodontitis, severe and progressing forms of periodontitis).

33. • Systemic antimicrobials should be used under the most optimal conditions to achieve
the best possible results.
These optimal conditions include that systemic antimicrobials are more effective when
the biofilm has been disrupted and still is not reorganized, which implies that the
needed debridement should be carried out in the shortest possible time span
(approximately 1 week) so as to achieve effective drug serum levels on the day of the
completion of debridement.
Mechanical biofilm disruption must be always combined with effective supragingival
plaque control by the patient.

35. An update of recent scientific evidence on the use of systemic antimicrobials in
the treatme nt of periodontitis
A search was conducted, to retrieve RCTs of at least 3 months’ duration, with a
comparison between groups with and without systemic antimicrobials, and published
between 2010 and 2012

39. Timing of systemic antibiotic therapy
The optimal timing of antimicrobial drug administration is one subject for discussion, as
it remains controversial whether adjunctive systemic antibiotics should preferably be
administered during the initial non-surgical phase, or during a subsequent surgical
treatment phase
A landmark study, published in 1992 by Loesche et al., sparked this controversy by
showing that systemic metronidazole, when given as an adjunct to scaling and root
planing, reduced the need for surgical therapy in periodontitis patients with elevated
levels of spirochetes in subgingival samples, thereby reducing the costs and the
inconvenience for the patient
These findings were contrary to the opinion that mechanical therapy should be
exploited to its limits before a decision is made to administer an antibiotic.

42. Selection of patients who may benefit most from systemic antibiotics
To limit the development of microbial antibiotic resistance in general, and to avoid the
risk of unwanted systemic effects of antibiotics for the treated individual, a
precautionary, restrictive attitude towards using antibiotics is appropriate
It has been recommended that systemic antibiotics should be considered as
adjuncts to SRP for patients with deep pockets, aggressive forms of disease, “active”
sites or specific microbiologic profiles (Lindhe & Palmer 2002).
The following criteria should considered in this regards :---
Disease severity, patient compliance, diagnosis as aggressive or chronic
periodontitis, microbiologic profile, and risk of adverse events

43. Minimizing the risk of the development of antimicrobial antibiotic resistance

44. Conclusion
All antimicrobial therapy should be preceded by mechanical debridement.
To limit their overuse, it is furthermore recommended to avoid antibiotics whenever
there is ample evidence that thorough non‐surgical mechanical debridement alone can
resolve the problem, as is the case for mild‐to‐moderate periodontitis (van der
Weijden & Timmerman 2002
Last but not least, the prophylactic use of antibiotics should be limited to
high‐risk patients and to the prevention of severe complications (Duval et al. 2006;
Esposito et al. 2008; Nishimura et al. 2008; Berbari et al. 2010).

46. The gold standard in the treatment of periodontitis is mechanical debridement of the
pockets by scaling and root planing (SRP) (Hung & Douglass 2002).
However, SRP is not free of limitations, and its impact in some patients [e.g. grade
C periodontitis (Tonetti et al., 2018)] or in specific sites, may be not enough to
achieve the desired results.
Therefore, other forms of therapies, including different debridement approaches or
adjunctive therapies (antimicrobials, probiotics, anti-inflammatory drugs,
antioxidant micronutrients…) have been proposed and tested (Graziani et al.,
2017)
Adjunctive antimicrobials can be used either systemically or locally.

47. The local application has been indicated in patients with localized pockets or
nonresponding and recurrent sites(Bonito AJ,et al, 2005 Killoy WJ, 2002)
Because---
1.There are fewer adverse effects.
2.Less chance of developing bacterial resistance.
3.Better compliance than with the use of systemic antimicrobials.(Etienne D, 2003 ,
Maestre JR et al 2007) .
This local application may avoid the need for surgical therapy(Kalkwarf KL, et al
1992, Lee JM et al, 2002 ) and, hence, there is a positive cost-benefit ratio.
(Antczak-Bouckoms AA, Weinstein MC, 1987)

48. It was in the year 1979, Dr. Max Goodson et al first proposed the concept of
controlled delivery in the treatment of periodontitis(Goodson JM, Hafajee A,
Socransky SS. Periodontal therapy by local delivery of tetracycline. J Clinical
Periodontol 1979; 6: 83-92.) to
Disadvantages of systemic antibiotics like bacterial resistance, superimposed
infections, uncertain patient compliance, nausea, vomiting and gastrointestinal
(Chadha VS et al, 2012) disturbances led to the introduction of local drug
delivery as the treatment option.
Rosling et al. (1983) first documented the therapeutic potential of adjunctive
local antimicrobial agents in a controlled clinical periodontitis trial.

49. Rationale for Local Delivery and Controlled Release
(Modified from Page RC, Kornman KS: The pathogenesis of human
periodontitis: an introduction. Periodontology 2000 14:9–11, 1997.)

50. Schematic representation of the inability to achieve therapeutically sufficient concentrations in the periodontal pocket for sufficient time with
antimicrobials delivered systemically or locally but not in controlled-release formulations. Left, Orally administered drug (A) is absorbed in
thegastrointestinal tract (B), transported by the portal pathway to the liver (C), and enters the circulatory system (D), from which drug exits the vasculature
into the periodontal pocket (E). Drug is quickly eliminated from the pocket into the oral cavity by the copious flow of gingival crevicular fluid (GCF) (F).
Locally administered drugs not in controlled-release formulations suffer from the same limitation. Right, Locally delivered, controlled-release antimicrobial
is administered into the periodontal pocket, where it remains until it degrades, continuously releasing drug into the GCF over time. Antimicrobial drug may
be active against plaque bacteria that have invaded the surrounding periodontal tissues. (Reprinted from Wolf HF, Hassell TM: Color atlas of dental
hygiene: periodontology, ed 1, Stuttgart, Germany, 2006,
Thieme, with permission.)

51. PHARMACOKINETICS OF CHEMOTHERAPETIC AGENTS
IN GINGIVAL SULCUS
 Gingival crevicular fluid is constantly replaced by new GCF
formed at the base of gingival sulcus.
 According to Parker , 1974 , fluid present in the gingival
crevice in a 5 mm periodontal pocket is replaced about 40
times an hour.
 Based on an assumed pocket volume of 0.5 mL and a GCF
flow rate of 20 μL/h, Goodson (1989) estimated that the
half‐time of a non‐binding drug placed into a pocket is about
1 minute.
 Even a highly concentrated, highly potent agent would thus
be diluted below a minimum inhibitory concentration (MIC)
for oral microorganisms within minutes.

52. Graph shows the release profile of locally delivered, sustained-release or controlled-release antimicrobials by
irrigation. Drug concentration in the gingival crevicular fluid (GCF) is diminished rapidly after irrigation (A). Drug
concentration can be extended for several days with drug administered in a modified,
sustained-release formulation (B). Drug concentration in the GCF can be maintained at therapeutically
relevant concentrations for up to 10 days with controlled-release formulations (C). Area under the
curve but above the minimal inhibitory concentration (MIC) line represents drug concentration in the gingival
crevicular fluid greater than MIC values. The MIC for subgingival plaque bacteria may be substantially greater
than typically reported bacterial MIC values because of the potentially protective effect of a subgingival biofilm
formation. CRD, Controlled-release delivery; SRD, sustained-release delivery; arrowhead, administration of
locally delivered agent. (Adapted from Wolf
HF, Hassell TM: Color atlas of dental hygiene: periodontology, ed 1, Stuttgart, Germany, 2006, Thieme, with
permission.)

54. Nonsustained subgingival drug delivery provides high pocket concentrations of
the antimicrobial agent for only short time periods.
• Subgingival irrigation with antiseptic agents lacking substantivity for oral
tissues (povidone-iodine) are examples of nonsustained subgingival drug
delivery.
Sustained subgingival drug delivery provides retention of the antimicrobial agent over
an extended time period within periodontal pockets. Provide drug delivery for less than
24 hours
• Controlled drug release can be provided with subgingival irrigation of agents
, intrinsically substantive for tooth root surfaces (aqueous tetracycline) or
pocket placement of commercial antimicrobial fibers, gel or films.
• Designed to provide drug release that at least exceeds 1 day or for at least 3
days following application(Kornman1993)
THOMAS E. RAMS& JORGEN SLOTS, 1996

55. Sustained subgingival drug delivery
Four locally delivered, controlled-release antimicrobial products
are available for dental use in the United States
.

56. Chlorhexidine-
Based
Products
Tetracycline-
Based
Products
Doxycycline-
Based
Products
• PerioCol-CG
• Chlo-Site
• PerioCol-TC
• Periodontal
Plus AB
• Ligosan Slow
Release
Non-U.S Locally Delivered, Controlled-Release Antimicrobials

57. Tetracycline-Based Products
An ethylene or vinyl acetate copolymer fiber containing the antibiotic
tetracycline (Actisite as a 12.7-mg, 9-inch filament), was the first product
introduced into the U.S. market in the early 1990s and was the prototypic
system

58. Consists of a monolithic thread of a biologically inert, non‐resorbable plastic
co‐polymer (ethylene and vinyl‐acetate) containing 25% tetracycline HCl powder.
The fiber is packed into the periodontal pocket, secured with a thin layer of
cyanoacrylate adhesive, and left in place for 7–12 days (Goodson et al. 1983, 1991).
Local placement of a ‘tetracycline- releasing’ ethylene vinyl acetate monolithic
fiber can yield tetracycline concentrations in excess of 1300 microgram/ml in
gingival crevicular fluid over 10 days (Theilade E, Wright WH, Jensen SB, Loe H,
1966)
In comparison, repeated systemic doses of tetracycline HCl can only provide
tetracycline levels of 4-8 microgram /ml in gingival crevicular fluid

59. PerioCol-TC is indicated for the treatment of chronic periodontitis
as an adjunct to SRP for pockets more than 5 mm deep, and it can
be administered every 3 months.
The fibers are moistened with saline and placed into the periodontal pocket to
the depth of the pocket base; they are biodegradable and do not have to be
removed.
PerioCol-TC releases tetracycline in vitro
for 8 to 10 days.

60. Periodontal Plus AB is a bioresorbable tetracycline fiber. It is 25 mg of pure
fibrillar collagen evenly impregnated with approximately 2 mg of tetracycline
hydrochloride.
The fiber biodegrades in the periodontal pocket within 7 days.(Chhina K,
Bhatnagar R, 2012) .The fiber should be retained with a periodontal dressing or
covered with a dental adhesive for 10 days.

61. At least nine randomized clinical trials have assessed the effect of tetracycline in this
vehicle (Minabe et al. 1991; Jeong et al. 1994; Newman et al. 1994; Drisko et al. 1995;
Tonetti et al. 1998; Wong et al. 1998; Kinane & Radvar 1999; Yalcin et al. 1999; Aimetti
et al. 2004).
PPD changes were calculated in all the studies, with reductions amounting to 0.4–1.2
mm and 1.3– 2.6 mm in the control and test groups, respectively; three studies found
statistically significant differences between the groups.
Changes in CAL were also reported in all studies, with differences between
groups ranging from 0.1 to 0.7 mm and 0.3 to 2.3 mm in the control and test
groups, respectively.
Changes in BoP ranged from 5% to 42% in the control groups and from 4% to
79% in the test groups, with significant differences found in five studies.
Andrea Mombelli and David Herrera 2015

62. A two‐syringe mixing system ----One syringe contains the delivery vehicle,
flowable bioabsorbable poly(dl‐lactide) dissolved in N‐methyl‐2‐pyrrolidone, and
the other a doxycycline hyclate powder.(equivalent to 42.5 mg of doxycycline)
Doxycycline-Based Products
The gel has been reported to release doxycycline in the GCF over 7
days.(Stoller NH et al, 1998).

63. Ligosan Slow Release is a 14% (w/w), resorbable doxycycline gel for
periodontal application provided in a laminate pouch
The maximal value in the GCF within the first 5 hours (i.e., at 15 minutes) was
19.97 ± 5.58 mg/mL;
after 3 days, the concentration was 577.1 ± 127.3 μg/mL.
Concentrations in the GCF remained above 16 μg/mL for at least 12 days.
Mechanical hygiene in the area should be avoided for 7 days.(Finkelman et al,
2018.)

64. At least seven randomized clinical trials have tested this formulation
(Wennström et al. 2001; Eickholz et al. 2002; Akalin et al. 2004; Agan et al. 2006;
Machion et al. 2006; Bogren et al. 2008; Gupta et al. 2008).
Changes of PPD were statistically significant between test and control groups in three
of these seven trials. Control groups demonstrated a mean change ranging from 1.1 to
3.1 mm, and the test groups from 1.2 to 4.0 mm.
Three trials reported statistically significant intergroup differences for CAL changes.
The magnitude of the differences between groups ranged from 0.5 to 1.6 mm in the
control and from 0.7 to 3.2 mm in the test groups.
Five papers reported BoP changes, with reductions ranging from 8% to 56% in the
control and from 13% to 64% in the test groups, but no significant differences
between groups.
Andrea Mombelli and David Herrera 2015

65. 2% ointment
Powder consisting of resorbable polymer
microspheres
At least 13 randomized clinical trials (Nakagawa et al. 1991; van Steenberghe et al.
1993; Jones et al. 1994; Graca et al. 1997; Jarrold et al. 1997; Kinane & Radvar 1999;
Williams et al. 2001; Henderson et al. 2002; Meinberg et al. 2002; Van Dyke et al.
2002; Goodson et al. 2007; Bland et al. 2010) were performed.
MINOCYCLINE BASED PRODUCT

66. Differences of changes in mean PPD were statistically significant between test and
control groups in five trials. Control groups demonstrated a mean change ranging from
0.4 to 1.9 mm, and the test groups from 0.9 to 2.6 mm.
Four trials reported a statistically significant intergroup difference for CAL changes.
The magnitude of the differences between groups ranged from 0 to 1.6 mm in the
control and from 0.8 to 1.9 mm in the test groups.
Three trials reported significant differences between groups with regards to Bleeding
on probing , with reductions ranging from 5% to 46% in the control and from 4% to
87% in the test groups.
Andrea Mombelli and David Herrera 2015

67. Chlorhexidine-Based Products
The chlorhexidine chip is a small chip (4.0 × 5.0 × 0.35 mm)
that contains 2.5 mg of the active ingredient chlorhexidine
gluconate in a resorbable, biodegradable matrix of
hydrolyzed gelatin that is cross-linked with glutaraldehyde
and packaged in individual foil containers .
The chlorhexidine chip is placed into the pocket directly from the foil container using a
forceps
After placement in the pocket, the chip has been reported to release chlorhexidine into
the gingival crevicular fluid (GCF) over 7 to 10 days.

68. PerioCol-CG is a small, 10-mg chip (4 × 5 ×
0.25–0.32 mm) designed as a collagen matrix into
which chlorhexidine gluconate (2.5 mg) is
incorporated from a 20% chlorhexidine
solution that is its active ingredient.
The chip is designed for insertion into the periodontal pocket and resorbs after 30 days,
but its coronal edge degrades within 10 days.(Archana B, et al 2012)
It releases chlorhexidine in vitro at a rate of approximately 40% to 45% in the first 24
hours, followed by a linear release for 7 to 8 days. (Archana B, et al 2012)

69. Chlo-Site is a xanthan gel, consisting of a
saccharide polymer as a three-dimensional
mesh containing 1.5% chlorhexidine in
0.5 mL of gel, which is injected into the
periodontal pocket.
The gel product is sterilized by gamma radiation at 2.5 Mrad and is individually packed for
delivery in 0.25-mL prefilled syringes fitted with a blunt side-exit needle.(Dodwad V,et al,
2012)
The gel contains two types of chlorhexidine: a slow-release chlorhexidine
digluconate (0.5%) and a rapid-release chlorhexidine dihydrochloride
(1.0%).(British Dent J. 2006)
The gel disappears from the pocket in 10 to 30 days and is reported to achieve a
chlorhexidine concentration in GCF of more than 100 μg/mL for anaverage of 6 to 9 days
and to maintain an effective concentration for at least 15 days.(Chhina K, Bhatnagar R.
2012)

70. Chlorhexidine chip has been extensively tested in at least 11 trials (Soskolne et al.
1997; Jeffcoat et al. 1998, 2000; Heasman et al. 2001; Azmak et al. 2002; Grisi et al.
2002; Mizrak et al. 2006; Carvalho et al. 2007; Kasaj et al. 2007; Paolantonio et al.
2008; Sakellari et al. 2010).
All of them assessed PPD. The improvements ranged from 0.3 to 2.3 mm in the control
and from 0.8 to 3.8 mm in the test groups. The differences between groups were
statistically significant in only six of the trials.
All 11 studies assessed CAL. The changes ranged from −0.4 to 1.6 mm in the control
and from −0.9 to +2.8 mm in the test groups and were significantly different between
groups in six studies.
Changes in BOP ranged from 33% to 64% in the control and from 22% to 63% in the
test groups, with differences between groups reaching a level of statistical significance
in two trials
Andrea Mombelli and David Herrera 2015

71. Metronidazole
The most extensively used device for metronidazole application is a gel consisting
of a semi‐solid suspension of 25% metronidazole benzoate in a mixture of glyceryl
mono‐oleate and sesame oil
The gel is applied with a syringe into the pocket, and its viscosity should increase
after placement.
Seven randomized clinical trials have evaluated the effects of this formulation as an
adjunct to non‐surgical mechanical therapy (Noyan et al. 1997; Lie et al. 1998; Kinane &
Radvar 1999; Palmer et al. 1999; Riep et al. 1999; Griffiths et al. 2000; Stelzel &
Flores‐de‐Jacoby 2000).
PPD changes were reported in all seven studies, with the mean differences between
groups ranging from 0.7 to 1.7 mm in the control groups and from 0.9 to 2.1 mm in
the test groups.

72. For CAL changes, the differences between groups ranged from 0.4 to
0.9 mm in the control and from <0.1 to 0.8 mm in the test groups, and the differences
between groups were statistically significant in three studies.
BOP was registered in six studies, with changes ranging from 6% to 48% and from
11% to 59% in the control and test groups, respectively, with statistically significant
differences between groups in only one trial.
Andrea Mombelli and David Herrera 2015

73. Azithromycin gel
Only one study has reported data on the adjunctive effect of local azithromycin on SRP
(Pradeep et al. 2008).
Differences in PPD reduction were statistically significant and CAL gains were
significantly greater in the test than in the control group after 3 months.
BOP was not assessed.
Andrea Mombelli and David Herrera 2015

77. Professional application of antimicrobial agents with nonsustained pocket delivery
Few antimicrobial agents professionally applied with nonsustained pocket delivery
(subgingival irrigation) show significant clinical benefits relative to conventional
mechanical root debridement alone.
Iodine and sodium bicarbonate was introduced professionally into periodontitis
lesions in conjunction with scaling and root planing have produced sustained (12
months) improvement in clinical periodontal attachment level compared to mechanical
root debridement alone
THOMAES. RAMS& JORGEN SLOTS 1996

78. Combination sodium bicarbonate, sodium chloride, hydrogen peroxide
and povidone-iodine
Professional subgingival placement of a sodium bicarbonate, sodium
chloride and hydrogen peroxide paste, followed by pocket irrigation of a povidone-
iodine solution, was shown to significantly augment subgingival mechanical root
debridement of adult periodontitis lesions.
Greater reductions in the subgingival microbiota, and statistically significantly
greater gains in clinical periodontal attachment and radiographic alveolar bone
mass over a 12-month post-treatment period occurred with the adjunctive locally
delivered antimicrobial regimen than with conventional mechanical root debridement.
Periodontal sites with probing depths of 7 mm or greater benefited the most from
the adjunctive local antimicrobial agent treatment.
Computer subtraction analysis of standardized radiographs exposed at baseline and at 6
months on initially severe sites revealed increased alveolar bone density for 73% of
sites receiving the adjunctive local antimicrobial regimen, as compared to only 28% of
sites treated with conventional scaling and root planing.

79. Povidone-iodine
Rosling et al. (Rosling BG,et al, 1986) and Christersson et al. (Christersson et al, 1988)
assessed the value of povidone-iodine irrigation of periodontitis lesions as an adjunct to
subgingival debridement in a controlled clinical trial.
At 12-months post-treatment, significantly more deep periodontal pockets
experienced 2 mm or more in gain of clinical attachment after ultrasonic root
debridement with a diluted povidone-iodine solution (final concentration 0.05% free
iodine) than with physiological saline
The adjunctive benefits of the povidone-iodine pocket irrigation were apparent when used
with a nonsurgical ultrasonic root debridement therapy, but not with modified Widman
flap surgery

80. Rosling et al. (Rosling BG, et al, 1983) and Hamada et al. (Hamada N, et al, 1986)
reported a favorable clinical and microbiological effect of adjunctive povidone-
iodine irrigation in periodontitis treatment, including furcation lesions on multi-
rooted teeth.
Subgingival povidone-iodine irrigation with no other treatment produced, after 15
days, significant decrease in gingival inflammation, a reduced number of plasma cells,
and a smaller volumetric density of infiltrated gingival connective tissue in advanced
periodontitis sites (Cigana et al, 1991)).
After pocket irrigation with a diluted povidone-iodine solution (0.2% free iodine), a
greater than 2-log subgingival decrease occurred immediately in black-
pigmented, gram-negative anaerobic rods (Nakagawa T,et al, 1990).

81. Sodium bicarbonate
A sodium bicarbonate toothpowder (Church & Dwight, Princeton, NJ) may enhance
periodontal healing when placed into periodontal pockets in conjunction with scaling
and root planing procedures.
In a study by Christersson et al. (1988), a sodium bicarbonate powder was
subgingivally packed during periodontal debridement by Hirschfeld files wetted with
water. At 12 months post-treatment,81% of sites initially 7 mm or greater showed 2
mm or more gain in clinical periodontal attachment after adjunctive sodium bicarbonate
placement, as compared to only 39% of deep sites treated solely with conventional
mechanical debridement.

82. Chlorhexidine
Chlorhexidine irrigation or gel placement into periodontal pockets during mechanical
root debridement sessions generally provides no adjunctive clinical benefits

84. The lack of clinical efficacy of chlorhexidine with nonsustained subgingival
delivery approaches may be due to----
1) use of subtherapeutic chlorhexidine concentrations during the drug’s brief
subgingival exposure following pocket irrigation (Caufield PW, et al, 1887).
2) Serum protein binding to chlorhexidine upon its introduction into subgingival sites,
demonstrating the apparent lack of chlorhexidine substantivity to root surfaces .
(Stabholz A et al, 1993)
Thus, nonsustained delivery of low-concentration chlorhexidine
solutions or gels in single or periodic pocket applications as an adjunct to
periodontal debridement does not appear scientifically justified.
The improved clinical findings detected with repeated chlorhexidine
pocket applications after the resolution of inflammation and bleeding by
mechanical root debridement supports this hypothesis(Southard SR et al,
1989).

85. Other topical antimicrobial agents
A 1.64% stannous fluoride gel, professionally irrigated without root debridement into
periodontitis sites, reduced gingival inflammation and decreased proportions of
subgingival motile organisms over 6- 10 weeks (Lazzaro AJ, Bissada NE,1989), but
had a negligible effect on subgingival black-pigmented anaerobic rods (Schmid E,
Kornman K, Tinanoff N. 1985).
No adjunctive clinical benefit has been found with single or multiple pocket irrigations
of stannous fluoride in the presence of root scaling (Perry DA, et al 1984).
similar lack of adjunctive clinical benefits to periodontal debridement have been found
with pocket irrigations with 3% hydrogen peroxide (Christersson LA et al, 1988),
1% chloramine-T (Herzog A, et al, 1988) and 1.25% amine fluoride gel (Oosterwaal et
al 1991)
Surprisingly despite the lack of adjunctive clinical benefits, A. actinomycetemcomituans
reportedly was eliminated in 46% of periodontitis sites treated biweekly over 6 months
with pocket irrigations with 3% hydrogen peroxide (Wikesjo et al, 1989).

86. An update of recent scientific evidence on the use of local antimicrobials in
the treatment of periodontitis
The efficacy of the local use of CHX adjunctive to nonsurgical periodontal therapy in
different pharmacological applications has been tested, reporting different clinical and
microbiological outcomes.
When formulated as CHX chips, (Paolantonio et al, 2008) found significant PPD
reductions in their adjunctive use compared with SRP
Other studies(Sakellari D,et al, 2010, Gonzales JR et al 2011) did not find
significant differences in terms of PPD reduction and CAL gain.

87. This molecule is chemically linked to CHX, favoring its slow release and thus
maintaining adequate CHX concentrations inside the periodontal pocket.(Heasman
et al 2001)
There is recent, although scarce evidence, suggesting that the adjunctive use of
this product to SRP may improve the results of SRP alone.(Killoy WJ,1999,
Paolantonio et al 2009)
The local application of CHX has also been evaluated when formulated
with a xanthan gel

88. The effect of local application of a biodegradable tetracycline fiber has been tested in a 3-
month RCT(Sachdeva,2011).
Even though beneficial outcomes were found in the test group, with differences of more
than 1 mm in terms of PPD reductions.
these differences were not statistically different when compared with the control group
and, therefore, the efficiency of this therapy was questioned.

89. Locally applied slow-release doxycycline has also been evaluated in different
RCTs, also reporting heterogeneous results.(Gupta R, 2008, Bogren A, et al
2008)
Although some studies(Gupta R et al, 2008, Sandhya YP et al, 2011) have reported
significant benefits.
Other studies(Bogren A, et al 2008) were not able to find significant differences
Gupta et al,2007 and Sandhya et al, 2011 found significant PPD reductions
and CAL gains when locally applying doxycycline as an adjunct to SRP, especially in
individuals who smoke.
In a study, Tonetti et al, 2012, when local doxycycline was used in combination with
SRP for the treatment of specific sites in patients with chronic periodontitis undergoing
maintenance therapy, neither the analysis by patient, nor by tooth or by furcation
rendered statistically significant results.

90. Azithromycin has been tested as a local delivery agent.(Pradeep AR, Sagar SV,
Daisy H, 2008).
Although the reported results were positive, the RCT was of a short follow-up
and these preliminary data deserve further research with this agent.
Moxifloxacin, a fourth-generation fluoroquinolone antibiotic with a broad
antimicrobial activity against aerobic and anaerobic bacteria has also been
recently tested when locally applied. The local application of 0.4% moxifloxacin
in combination with SRP demonstrated statistically significant benefits in
moderate to severe chronic periodontitis, when compared with SRP alone.(
Flemmig TF et al, 2011)

92. The adjunctive use of locally delivered subgingival antimicrobials results in statistically
significant benefits in terms PPD reduction and (only short-term) CAL gain.
Significant heterogeneity was observed in most of the analyses, since they combined
different products with different active agents, and also influenced by the study design (larger
benefits for split-mouth studies and for partial-mouth assessments).
No increase in adverse effects or differences in PROMs ( Patient Reported Outcome
Measures and Adverse event)were observed.

93. CONCLUDING COMMENTS
As a monotherapy, local drug delivery systems incorporating a variety of drugs
can improve periodontal health
There is no single universal drug that would be effective
in all situations.
Local delivery may be an adjunct to conventional therapy. The sites most likely
to be responsive to refractory or recurrent Periodontitis, or specific locations
where it is difficult to instrument root surfaces. However, the data are limited to
support this concept.
 There are preliminary, but very limited data, regarding the ability of local
delivery to help suppress future disease progression
Additional studies are needed to evaluate if local delivery is effective against
tissue invasive organisms.

94. The use of local antimicrobials can be used
in the treatment of localized periodontitis
lesions, either as an adjunct to SRP in the
treatment of chronic periodontitis or in the
treatment of relapsing periodontal lesions
in patients undergoing maintenance
therapy.

95. THANK YOU