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Systemic antimicrobial therapy in periodontal diseases (3).ppt
1. Chemotherapy: Treatment of systemic infections
with specific drugs that selectively suppress the
infecting microorganism without significantly
affecting the host.
Chemotherapeutic Agent: A chemical substance
that provides a clinical therapeutic benefit.
Clinical benefits can be derived through
antimicrobial actions or an increase in the host’s
resistance.
2. Antimicrobial Agent: is a chemotherapeutic agent
that works by reducing the number of bacteria
present.
Antibiotics: are naturally occurring, semi-synthetic
or synthetic type of antimicrobial agents that
destroy or inhibit the growth of selective
microorganisms, generally at low concentrations.
3. Antiseptics: are chemical antimicrobial agents that
are applied topically or subgingivally to mucous
membranes, wounds, or intact dermal surfaces to
destroy microorganisms and inhibit their
reproduction or metabolism.
In dentistry, antiseptics are widely used as the active
ingredients in anti-plaque and anti-gingivitis
mouthrinses and dentifrices.
Disinfectants: A subcategory of antiseptics, are
antimicrobial agents that are generally applied to
inanimate surfaces to destroy microorganisms.
4. CLASSIFICATION
Based on chemical structure
Sulfonamides and related drugs – Sulfadiazene,
Dapsone
Diaminopyrimidines – Trimethoprim
Quinolones – Ciprofloxacin, Norfloxacin
Beta-lactam drugs – Penicillins, Cephalosporin
Tetracyclines – Oxytetracycline, Doxycycline
Nitrobenzene derivatives - Chloramphenicol
7. Mechanism of action
Inhibit cell wall synthesis – Penicillins
Cause leakage from cell membranes –
Polypeptides, Polyenes
Inhibit protein synthesis – Tetracyclines,
Erythromycin
Cause misreading of mRNA code and affect
permeability - Aminoglycosides
8. Inhibit DNA gyrase – Fluoroquinolones
Interfere with DNA function – Metronidazole
Interfere with DNA synthesis – Idoxuridine,
Acyclovir
Interfere with intermediary metabolism –
Sulfonamides, Sulfones
9. Type of organism against which primarily active
Antibacterial – Penicillins, Aminoglycosides
Antifungal – Amphotericin, Ketoconazole
Antiviral – Acyclovir, Amantadine
Antiprotozoal – Chloroquine, Metronidazole
Anthelminthic - Mebendazole
10. Spectrum of activity
Broad spectrum
Tetracyclines
Chloramphenicol
Extended spectrum Penicillins
Newer Cephalosporins and aminoglycosides,
fluoroquinolones
Narrow spectrum
Penicillin G
Streptomycin
Erythromycin
11. Type of action
Primarily bacteriostatic
Tetracyclines
Erythromycin
Primarily bactericidal
Penicillins
Ciprofloxacin
Cephalosporins
12. Chemotherapeutic agents in
periodontal disease
The various periodontal diseases result from
susceptible hosts having their periodontal
tissues colonized by specific oral pathogens in
numbers sufficient to overwhelm their tissue
defenses.
Clinical success in the treatment of these
diseases requires reduction of the bacterial load
or enhancement of the host tissues’ ability to
defend or repair itself.
13. Traditionally, the foundations of clinical success
include -
Education of patients in daily oral hygiene
Nonsurgical and surgical mechanical root
debridement to remove subgingival bacteria and
their accretions from root surfaces
Supportive periodontal therapy generally at 3-6
month intervals
15. Most periodontal investigators agree that
bacteria are the primary etiologic agents of
destructive periodontal diseases, although there
is some recent evidence that implicates certain
viral agents e.g. cytomegalovirus, Epstein–Barr
virus, papillomavirus, and herpes simplex virus
the primary host challenge and disease initiator
continues to appear bacterial in nature
16. Is periodontal disease an anaerobic
infection of micro-aerophilic infection?
This question can be answered by studies which
monitor the majority of the plaque bacterial
types.loesche et al
A. actinomycetemcomitans in about 20 to 50% of
the plaques (Loesche et al., 1992b). However, P.
gingivalis, T. forsythensis , Treponema
denticola, and spirochetes were present in 80 to
100% of the plaques, indicating that these-
anaerobes were more prevalent relative to A.
actinomycetemcomitans.
17. At least 12 other groups have found
anaerobic species to be more prevalent than
A. actinomycetemcomitans in plaques taken
from diseased periodontal sites.
18. Ashimoto et al. (1996), using a PCR technique,
found the prevalence of anaerobes such as
T. forsythensis to increase 10.7-fold, of
P. gingivalis to increase five-fold, and
T. denticola to increase 3.4-fold,
when plaques from diseased sites in
adults were compared with plaques removed
from sites of gingivitis in children.
Micro-aerophilic species showed minimal
changes, i.e., A. actinomycetemcomitans
increased 2.1-fold.
19. These studies, from many laboratories involving
large numbers of samples and using diverse
methods, indicate that anaerobes, rather than A.
actinomycetemcomitans, are more likely to be
present in, or dominate, plaques associated with
disease.
20.
21. The microbial etiology of inflammatory
periodontal diseases provides the rationale for
the use of antimicrobial medication in
periodontal therapy.
The vast majority of periodontitis cases respond
well to conventional nonsurgical periodontal
therapy, i.e. scaling and root planing (SRP),
improved oral hygiene and supportive
periodontal recall.
However, certain patients, for various reasons,
do not respond favorably to mechanical therapy
alone. For these patients, the use of an
appropriate adjunctive antimicrobial is often
beneficial.
22. Studies also reveal that micro-organisms can
penetrate into the soft tissues (Christersson et al,
1987), albeit to a limited depth, and into the
dentinal tubules to a considerable distance
(Adriaens et al, 1988).
Furthermore, there are other oral sites where
periodontal pathogens can be found, in
particular on the tonsils and tongue. And this
may compromise the long term stability of
surgical or non-surgical periodontal therapy,
bringing the need for antimicrobial intervention.
23. Systemic antibiotic therapy has certain
advantages over topical application of
antimicrobial agents.
Systemic antibiotics may enable the
simple, easy administration of the drug to
multiple sites of disease activity.
They may also eliminate or reduce
pathogens colonizing on oral mucosa and
on other extra-dental sites including the
tongue and tonsilar areas.16-18
24. The possibility of markedly suppressing or
eliminating periodontal pathogens from virtually
the entire mouth may reduce the risk for future
translocation of organisms and recolonization of
the periodontal pocket, thereby potentially
reducing the risk for recurrent disease progression.
moreover systemic antibiotic therapy is carried out
with relativey low financial cost to the patients
25. Issue Systemic Local
Drug distribution Wide Narrow effective
range
Drug
concentration
Variable levels in
different body
compartments
High doses at
treated sites, low
levels elsewhere
Therapeutic
potential
May reach widely
distributed
microorganisms
better
May act better
locally on biofilm
associated
bacteria
26. Issue Systemic Local
Problems Systemic side effects Reinfection from
non-treated sites
Clinical limitations Requires good
patient compliance
Infection limited to
the treated site
Diagnostic problems Identification of
pathogens, choice of
drug
Distribution pattern
of lesions and
pathogens,
identification of sites
to be treated
27. Two questions arise
I. First, how does the practitioner recognize
patients who will benefit from adjunctive
antimicrobial therapy?
II. Second, which antimicrobial agent is most
likely to provide the beneficial response
desired with minimal adverse effects?
28. Whom to treat???
Prime candidates:
Patients who exhibit continuing loss of periodontal
attachment despite diligent conventional
mechanical periodontal therapy.
Recurrent/ refractory periodontitis: often related to
persistent subgingival pathogens and impaired host
resistance.
Patients with aggressive type of periodontitis
Patients with medical conditions predisposing to
periodontitis.
29. Patients with acute or severe periodontal
infections (periodontal abscess, acute necrotizing
gingivitis/periodontitis)may also need antibiotic
therapy.
evidence exists suggesting that antibiotic use in
chronic periodontitis may result in improvement
in clinical attachment level, although many
questions regarding the indications for this
therapy remain unanswered.
30. What Agent to Use?
Based on predominantly anaerobic nature of
periodontal diseases, the agents which are
effective against anaerobic organisms hold a key
place in periodontal therapy.
32. Mechanism of action
It is now known that cytotoxic metabolites of
metronidazole directly interact with bacterial
DNA, and possibly other macromolecules,
resulting in cell death.
Upon entry into an anaerobic organism,
metronidazole is reduced at the 5-nitro position
by electron transport proteins that are part of
anaerobic metabolic energy-yielding pathways.
33. Alteration of the metronidazole molecule creates
a continuous concentration gradient favoring
diffusion of additional metronidazole into the
cell.
Reduction of the parent compound yields many
short-lived cytotoxic free radicals.
These free radicals react with macromolecules,
particularly DNA, resulting in cell death.
35. Metronidazole readily penetrates into the
gingival crevicular fluid (Van Oosten MA 1986)
and achieves concentrations in excess of the
MICs established in vitro for most putative
periodontal pathogens (Kleinfelder JW,1999.)
However, a significant proportion of the A.
actinomycetemcomitans isolates tested have
demonstrated resistance to metronidazole
(Madinier 1999).
37. Chronic periodontitis
Studies by Loesche et al. enrolling adult
periodontitis subjects indicated that
metronidazole in conjunction with mechanical
debridement decreases the number of teeth
requiring periodontal surgery or extraction due
to periodontitis (Loesche WJ,1984,1992).
38. In a 5-year monitoring study of the effects of
metronidazole in conjunction with debridement,
Loesche et al. reported reduced need for
periodontal surgery or tooth extraction.
This reduction was maintained for at least 5
years after completion of the initial therapy
(Loesche WJ, 2002)
39. Refractory periodontitis
Van Winkelhoff et al. used metronidazole (500 mg
tid for 7 days) as an adjunct to debridement in the
treatment of 27 refractory periodontitis patients.
Subjects were selected based on detectable levels of
T. forsythia and nondetectable levels of A.
actinomycetemcomitans.
Mean probing depths, probing attachment levels
and bleeding indices showed significant
improvement following metronidazole treatment.
40.
41. Aggressive periodontitis
Metronidazole has been used as an adjunct in
the treatment of aggressive juvenile
periodontitis, particularly localized juvenile
periodontitis.
Therapy markedly reduced levels of A.
actinomycetemcomitans but did not eradicate
the organism (Saxen L, Asikainen S in 1993).
42. Unlike most other gram-negative
periodontopathogens, A. actinomycetemcomitans
is relatively resistant to metronidazole in vitro
(Poulet PP,1999; Muller 2002).
Consequently, use of metronidazole as an adjunct
to mechanical debridement is not considered an
optimal choice for management of juvenile
periodontitis.
43. Adverse effects
The most common adverse reactions associated
with metronidazole involve the gastrointestinal
tract.
nausea which may be accompanied by
headache, anorexia, and vomiting.
Drowsiness, depression, skin rashes, and
vaginal and ⁄or urethral burning have been
reported.
44. Metronidazole affects the activity of hepatic
enzymes involved with the metabolism of
ethanol, producing unpleasant symptoms due to
the accumulation of acetaldehyde in the blood.
(Disulfiram like reaction) Alcohol ingestion is
strictly contraindicated in patients receiving
metronidazole.
45. Metronidazole crosses the placenta barrier,
entering the fetal circulation system. It is also
secreted in breast milk.
Because of the association of metronidazole with
tumorigenicity in some animals (some small
rodent as detected by Ames test), the drug is
contraindicated in pregnant women or nursing
mothers.
46. In summary, the adjunctive use of
metronidazole in conjunction with thorough
mechanical debridement results in reduction in
spirochetes and gram negative anaerobic rods,
including P. intermedia, P. gingivalis, and T.
forsythia.
Summary- Metronidazole
47. Relative to either baseline or mechanical
debridement alone, some improvement is
generally obtained in probing pocket depth and
in clinical attachment level.
Generally speaking, deeper sites (> 5 mm
probing pocket depth) tend to respond better
than moderate sites (4–5 mm probing pocket
depth)
48. Tetracyclines
The tetracyclines, tetracycline-HCl, doxycycline
hyclate and minocycline-HCl, are broad-spectrum
antibiotics active against both gram-positive and
gram-negative bacteria.
Structurally, tetracyclines
consist of four fused rings,
hence the name
tetracyclines (Fig. 4).
49. Tetracycline derivatives, primarily doxycycline and
minocycline, differ from the parent compound by
minor alterations of chemical constituents attached
to the basic ring structure.
These minor alterations in the molecular structure
make both doxycycline and minocycline more
lipophilic than the parent compound, resulting in
better adsorption following systemic delivery and
better penetration into the bacterial cell.
Thus, lower and less frequent doses of doxycycline
and minocycline can be given.
50. Mechanism of action
The tetracyclines bind to the bacterial 30S
ribosomal subunit and inhibit protein synthesis in
the bacterial cell.
Thus, these are normally bacteriostatic Antibiotics.
However, at high concentrations, the tetracyclines
may exert a bactericidal effect due to their ability to
cause alterations in the cytoplasmic membrane.
This may result in leakage of nucleotides and other
components from the bacterial cell and result in its
death.
51. Microbial inhibition, in combination with
elevated gingival crevicular fluid levels achieved
during systemic administration , provided
support for the use of tetracycline as an
adjunctive antibiotic.
Tetracyclines have a distinctive property of
concentrating in GCF at levels from two to 10
times greater than that of the serum after a
single 250-mg dose (Gordon et al., 1981a).
52. Consequently, tetracycline was one of the
first antibiotics to receive thorough
scientific evaluation aimed at treatment of
periodontal diseases.
53. Several small scale clinical trials, evaluating the
efficacy of tetracycline as an adjunct to SRP in
the treatment of adult periodontitis, failed to
demonstrate statistically significant differences
compared to SRP alone.
However, mean probing depth and attachment
level were slightly improved. (Scopp 1980, Slots
1979)
54. Tetracyclines seem to be more effective against
subgingival spirochetes.
Tetracycline-HCl for two periods of 14 days
separated by a 4-week interval and tetracycline
for 1 year suppressed spirochetes below
detectable levels. (Listgarten MA et al., 1978)
Doxycycline for 14 days reduced spirochetes in
advanced periodontitis lesions to below
detectable levels for at least 3 months.
(Lundstrom et al., 1984)
55. Refractory periodontitis
Double-blind clinical studies enrolling patients
characterized as having refractory or recurrent
periodontitis found systemic tetracycline and
doxycycline, in conjunction with SRP, significantly
reduced probing pocket depth and resulted in
increased attachment gain relative to SRP and
placebo (McCulloch CAG et al 1990).
Although adjunctive doxycycline was effective in
reducing the risk of recurrent disease in some
patients, it failed to prevent additional disease
progression in others (Walker CB,1993).
56. Aggressive periodontitis
Results obtained following adjunctive use of
tetracycline in the treatment of localized aggressive
periodontitis were often clinically profound.
Such improvements were likely due to the
elimination or severe repression of A.
actinomycetemcomitansin the infected site.
However, tetracycline and SRP did not suppress A.
actinomycetemcomitans in all localized aggressive
periodontitis patients (94).
57. Lindhe reported that renewed disease activity
occurred in up to 25% of localized aggressive
periodontitis patients treated with adjunctive
tetracycline therapy despite a strict 3-month
follow-up interval (Lindhe J.1981).
58. STUDY AMA
& DOSE
TEST CON OUTCOME
Listgarten
et al.
1978
6 months
TC 250 mg
daily for 14
days repeated
after 28 day
interval
SRP SRP No
Advantage
Hellden et
al.
1979
98 days
TC 250 mg
daily for 14
days repeated
after 28 day
interval
SRP SRP No
Advantage
59. Muller et al.
1989
3 months
MC 100
mg bid
for 21
days
SRP,
MWF -
A.a
eliminated
with
MC+SRP+
MWF
Muller et al.
1990
1 month
MC 100
mg bi d
for 7 days
alone or
21 days
with SRP
SRP
-
A.a
elimination
from
positive
sites.
Freeman et al.
1992
15 days
MC 100
mg daily
or twice
daily for
8 days
-
-
No clinical
differences
b/w
regimes
60. Bacterial resistance to tetracycline
The development of resistant strains of bacteria
can reduce the benefits of tetracyclines in the
treatment of infections.
However, the increase in resistant bacteria may
be transient (Fiehn and Westergaard, 1990;
Goodson and Tanner, 1992).
61. Mechanism of resistance
Bacteria become resistant to tetracycline by
natural selection, whereby susceptible strains are
eradicated while the resistant strains remain
(Walker, 1996).
62. Three mechanisms of resistance to tetracyclines
have been identified (Chopra et al., 1992; Speer et
al., 1992).
The first mechanism involves an efflux pump
system, whereby tetracycline-resistant cells
actively transport the drug out of the cell,
thereby decreasing the intracellular drug
concentration (Walker, 1996).
Another category of resistance is ribosome
protection, whereby tetracyclines cannot bind
efficiently to a modified ribosome, thus
preventing the inhibition of protein synthesis
(Salyers et al., 1990).
63. The third type of resistance, which is not well
understood, involves a chemical alteration of the
tetracycline molecule (Speer et al., 1992).
64. different genes that encode for resistance to
tetracyclines
. Bacteria with a tet M, tet 0, tet 0, and tet S
determinant reflect a ribosomal protection-resistant
mechanism that confers resistance equally to
tetracycline, doxycycline, and minocycline
(Charpentier et al., 1993; Walker, 1996).
Tet A through tet F, tet K, and tet L determinants
mediate the efflux of tetracyclines (Charpentier et al.,
1993) and are less effective against doxycycline and
somewhat ineffective against minocycline (Walker,
1996).
65. Tet 0, a gene cloned from intestinal Bacteroides
fragilis, is widespread among tetracycline-
resistant Bacteroides spp (Fletcher and Macrina,
1991) and Prevotella intermedia and Prevotella
denticola in refractory periodontitis (Olsvik and
Tenover, 1993).
66. Adverse reactions
Pregnancy: discoloration and hypoplasia of
teeth, depressed skeletal growth
Children: discoloration and hypoplasia of teeth,
depressed skeletal growth
Doxycycline: photosensitivity
67. Glycylcyclines
A new generation of semi-synthetic tetracycline
compounds called glycylcyclines has recently
been developed.
Glycylcyclines are effective not only against
tetracycline-sensitive bacteria, but also against
tetracycline- resistant Gram-positive and -
negative microorganisms possessing tetracycline
efflux pump and ribosome protection-resistant
determinants (Testa et al., 1993; Rasmussen et
al., 1994).
68. The glycylcyclines are chemical modifications of
minocycline (Sum et al., 1994).
Two new glycylcyclines have been identified
thus far and show no bacterial resistance in vitro
(Tally et al., 1995). Currently, these products are
undergoing clinical studies for safety in
humans.
69. Summary-tetracyclines (as antimicrobial agent)
Tetracyclines (tetracycline-HCl, doxycycline,
minocycline) may be indicated in periodontal
infections in which Actinobacillus
actinomycetemcomitans is the prominent
pathogen; however, in mixed infections
tetracycline antibiotics may not provide
sufficient suppression of subgingival pathogens
to arrest disease progression. (van Winkelhoff 1996)
70. Contrary to earlier concepts, the average gingival
crevicular fluid concentration of tetracycline after
systemic administration seems to be less than the
that of plasma concentration and varies widely
among individuals (between 0 and 8 μg/ml) with
approximately 50% of samples not achieving levels
of 1 μg/ml, possibly explaining much of the
variability in clinical response to systemic
tetracyclines observed in practice.
(Sakellari D, Goodson JM, Kolokotronis A, Konstantinidis A.
Concentration of 3 tetracyclines in plasma, gingival crevice fluid and
saliva. J Clin Periodontol 2000;27: 53-60.)
71. In summary, systemic administration of the
tetracyclines as an adjunct to SRP may yield
benefits in certain patients, particularly some
with localized aggressive periodontitis and in
some patients refractory to previous mechanical
therapy.
However, there currently seem to be better
choices of an antibiotic for systemic use.
72. Tetracyclines in host modulation
TC have traditionally been advocated as useful
adjuncts in periodontal therapy based on three
percieved advantages:
Their effectiveness against anaerobic gram-negative
pathogens in plaque.
Unique ability to be highly concentrated in the GCF
at levels much greater than those found in serum.
Ability to bind to tooth surface and then be slowly
released as an antimicrobial that is still active,
prolonged efficacy.
73. However TC are now recognized to have nonantimicrobial
properties that appear to modulate host response.
Direct inhibition of the activity of extracellular
collagenase and other matrix metalloproteinases such
as gelatinases
Prevention of the activation of its proenzyme by
scavenging reactive oxygen species generated by other
cell types (e.g. neutrophils, osteoclasts)
Inhibition of the secretion of other collagenolytic
enzymes( lysosomal cathepsins)
A direct effect on other aspects of osteoclast structure
and function.
75. Ramamurthy & Golub study 1983
It was noted that there was abnormally elevated
collagenase activity in the gingiva of diabetic rats
by Ramamurthy & Golub 1983 and it was initially
hypothesized that this may be a result of a change
in the microflora in the gingival crevice.
Thus, an experiment was performed in which
minocycline was administered to the diabetic rats
(the hypothesis being that minocycline would
result in a decrease in collagenase levels by
inhibiting the microflora), and, indeed, a fall in
gingival collagenase levels was observed (Golub
et al. 1983).
76. More notably, however, minocycline treatment also
suppressed gingival collagenase levels in germ-free
diabetic rats, indicating that this ability was not
related to any effect of the drug on the microbial flora.
77. Mechanism of anticollagenolytic action
A mechanism proposed was the interaction of
the drug with the metal ion constituents of the
enzyme, Zn at the active site and Ca as an
exogenous cofactor.
78. Golub et al reviewed some of the characteristics of the
antiproteolytic activity of TCs including,
Their specificity against collagenases from different
cellular sources (eg., collagenase from inflammatory cells
is quite sensitive to TC, while that from fibroblasts is
relatively resistant.
The site on the TC molecule responsible for
anticollagenase activity.
TC most potent against PMN produced collagenases.
Type IV collagenase/gelatinase. Stromelysin. Elastase
(produced by macrophages)
MMPs resistant to TC Collagenase produced by
fibroblasts in LJP patients. (Ingman 1993, Golub et al
1995)
79. Recognizing that the antimicrobial and anticollagenase
properties of TC may reside in different parts of the
molecule Golub et al 1998 modified the drug by well-
known techniques to eliminate the former.
The dimethylamino group from carbon-4 position
(the side-chain required for antimicrobial activity in
TCs) of the A ring of the four ringed structure is
removed.
The resulting CMT lost its antimicrobial efficacy but
still retained its anticollagenase activity.
80. The CMTs comprise a group of at least 10 (CMTs 1-10)
analogues plus some special modified CMTs that differ in
their MMP specificity and potency.
81. Subantimicrobial dose doxycycline (SDD)
A new approach to non-antibacterial periodontal therapy
is the administration of specially prepared low-dose
capsules containing as low as 20 mg of doxycycline.
Doxycycline is the most potent collagenase inhibitor of
commercially available TCs. Collagenase activity was
inhibited by 70% in the presence of doxycycline, 45% with
minocycline, and 23% with tetracycline (Yanagimura et al.,
1989).
To date, this is one approved, systemic therapy that is
prescribed as a host response modifier in the treatment of
periodontal disease, and that is adjunctive
subantimicrobial dose doxycycline (SDD) (Periostat@,
CollaGenex Pharmaceuticals Inc., Newtown, P A, USA),
which downregulates the activity of MMPs.
82. Why doxycycline, is the most potent anti-
collagenase?
Doxycycline has a much lower inhibitory concentration
Doxycycline -IC50 = 15 µM
Minocycline- IC50 = 190 µM or
Tetracycline- IC50 = 350 µM
indicating that a much lower dose of doxycycline is
necessary to reduce a given collagenase level by 50%
compared with minocycline or tetracycline (Burns et
a1. 1989).
83. Furthermore, doxycycline has been found to be more
effective in blocking PMN-type collagenase activity
(MMP-8) than fibroblast-type collagenase activity (MMP-
l) (Golub et al. 1995, Smith et al. 1999), suggesting that
doxycycline can provide a safe therapeutic method for
reducing pathologically elevated collagenase levels
without interfering with normal connective tissue
turnover.
84. Mechanism of action of SDD
Doxycycline downregulates collagenolytic activity by
several synergistic mechanisms.
Doxycycline inhibits active MMPs directly by a
mechanism that is dependent on its calcium- and zinc-
binding properties (Golub et a1. 1998a).
In addition, tetracyclines are known to scavenge for, and
inhibit, the production of PMN-derived reactive oxygen
metabolites, including hypochlorous acid (HOCl) (Wasil
et al. 1988).
85. This ability may further contribute to the non-
antimicrobial, anti-inflammatory properties of
doxycycline by inhibiting HOCI from activating latent
pro-MMPs (Ramamurthy et al 1993). Thus, the ability of
tetracyclines to directly inhibit MMP activity and also
scavenge for, and inhibit, reactive oxygen metabolites
such as HOCl, represents an important pathway for
modulation of the destructive connective tissue events
that occur in periodontitis.
86. Tetracyclines inhibit osteoblast- and osteoclastderived
MMPs, thereby inhibiting bone resorption (Rifkin et al.
1994).
Doxycycline can inhibit production of epithelial cell-
derived MMPs by inhibiting intracellular expression or
synthesis of these enzymes (Nip et al. 1993, Ditto et al.
1994).
Doxycycline also contributes to decreased connective
tissue breakdown by downregulating the expression of
pro-inflammatory mediators and cytokines (including
IL-1 and TNF-α) (Milano et al. 1997), and increasing
collagen production, osteoblast activity and bone
formation (Golub et al. 1998a)
88. Penicillins
The penicillins are a broad class of antibiotics that
inhibit bacterial cell wall synthesis and directly result
in the death of the cell.
All penicillins consist of ab-lactam ring, a thiazolidine
ring, and an acyl side chain
89. Amoxicillin,
Amoxicillin, a semisynthetic penicillin, has excellent
activity against both gram-negative and grampositive
bacteria, is absorbed well following oral administration,
and penetrates into the gingival crevicular fluid.
Unfortunately, amoxicillin is also highly susceptible to
bacterial b-lactamases. b-Lactamase is an enzyme
produced by a number of different bacteria which
hydrolyzes the b-lactam ring.
90. Hydrolysis of this ring destroys all antimicrobial activity
of the penicillin. As a result, amoxicillin’s use as an
adjunct to periodontal therapy has been limited.
b-Lactamases are relatively common in periodontal
pockets, with the incidence showing a positive
correlation with pocket depth (129).
91. Augmentin, amoxicillin with a b-lactamase inhibitor,
clavulanic acid.
Clavulanic acid exhibits no antimicrobial activity, but it
does contain an unprotected b-lactam ring Many b-
lactamase enzymes of oral origin have a greater affinity for
clavulanic acid than for amoxicillin, are preferentially
bound to the clavulanate moiety, and are competitively
removed from hydrolyzing the b-lactam ring in amoxicillin.
Thus, bacteria normally resistant to amoxicillin due to the
production of b-lactamase may be susceptible to the
combination of amoxicillin and clavulanic acid.
93. Magnusson
et al
Augmentin for 2 weeks in
refractory periodontitis
(based on microbial
testing)
2mm CAL gain
Haffajee et al. Augmentin, tetracycine,
ibuprofen, or placebo, in
conjunction with Widman
flap procedure.
Augmentin or
tetacycline more
attach-ment gain
(but no diff bet
the two)
Winkel et al. Augmentin Vs Placebo No added benefit
(clinical or
microbiological)
94. Although the data are limited, clinical studies do not
support the use of Augmentin as a particularly effective
adjunctive antibiotic.
95. Clindamycin
Clindamycin is a lincosamide antibiotic used in the
treatment of infections caused by susceptible
microorganisms—mostly anaerobic bacteria
Clindamycin has a bacteriostatic effect. It interferes
with bacterial protein synthesis, in a similar way to
erythromycin, azithromycin and chloramphenicol,
by binding to the 50S subunit of the bacterial
ribosome.
96. The drug is active against most gram-positive
bacteria, including both facultative and anaerobic
species.
It is particularly active against gram-negative
anaerobes and is very active against the gram-
negative anaerobes associated with the periodontal
flora
97. However, Eikenella corrodens, a common inhabitant
of the periodontal flora and a suspected periodontal
pathogen, is inherently resistant to clindamycin
(121).
A. actinomycetemcomitans also demonstrates
intrinsic in vitro resistance to this antibiotic.
98. penetrate into the gingival crevicular fluid and to
achieve and maintain concentrations that exceed the
MICs of the periodontopathic gram-negative
anaerobic bacteria (123).
adverse effects such as diarrhea, abdominal
cramping, esophagitis, and stomach irritation are
relatively common. There have been numerous
reports of pseudomembranous colitis linked to the
use of clindamycin.
99. Gordon et
al.
refractory to
mechanical
debridement,
periodontal
surgery, and both
tetracycline and a
b-lactam antibiotic
clindamycin-
HCL for 7
days after
microbial
sensitivity
test
Active sites ↓
from an 10.7%
to 0.5%
One pt---
pseudomembra
nous colitis.
Magnusson
et al. (57),
Chronic
periodontitis
adjunctive
use of
clindamycin
after
microbial
sensitivity
test
gain in clinical
attachment
level and
reduction in
gram-negative
anaerobes
100. summary
clindamycin-HCl may be a useful adjunct in the
treatment of truly refractory patients who have
not responded favorably to other modes of
periodontal therapy including other
antimicrobials.
Prior to initiating clindamycin therapy, culture
and sensitivity testing is strongly recommended
to screen for the presence of E. corrodens and A.
actinomycetemcomitans.
Presence of either contraindicates clindamycin use
101. Azithromycin
Azithromycin belongs to the same general class of
macrolide antibiotics as erythromycin but differs in
several important aspects.
Unlike erythromycin, it has broad-spectrum activity
against a number of bacteria including gram-negative
anaerobes and provides excellent and prolonged drug
concentrations in tissue and serum.
Convenient dosing is a major advantage. Azithromycin is
usually prescribed as a 500 mg initial loading dose
followed by 250 mg⁄day once daily for 4 days. This
schedule provides therapeutic concentrations for 10 days.
102. Azithromycin demonstrates good in vitro activity
against a number of gram-negative periodontal
pathogens including all serotypes of A.
actinomycetemcomitans (71) and P. gingivalis (70).
The drug is relatively nontoxic and only a few
adverse side-effects have been associated with its
usage.
103. Azithromycin is excreted in human breast milk and
is therefore contraindicated in nursing mothers.
Azithromycin has been reported to penetrate both
healthy and diseased periodontal tissues and to
maintain chemotherapeutic levels in excess of the
MICs of the majority of periodontopathogens
thought to be involved in chronic inflammatory
periodontal diseases (8).
104. Azithromycin is concentrated in
polymorphonuclear and mononuclear cells (Calia
and Oldach, 1998}, and since many of these cells exit
into the pocket (Skapski and Lehner, 1976), they
would, after lysis, release elevated levels of this
agent in the vicinity of plaque anaerobes.
Azithromycin has been able to reduce secondary
medical outcomes in patients with cardiovascular
disease (Gupta et al., 1997).
105. Gomi K et al 2007
full-mouth SRP using azithromycin
Vs
conventional SRP.
full-mouth SRP using systemically administered
azithromycin was a clinically and bacteriologically
useful basic periodontal treatment for severe chronic
periodontitis.
106. Herrera et al 2002
azithromycin
Vs
amoxicillin/clavulanate.
For the treatment of periodontal abscess
both antibiotic regimes were effective in
the short-term treatment of periodontal abscesses
in periodontitis patients.
107. Dastoor et al 2007
surgery plus 3 days of AZM, 500 mg)
Vs
control group (surgery plus 3 days of placebo)
Results
adjunctive systemic AZM in combination with pocket
reduction surgery did not significantly enhance PD
reduction or CAL gain. However, the clinical value
of adjunctive AZM may be appreciated by more
rapid wound healing, less short-term gingival
inflammation, and sustained reductions of
periopathogenic bacteria
108. there is insufficient data evaluating azithromycin’s
potential effectiveness as an adjunctive antiobiotic
for successful treatment of periodontal diseases.
However, azithromycin, due to its unique
pharmacokinetic properties and its spectrum of
activity, may prove beneficial in certain
circumstances.
109. Ciprofloxacin
belonging to a group called fluoroquinolones.
Ciprofloxacin is bactericidal.
Its mode of action depends upon blocking bacterial
DNA replication by binding itself to an enzyme called
DNA gyrase, thereby causing double-stranded breaks in
the bacterial choromosome.
Ciprofloxacin is a broad-spectrum antibiotic that is
active against both Gram-positive and Gram-negative
bacteria.
110. Cacchillo and Walters in 2002 demonstrated that
PMNs loaded with ciprofloxacin maintained
therapeutic levels of the agent and killed A.
actinomycetemcomitans more rapidly than did
unloaded PMNs.
In addition, Holm and colleagues34 noted that
laboratory strains of this organism appeared to
be more susceptible to killing by PMNs than
were fresh isolates. Therefore, ciprofloxacin may
have a greater impact on A.
actinomycetemcomitans in vivo than it has had in
laboratory studies.
111. Tolga et al in 2004
found that ciprofloxacin concentrations in serum
and GCF were high at all time points. The results
also demonstrated a twofold-to-threefold higher
ciprofloxacin level in GCF compared with that in
serum during the entire sampling period.
112. Previous vitro studies, Cacchillo and Walters in 2002
have demonstrated that PMNs enhanced the
distribution of the drug to inflamed sites, PMNs
enhanced local concentrations of the drug, and
similar could be the reason for its GCF concentration
Thus, fluoroquinolones were shown to be a
promising candidate for adjunctive, systemic,
antibiotic therapy compared with
penicillin/sulbactam, macrolides and nitroimidazole.
113. Müller HP et al 2002
In vitro antimicrobial susceptibility of oral strains
of Actinobacillus actinomycetemcomitans to
seven antibiotics. ampicillin/sulbactam,
roxithromycin, azithromycin, doxycycline,
metronidazole, ciprofloxacin, and moxifloxacin.
114. A. actinomycetemcomitans was highly
susceptible to both fluoro-quinolones (MIC90 of
0.006 microgram/mL of ciprofloxacin and 0.032
microgram/mL of moxifloxacin). Good
susceptibilities were found for
ampicillin/sulbactam and doxycycline (MIC90
of 0.75 microgram/mL and 1 microgram/mL,
respectively), and moderate susceptibilities for
azithromycin (MIC90 of 3 microgram/mL).
115. Kleinfelder et al 2000
OFS + ofloxacin (2x200 mg/d or 5 days)
Vs
OFS
Systemic ofloxacin as an adjunt to OFS is able to
suppress Aa below detectable level in patients
harbouring this organism at baseline.
116. Combination therapy
Metronidazole plus amoxicillin provides a relatively
predictable eradication of Actinobacillus
actinomycetemcomitans and marked suppression of
Porphyromonas gingivalis in aggressive forms of
adolescent periodontitis and in recalcitrant adult
periodontitis.23,44,76
Metronidazole plus amoxicillin
117.
118. Moeintaghavi A et al.2007
a full-mouth scaling and root planing along with systemic
metronidazole /amoxicillin (T group)
Vs
scaling and root planing with a placebo (P group).
The significant differences between treatment and
placebo groups are in line with other studies and
support the considerable adjunctive benefits of the
combination of amoxicillin and metronidazole in the
treatment of chronic periodontitis.
119. Metronidazole plus ciprofloxacin
Metronidazole plus ciprofloxacin may substitute
for metronidazole plus amoxicillin in
individuals who areallergic to β-lactam drugs
and are at least 18 years of age.
Metronidazole plus ciprofloxacin is also a
valuable drug combination in periodontitis
patients having mixed anaerobic-enteric rod
infections.65
120. Nonperiodontopathic viridans streptococcal species
that have the potential to inhibit several pathogenic
species (beneficial organisms) are resistant to the
metronidazole-ciprofloxacin drug combination and
may recolonize in treated subgingival sites.
121. Metronidazole⁄Augmentin
metronidazole ⁄Augmentin may have a use in
the treatment of periodontal infections involving
penicillin-resistant E. corrodens.
As previously discussed, this organism is
relatively resistant to metronidazole and can be
resistant to amoxicillin due to the production of
b-lactamase.
122. The combination of metronidazole with
amoxicillin ⁄clavulanate does not offer any real
advantage over metronidazole ⁄amoxicillin in the
vast majority of periodontal cases.
The clavulanate moiety is strongly acidic and is
often difficult for patients to tolerate.
123. An industry-formulated combination of 125 mg
metronidazole and 750,000 IU of spiramycin in a
drug known as Rodogyl has been evaluated in a
double-blind clinical trial (Quee et al., 1987).
This formulation was based on in vitro data which
showed this combination to require one-tenth the
spiramycin and one-thirtieth the metronidazole to
inhibit anaerobic bacteria than when they were used
individually.
Rodogyl
124. Spiramycin was found at higher concentrations in GCF
than in blood, although this feature was not found for
metronidazole, which was administered simultaneously
and showed similar concentrations in both fluid and
serum. Such high concentrations persist for a long time,
and suggest the potential of this compound in the
treatment of severe cases of periodontitis.
Clin Periodontol. 1994 Oct;21(9):595-600.
Kinetics of spiramycin/metronidazole (Rodogyl) in
human gingival crevicular fluid, saliva and blood.
Rotzetter PA, Le Liboux A, Pichard E, Cimasoni G.
125. Rodogyl has been evaluated in a double-blind
clinical trial (Quee et al., 1987).
In the double-blind study, 50 adult periodontitis
patients were subjected to scaling and root planing and
were given three tablets of Rodogyl or placebo per day
for 14 days.
Compared with the placebo group, the Rodogyl group
exhibited a significant average gain of 0.67 mm in
attachment levels and almost complete suppression of
spirochetes in the plaque for up to 6 months after
treatment.
126. sequence of antimicrobial agents
It has been suggested that a sequence of
antimicrobial agents may be more effective than
either agent used alone or in combination.
This possibility was based on the finding that
refractory patients, who did not respond to
doxycycline, were more responsive to a subsequent
treatment with metronidazole than were the former
placebo patients when they were also treated with
metronidazole (Aitken et al., 1992)
127. (Loesche et al., 1996), patients who still had > 6
teeth in need of periodontal surgery or extraction
after the first round of systemic agents were re-
treated with the antimicrobial opposite that with
which they had initially been treated.
Both the metronidazole/doxycycline sequence
patients and the doxycycline/metronidazole
sequence patients responded equally well to the
second treatment.
This suggests that the additional improvements
noted by Aitken et al. were more a function of
dosage, i.e., being treated twice, than of any
uniqueness associated with the sequence.
128. CLINICAL DIAGNOSIS
HEALTH CP AgP, REFRACTORY or
MEDICALLY RELATED
MICROBIAL
ANALYSIS
PERIODONTAL THERAPY INCLUDING:
•ORAL HYGIENE
•ROOT DEBRIDEMENT
•SPT
•SURGICAL ACCESS FOR RD/RT
ANTIBIOTICS BY MICROBIAL ANALYSIS
EFFECT INEFFECT
SUPPORTIVE PERIODONTAL TREATMENT
