education

1. Systemic Antibiotics in Periodontal
Therapy
Cont…..

2. Tetracyclines
The tetracyclines are a group of broad-spectrum
antibiotics active against both gram-positive and gram-
negative bacteria.
Structurally, tetracyclines consist of four fused rings,
hence the name tetracyclines
Examples include tetracycline hydrochloride,
demeclocycline, doxycycline, lymecycline, minocycline,
and oxytetracycline.

3. Structure of (A) tetracycline, (B) doxycycline, (C) minocycline

4. Outside dentistry (especially in the management of
periodontal diseases), this group of antibiotics is
decreasing in therapeutic value because of increasing
bacterial resistance.
They remain the treatment of choice in infections caused
by Chlamydia, Rickettsia, and Brucella species.
They are also useful in the management of acne and
certain respiratory infections.

5. 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.

6. The oral administration of tetracycline results in
detectable serum levels within 30 minutes, with peak
concentrations achieved after 1 to 3 hours.
The half-life of tetracycline HCl is about 8 hours. Longer
half-lives of 18 hours for doxycycline hyclate and 16
hours for minocycline HCI (Kastrup, 1993) permit a
lower initial dose and less frequent dosing than for
tetracycline HCI.

7. After absorption, the tetracyclines are widely distributed
in the body tissues and fluids.
Selective distribution results in the accumulation of
tetracycline by adsorption into newly formed bone
crystal surfaces, and eventually it becomes incorporated
into the crystal lattice (Goodman and Gilman, 1990).
If tetracycline is administered during fetal development
or permanent tooth formation, permanent discoloration
and inadequate calcification of deciduous and permanent
teeth are commonly seen. Hence it is advised to avoid
tetracyclines from last half of pregnancy through the 8th
year of life.

8. Mechanism of action
Tetracyclines are bacteriostatic inhibitors of protein
synthesis.
They accumulate intracellularly by way of energy
dependent transport systems present in bacterial
membranes (Chopra, 1985).
Once inside the cell, the drug may be transported out
again, bind to cellular constituents, or chemically
modified so that efflux does not occur (Levy, 1984).

9. If tetracycline remains inside the bacterial cell, it binds
to the 30S ribosomal subunit, thereby preventing the
binding of aminoacyl-transfer RNA to the "A" receptor
site on the 30S messenger RNA-ribosome complex.
Thus, protein synthesis is suppressed by the inhibition of
chain elongation.

10. 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).

11. Doxycycline achieved GCF levels of 4 to 10 μg/mL after
the administration of 100 mg every 12 hours for the first
day, followed by 100 mg/day for 14 days (Pascale et al.,
1986).
GCF concentrations of minocycline are 5 times as high
as serum when 150-200 mg/day are given for 8 days, and
can remain bacteriostatic for at least one week after
treatment is discontinued (Ciancio et al., 1980). Lower
doses of minocycline (100 mg/day) were also detected in
the GCF in concentrations of 4.77 μg/mL but with fewer
side-effects (Freeman et al., 1992).

12. 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)

13. Consequently, tetracycline was one of the first antibiotics
to receive thorough scientific evaluation aimed at
treatment of periodontal diseases.

14. 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)
Adult Periodontitis

15. The current consensus is that the adjunctive use of
tetracycline with conventional scaling and root planing
in adult periodontitis is not indicated, because it will not
confer any additional long-term benefit when compared
with mechanical debridement alone.
The microbial population will revert to pre-treatment
levels within a few weeks after the antibiotic is
discontinued.

16. Aggressive periodontitis
Aa, which is consistently found in lesions of LAP
patients, may elude mechanical or surgical debridement
because of its ability to invade the gingival connective
tissue (Renvert et al., 1990).
Aa is recovered post-treatment not only from subgingival
sites, but also from connective tissue, buccal mucosa, the
tongue, and saliva, indicating that the therapeutic
endpoint of elimination of Aa is not usually met
(Asikainen et al., 1991).

17. To avoid repopulation of sites with Aa, it has been
suggested that tetracycline be continued for one week
following negative cultures, thus extending therapy to
three weeks (Slots and Rosling, 1983).
Tetracycline alone for eight weeks reduced pocket depths
and attachment loss, but Aa was present in 50% of the
lesions (Christersson et al., 1986).

18. While systemic tetracycline therapy can initially slow the
progression of disease, there is a possibility of 25%
recurrence of disease (Mandell and Socransky, 1988),
and re-treatment may be necessary.
Further attachment loss was noted in sites with high
post-treatment levels of Aa (Slots and Rosling, 1983;
Mandell and Socransky, 1988).

19. 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

20. Muller et al.
1989
3 months
MC 100 mg bid
for 21 days
SRP,
-
A.a eliminated
with MC+SRP
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

21. However, tetracycline and SRP did not suppress Aa in all
localized aggressive periodontitis patients.
To overcome or avoid the possibility of tetracycline-
resistant Aa strains, culture and sensitivity testing should
be performed.

22. Refractory periodontitis
Doxycycline administered for three weeks reduced
probing depths significantly more than a placebo and
resulted in more gain of clinical attachment, but only in
sites with recent disease activity.
In addition, one-third of the patients treated with
doxycycline and repeated debridement continued to
show signs of active disease (McCulloch et al., 1990).

23. (Kulkarni et al., 1991)
In patients identified as having refractory periodontitis,
based on recent attachment loss ≥ 2 mm and the presence
of periodontal abscesses despite regular periodontal
supportive treatment, the administration of doxycycline
for three weeks showed no further disease activity for up
to seven months.
Most pathogens were reduced except for Aa.
This long-term effect may be due to a combination of
doxycycline's antibacterial and anti-collagenolytic action

24. 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).

25. 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).

26. Mechanism of resistance
Bacteria become resistant to tetracycline by natural
selection, whereby susceptible strains are eradicated
while the resistant strains remain. (Walker, 1996)
Tetracycline resistance is nearly always associated with
the acquisition of new plasmid and ⁄ or transposon-
associated genetic material, which has been designated
as tet or otr for tetracycline and oxytetracycline
resistance respectively.

27. Currently 38 tetracycline-resistance genes have been
identified, of which 23 encode efflux pumps, 11 encode
ribosomal protection proteins, three encode inactivating
enzymes, and one is of unknown function. (Chopra et al
2001, Roberts MC 2005)

28. 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).

29. The third type of resistance, which is not well
understood, involves a chemical alteration of the
tetracycline molecule (Speer et al., 1992).

30. Different genes that encode for resistance to
Tetracyclines
Bacteria with a tet M, tet 0, tet Q, 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).

31. 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).

32. 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).

33. 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.

34. In conclusion, Tetracyclines (tetracycline-HCl,
doxycycline, minocycline) may be indicated in
periodontal infections in which A
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)

35. 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.)

36. 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.

37. 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.

38. 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.

39. matrix
metalloproteinases
proenzyme
reactive oxygen species
lysosomal cathepsins
osteoclast
Connective
tissue
degradation
Tetracyclines

40. 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).

41. 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.

42. 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.

43. 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)

44. 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.

45. 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.

46. 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).

47. 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.

48. 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).

49. 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.

50. 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).

51. 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.

52. 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)

53. PMN’s
reactive oxygen
metabolites-(HOCl)
Proenzyme
MMP
Doxycycline IL-1 and TNF-α

54. 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.

55. 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.

56. However, Eikenella corrodens, a common inhabitant of
the periodontal flora and a suspected periodontal
pathogen, is inherently resistant to clindamycin.
A. actinomycetemcomitans also demonstrates intrinsic
in vitro resistance to this antibiotic.

57. It penetrates into the gingival crevicular fluid to achieve
and maintain concentrations that exceed the MICs of the
periodontopathic gram-negative anaerobic bacteria.
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.

58. 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---
pseudomembran
ous colitis.
Magnusson
et al.
Chronic
periodontitis
adjunctive use
of
clindamycin
after microbial
sensitivity test
gain in clinical
attachment level
and reduction in
gram-negative
anaerobes

59. 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.

60. 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.

61. Azithromycin demonstrates good in vitro activity against
a number of gram-negative periodontal pathogens
including all serotypes of A. actinomycetemcomitans
and P. gingivalis.
The drug is relatively nontoxic and only a few adverse
side-effects have been associated with its usage.

62. 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 (Blandizzi
C et al. 1999)

63. 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).

64. Gomi K et al 2007
500 mg once daily for 3 days
On day 7, the AZM concentration in the tissues lining the
periodontal pockets was 50% of that on day 4, and on
day 14 only 20%.
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.

65. 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.

66. Dastoor et al 2007
30 patients with a greater than one pack/day smoking
habit and generalized moderate to severe chronic
periodontitis were randomized to the test (surgery plus 3
days of AZM, 500 mg) or 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

67. Mascarenhas P et al 2005
Thirty-one subjects , who smoked ≥1 pack per day of
cigarettes at least five sites with probing depths (PD) of
≥ 5 mm with bleeding on probing (BOP)
SRP alone or SRP + AZM
The results demonstrated that both groups displayed
clinical improvements in PD and CAL that were
sustained for 6 months.
SRP + AZM showed enhanced reductions in PD and
gains in CAL at moderate (4 to 6 mm) and deep sites (>6
mm) (P <0.05).
Furthermore, SRP + AZM resulted in greater reductions
in BANA levels compared to SRP alone (P <0.05) while
rebounds in BANA levels were noted in control group at
the 6-month evaluation.

68. AZM & Gingival overgrowth
Gingival overgrowth usually characterized by increased
cellular growth of gingival fibroblasts appears to be
multifactorial.
In patients receiving CyA for more than 3 months, the
incidence can approach 70% and can be attributed to
pharmaceutical immunosuppression. Case reports have
reported regression of overgrowth with both
metronidazole and azithromycin.

69. Chand DH et al. 2005
Twenty-five patients
Grouped either 5-days of azithromycin or 7-days of
metronidazole given at baseline only. Gingival
overgrowth at baseline was not statistically different
between groups
The mean degree of gingival overgrowth after treatment
was different across all time intervals (p = 0.0049)
showing azithromycin to be more effective than
metronidazole.

70. Mesa FL et al. 2003
Cyclosporin A-induced GO in 40 adult renal transplanted
patients
At the end of the study (30 days), the GO index score
was lower in 54.4% and 62.3% of the Metronidazole and
AZT groups, respectively.

71. Ramalho VL et al 2007
Azithromycin associated with efficient Oral Hygiene
Program (OHP) induced a striking reduction in
cyclosporine-induced GH, while efficient OHP alone
improved oral symptoms but did not decrease
cyclosporine-induced GO.

72. Treatment of cyclosporine-induced gingival overgrowth
with azithromycin-containing toothpaste
Argani H et al 2006
Twenty stable renal transplanted patients (10 men and 10
women) with cyclosporine induced gingival hyperplasia
AZM containing toothpaste had 85 mg AZM per gram of
toothpaste. Both toothpastes were prescribed b.i.d., each
time using 1.5 cm, for 1 month
Gingival overgrowth index decreased significantly in the
AZM-containing toothpaste group from 1.1+/-0.56 to
0.51+/-0.47, P<.001); however, in the control group, this
decrease was not significant (P=.22).

73. Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat
pharyngitis, tonsillitis, acute maxillary sinusitis, acute
bacterial exacerbation of chronic bronchitis, pneumonia
(especially atypical pneumonias associated with
Chlamydia pneumoniae), skin and skin structure
infections, and, in HIV and AIDS patients to prevent,
and to treat, disseminated Mycobacterium avium
complex (MAC).

74. Interferes with their protein synthesis. Clarithromycin
binds to the subunit 50S of the bacterial ribosome and
thus inhibits the translation of peptides.
Clarithromycin has similar antimicrobial spectrum as
erythromycin but is more effective against certain gram-
negative bacteria, particularly Legionella pneumophila.

75. Unlike erythromycin, clarithromycin is acid-stable and
can therefore be taken orally without being protected
from gastric acids.
It is readily absorbed, and diffused into most tissues and
phagocytes.
Due to the high concentration in phagocytes,
clarithromycin is actively transported to the site of
infection. During active phagocytosis, large
concentrations of clarithromycin are released.
The concentration of clarithromycin in the tissues can be
over 10 times higher than in plasma.

76. A study by Piccolomini R, Catamo G, Di bonaventura
G.1998 indicated that clarithromycin is highly effective
in vitro against A. actinomycetemcomitans; 94% of the
strains were inhibited at a concentration of  2.0 μg/ml
Recently it has been shown that Gingival Fibroblasts and
Epithelial Cells take up clarithromycin via a
concentrative active transport system. By increasing
intracellular clarithromycin levels, this system may
enhance the effectiveness of clarithromycin against
invasive periodontal pathogens. (C.-H. Chou, and J.D.
Walters 2008 Aug)

77. Clarithromycin reduces recurrent cardiovascular
events in subjects without periodontitis
Paju S et al. 2006
Long-term clarithromycin therapy seems to be beneficial
in prevention of recurrent cardiovascular events in non-
periodontitis but not in periodontitis patients.

78. Eguchi T et al 2002
Clarithromycin effected P. gingivalis (MIC90 0.1 μ/ml)
and Levofloxacin and Ciprofloxacin showed high-
potency antibacterial activity against clinical isolated A.
actinomycetemcomitans (MIC90 0.013-0.025 μ/ml).

79. Ciprofloxacin
Belongs to a group called fluoroquinolones.
Bactericidal.
Blocks bacterial DNA replication by binding itself to an
enzyme called DNA gyrase, thereby causing double-
stranded breaks in the bacterial choromosome.
Broad-spectrum antibiotic that is active against both
Gram-positive and Gram-negative bacteria.

80. 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 colleagues 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.

81. Tolga et al in 2004
Found that ciprofloxacin concentrations in serum and
GCF were high at all time points.
The results also demonstrated a two-to-threefold higher
ciprofloxacin level in GCF compared with that in serum
during the entire sampling period.

82. Previous in vitro studies by 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.

83. 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.
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).

84. Tomás I et al. 2007
Pathogenic, opportunistic and non-pathogenic obligate
anaerobes showed high percentages of resistance to
Amoxicillin and Clindamycin, and high MIC values for
AZM in the absence of recently administered antibiotics.
MXF showed a higher activity than telithromycin (TLM),
similar to that detected for AMX-CLA and MTZ.
In consequence, MXF could represent a possible
alternative antimicrobial against obligate anaerobes of
oral origin, particularly in those patients with allergy,
intolerance or lack of response to AMX-CLA or MTZ.

85. Thus, for maximal suppression of subgingival A.a. the
combination of MNZ+AMX is recommended.
For patients who cannot tolerate AMX, it has been
suggested to combine MNZ with ciprofloxacin or
cefuroximaxetil (Rams et al. 1992; van Winkelhoff
&Winkel 2005)

86. Metronidazole plus ciprofloxacin
Metronidazole plus ciprofloxacin may substitute for
metronidazole plus amoxicillin in individuals who are
allergic to β-lactam drugs.
Metronidazole plus ciprofloxacin is also a valuable drug
combination in periodontitis patients having mixed
anaerobic-enteric rod infections.
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.

87. Ornidazole
Kamma JJ et al 2000
30 individuals exhibiting EOP
After Ornidazole administration, P. gingivalis, P.
denticola, P. intermedia, T. forsythus, C. rectus, and S.
sputigena were no longer detectable in either scaled or
non-scaled sites. A statistically significant long-term (2,
6, and 12 months) reduction of P. gingivalis, P.
intermedia, P. loescheii, T. forsythus, and C. rectus and
a pronounced increase of S. milleri, S. oralis, and S.
sanguis counts in both scaled and non-scaled sites were
detected in comparison to baseline.

88. Conclusion
Overall antibiotics group showed beneficial effects when
used as an adjunct to conventional mechanical therapy.
By providing an additional treatment benefit specially in
deep pockets, systemic antibiotics can reduce the need
for further, surgical therapy.
In recent years metronidazole plus amoxicillin has
become the favorite treatment modality for many
practitioners.

89. Immediately before starting the antibiotic regime the
subgingival area should be reinstrumented once more to
reduce the bacterial mass as much as possible and to
disrupt the biofilm.
This is implicated even when no mechanical therapy
seems necessary from a clinical point of view.

90. Since the antimicrobial profiles of most of the putative
periodontal pathogens is quite predictable, susceptibility
is not routinely performed.
Optimal plaque control is of paramount importance for a
favorable clinical response and long term stability.
So, systemic antibiotics should never be applied as a
means to compensate for inadequate oral hygiene.

91. However, to limit the development of microbial
antibiotic resistance in general, and to avoid the risk of
unwanted adverse effects, a precautionary, restrictive
attitude towards antibiotic use is recommended.