Periodontology 2000, Vol.
28, 2002, 72–90
Printed in Denmark ¡ All rights reserved
Topical antiseptics and antibiotics
in the initial therapy of chronic
adult periodontitis:
microbiological aspects
M ARC Q UIRYNEN, W IM T EUGHELS, M ARC D E S OETE
& D ANIEL VAN S TEENBERGHE
Epidemiological studies indicate that 5–20% of most
populations suffer from severe forms of periodontitis
(15, 59). Active periodontitis occurs in a susceptible
host and in the presence of pathogenic species in
combination with low concentrations of so-called
‘‘beneficial bacteria’’ (52, 142, 146, 147, 188).
The susceptibility of the host is partly hereditary
(such as inadequate or unregulated immune re-
sponse) but can be influenced by environmental and
behavioral factors such as viral infections, smoking
and stress. Since it is impossible, so far, to alter the
hereditary part of patients’ susceptibility, the success
of periodontal therapy primarily depends upon deal-
ing with the negative environmental and behavioral
factors and the reduction or elimination of peri-
odontal pathogens in combination with the re-estab-
lishment, often by surgical pocket elimination, of a
more suitable environment (less anaerobic) to obtain
a beneficial microbiota. There are sufficient data to
consider the species Actinobacillus actinomycetem-
comitans, Bacteroides forsythus and Porphyromonas
gingivalis as key periodontal pathogens, whereas for
the following list of bacteria moderate evidence for
causation has been reported, at least if their concen-
tration surpasses a certain threshold level: Prevotella
intermedia, Campylobacter rectus, Peptostreptococcus
micros, Fusobacterium nucleatum, Eubacterium nod-
atum, Streptococcus intermedius and spirochetes (3,
142, 146, 188). Recent findings have associated yeasts,
staphylococci, enterococci, pseudomonads, various
enteric rods and/or some herpesviruses (cytomegalo-
virus and Epstein-Barr virus type 1) with destructive
periodontal disease (25, 85, 145). The clinical im-
provement after periodontal therapy indeed corre-
lates directly with the degree to which pathogenic
72
Copyright C Munksgaard 2002
PERIODONTOLOGY 2000
ISSN 0906-6713
subgingival species are reduced or eradicated (29, 54,
117, 122, 123, 138, 141, 147). To achieve reduction or
elimination of pathogens, a subgingival application of
antiseptics and/or antibiotics has often been con-
sidered. This chapter reviews the clinical and espe-
cially the microbiological benefits of such a chemo-
therapeutic approach.
Methodology
This chapter emphasizes articles that contain micro-
biological data and fulfill the following criteria:
O Antimicrobial agents had to be used as an adjunc-
tive therapy, in conjunction with scaling and root
planning and preferably be applied professionally
(the effects of personal self-care use of antiseptics
were reviewed by Rams & Slots (118)). We are con-
vinced that, considering possible side effects
(such as increased bacterial resistance), local anti-
biotics should only exceptionally be proposed or
applied as a replacement for the classical subgin-
gival instrumentation. Although side effects are
less frequent for antiseptics, we also believe that
such drugs should be used in conjunction with
thorough scaling and root planing. Thorough sub-
gingival instrumentation is the basic step in the
treatment of periodontitis.
O Only in vivo studies published in English have
been considered, and only if data were available
on intra- or inter-subject comparison between
scaling and root planing with and without the ad-
ditional use of subgingival antiseptics or anti-
biotics.

O The article had to contain microbiological par-
ameters such as: total number of colony-forming
units per ml, proportions or detection frequency
of A. actinomycetemcomitans, P. gingivalis, P. inter-
media, spirochetes and/or motile organisms.
The adjunctive effect of each topical drug was esti-
mated by comparing the data with the effects ob-
tained by scaling and root planing. The ‘‘clinical’’
outcome of locally applied antibiotics or antiseptics
has been reviewed previously and is only briefly dis-
cussed here (50, 118, 165).
Microbial shifts after subgingival
debridement without adjunctive
antimicrobial agents
The microbial effects of subgingival root planing
have been previously reviewed in detail (10). Results
are often reported for four time intervals: 1, 2, 3 and
4 to 6 months after therapy. In general, differential
phase-contrast microscopy shows a marked im-
provement during the first 2 months, with an in-
crease in the proportion of cocci and a decrease in
the proportion of spirochetes and motile organisms.
Eight to 12 weeks after a single course of scaling and
root planing, the proportion of spirochetes and mo-
tile organisms increases again and, during the next 3
months, the beneficial effect of the instrumentation
disappears. Culture studies show that the total num-
ber of colony-forming units decreases only during
the first 2 months. During this period the proportion
and detection frequency decrease for A. actinomyce-
temcomitans and P. gingivalis but increase for P. in-
termedia. During month 3, the proportions of these
periodontal pathogens slowly increases, to stabilize
during the next 3 months. Subgingival root planing
may also induce higher titers of antibodies to these
specific organisms (38), and repeated scaling and
root planing within 24 hours can even introduce a
Shwartzman type immune reaction (113), two im-
mune mechanisms that may improve the final out-
come of the therapy.
Some studies do not report significant microbial
improvements after subgingival debridement, poss-
ibly because of insufficient oral hygiene follow-up
and/or limited subgingival instrumentation. With
poor oral hygiene, a pathogenic subgingival micro-
flora may be already re-established within 2 months
after a single debridement session (88, 134). Adequate
access for subgingival debridement is more difficult
Topical periodontal therapy
as probing depth increases (16, 17, 33, 120, 179), and
it is suggested that complete plaque and calculus re-
moval is nearly impossible in pockets exceeding 4 mm
in depth for hand instruments (155) and slightly
deeper for power-driven instruments (33).
Many studies have focused on differences between
hand and powered instrumentation; in general, simi-
lar reductions in probing depth and bleeding upon
probing have been reported for both debridement
techniques (36). With sonic and ultrasonic scalers, the
mean change in probing depth ranges from 1.2 to 2.7
mm (36) which is comparable with data from a review
of 27 studies indicating mean probing depth reduc-
tions of 1.3 mm for moderate pockets and 2.2 mm for
deep pockets following scaling and root planing with
hand instruments (24). The few studies investigating
the effect of power-driven scalers on the subgingival
microflora demonstrated an equal effect compared
with that of hand scaling (24). However, due to the di-
mensions of hand instruments, sonic and ultrasonic
instruments with special tips seem more efficient in
class II and III furcations (36). On the other hand,
these devices might leave the root surface rougher
than curettes (36).
Shortcomings of subgingival
debridement
The temporary effect of subgingival root planing and
its inability to eradicate all periodontal pathogens
are explained by the unfavorable anatomy or dimen-
sion of periodontal pockets, which jeopardize the
mechanical instrumentation (115, 179), the incom-
plete removal of plaque and calculus (see above), the
existence of an intraoral microbial translocation
and/or the fact that pathogens can escape the de-
bridement by invading the periodontal tissues.
Most periodontal pathogens colonize – besides
the periodontal pocket – other intraoral niches such
as the tongue, the tonsils and the mucous mem-
branes. In periodontitis patients, key pathogens such
as A. actinomycetemcomitans, P. gingivalis and P. in-
termedia can be detected in all above-mentioned
niches (5, 31). The existence of an intraoral translo-
cation (from one niche to another) of periodontal
pathogens has been demonstrated (114). Recently
scaled and root-planed pockets can thus rapidly be
re-colonized by pathogenic bacteria from remaining
untreated pockets, or from other intraoral niches,
before a new and less pathogenic ecosystem has
been established. This occurs during the universally
73
Quirynen et al.
used phased periodontal therapy where instrumen-
tation is performed quadrant by quadrant with 1- to
2-week intervals. ‘‘One-stage full-mouth’’ disinfec-
tion – obtained by performing all scaling and root
planing within 24 hours together with repeated ap-
plication of chlorhexidine to all intraoral niches –
has led to significant additional improvements for
up to 8 months, both clinical and microbial, and
both in chronic adult and early-onset periodontitis
patients (10, 87, 111, 112, 170). These benefits were
mainly due to the one-stage scaling and root planing
and only to a lesser extent to the use of chlorhex-
idine (113).
Another explanation for the fast re-colonization of
periodontal pockets after mechanical debridement is
the capacity of several periodontal pathogens to in-
vade the epithelium or connective tissues (8, 19, 20,
40, 73, 90, 105, 131, 132) or perhaps even the dentinal
tubules (1) from which they can regrow. One should
also realize that subgingival instrumentation is not
equally effective for all species. Especially A. actino-
mycetemcomitans, and to a lesser extent P. gingivalis,
seem to be quite resistant to subgingival instrumen-
tation, and the degree of their persistence is corre-
lated with a reduced healing response (121–123). With
the use of the checkerboard DNA-based identifi-
cation, it has been shown that scaling and root plan-
ing alone often does not result in an eradication of key
periodontal pathogens (29, 54).
It therefore seems logical that the local application
of antimicrobial agents can further suppress peri-
odontal pathogens and thereby increase the clinical
and microbial benefit of mechanical debridement.
Pharmacokinetic parameters in the
periodontal pocket and impact of
biofilm formation
In order to be effective, a pharmaceutical agent
should reach the entire periodontal pocket (such as
the bottom) and should be maintained long enough
at a sufficient concentration for the intended phar-
maceutical effect to occur (45). Periodontal pockets,
however, possess complicating anatomic character-
istics (50, 165).
Reaching the entire periodontal pocket is difficult
because of its very small entrance (150 mm for a 4-
mm deep pocket (162). The outflow of crevicular
fluid, 20 ml/h, indicating a pocket fluid replacement
rate of 40 times per hour (7), makes spontaneous
inflow into a pocket fairly impossible. Mouthrinsing
74
and supragingival irrigation do not reach subgingival
areas (37, 108). Only subgingival irrigation can over-
come this obstacle (55, 108). Furthermore, the con-
stant outflow of crevicular fluid explains the ex-
tremely fast clearance of any topically applied prod-
uct (6, 45). The expected half-life of a pharmaceut-
ical agent in the gingival pocket is about 1 minute
(45, 100).
Furthermore, periodontal pathogens in the sub-
gingival environment reside in a biofilm adhering to
the exposed root cementum or to the soft tissue, or
even invading the pocket epithelium, the underlying
connective tissue and/or the root dentine. The ag-
gregation of bacteria in a biofilm impairs the dif-
fusion or may even inactivate antimicrobial agents.
High concentrations of the active ingredient are
needed before a beneficial effect can be expected.
Biofilm experiments indicate that the necessary
minimum inhibitory concentrations of antimicrobial
agents are at least 50 times (or even 210,000 times)
higher than for bacteria growing under planktonic
conditions (4, 14, 18, 42, 67, 144, 168, 187). Moreover,
the minimum contact time for an antimicrobial
agent to be active depends on the mechanism by
which the agent inhibits or destroys target bacteria.
Chlorhexidine (which kills microorganisms by com-
promising the integrity of the cell membrane) and/
or povidone-iodine (which kills bacteria on contact)
require a shorter exposure time than, for example, a
bacteriostatic agent, such as tetracycline, which in-
hibits protein synthesis. Even the shorter killing
time, however, is not reached after a single drug ap-
plication, but may be obtained after repeated sub-
gingival irrigation within a short period of time (101,
102). An antiseptic can be used in conjunction with
power-driven scalers as a coolant instead of water.
As such, a prolonged contact time can be estab-
lished.
With the above-mentioned half-life data for sub-
gingivally applied drugs, the minimal contact time
needed for antibiotics cannot be reached in practice
even with repeat subgingival irrigation (165). How-
ever, the substantivity of a topically applied agent
may increase spontaneously if it binds to the soft
and/or hard tissue surfaces within the pocket. This
establishes a drug reservoir from which the anti-
microbial agent can be slowly released (165). An-
other means to increase the subgingival substantiv-
ity of an agent is by its incorporation in a slow-re-
lease device, a reservoir with a limiting element that
controls the rate of drug release (Fig. 1). The local
delivery devices used in periodontology (Table 1)
can be divided into two classes according to the dur-
 Topical periodontal therapy

References

160, 161
164

133
159
150
Table 1. Pharmacokinetic parameters of most relevant sustained-release devices or controlled-delivery devices for subgingival application of

Time
264
16
21

235
?
concentration-90a
inhibitory
Minimum

mg/ml
50
32
16

100
?
of reservoir
Fig. 1. Subgingival concentration of an antimicrobial agent

Duration
after subgingival irrigation (IRRaΩwithout substantivity,

⬎7 days
⬎240 h

⬎200 h
⬍12 h
IRRbΩwith substantivity), or incorporated in a device with
sustained release (SRD: drug delivery for less than 24

–
antimicrobial agents in relation to minimum inhibitory concentrations (based on in vitro experiments)
hours) or with controlled delivery (CDD: drug delivery over

2¿ exponential
a longer period). Source: adopted from Tonetti (165).

Pseudo zero
Exponential

Exponential
Decay
ation of drug release (74): sustained-release devices
(drug delivery for less than 24 hours) and controlled-

Controlled-delivery device

Controlled-delivery device
Controlled-delivery device
delivery devices (drug release exceeding 1 day). Sev-

Sustained-release device
Sustained-release device
eral different types of delivery devices (nonre-
sorbable and bioabsorbable matrices) have been de-
veloped.
Besides the pharmacokinetics, the patient’s com-
fort and the cost–benefit ratio are key elements. Be-
Type

cause of the high costs of slow-release devices and

because their application is often exceedingly time-
Device composition of delivery device

consuming or requires several visits, they should

Ethylene-vinyl acetate monolytic fiber
Glyceryl monooleateπsesame oil gel

only be promoted for routine use if they add sub-

stantial adjunctive benefits to mechanical debride- Based on calculations from Mombelli & van Winkelhoff (86) and Tonetti (165).
ment. So far, the clinical benefits of most slow-re-
lease devices, even when showing statistical signifi-
cance, have not been very impressive.
Cross-linked gelatin

Microbial shifts after subgingival

LS-007 gel
Polymer

application of antiseptics
Chlorhexidine
Concen-

Chlorhexidine has wide-spectrum antibacterial ac-

tration

8.5%
25%
25%

34%

tivity encompassing gram-positive and gram-nega-

2%

tive bacteria, yeasts, dermatophytes and some lipo-

philic viruses (32). The antibacterial mode of action
Tetracycline fibres

is explained by the fact that the cationic chlorhex-

Minocycline gel
Metronidazole

Chlorhexidine

idine molecule is rapidly attracted by the negatively

Doxycycline

charged bacterial cell surface. After adsorption, the

integrity of the bacterial cell membrane is altered,
Drug

which results in a reversible leakage of bacterial low-

a

molecular-weight components at low dosage (32) or

75
Quirynen et al.
more severe membrane damage at higher doses (72,
127). Moreover, chlorhexidine has the advantage of
prolonged supragingival substantivity because it can
bind to the intraoral soft and hard tissues (11).
Table 2 summarizes the antimicrobial effects of
chlorhexidine after a subgingival application via dif-
ferent techniques (gel, irrigation) and in various con-
centrations in conjunction with root planing. Most
studies report minor clinical benefits after the sub-
gingival use of chlorhexidine, and the adjunctive
antimicrobial effects of chlorhexidine used in com-
bination with root planing are in general negligible
and only temporary (12, 53, 71, 81, 82, 101, 102, 112,
113, 124, 138, 140, 151, 169, 184). A single or repeated
subgingival professional irrigation (Table 2) with
chlorhexidine in different concentrations results in
only minor shifts in the subgingival flora during the
first 2 months (71, 138, 140, 151, 169, 184). Even
when used simultaneously with ultrasonic scaling,
the additional improvements are limited (53, 124).
After the professional application of a 1% or 2%
chlorhexidine gel (Table 2) only minor microbiologi-
cal changes are observed (81, 101, 102), unless this
is combined with one-stage full-mouth disinfection
(111, 112). A later study from the Leuven group, how-
ever, illustrated that these beneficial aspects were
not related to the use of chlorhexidine but to the
completion of the mechanical debridement within
24 hours, to prevent bacterial translocation from un-
treated pockets (113).
The disappointing efficacy of chlorhexidine in the
subgingival area can be explained by either the use
of ineffective concentrations and/or the low subgin-
gival substantivity of this drug (poor adherence to
the root surface) (153), resulting in subtherapeutic
concentrations a short time after application (99).
Moreover, chlorhexidine has high affinity for salivary
or serum proteins and blood, which further explains
a rapid decrease in concentration in the subgingival
area (58, 116, 126, 152, 178). Finally, some peri-
odontal microorganisms are only moderately sus-
ceptible to chlorhexidine (143). There is also some
evidence that P. gingivalis releases vesicles that bind
to and inactivate chlorhexidine, protecting them-
selves and other bacteria from the bactericidal activ-
ity (51). Oosterwaal et al. (101, 102) reported, how-
ever, a significant increase in antimicrobial activity
(99% reduction in periodontal pathogens) when the
product was applied repeatedly (chlorhexidine 2%, 3
times within 10 min), but the adjunctive effect soon
disappeared.
Recently a biodegradable chlorhexidine chip has
been introduced that enables slow subgingival re-
76
lease of the chlorhexidine, maintaining over 7 to 10
days an average concentration of more than 125 mg/
ml in the crevicular fluid (28, 150), which would in-
hibit 99% of the gingival bacteria in vitro (99, 154).
Some clinical studies demonstrated that the adjunc-
tive use of the chlorhexidine chip resulted in a
limited additional reduction of both probing depth
and loss of alveolar bone (60, 61, 149). A recent in
vivo study comparing the microbial shift after scal-
ing and root planing with or without the use of the
chlorhexidine chip failed, however, to demonstrate
any adjunctive microbial benefit of the chlorhex-
idine chip (30).
Povidone-iodine
The antibacterial activity of povidone-iodine is due to
the oxidation of amino (NHª), thiol (SHª) and phe-
nolic hydroxy (OHª) groups in amino acids and nu-
cleotides and its interaction with unsaturated fatty
acids in cell walls and organelle membranes. Povi-
done-iodine is microbicidal for gram-positive and
gram-negative bacteria, fungi, mycobacteria, viruses
and protozoans (136). Only a few studies have exam-
ined the additional antimicrobial effects of povidone-
iodine irrigation (sometimes combined with other
products) in combination with subgingival debride-
ment (49). In general, significant but small additional
effects (21, 91, 128, 129) have been reported. Immedi-
ately after pocket irrigation with a diluted povidone-
iodine solution (0.2% free iodine), a good antibac-
terial effect against black pigmented, gram-negative
anaerobic rods can be detected (91). The proportions
of spirochetes and motile organisms are even reduced
until 26 weeks after irrigation. A single professional
pocket irrigation with 0.05% povidone iodine results,
compared with 0.2% chlorhexidine, in a more pro-
longed antimicrobial effect (176). These beneficial ef-
fects are translated into slightly improved clinical out-
comes. Special attention should be paid to possible
side effects such as a short-lasting staining of teeth
and tongue (49), and possible thyroid dysfunction
(95). Thus povidone-iodine seems to be a promising
antimicrobial product in periodontics, especially
when higher concentrations (such as 10%, corre-
sponding to 1% free iodine (128)) are used, but more
research is needed.
Stannous fluoride
Compared with scaling and root planing alone, no
supplementary microbial benefits have been re-
ported after additional single or multiple pocket irri-
 Table 2. Microbial changes after scaling and root planing with or without the adjunctive use of chlorhexidine (selection of most relevant
articles and intervals). Variables include colony-forming units (anaerobic growth), darkfield microscopy data (proportions) and detection frequency
or proportion of periodontal pathogens
Design of study Microbiological findings

Authors
Concept
% and frequency
Type of infection and
number of patients
Therapy
Interval
Treatment
Probing depth in mm
No. of sites
Colony-forming units/ml
after anerobic growth
% cocci
% motile organisms
% spirochetes
A. actinomycetemcomitans
P. gingivalis
P. intermedia

Wennström Intrasubject 0.2% irrigation Chronic adult Irrigation Baseline Scaling and 18 18.4
et al. (184) split mouth 3¿/week in periodontitis Scaling 8 weeks root planing 18 0.4
weeks: ª32, nΩ10 supragingival 20 weeks π placebo 18 1.4
ª31, ª27, ª26 (every 4 weeks)
Baseline Scaling and 28 1.7
and 1, 2, 5, 6 Oral hygiene
8 weeks root planing 28 0.4
instruction
20 weeks π chlorhexidine 28 0.6
Scaling and root
planing
Oosterwaal Intrasubject 2% gel day: 0 Chronic adult Oral hygiene Baseline Scaling and 8.2 40 1.3¿106 58.3 6.3 17.1 No data
et al. (102) split mouth 3¿/10 min periodontitis instruction 4 weeks root planing 4.6 40 2.0¿105 95.4 0.3 1.9 No data
nΩ10 Scaling and root 12 weeks π placebo 4.4 40 1.3¿105 95.4 0.1 0.7 No data
planing 36 weeks 4.5 40 2.5¿105 93.7 0.1 1.4 No data
Baseline Scaling and 7.5 40 6.3¿105 58.8 4.4 20.1 No data
4 weeks root planing 4.8 40 2.5¿105 95.4 0.2 0.7 No data
12 weeks π chlorhexidine 4.1 40 1.6¿105 93.7 0.6 1.0 No data
36 weeks 4.3 40 1.3¿105 90.3 0.3 3.6 No data
Quirynen Intersubject 1% gel day 0 Chronic adult Scaling and Baseline Scaling and 6.0 1.2¿109 23.0 10.6 3.7¿108 c*
et al. (112) parallel 3¿/10 min periodontitis root planing 4 weeks root planing 4.9 5.0¿108 9.3 1.8 7.0¿107
study nΩ12 Oral hygiene 8 weeks 4.7 5.1¿108 10.0 3.3 1.1¿108
instruction 16 weeks 4.9 4.6¿108 9.3 3.7 1.0¿108
Chronic adult Baseline Full-mouth 6.2 1.3¿109 21.3 15.6 2.8¿108
periodontitis 4 weeks scaling and 3.9 1.7¿107 0.3 0.6 1.2¿107
nΩ12 8 weeks root planing 3.8 3.0¿107 1.8 1.3 2.0¿107
16 weeks π chlorhexidine 3.9 9.5¿107 2.2 0.3 9.0¿106
π rinse
Intrasubject, intersubject: comparison between sites treated via scaling and root planing alone or with topic application. cCulture technique. *Number of colony-forming units of black-pigmented species listed as mean of
all sites. Underlined dataΩresult obtained from charts.

77
Topical periodontal therapy
Quirynen et al.
gations with stannous fluoride (SnF2) (71, 101, 102).
Repeated professional subgingival irrigation (6 times
in 18 weeks) with 0.25% AmF and 0.25% SnF2 may
result in a temporary suppression of black-pig-
mented bacteria that could not be obtained with sa-
line rinsing (137). A subgingival application of 1.64%
SnF2 in untreated pockets showed a temporary and
small reduction of 0.5 log for black-pigmented spe-
cies and spirochetes, which was only slightly better
than after the use of a saline solution (84, 135).
Hydrogen peroxide
Neither repeated professional nor self-performed
subgingival application of 3% hydrogen peroxide can
induce additional microbial shifts compared with sa-
line irrigation, at least when applied in combination
with thorough subgingival debridement (78, 184). Bi-
weekly professional subgingival irrigation of deep
pockets after root planing, however, resulted in a
temporary suppression of A. actinomycetemcomitans
(186).
Self-applied daily subgingival irrigation
The above-mentioned transient antimicrobial effect
after a single professional irrigation with an antisep-
tic can be prolonged via daily self-applied irrigation
(Table 3). Effective drugs, at the clinical level, are
chlorhexidine and to a lesser extent hydrogen per-
oxide (12, 39, 63, 78, 82, 148, 183, 185). Daily admin-
istration of povidone-iodine is not recommended
because of the risk of adverse thyroid reactions after
long-term use. In order to reach the bottom of the
pocket, a subgingival application (3 mm below gingi-
val margin for deep pockets) of the drug (such as
via a syringe) is necessary (37, 55, 108). Since home
irrigation regimens provide little or no improvement
in the absence of mechanical root debridement,
these approaches are best used as adjuncts to pro-
fessionally delivered periodontal therapy (94, 118).
Microbial shifts after subgingival
application of antibiotics
Minocycline
Minocycline-HCl, bacteriostatic at normal thera-
peutic doses, was initially marketed as a 25% pow-
der, microencapsulated in a biodegradable polymer
(poly(glycolide-co-DL-lactide)) for subgingival appli-
cation. A single application as an adjunct to root
78
planing results in an additional reduction in the pro-
portion of spirochetes and motile organisms as well
as in the number of black-pigmented species (64,
98), which may be responsible for a slightly im-
proved clinical outcome.
Minocycline has subsequently been incorporated
in an ointment (2% minocycline-HCl in a matrix of
hydroxyethyl-cellulose, aminoalkylmethacrylate, tri-
acetine and glycerine), yielding sustained release
(over 16 hours, Table 1) with antibacterial activity
in pockets for up to 21 hours (92, 133). The clinical
and microbial benefits of minocycline ointment,
after repeated subgingival application and in com-
bination with thorough subgingival root planing,
have been tested in several studies (172) (Table 4).
A multicenter study on patients with habitual oral
hygiene efforts (173) revealed limited but signifi-
cant additional microbial benefits (more reduction
of P. gingivalis, P. intermedia and A. actinomycetem-
comitans) accompanied by additional clinical im-
provements (additional pocket reduction of 0.3 mm
for pockets Ø5 mm and 0.9 mm for pockets Ø7
mm). These observations were in accordance with
a previous split-mouth design study using a similar
protocol (92). A more recent international multi-
center study confirmed these data for up to 15
months (174). A portion of the multicenter study
was published independently (163). However, with
the low number of study subjects, no significant
differences could be detected. Other clinical studies
including optimal oral hygiene and antimicrobial
gel application at 0, 2 and 4 weeks (47, 66) showed
only small or no additional clinical improvement.
Both oral hygiene and frequency of minocycline
application seem to influence clinical outcome.
Doxycycline polymer
A controlled-delivery device (reservoir for ⬎7 days)
with an 8.5% concentration of doxycycline (biode-
gradable poly(glycolide-co-DL-lactide)) is commer-
cially available (Table 1) (159). At present, however,
no studies are available showing additional mi-
crobial benefits of the subgingival application of this
drug in combination with root planning. Clinical
studies in which doxycycline was tested as an alter-
native to root planing or to well-controlled oral hy-
giene showed comparable improvements for both
monotherapies (35, 41, 42, 109, 182). There is a need
for controlled studies in which the doxycycline poly-
mer is used in combination with root planing, since
the above-mentioned monotherapy seems less ac-
ceptable, because comparable or even better im-
 Table 3. Microbial changes after scaling and root planing with or without self-applied daily irrigation using chlorhexidine or hydrogen peroxide
(selection of most relevant articles and intervals). Variables include darkfield microscopy data (proportions)
Design of study Microbiological findings
Type of infection Probing
% and and number depth in No of % motile %
Authors Concept frequency of patients Therapy Interval Treatment mm sites % cocci organisms spirochetes
Braatz Intrasubject 2% irrigation Chronic adult Scaling and Baseline Scaling and 7.5 52 9.2
et al. (12) split mouth day: 0–167 periodontitis root planing 12 weeks root planing 4.5 52 0.3
(1/day) nΩ14 Oral hygiene 24 weeks 4.5 52 1.2
(self-applied) instruction
Baseline Scaling and 7.6 54 6.8
12 weeks root planing 4.4 54 0.6
24 weeks π chlorhexidine 4.3 54 0.8
Macaulay Intersubject 0.02% irrigation Chronic adult Scaling and Baseline Scaling and 6.4 24 32.3 36.0 10.1
et al. (82) parallel study day: 1–28 periodontitis root planing 4 weeks root planing 24 49.2 17.2 1.5
(1/day) nΩ6 Oral hygiene 8 weeks 24 59.2 18.0 2.2
(self-applied) instruction 12 weeks 24 46.2 25.6 4.3
Chronic adult Baseline Scaling and 6.7 24 34.6 37.2 4.7
periodontitis 4 weeks root planing 24 77.7 6.8 1.0
nΩ5 8 weeks π chlorhexidine 24 69,2 13.2 2.4
12 weeks 24 50.0 30.4 2.5
Listgarten Intersubject 7% irrigation Early onset Scaling and Baseline Scaling and 6.2 17.6 12.5 37.3
et al. (78) parallel study day: 0–56 periodontitis– root planing 4 weeks root planing 4.8 37.7 4.9 10.2
(2/day) chronic adult Habitual 8 weeks π placebo 4.8 37.2 3.8 16.8
(self-applied) periodontitis oral hygiene
nΩ20
Early onset Baseline Scaling and 6.4 15.8 12.6 35.5
periodontitis– 4 weeks root planing 4.8 46.6 4.5 14.1
chronic adult 8 weeks π hydrogen 4.3 44.3 6.5 11.4
periodontitis peroxide
nΩ20
Underlined dataΩresult extracted from charts.

79
Topical periodontal therapy
80
Table 4. Microbial changes after scaling and root planing with or without the adjunctive use of minocycline ointment (selection of most relevant
articles and intervals). Variables include colony-forming units (anaerobic growth), darkfield microscopy data (proportions), and detection frequency or
proportion of periodontal pathogens
Quirynen et al.

Design of study Microbiological findings

Authors
Concept
% and frequency
Type of infection and
number of patients
Therapy
Interval
Treatment
Probing depth in mm
No. of sites
Colony-forming units/ml
for anaerobic growth
% cocci
% motile organisms
% spirochetes
A. actinomycetemcomitans
P. gingivalis
P. intermedia

Nakagawa Intrasubject 2% ointment Nonresponding Scaling and Baseline Scaling and 7.2 11 53.1¿106 39.6 31.9 12.2 5c,. 6 9
et al. (91) split mouth weeks: periodontitis root planing 4 weeks root planing 6.3 11 9.3¿106 53.7 15.4 7.0 5 4 7
0, 1, 2, 3 nΩ11 Habitual 12 weeks π placebo 6.5 11 14.3¿106 60.4 9.3 11.2 2 4 8
oral hygiene
Basline Scaling and 7.0 22 50.7¿106 39.5 32.5 7.2 10 17 22
4 weeks root planing 5.1 22 1.1¿106 82.6 2.6 0.2 1 1 7
12 weeks π minocycline 5.2 22 4.8¿106 73.9 6.5 6.5 6 5 16
van Intersubject 2% ointment Chronic adult Scaling and Baseline Scaling and 5.9 265 26%d 72% 70%
Steenberghe multicenter weeks: periodontitis root planing 4 weeks root planing 4.8 265 16% 41% 52%
et al. (173) parallel 0, 2, 4, 6 nΩ42 (3 min/tooth) 12 weeks π placebo 4.5 241 20% 46% 57%
study Habitual
Chronic adult Baseline Scaling and 5.9 307 35% 73% 75%
oral hygiene
periodontitis 4 weeks root planing 4.5 300 21% 29% 42%
nΩ48 12 weeks π minocycline 4.2 260 9% 33% 44%
Timmer- Intersubject 2% ointment Chronic adult Scaling and Basline Scaling and 6.8 85 60¿103 d,* 201¿103 45¿103
man et al. parallel weeks: periodontitis root planing 4 weeks root planing 5.4 85 8¿103 71¿103 10¿103
(163) study 0, 2, 13, 26, 39 nΩ10 (3 min/tooth) 13 weeks π placebo 5.5 85 2¿103 30¿103 9¿103
Oral hygiene 26 weeks 5.1 85 2¿103 64¿103 9¿103
instruction
Chronic adult Baseline Scaling and 6.5 71 61¿103 d,* 235¿103 43¿103
π repeated
periodontitis 4 weeks root planing 4.7 71 0.8¿103 15¿103 28¿103
root planing at 6
nΩ10 13 weeks π minocycline 4.9 71 0 7¿103 12¿103
and 12 months
26 weeks 4.5 71 0.2¿103 38¿103 13¿103
van Intersubject 2% ointment Chronic adult Scaling and Baseline Scaling and 6.3 33d 61 64
Steenberghe parallel weeks: periodontitis root planing 4 weeks root planing 5.2 20 33 46
et al. (174) study 0, 2, 4, 12, 26, nΩ47 (15 min/quadrant) 12 weeks π placebo 5.1 23 33 48
multicenter 38, 52 Oral hygiene 26 weeks 5.2 22 29 49
instruction
Chronic adult Baseline Scaling and 6.5 77 67 71
π repeated
periodontitis 4 weeks root planing 5.3 16 29 45
root planing at 6
nΩ46 12 weeks π minocycline 5.1 22 31 42
and 12 months
26 weeks 4.8 18 33 46
Species: *Number of colony-forming units as mean of all sites or .number of positive sites. Microbial analyses: cculture, dDNA.

provements can be obtained by mechanical debride-
ment alone without the adverse effects of the doxy-
cycline monotherapy (especially the risk for bacterial
resistance).
Metronidazole gel
Metronidazole was introduced in the treatment of
periodontal infections because this drug is accumu-
lated by obligate anaerobic bacteria and leads to cell
death (89) by interfering with the synthesis of nuc-
leic acids (180). The metronidazole gel for subgingi-
val application consists of a bioabsorbable delivery
device (Table 1) containing 25% metronidazole ben-
zoate in a matrix from a mixture of glycerol
monooleate and sesame oil (96). The decay of me-
tronidazole over time in the crevicular fluid follows
an exponential curve with a reservoir maintained for
up to 12 hours (161). After 24 hours, the metronida-
zole concentration in the crevicular fluid still re-
mains above the minimum inhibitory concentration
for 50% killing of key periodontal pathogens (160).
Table 5 summarizes a series of studies in which
the metronidazole gel was used as an adjunct to
scaling and root planing. In general, no additional
improvements were detected, neither in the micro-
biological nor in the clinical data (83), when scaling
and root planing was combined with the metronida-
zole gel application (77, 97, 103, 104, 125, 156, 158),
not even after frequently repeated (5 times in 1
week) gel application (125). Two other slow-release
systems (an acrylic strip with a 50% w/w incorpor-
ation of the antimicrobial agent and a 95% collagen/
5% metronidazole device) also showed only minor
additional improvements when used in combination
with scaling and root planing (57, 177).
As could have been expected, a series of studies
comparing the effect of a sequential application of
metronidazole (monotherapy) with that of a positive
treatment control consisting of scaling and root
planing failed to show any supplementary benefit for
the antimicrobial agent (2, 66, 68, 107, 130, 157).
Tetracycline
Tetracycline-HCl is a bacteriostatic agent that in-
hibits bacterial protein synthesis and, as such, re-
quires a significantly longer exposure time than, for
example, metronidazole or chlorhexidine (166). It,
however, has the ability to bind to the hard tissue
walls of pockets to establish a drug reservoir (22,
164). The subgingival topical application of tetracy-
cline has been promoted in several systems (powder,
Topical periodontal therapy
gel, irrigation solution, incorporated in nonre-
sorbable fibers (dialysis tubing or ethylene-vinyl ace-
tate monolithic fibers)).
Table 6 summarizes studies with tetracycline de-
vices used in conjunction with thorough root plan-
ing (44, 56, 62, 77, 80, 81, 138). Tetracycline fibers
consist of a nonresorbable but biologically inert
plastic copolymer (ethylene-vinyl acetate) loaded
with 25% tetracycline-HCl powder and function as a
controlled-delivery device (Table 1) that is able to
maintain subgingival concentrations above 1300 mg/
ml crevicular fluid for 7 days (164). The tetracycline
was found to penetrate the superficial portion of the
soft tissue pocket wall (22). Most studies, especially
those with the fibers, show a small and only tempor-
ary (up to 12 weeks) antimicrobially adjunctive effect
for the subgingivally applied drug. The accompany-
ing clinical data nearly always demonstrate ad-
ditional probing depth reductions, but limited to
⬍0.5 mm.
A series of clinical articles have reported signifi-
cant (∫0.5 mm) additional probing depth reduction
and/or attachment gain when tetracycline fibers
were applied after thorough scaling and root planing
(34, 66, 93, 167, 189). Also, maintenance patients
with non-responding sites seem to benefit from the
local application of tetracycline fibers. In general, the
application of tetracycline fibers in combination
with repeated subgingival instrumentation reduced
the clinical signs of periodontal disease and im-
proved attachment levels (27, 171). The slightly su-
perior results with tetracycline might be explained
by its substantivity and by the improved accessibility
of the subgingival area for mechanical debridement
at the time of fiber removal.
Adverse reactions with locally
applied antibiotics
Topical application of antibiotics has several advan-
tages compared with their systemic use. Systemic
antibiotic therapy might result in a series of adverse
effects such as hypersensitivity, nausea, diarrhea,
gastrointestinal intolerance, candidasis, interaction
with oral contraceptives, AntabuseA effect, rashes
and unpleasant taste (86, 181). Locally applied anti-
biotic therapy also overcomes the uncertain compli-
ance of the patient (79). However, local delivery of
antimicrobial agents may require the same caution
as the systemic use of drugs. First of all, patients with
a known allergy to a drug will show reaction also
after local application, since part of the locally ap-
81
82
Table 5. Microbial changes after scaling and root planing with or without the adjunctive use of metronidazole (selection of most relevant articles
and intervals). Variables include colony-forming units (anaerobic growth), darkfield microscopy (proportions) and detection frequency or proportion
of periodontal pathogens
Design of study Microbiological findings
Quirynen et al.

Authors
Concept
% and frequency
Type of infection and
number of patients
Therapy
Interval
Treatment
Probing depth in mm
No. of sites
Colony-forming units/ml
after anaerobic growth
% cocci
% motile organisms
% spirochetes
A. actinomycetemcomitans
P. gingivalis
P. intermedia

Stelzel Intrasubject 25% gel Nonresponding Scaling and Baseline Scaling and 5.6 304 14.7
et al. (156) split mouth day: 0, 7 periodontitis root planing 3 weeks root planing 4.5 304 6.4
nΩ30 3 weeks: 13 weeks 4.2 304 8.2
Oral hygiene
instructions Baseline Scaling and 5.6 808 11.7
3 weeks root planing 4.5 808 5.8
13 weeks π metronidazole 4.2 808 6.4
Noyan Intrasubject 25% gel Chronic adult Oral hygiene Baseline Scaling and 5.2 30 1.16¿106
et al. (97) split mouth day: 0, 7 periodontitis instructions 7 weeks root planing 3.9 30 2.17¿105
nΩ5 Scaling and
root planing Baseline Scaling and 5.6 30 8.16¿105
7 weeks root planing 3.5 30 5.92¿104
π metronidazole
Palmer Intersubject 25% gel Chronic adult Oral hygiene Baseline Scaling and 5.9 108 18.0 33.4 47.2
et al. (103) parallel day: 0, 7 periodontitis instructions 8 weeks root planing 4.4 108 51.9 25.6 21.9
study nΩ27 Scaling and 24 weeks 4.2 108 48.0 27.4 25.6
root planing
Chronic adult (2¿90 min) Baseline Scaling and 5.9 112 17.2 37.7 40.6
periodontitis Oral hygiene 8 weeks root planing 4.2 112 45.8 29.8 26.9
nΩ26 instructions 24 weeks π metronidazole 4.3 112 46.5 24.9 23.5
(1 month)
Lie Intrasubject 25% gel Chronic adult Oral hygiene Basline Scaling and 5.1 18 0/18t,. 12/18 7/18
et al. (77) split mouth day: 0 periodontitis instructions 12 weeks root planing 3.7 18 1/16 2/16 5/16
nΩ18 Scaling and root 24 weeks 4.0 18 0/10 3/10 1/10
planing
(2 sessions) Baseline Scaling and 5.0 18 0/18t,. 9/18 6/18
12 weeks root planing 3.2 18 0/16 2/16 5/16
24 weeks π metronidazole 3.4 18 1/10 2/10 2/10
Riep Intrasubject 25% gel Maintenance Scaling and Baseline Scaling and 6.6 29 7/29c,. 7/29 15/29
et al. (125) split mouth day: 0, 2, 4, nΩ29 root planing 3 weeks root planing 29 3/29 1/29 7/29
6, 8 Habitual 12 weeks 4.9 29 2/29 1/29 2/29
oral hygiene
Scaling at Baseline Scaling and 6.8 29 7/29c,. 12/29 13/29
months 1 and 3 3 weeks root planing 29 2/29 2/29 10/29
12 weeks π metronidazole 5.1 29 5/29 4/29 8/29
Data for specific species: either number of positive sites on total number of sites or .number of positive sites compared with number of tested sites. Microbial analyses: cculture, tchairside ELISA: EvalusiteA. Underlined
dataΩresult extracted from charts.
 Table 6. Microbial changes after scaling and root planing with or without the adjunctive use of tetracycline (selection of most relevant articles and
intervals). Variables include colony-forming units (anaerobic growth), darkfield microscopy data (proportions) and the detection frequency or proportion
of periodontal pathogens
Design of study Microbiological findings

Authors
Concept
% and frequency
Type of infection and
number of patients
Therapy
Interval
Treatment
Probing depth in mm
No. of sites
Colony-forming units/ml
after anaerobic growth
% cocci
% motile organisms
% spirochetes
A. actinomycetemcomitans
P. gingivalis
P. intermedia

Goodson Intrasubject 25% hollow Chronic adult Scaling and Baseline Scaling and 5.7 19 5.6¿105 1.2 22.4 18.6
et al. (44) split mouth fiber periodontitis root planing 10 days root planing 20 1.3¿105 4.4 37.5 16.2
day: 0–10 nΩ10 (scaling-group 4 weeks 16 2.0¿105 3.2 21.4 18.6
also on day 10) 12 weeks 20 2.8¿105 3.2 17.8 15.1
Baseline Scaling and 5.7 19 5.1¿105 1.0 25.1 12.9
10 days root planing 19 3.8¿104 14.1 49.0 22.4
4 weeks π tetracycline 15 4.2¿104 16.2 30.2 21.4
12 weeks 18 2.2¿105 3.0 27.5 8.7
Heijl Intrasubject 25% fiber Chronic adult Supragingival Baseline Scaling and 6.6 26 3.7¿106 74.1 7.2 5.4 18.5%c,e,*
et al. (56) split mouth day: 0–10, periodontitis scaling 20 days root planing 5.3 26 1.5¿106 91.4 0.7 1.0 6.1%
11–20 nΩ10 Oral hygiene 62 days 4.8 26 4.1¿105 90.8 1.7 1.4 1.4%
instruction
1 month Baseline Scaling and 6.6 24 4.2¿106 67.0 10.6 8.6 27.3%
(before baseline) 20 days root planing 5.9 24 4.1¿104 95.0 0.1 0.0 1.3%
Weekly 62 days π tetracycline 4.4 24 4.2¿104 89.3 2.8 1.9 0%
professional
cleaning
Mouthrinse
chlorhexidine:
0.2%
Lowenguth Intrasubject 25% fiber Chronic adult Supragingival Baseline Scaling and ±5 53 0%d 50.9% 77.4%
et al. (80) split mouth day: 0–10 periodontitis scaling 4 weeks root planing 49 2.1% 20.4% 53.1%
multicenter nΩ31 (10 days before 12 weeks 50 0% 24.0% 42.0%
baseline) 26 weeks 48 0% 25.0% 35.4%
Scaling and
root planing Baseline Scaling and ⬎5 57 3.6% 36.8% 61.4%
(5 min/site) 4 weeks root planing 52 0% 9.6% 40.4%
Habitual oral 12 weeks π tetracycline 53 3.8% 5.7% 28.3%
hygiene 26 weeks 51 3.9% 13.7% 17.6%

Lie Intrasubject 3% ointment Chronic adult Oral hygiene Baseline Scaling and 5.1 18 0/18t,. 12/18 7/18
et al. (77) split mouth day: 0 periodontitis instruction 12 weeks root planing 3.7 18 1/16 2/16 5/16
nΩ18 scaling and 24 weeks 4.0 18 0/10 3/10 1/10
root planing
(2 sessions) Baseline Scaling and 5.2 18 1/18 9/18 7/18
12 weeks root planing 3.8 18 1/16 1/16 4/16
24 weeks π tetracycline 3.5 18 0/10 2/10 1/10

83
Data for specific species: either percentage positive sites on total number of sites or .number of positive sites compared with number of tested sites or emean percentage on the total number of colony-forming units, *black-
Topical periodontal therapy

pigmented Bacteroides. Microbial analyses: cculture, dDNA, tchair-side ELISA: EvalusiteA. Underlined dataΩresult extracted from charts.
Quirynen et al.
plied drug will be absorbed by the human body and
may even show significant serum levels (106, 119,
159, 160). Moreover, there is still a possibility of a
transient selection, subgingivally, of resistant bac-
terial strains following local delivery, however, which
seem to disappear after 3 to 6 months (46, 75, 76,
110, 182). So far, no definitive data are available on
possible adverse effects of subgingival antibiotic
slow-release devices on the microbiota of the gastro-
intestinal tract. This lack of data has spurred specu-
lations and concerns of possible spread of bacterial
resistance and even increases in the likelihood of the
transfer of multi-drug resistance after local appli-
cation of antibiotics (48, 50, 65, 165).
Finally, one should realize that, as after any type
of periodontal therapy, optimal supragingival plaque
control is essential for the achievement of clinical
improvement even after local application of anti-
biotics (13, 26, 70). In general, application of subgin-
gival antibiotics should be postponed until meticu-
lous plaque control is achieved.
Conclusion
A series of articles have analyzed the effect of mono-
therapy of subgingival antibiotics and antiseptics, as
an alternative to scaling and root planing. Both the
possibility of adverse effects of the drugs and the in-
ability to achieve the improvements obtainable with
a single session of root planing make monotherapy
unacceptable, especially where antibiotics are con-
cerned.
The adjunctive benefits of locally applied anti-
biotics or antiseptics in conjunction with subgingival
debridement are limited in general. Available data
seem to support the concept that, in deep (⬎7 mm)
periodontal pockets, the prolonged delivery of an
antimicrobial agent in conjunction with subgingival
root planing can provide some microbial and clinical
benefit. The clinician should take into account the
clinical and microbial advantages of topical chemo-
therapeutic therapy on one hand and the possible
disadvantages and adverse effects of the topical
agent on the other hand. So far, ‘‘routine’’ use of top-
ical antibiotics cannot be justified, especially not
where efficacious results can be accomplished with
subgingival debridement. The increasing resistance
of the periodontal pocket microbiota to several com-
monly used antibiotics should remind clinicians to
restrict the use of antibiotics to exceptional cases
(175). Local antibiotics may, however, be of signifi-
cance when relapse of periodontitis occurs and/or
84
when surgical reintervention conflicts with the pa-
tient’s emotions.
Subgingival antiseptics have some beneficial ef-
fects, especially when professional application is
combined with self-applied irrigation. Since these
drugs are inexpensive and relatively easy to use and
have minimal risks, their routine application is justi-
fied. Intraoral translocation of periodontal patho-
gens resulting in rapid recolonization of treated
pockets can be markedly decreased by completing
the subgingival debridement in a short period of
time (such as 2 consecutive days). When performed
in combination with one-stage full-mouth debride-
ment, topical application of antimicrobial agents
may enhance the microbial and clinical outcome.
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