Periodontology 2000, Vol. 71, 2016, 82–112 © 2016 John Wiley & Sons A/S.
& Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Antibiotics/antimicrobials:
systemic and local
administration in the therapy of
mild to moderately advanced
periodontitis
KARIN JEPSEN & SØREN JEPSEN
Periodontitis is a plaque-induced inflammatory con-
dition that affects the periodontium; it is caused by
the adherence to tooth surfaces of pathogenic bacte-
rial species organized in complex communities that
form biofilms (129, 130). Standard periodontal treat-
ment consists of mechanical debridement to remove
biofilm and calculus from the affected root surfaces.
This approach has proven successful for most
patients (48, 49, 154, 175). However, mechanical
debridement is a highly demanding procedure with
some limitations, such as the inability to access deep
pockets, surface irregularities and furcation areas
(104). Because of the infectious nature of periodonti-
tis, the rationale for using adjunctive antimicrobial
agents is to eradicate or reduce the numbers of
pathogenic bacteria in deep pockets, root furcations
and concavities or those residing at or within the
periodontal tissues at the biofilm–gingival interface. lt
is hoped that pathogenic organisms which are not
accessible to mechanical removal by hand or power-
driven instruments can be reduced in number or
eliminated by antimicrobial therapy (220). Biofilm-
associated infections in general are difficult to treat
with antibiotics unless the biofilm is disrupted
mechanically, as in anti-infectious periodontal ther-
apy (129, 130). Therefore, the current general consen-
sus is that if antimicrobial therapy is considered, it
should be preceded by thorough mechanical debride-
ment to disrupt the structured biofilm (66).
Adjunctive antimicrobial therapy can be delivered
either systemically or locally. The possible advantages
82
PERIODONTOLOGY 2000
and limitations of both forms of administration are
listed in Table 1. Systemic delivery has the potential
advantage of reaching pathogens widely distributed
in the oral cavity, including those in nondental oral
niches, such as the dorsum of the tongue and the
crypts of the tonsils. However, it requires high patient
compliance, can lead to unwanted systemic side
effects affecting compliance and may contribute to
bacterial resistance (160, 189, 228). In contrast, local
administration is independent of patient compliance
and allows the application of drugs to the site of
infection at a concentration that cannot be reached
by the systemic route. However, their application is
limited to isolated clinically detected lesions, and
reinfection from nontreated sites or nondental oral
niches may occur.
This review aims to update the current knowledge
of adjunctive antimicrobial therapy of periodontitis
based on the most recent scientific evidence. Special
emphasis is given to the implications for mild and
moderate forms of the disease. Mild to moderately
advanced periodontitis refers to findings from the
clinical examination and is generally characterized by
periodontal probing depths of up to 6 mm with clini-
cal attachment loss of up to 4 mm. Signs and symp-
toms of edema, erythema, gingival bleeding upon
probing and/or suppuration may be present and
associated with increased tooth mobility as well as
radiographic evidence of bone loss (16–30% or
>3 mm but ≤5 mm) (1, 10). The effects of standard
nonsurgical periodontal therapy with regard to

Table 1. Comparison of local and systemic antimicrobial therapy
Source: Mombelli (139).
pocket reduction and attachment Ievel gain for the
different categories of initial periodontal probing
depth are well documented and can serve as a bench-
mark against which the possible additional effects of
adjunctive antimicrobials can be compared.
Effects of adjunctive systemic
antibiotics
A wide range of systemic antibiotics, including amoxi-
cillin (with or without clavulanic acid), azithromycin,
clindamycin, doxycycline, metronidazole, spiramycin
and tetracycline, have been tested in clinical studies.
The effects of such adjunctive systemic antimicrobial
therapy in chronic and aggressive periodontitis have
been evaluated in a number of reviews and system-
atic reviews with meta-analyses (57, 58, 66, 84, 94–96,
112, 113, 161). Herrera et al. (96) performed a meta-
analyses of 25 clinical trials (randomized controlled
trials and controlled clinical trials) of ≥6 months’
duration, comparing subgingival debridement (scal-
ing and root planing) with adjunctive systemic antibi-
otics vs. scaling and root planing alone or with
placebo. The authors reported statistically significant
additional benefits for spiramycin (probing-depth
change = 0.41 mm) and amoxicillin plus metronida-
zole (clinical attachment level change = 0.45 mm) in
deep pockets (>6 mm). They concluded that in speci-
fic clinical situations, such as patients with deep
pockets or with progressive ‘active’ disease or with
specific profiles, use of adjunctive systemic antimi-
crobials could be clinically relevant. Haffajee et al.
(84) published a systematic review including 29 stud-
ies (26 randomized controlled trials and three cohort
studies) with a duration of more than 1 month.
Periodontal conditions were aggressive, chronic or
recurrent periodontitis, as well as periodontal
abscesses. The authors concluded that metronida-
zole, tetracycline and the combination of metronida-
Adjunctive antibiotic/antimicrobial therapy in periodontitis
zole plus amoxicillin achieved the best results but the
aspects related to appropriate dosage and duration
remained unclear. Herrera et al. (94) updated their
previous work to include 32 publications and 45 com-
parisons. The consensus paper of the corresponding
workshop for this paper (176) concluded that, if sys-
temic antimicrobials were used, this should be as part
of nonsurgical periodontal therapy. Indirect evidence
suggests that antibiotic intake should start on the day
of debridement completion and be completed within
a short period of time. Furthermore, because of prob-
lems related to the indiscriminate use of antimicro-
bials (i.e. systemic side effects, adverse effects and
increase in bacterial resistance), the use of systemic
antimicrobials in periodontitis should be restricted to
patients with aggressive, severe and progressing
forms of periodontitis. Keestra et al. (112, 113) pub-
lished two systematic reviews and meta-analyses on
the adjunctive use of systemic antibiotics in patients
with untreated chronic periodontitis (43 randomized
controlled trials) and aggressive periodontitis (14 ran-
domized controlled trials). The authors reported sig-
nificant additional pocket depth reduction with the
use of antibiotics for either condition of periodontal
disease. Statistically, no specific type of antibiotic was
superior over another. Separate meta-analyses were
performed for moderately deep and deep pockets. A
recent systematic review published by Garcia Canas
et al. (66) was designed as an update of the system-
atic review conducted by Herrera et al. (96) and
selected 23 clinical trials published after 2001 with a
minimum of 6 months’ follow up and patients diag-
nosed with chronic periodontitis or aggressive peri-
odontitis. Overall, a tendency toward improvement
was found in studies in which systemic antibiotics
were used as adjunctive therapy with scaling and root
planing, but because of the high level of heterogene-
ity of the studies the authors could not establish
definitive conclusions for chronic periodontitis and
guidelines regarding the use of adjunctive systemic
83
Jepsen & Jepsen
antibiotics. Therefore, clinicians should make their
treatment decisions for each patient individually after
weighing the benefits and the risks.
Amoxicillin and metronidazole
In recent years, the antibiotic therapy most widely
documented in clinical reports has been the combina-
tion of metronidazole and amoxicillin (190, 191, 238).
Sgolastra et al. (190, 191) published two systematic
reviews on the efficacy of adjunctive amoxicillin plus
metronidazole: one in patients with chronic periodon-
titis (four randomized controlled trials) and the other
in patients with aggressive periodontitis (six random-
ized controlled trials). All patients had been treated
with scaling and root planing, alone, or in combina-
tion with amoxicillin and metronidazole. The results
of the meta
analysis in patients with aggressive peri-
odontitis, in which full-mouth data were analyzed,
showed significantly more clinical attachment gain
(0.4 mm) and probing depth reduction (0.6 mm) after
full-mouth scaling and root planing in combination
with systemic administration of these two antibiotics.
Patients with chronic periodontitis also seemed to
experience a clinical benefit of this antibiotic combi-
nation compared with scaling and root planing alone.
The results of the meta-analyses showed significantly
more mean clinical attachment gain (0.2 mm) and
probing depth reduction (0.4 mm) after adjunctive
amoxicillin and metronidazole, although the addi-
tional mean benefit was less distinct than in the
patient group with aggressive forms of the disease
(Table 2). Therefore, these systematic reviews, based
on full-mouth clinical data, seem to support a statisti-
cal benefit for the adjunctive use of amoxicillin plus
metronidazole in the treatment of chronic and aggres-
sive periodontitis; however, the observed weighted
Table 2. Therapeutic efficacy of nonsurgical periodontitis treatment, with and without adjunctive systemic amoxicillin
and metronidazole, in patients with chronic periodontitis and aggressive periodontitis
From Sgolastra et al. (190, 191). Follow up varied from 3 to 24 months.
84
mean differences were small. In another systematic
review, Zandbergen et al. (238) analyzed 28 clinical
trials (including 19 randomized controlled trials) on
the effect of concomitant administration of amoxi-
cillin plus metronidazole adjunctive to scaling and
root planing over at least 1 month in patients with
aggressive or chronic periodontitis. The authors con-
cluded that the clinical benefits of nonsurgical peri-
odontal therapy can be enhanced by adjunctive
systemic antimicrobial therapy in adults who are
otherwise healthy. Rabelo et al. (161) performed a sys-
tematic review and a Bayesian network meta-analysis
to assess the effects of adjunctive systemic antibiotics
in aggressive periodontitis. They found that for clinical
attachment gain/reduction in probing depth, and
compared with scaling and root planing alone, the
combinations of scaling and root planing + metron-
idazole (mean difference = 1.08 mm/1.05 mm) and
scaling and root planing + metronidazole + amoxi-
cillin (mean difference = 0.45 mm/ 0.53 mm) had the
most beneficial outcomes.
Effects of systemic antibiotics in initially
moderate or deep periodontal sites
To put the observed weighted mean differences of
1.4 mm for pocket depth reduction and 0.9 mm for
clinical attachment level gain into perspective, and
because not all studies included had a comparative
treatment arm of scaling and root planing only, Zand-
bergen et al. (238) made an indirect comparison with
data originating from another review published by
one of the co-authors (35) by analyzing the overall
effect of nonsurgical therapy alone. In this explora-
tory analysis, data stratified according to baseline
pocket depth were compared with data previously
reported by Cobb (34), for nonsurgical debridement
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

antibiotics. Patients who received antibiotics at initial sites improving above clinically relevant thresholds,
therapy showed statistically significant improvement compared with patients who received antibiotics at
in pocket depth reduction and in the percentage of retreatment in sites with remaining pockets ≥5 mm.

A D

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 Table 4. Evaluation of initially deep sites in five studies: probing-depth reduction and clinical attachment gain were determined in test subjects after treatment of gen-
eralized aggressive periodontitis using scaling and root planing in conjunction with amoxicillin + metronidazole compared with placebo control

Initially deep sites (probing depth varied from ≥6 mm to ≥7 mm).

†
Mann–Whitney U-test.
‡
From Mestnik et al. (136).
*Bonferroni-corrected t-test.
**Student’s t-test.
***Kruskall–Wallis test.
****Mann–Whitney U-test.
*****Analysis of covariance.
******One-way analysis of variance P-value.
Adjunctive antibiotic/antimicrobial therapy in periodontitis

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Jepsen & Jepsen
Table 5. Mean reduction of pocket depth and gains in
clinical attachment following scaling and root planing
*From Hung & Douglass (100). References from which the results were calcu-
lated were 5, 15, 40, 122, 126, 142, 155, 156. Mean numbers, weighted according
to sample size, after scaling and root planing were analyzed using baseline
measures of initial probing depth as covariant.
deep sites. For patients diagnosed with mild to mod-
erate periodontitis (1), the majority of probing depths
recorded at baseline usually do not exceed 6 mm.
The effects of mechanical debridement alone are well
documented for moderately deep sites (4–6 mm),
and clinicians can expect a mean reduction in pocket
depth of approximately 1 mm and a gain in clinical
attachment level of approximately 0.5 mm (100)
(Table 5). Thus, the risk is low for residual deep sites
(>5 mm) with persistence of high loads of bacterial
pathogens, the limited additional benefit of the use of
systemic antibiotics in moderately deep sites does not
justify their use. Exceptions may be very rare cases of
young patients with moderate disease who are
infected with the JP2 genotype of Aggregatibacter acti-
nomycetemcomitans (Fig. 11A–G); This distinct geno-
type of A. actinomycetemcomitans has been found to
be strongly associated with aggressive forms of peri-
odontitis, particularly in patients from African medi-
terranean regions (e.g. Morocco), but is not
associated with known systemic conditions or genetic
Fig. 1. (A) A 23-year-old patient from North Africa
unhappy with her smile line. Her maxillary incisors
showed distinct migration (flaring) with incomplete lip
closure. This patient has localized periodontitis not associ-
ated with known systemic conditions or genetic
syndromes. (B) Clinical view at baseline: distinct black-
stained calculus on the lower right canine. (C) Radio-
graphic documentation; upper incisors show moderate
bone loss. (D) Periodontal attachment status and plaque
index at baseline. Probing depths ranged from 2 mm to 6
mm and in localized areas (e.g. upper right wisdom tooth)
were up to 9 mm, generalized attachment loss was
88
syndromes that substantially modify susceptibility
and/or progression of disease (11, 89, 98, 202). An
example of a patient with generalized severe peri-
odontitis treated with adjunctive systemic antibiotics
in a specialist practice is shown in Fig. 2(A–H).
Effects of adjunctive locally
delivered antimicrobials
Various antimicrobials and delivery systems have
been developed with the aim to minimize systemic
uptake of the antimicrobial agent whilst maintain-
ing high levels in the crevicular fluid at the target.
These agents, which provide substantivity of an
antimicrobial system at an effective drug concentra-
tion over time, have been investigated mostly in
localized forms of periodontitis and in nonrespond-
ing, persistent and recurrent sites (60, 114, 221). Sci-
entific evidence using adjunctive locally delivered
antibiotics is currently based on three systematic
reviews and one meta-analysis (20, 86, 100, 133).
Hanes & Purvis (86) published a systematic review
of 19 studies that evaluated the efficacy of different
nonsurgical periodontal therapies, including admin-
istration of local sustained-release agents (minocy-
cline gel, microencapsulated minocycline,
chlorhexidine chip and doxycycline gel). In a subse-
quent systematic review, the statistically significant
adjunctive benefit for adjunctive tetracycline,
minocycline, metronidazole and chlorhexidine
could be confirmed with modest clinical improve-
ments in probing depth reductions compared with
scaling and root planing alone (20).
A recent systematic review (133) was based on data
extracted from 52 randomized controlled trials,
reported in 56 publications. In most of the studies,
site selection for the application of antimicrobial
delivery systems was based on the presence of sites
with pockets of >5 mm in patients with chronic peri-
observed and plaque index was 54%. (E) Explanation of
periodontal status. (F) Re-evaluation 8 weeks after com-
pletion of debridement on two consecutive days with
adjunctive systemic azithromycin; periodontal conditions
are clearly improved. Azithromycin was used because of its
potent activity against periodontal pathogens, short treat-
ment regimen (ensuring good patient compliance), low
incidence of side effects, persisting antibiotic effects and
even longer-lasting immunomodulatory effects after a sin-
gle course (97). (G) Clinical view 8 weeks after nonsurgical
therapy. Fig. 1 (A), (B) and (G) are photographs courtesy of
T. Waller.
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

odontitis. The overall meta-analysis, combining all with the control groups. Therefore, through subgingi-
antimicrobial products, showed significant pocket val application of an antimicrobial adjunct, an addi-
depth reductions and gains in clinical attachment tional clinical benefit in reductions of pocket probing
level (0.4 and 0.3 mm, respectively) when compared depth could be demonstrated (Table 6a) (133). The

A B

89
Jepsen & Jepsen
Fig. 2. (A) Clinical status of a 48-year-old patient with sev-
ere generalized periodontitis, showing distinct signs of
acute infections on the upper incisors and lower left
canine. (B) Radiographs of the same patient showing mod-
erate-to-severe bone loss. (C) Periodontal status before
treatment, with pocket depth up to 12 mm and a bleeding
score of 100%. (D) Explanation of periodontal status. (E)
Clinical status 6 months after completion of debridement
on two consecutive days with adjunctive systemic antibi-
largest effect was demonstrated with the application
of tetracycline fibers, resulting in a pocket depth
reduction of 0.7 mm, followed by doxycycline
(0.5 mm pocket depth reduction) and minocycline
(0.4 mm pocket depth reduction). The effect of
chlorhexidine chips and metronidazole rendered
minimal additional probing improvements, below
0.4 mm. Regarding clinical attachment level gain, the
highest effect (0.9 mm) was demonstrated by the
application of chlorhexidine–xanthan gel, although
these data are based on only one study (133)
(Table 6b). Other antimicrobials yielded additional
clinical attachment level gains of 0.2–0.6 mm. How-
ever, the application of metronidazole and other
chlorhexidine products did not add any benefit over
scaling and root planing alone. In spite of no signifi-
cant changes in bleeding, and a high heterogeneity of
data, Matesanz-Pe
rez et al. (133) concluded that
scientific evidence supports the adjunctive use of
local antimicrobials to debridement in deep or recur-
rent periodontal sites, mostly when using vehicles
with proven sustained release of the antimicrobial.
An example of a tooth treated with adjunctive locally
delivered antibiotics as part of the initial treatment
phase is shown in Fig. 3(A–G).
Local adjunctive antimicrobials for
recurrent or persistent periodontal lesions
Although the probability of observing a high percent-
age of deep residual pockets after anti-infective ther-
apy in patients with mild to moderate periodontitis is
low (Table 5), sites with pocket depth >5 mm repre-
sent an incomplete periodontal treatment outcome
and require further therapy (134). In particular,
bleeding sites, which carry an increased risk of dis-
ease progression, are difficult to control. Renvert &
Persson (167) reported that the presence of deep
residual pockets after treatment was associated with
further disease progression. Tonetti et al. (209) evalu-
ated the efficacy of a slow-release doxycycline gel
adjunctively administered with nonsurgical therapy
in subjects with recurrent or persistent periodontitis.
90
otics (amoxicillin 500 mg, three times daily for 8 days; and
metronidazole 400 mg twice daily for 8 days). (F) Peri-
odontal status 6 months after debridement and adjunctive
systemic antibiotics; the bleeding score is 8%. (G) Clinical
status 6 months after localized corrective surgery as well
as supportive periodontal therapy, presenting a bleeding
score of 4%. (H) Periodontal status 6 months after local-
ized corrective surgery as well as supportive periodontal
therapy; the bleeding score is 4%.
Antibiotics, in addition to sonic/ultrasonic subgingi-
val instrumentation, were applied to sites with
pocket depth ≥5 mm. The authors concluded that
topically administered slow-release doxycycline gel
may provide a short-term benefit in controlling
inflammation and deep pockets in treated periodon-
tal patients participating in a secondary prevention
program and able to maintain a satisfactory Ievel of
oral hygiene. Bogren et al. (19) studied a total of 128
periodontal maintenance patients, with at least four
teeth with pocket depth ≥5 mm treated with local
application of doxycycline gel, at baseline and at 1
and 2 years, as an adjunct to mechanical debride-
ment or mechanical debridement only. The authors
concluded that although short-term effects on clini-
cal parameters were found with the adjunctive use of
locally delivered doxycycline, applications repeated
annually had no clinical effects beyond those
observed with mechanical debridement alone in
maintenance patients. Tomasi et al. (207) studied 22
patients with chronic periodontitis, who received ini-
tial root debridement by ultrasonic instrumentation,
followed by random assignment to retreatment of
residual furcation pockets at 3 months by ultrasonic
instrumentation, with or without adjunctive local
application of a 8.8% doxycycline gel, and concluded
that the improvement in molar furcation involve-
ment after nonsurgical periodontal therapy was not
enhanced by adjunctive locally applied doxycycline.
An example of a patient treated with adjunctive
locally delivered antibiotics for recurrent disease is
shown in Fig. 4(A–H).
Treatment protocols for adjunctive
antibiotics
Time of administration
Griffiths et al. (76), in a follow-up study of a random-
ized controlled trial performed by Guerrero et al. (80)
evaluated whether retreatment with adjunctive
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

A B

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Jepsen & Jepsen

Table 6. Clinical therapeutic efficacy of scaling and root planing vs. scaling and root planing plus different local
antimicrobials on (a) probing pocket depth and (b) clinical attachment level in patients with chronic periodontitis

From Matesanz-P

erez et al. (133). Follow up varied from 6 months to more than 12 months.

metronidazole and amoxicillin would give the original 2 months and the two study groups were crossed-
placebo group benefits comparable with the original over for treatments. The test group was treated with
test group. The previous study was extended for debridement and the control group with systemic

Fig. 3. (A) Frontal view of a 52-year-old man with an acute
periodontal lesion on an upper left incisor and generalized
moderate periodontitis (from (106) Quintessence with per-
mission). (B) Periodontal status before treatment: the
probing depth ranged from 2 to 6 mm (localized up to
10 mm on the upper-left central incisor), the plaque index
was 100% and the bleeding score was 73%. (C) Radio-
graphs of the same patient showing generalized slight to
moderate bone loss and the upper left central incisor
showing severe bone loss. (D) Clinical status 8 weeks after
administration of local antibiotics (Arestinâ; OraPharma,
Horsham, PA, USA), gentle debridement of the upper left
central incisor and nonsurgical periodontal therapy. Areas
of inflammatory reactions are still evident in the lower
incisors. (E) Re-evaluation 8 weeks after root surface
debridement using piezo-surgical instruments (EMS,
Electro Medical Systems, Nyon, Switzerland) and adminis-
tration of local antibiotics (Arestinâ, OraPharma)
subgingivally on the upper left central incisor. Probing
depths on that tooth were still between 3 and 10 mm but
there were no visible signs of suppuration. (F) Clinical sta-
tus: stable condition 2 years after regenerative procedures
and one year after orthodontics. (G) Periodontal status
3 years after regenerative procedures on the upper left
central incisor and 3-monthly supportive periodontal
therapy.

92
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

antibiotics. Patients who received antibiotics at initial sites improving above clinically relevant thresholds,
therapy showed statistically significant improvement compared with patients who received antibiotics at
in pocket depth reduction and in the percentage of retreatment in sites with remaining pockets ≥5 mm.

A D

B E

C F

93
Jepsen & Jepsen
A C
E
D
Fig. 4. (A) Clinical status of a 65-year-old otherwise sys-
temically healthy patient receiving supportive periodontal
therapy. Recurrent disease with evidence of suppuration is
apparent on the lower right canine. (B) Two periodontal
examinations carried out 3 months apart. Sudden peri-
odontal breakdown the lower right canine, full-mouth pla-
que/bleeding score: 10%/12%. (C) Results of a microbial
test taken from the subgingival biofilm of the canine,
including a susceptibility profile to different antibiotic sub-
stances. (D) Situation after root surface debridement and
application of adjunctive minocycline microspheres
In deep pockets (≥7 mm), the mean difference was
0.9 mm (P = 0.003) and in moderate pockets (4–
6 mm) it was 0.4 mm (P = 0.036) (Table 7a). Clini-
cally relevant changes of >2 mm in probing depth
94
H
(Arestinâ; OraPharma, Inc.). Before surgery there was no
suppuration, but pocket depth remained unchanged. (E)
Evidence of a large intrabony defect to the mesial of the
lower canine. Monophilic sutures in place after treating the
defect with enamel matrix proteins and bone replacement
material (Emdogainâ, Straumann; Bioossâ, Geistlich,
Switzerland). (F) Clinical situation 1 year after regenerative
surgery. (G) Radiographs taken at patient0 s first visit/exam-
ination with an unexpected periodontal breakdown 2 years
later. Radiographic defect fill 1 year after regenerative sur-
gery. (H) Examination 1 year after regenerative surgery.
reductions, and changes in the number of pockets
that were in need of further treatment at 2, 6 and 8
months, are presented in Table 7b. For pockets con-
verting from ≥5 mm to ≤4 mm, the difference was
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

83% for initial antibiotic treatment compared with
67% for delayed antibiotic treatment (P = 0.041); and
for pockets converting from ≥4 mm to ≤3 mm, the
difference was 63% for initial antibiotic treatment
compared with 49% for delayed antibiotic treatment
(P = 0.297). The authors concluded that: ‘patients
that received the antibiotics at the initial therapy
showed significant additional benefits compared to
those who received the same regime at the re-treat-
ment phase.’ A limitation of the study design was dif-
ferent follow-up times of 6 months from initial
antibiotic treatment vs. 2 months for delayed
antibiotic treatment. Very recently, Mombelli et al.
(140) investigated the possible benefits of amoxicillin
and metronidazole in the different phases of perio-
dontal therapy. They performed a randomized con-
trolled crossover clinical trial and investigated the
adjunctive effect of systemic antibiotics on the
nonsurgical and surgical treatment phases. The
authors reported similar long-term results, but stated
that antibiotic therapy during the first nonsurgical
treatment phase resolved the disease more quickly
and thus reduced the need for additional surgical
intervention.
Systemic antibiotics and full-mouth
disinfection
In patients with generalized aggressive periodontitis,
the clinical and microbiological effects of a full-

Table 7. (a) Improvements in pocket-depth reduction and in the percentage of sites above clinically relevant thresh-
olds, compared with patients who received antibiotics at retreatment in sites with remaining pockets ≥5 mm; (b) tim-
ing of systemic antimicrobials (metronidazole and amoxicillin) given at either initial therapy or in the retreatment
phase in patients with generalized aggressive periodontitis

From Griffiths et al. (76).

*Analysis of covariance for probing pocket depth reduction and gain in lifetime cumulative attachment loss.
**Subset analysis showing clinically relevant changes in probing pocket depth presented at median and interquartile range (IQ) using the Mann–Whitney U-test.

95
Jepsen & Jepsen
mouth disinfection protocol comprising debride-
ment combined with chlorhexidine irrigation, rins-
ing and tongue brushing, with or without amoxicillin
plus metronidazole, were studied (92, 214). Although
some short-term advantages were observed for clini-
cal variables, both clinical and microbiological
observations suggested an important impact, in both
groups, of the therapy provided; however, after
6 months there were no relevant differences
between groups with or without the additional
adjunctive antibiotic therapy. On the other hand,
Aimetti et al. (2) assessed the adjunctive effect of
amoxicillin and metronidazole over a complete full-
mouth disinfection protocol, and both clinical and
microbiological findings revealed significant benefits
of adjunctive antibiotics after 6 months. In patients
with chronic periodontitis, no differences in clinical
attachment level gain or pocket depth reduction
were found when a full-mouth disinfection protocol
with metronidazole was compared with the same
protocol with placebo (158).
Best maintained clinical results over time
A study designed to find a periodontal treatment
with the best clinical results that were maintained
over 24 months, as evaluated by changes in pocket
depth and clinical attachment level, was performed
by Goodson et al. (71). Treatment outcomes of
scaling and root planing, alone, or in combination
with systemic antibiotics, local antibiotic therapy
and/or periodontal surgery, were compared under
a common protocol. The authors concluded that
patients receiving adjunctive therapies generally
exhibited improved attachment gain and/or prob-
ing depth reduction when compared with debride-
ment alone. Adjunctive locally delivered
tetracycline had no statistically significant effects.
Adjunctive combination of amoxicillin and metron-
idazole provided additional benefits regarding
attachment level gain and pocket reduction. Peri-
odontal surgery provided pocket reduction, but was
not associated with attachment level gain (Table 8).
This study was conducted with a factorial design to
test whether or not treatments interact with each
other. The test of interaction between therapies
(cross products) for 24-month clinical attachment
level gain and probing pocket depth reduction
revealed no statistical significance. The investigators
therefore concluded that among adjunctive thera-
pies, an additive effect, but no synergistic or antag-
onistic impact, was observed.
96
A prospective multicenter randomized controlled
trial designed to investigate the course of peri-
odontal disease and the long-term impact of
adjunctive systemic antibiotics was performed by
Harks et al. (87). Four-hundred and six patients
with moderate-to-severe periodontitis received
nonsurgical periodontal therapy and adjunctive
systemic antibiotics (amoxicillin plus metronida-
zole) and maintenance therapy at 3-month inter-
vals. After a 27.5-month observation period, both
treatments were found to be effective in preventing
disease progression (the percentage of sites show-
ing further attachment loss was ≥1.3 mm). The
median percentage of sites showing further attach-
ment loss was 7.8% in the placebo group
compared with 5.3% in the group receiving adjunc-
tive antibiotics. Empiric therapy with adjunctive
systemic antibiotics showed a small absolute,
although statistically significant, additional reduc-
tion of further attachment loss.
Smokers
Smokers are at a greater risk of developing periodon-
tal disease and tooth loss compared with nonsmokers
(17, 146, 203, 204) and respond less favorably to peri-
odontal treatment (92, 108, 146). In general, smoking
reduced clinical responses to all therapies applied,
namely nonsurgical, surgical and adjunctive therapies
(71). In the maintenance phase of periodontal ther-
apy, heavy smoking was one of the main risk factors
for disease progression (134). Most of the clinical tri-
als addressing post-therapy microbiological changes
agree that it is more difficult to control subgingival
pathogens by mechanical periodontal therapy in
smokers than in nonsmokers (43, 78, 131, 212, 227).
This is probably because of the reduced capacity of
smokers to combat periodontal pathogens (81), as it
has been demonstrated that smoking affects the cel-
lular and humoral inflammatory responses (172).
Therefore, adjunctive therapeutic approaches have
been suggested for treating periodontitis in smokers.
Superior clinical outcomes have been reported in
smokers compared with nonsmokers, with nonsurgi-
cal treatment using adjunctive systemic or locally
applied antimicrobial agents (115, 132, 198, 206). For
persistent pockets of >5 mm after a course of debride-
ment, Kinane & Radvar (115) concluded that smoking
may have an important role in determining the prog-
nosis of periodontal treatment. Treatment outcomes
may be improved by application of locally delivered
antimicrobial systems as adjuncts to scaling and root
planing. Tomasi et al. (206) studied 103 patients (42
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

Table 8. Clinical attachment level gain and probing pocket depth reduction, from baseline to 24 months, in sites with
pocket depth >5 mm at baseline, of patients randomized to eight treatment groups

From Goodson et al. (71).

Data were evaluated using analysis of covariance with treatment as the dependent variable in the eight groups; a matrix of 56 pairwise comparison probabilities was
obtained. Attachment level gain and pocket depth reduction values are given as adjusted means  standard error of the mean, with the same superscript letter
within each column indicating a significant difference at P < 0.0009; significant pairwise differences were determined by post-hoc analysis using Fisher’s Protected
Least Significant Difference test.

smokers and 61 nonsmokers), each having at least
eight periodontal sites with probing pocket depth of
≥5 mm, treated with root planing or ultrasonic instru-
mentation and application of an 8.5% doxycycline gel.
The authors concluded that locally applied antibiotics
may partly counteract the negative effect of smoking
on periodontal healing following nonsurgical therapy.
Matarazzo et al. (132) evaluated the clinical and
microbiological effects of scaling and root planing,
alone, or combined with metronidazole or with
metronidazole and amoxicillin, in the treatment of
smokers with chronic periodontitis over a short time
period, and found that the greatest benefits in clinical
parameters and in the composition of the subgingival
microbiota are obtained with the adjunctive use of
metronidazole and amoxicillin (Table 9). However, a
systematic review concluded that the evidence for an
additional benefit of adjunctive antibiotic therapy in
smokers with chronic periodontitis is insufficient and
inconclusive. Additional well-designed randomized
controlled trials are required to assess the effect of
antibiotics in conjunction with periodontal treat-
ments in smokers (7). Thus, from an overall health-
care perspective it can be argued whether it is reason-
able to compensate for the reduced treatment
response in smokers by the use of antibiotics or
whether these patients should be involved in a smok-
ing-cessation program (165).

Table 9. Treatment effect in smokers with chronic periodontitis: probing-depth reduction and clinical attachment
gain (pre- and post-treatment) following scaling and root planing, in conjunction with the combination of amoxicillin
and metronidazole, compared with placebo controls, after 3 months

From Matarazzo et al. (132).

*Kruskal–Wallis/Mann–Whitney U-test.

97
Jepsen & Jepsen

Patients with type II diabetes significant improvement in the glycemic parameters

Miranda et al. (138) studied the effects of adjunctive
systemic amoxicillin and metronidazole in 58 patients
with uncontrolled type II diabetes and generalized
chronic periodontitis. The group receiving debride-
ment in combination with antibiotics showed greater
mean probing depth reductions and clinical attach-
ment gains (Table 10a), as well as a lower number of
sites with probing depths of ≥5 mm as the primary
outcome variable and a reduced number of subjects
with nine or more of these residual pockets compared
with the control group up to 1 year post-treatment
(P < 0.05). The authors concluded that the adjunctive
use of amoxicillin and metronidazole significantly
improved the clinical outcomes of debridement alone
in the treatment of patients with type II diabetes and
chronic periodontitis. Despite the clinical improve-
ments obtained with the adjunctive use of antimicro-
bials, none of the therapies yielded statistically
at any time point (Table 10b).
Patients with specific microbiologic
profiles
As a result of its proven ability to suppress A. actino-
mycetemcomitans in periodontitis lesions and other
oral sites (69), the combination of amoxicillin and
metronidazole appears well suited, especially to treat
A. actinomycetemcomitans-associated periodontitis.
Van Winkelhoff et al. (229) reported on the microbio-
logical and clinical effects of mechanical debride-
ment, in combination with metronidazole plus
amoxicillin therapy, in patients with A. actino-
mycetemcomitans-associated periodontitis. The
results showed that the combined treatment was very
effective in suppressing subgingival A. actino-
mycetemcomitans in patients with severe periodonti-

Table 10. (a) Treatment effect in patients with uncontrolled type II diabetes and chronic periodontitis: probing-depth
reduction and clinical attachment gain (pre- and post-treatment) following scaling and root planing in conjunction
with the combination of amoxicillin and metronidazole compared with placebo controls after 1 year; (b) Changes in
glycated hemoglobin and fasting plasma glucose with time and according to treatment

From Miranda et al. (138).

Values are given as mean  standard deviation.
Changes within groups in glycated hemoglobin and fasting plasma glucose levels over time were tested by repeated-measures analysis of variance (P > 0.05).
P-values were calculated using analysis of covariance.
*Differences between groups were tested using the Student’s t-test (P > 0.05).

98

tis, but the variation in clinical treatment responses
between the patients could not be correlated with the
microbial flora. Dannewitz et al. (41) evaluated the
clinical and microbiological effects of the combina-
tion of mechanical and antibiotic periodontal therapy
in subjects who tested positive for subgingival A. acti-
nomycetemcomitans. At an average follow up of
39 months with an antibiotic regime of either amoxi-
cillin/metronidazole or ciprofloxacin/metronidazole,
the clinical situation had improved significantly in all
subjects after systemic periodontal therapy and
remained stable during the course of the postopera-
tive follow up. No differences in the clinical data were
found between the subjects that tested positive and
negative for A. actinomycetemcomitans in the postop-
erative period. Mombelli et al. (141) studied the
effects of adjunctive amoxicillin in patients with mod-
erate to advanced periodontitis, with or without
A. actinomycetemcomitans. No specific benefits of the
antibiotics were seen in patients positive for A. acti-
nomycetemcomitans. Oteo et al. (148) investigated
systemic azithromycin, as an adjunct to debridement,
in Porphyromonas gingivalis-positive patients with
moderate chronic periodontitis. This systemic antimi-
crobial was chosen because of its convenient dosage,
and the results showed significant benefits in both
clinical and microbiological outcome variables after
6 months. These results, however, were not corrobo-
rated in a similar study, in which patients were not
selected based on a specific microbiological profile,
and where no adjunctive effect was observed at the 1-
year evaluation (174). Altogether the studies showed
inconclusive results. One reason for this may be vari-
ations in the susceptibility profiles of these clinically
relevant oral pathogens, of which knowledge is criti-
cal to provide the patient with the appropriate antibi-
otic therapy.
Side effects of antibiotics
The side effects and adverse reactions related to the
use of antibiotics in the treatment of periodontitis, or
of infectious diseases in general, must always be
weighed against the possible benefits. Antibiotic-
induced pharmacotoxic adverse reactions are listed
in the summary of characteristics of every product
and should be taken into account. In addition, the
anti
inflammatory or immune-suppressive effects of
antibiotics, able to mimic a successful therapy out-
come of the infection, are not well understood. The
intake of multiple antibiotics at the same time leaves
a patient susceptible to development of yeast infec-
Adjunctive antibiotic/antimicrobial therapy in periodontitis
tions. Another complication may be that even com-
mensal bacteria can trigger an immune response if
they reach critically high numbers or are present in
an inappropriate habitat within the host.
Morbidity/adverse events for systemic
and local antibiotics
Nausea, vomiting and gastrointestinal discomfort are
the most common adverse events reported in studies
on the use of adjunctive systemic antibiotics in
patients with periodontitis (28, 31, 32, 52, 53, 61, 71,
79, 80, 121, 132, 136, 168, 194, 233). Other reported
adverse effects include headaches (31, 32, 92, 214), a
metallic taste (31, 32, 92, 194, 214), general malaise
(79, 80) or a burning sensation of the mouth or ton-
gue (92, 214). Other side effects include muscu-
loskeletal and respiratory disorders (31, 32), dry
mouth, erythema oral ulceration, dizziness, staining
of tongue or teeth (92, 214), irritability (194), a rash on
the face or neck and nausea after the use of alcohol
(61). Griffiths et al. (76) reported a high incidence of
adverse events, with 42% of subjects affected
(Table 11). The majority of these side effects were
considered to be minor, but serious adverse events,
sufficient to withdraw the medication, occurred in
two patients. One subject developed a severe rash
and the other had to discontinue the medication
because of nausea, diarrhea and drowsiness. For most
published reports and studies on locally administered
antibiotics, no significant patient-centered adverse
events have been reported (20, 86). However, gingival
redness, pain on the first day of local administration,
gingival tingling, fever, headache, diarrhea, periodon-
Table 11. Adverse events reported following antibiotic
treatment in a study with 19 patients
From Griffiths et al. (76).
Values are given as n (%).
99
Jepsen & Jepsen
tal abscesses, root sensitivity, taste disturbances and
stomatitis have been noted in a recent systematic
review (133).
Impact of antibiotic therapy on the
gastrointestinal microbiome
Antibiotics have changed the way we are treating
infectious diseases, but we are just beginning to
assess the collateral damage on the symbiotic
microorganisms living in the gastrointestinal tract
(18). Repeated exposure to broad-spectrum antibi-
otics dramatically alters the composition of human
gut microbial communities, which may persist for
long periods of time (46). Experiments in mice have
demonstrated that antibiotic exposure disrupts
intestinal homeostasis and, in addition, has a pro-
found impact on the intestinal metabolome, affecting
the levels of over 87% of all detectable metabolites
(8). The consequences of such microbial shifts in the
intestine can alter the proper maturation of mucosal
immunity and render individuals more susceptible to
infection (186). Antibiotic-associated diarrhea caused
by Clostridium difficile, reflecting colonization of a
disrupted microbial community with a specific
microbe, can cause severe intestinal illness with
potentially life-threatening complications (29).
The current view of the impact of antimicrobial
treatment on the gastrointestinal microbiota is that
culture-independent studies may show persistent
changes in the microbiota that last for years (36, 106).
The clinical significance of these changes is currently
unknown, but there is growing evidence that chronic
diseases are linked to dysbiosis of the intestinal
microbiota. These include asthma and allergic dis-
eases (99, 218), autoimmune diseases (22, 23), type 1
diabetes (211, 223), type 2 diabetes (25, 240), obesity
(24, 120, 137), metabolic syndrome (30, 50), chronic
disorders of the gut (51, 111), atherosclerosis (74),
undernutrition (72, 117, 119), celiac disease (157, 187)
and chronic lung infections (21, 45). In addition,
many investigators have proposed that the vast gath-
ering of microflora in our intestines could have a
major impact on our state of mind. To paraphrase
one of these opinions regarding this link: ‘The micro-
biome may yield a new class of psychobiotics for the
treatment of anxiety, depression and other mood dis-
orders’ (185).
Bacterial resistance
The development of bacterial resistance has
increased dramatically as a result of the indiscrimi-
100
nate use of antimicrobials (149) and has generated
great concern among health authorities. Whilst the
discovery of antibiotics 70 years ago has revolution-
ized medicine, this increase of antibiotic resistance in
bacteria is the subject of intense debate driven by
economic and political concerns. In nature0 s complex
ecosystem, antibiotics are found in multiple environ-
ments, fauna and flora. Researchers discovered that
microbes produced metabolites with antibiotic activ-
ity mainly in low concentrations, serving primarily as
signaling molecules for bacterial cooperation and
only became antimicrobial at much higher concen-
trations (62). Studies have also shown that ‘antibiotic
resistance is ancient’ (44) and much larger numbers
of antibiotic-resistance genes are naturally present in
human commensal microbial genomes, as well as in
soil samples throughout the world, than previously
recognized (42, 199) Remarkably, resistance has also
been detected to antibiotics that have only been
recently introduced for clinical use (e.g. telithomycin
and tigecycline) (44). Therefore, the reservoir of
antibiotic-resistance genes has definitely increased
since the discovery of antibiotics more than 70 years
ago (118). The global pandemic of antibiotic resis-
tance (Fig. 5) represents a major health and eco-
nomic burden (Fig. 6), and, together with a relative
lack of innovation in generating new antibiotics, can
only be solved if scientists, politicians, society and
business work together, nationally and internation-
ally, pursuing diverse, coordinated approaches. In the
present day, pathogens can spread quickly through
the globalized system of travel, trade and food distri-
bution, presenting a threat to the entire world (171,
210). We have to realize the danger of returning to a
pre-antibiotic era, with the risk of many infectious
diseases becoming untreatable and uncontrollable.
The problem of antibiotic resistance is also of great
concern to the dental profession and has been
addressed by Walker et al. (219, 220). To date, most
periodontal antibiotic treatment regimens appear to
have been empirically prescribed without guidance
from a microbiologic analysis of the subgingival bac-
terial biofilm populations (56). Patients with peri-
odontitis frequently yield multiple species of
periodontal pathogens that may vary in their degree
of resistance to antibiotics (197). To provide a patient
with an appropriate antibiotic therapy, it may be criti-
cal to know the susceptibility profiles of clinically rel-
evant oral pathogens. The oral microbiota also seems
to be an important reservoir for transferable antimi-
crobial resistance (166, 170, 216, 217). Approximately
50% of the Enterococcus faecalis strains isolated from
patients with marginal and apical periodontitis were
 Adjunctive antibiotic/antimicrobial therapy in periodontitis

Fig. 5. Available national data on resistance for nine selected bacterial/antibacterial drug combinations, 2013 (Source:
World Health Organization, with permission).

Fig. 6. Estimates of burden of antibacterial resistance (Source: World Health Organization, with permission).

101
Jepsen & Jepsen
found to be resistant to one or more of the antimicro-
bial agents tested, mostly tetracycline and/or ery-
thromycin (164). A description of resistance in the
oral biofilm as a result of horizontal gene transfer was
reported in vivo, when Streptococcus cristaceus
acquired a transposon that conferred doxycycline
resistance from a strain of Streptococcus oralis. Both
strains were isolated from the subgingival biofilm of
patients undergoing doxycycline therapy as part of
their periodontal treatment (224). Recently, a
plasmidome within E. faecalis, isolated from patients
with marginal periodontitis in Norway, was charac-
terized and the authors concluded that the majority
of E. faecalis strains in marginal periodontitis lesions
are likely to be a reservoir for diverse mobile genetic
elements and associated antimicrobial resistance
determinants (200).
In northern European countries, where antibiotic
usage is generally restricted and infrequent, antibiotic
resistance was reported to be rare among periodontal
pathogens tested from patients with periodontitis
(215). This is in contrast to southern Europe, Colum-
bia and South America, where access to antibiotics is
less stringently controlled and there is more non-
supervised consumption of these drugs, and where a
clearly higher level of periodontal pathogen antibiotic
resistance has been found (9, 228). Veloo et al. (215)
investigated the antibiotic-susceptibility profiles of
five periodontal pathogens (Prevotella intermedia,
Fusobacterium nucleatum, A. actinomycetemcomi-
tans, P. gingivalis and Parvimonas micra) to six com-
monly used antibiotics in periodontics using the
European Committee on Antimicrobial Susceptibility
Testing and Clinical and Laboratory Standards Insti-
tute breakpoints for interpretation of the results. In
comparison with a previous study from the Nether-
lands (227) minor differences in susceptibility profiles
were noted, but the minimum inhibitory concentra-
tions for amoxicillin, clindamycin, azithromycin and
tetracycline were higher for 90% of A. actinomycetem-
comitans strains. In general, geographical differences
were found in the susceptibility profiles of P. gingi-
valis and A. actinomycetemcomitans between Euro-
pean countries. A comparison of susceptibility
profiles between European subjects and Colombian
subjects revealed a much higher level of resistance in
the latter.
Rams et al. (162) studied subgingival plaque speci-
mens from deep periodontal pockets of 564 adults
with severe chronic periodontitis before treatment.
Fifty-two per cent of the patients yielded beta
lacta-
mase-producing species. The authors concluded that
this finding would raise questions about the
102
therapeutic potential of single-drug regimens with
beta-lactam antibiotics in periodontal therapy. The
in vitro effectiveness of metronidazole against nearly
all beta-lactamase-producing subgingival bacterial
species recovered further supports clinical periodon-
titis-treatment strategies involving the combination
of systemic amoxicillin plus metronidazole. Recently,
Rams et al. (163) investigated subgingival biofilm
specimens from inflamed deep periodontal pockets
taken from 400 adults with chronic periodontitis in
the USA. Overall, 74.2% of the patients were reported
to have subgingival periodontal pathogens resistant
to at least one of the antibiotics commonly used in
clinical periodontal practice. The authors concluded
that the wide variability found in periodontal patho-
gen antibiotic-resistance patterns should concern
clinicians empirically selecting antibiotic treatment
regimens for patients with chronic periodontitis.
Future challenges and
considerations
In the coming years there will be major conceptual
changes in health and disease diagnostics followed by
appropriate treatment concepts. Microorganisms
inhabit almost every imaginable environment in our
biosphere and play an integral and unique role in all
ecosystems. We have learned that there are thou-
sands of microbial strains and species associated with
the human body, contributing significantly more
genes than the host genome itself. Their structure,
function, interaction and dynamics are critical to our
existence, and intense research efforts have been
made to understand the impact of the human micro-
biome on health and disease (16, 75, 152, 195). Signifi-
cant progress has been made in the development and
application of high-throughput technologies for ana-
lyzing microbial community structure and functions.
Complex analysis systems are transforming our ability
to investigate the composition of microbial commu-
nities with its full spectrum of host–microbe interac-
tions (241). Many challenges still remain, although
metagenome-specific assembly algorithms (159) and
methods for ‘binning’ genomes from metagenome
data (192, 231) have led to numerous successes, and
the current stage of cataloging and functional analy-
ses will continue to progress with DNA and RNA
sequencing.
In the case of periodontitis, dysbiotic and highly
organized climax biofilm communities resist host
elimination and have optimal conditions for growth

in a nutritionally favorable inflammatory environ-
ment. Mature subgingival biofilms may have
immune-subversive and pro-inflammatory roles,
thereby causing collateral damage to the periodon-
tium. The magnitude of this damage is host depen-
dent, relative to its genetic predisposition, and
environmental factors may also play a role (85). A
combination of the ongoing exploration of the indi-
vidual0 s own genome (68, 145, 147, 177–184, 193) and
computer science (63) should make it possible to
generate specific microbiomes for each individual
using metagenomic codes for identifying health and
disease. These new approaches may change our
current concepts concerning the prevention, diagno-
sis and treatment of periodontal diseases (239, 241).
The concepts of keystone pathogens, along with
polymicrobial synergy and dysbiosis, may serve as the
basis for more promising therapeutic options in peri-
odontal disease. The health benefits of antibiotic use
are undoubtedly a major success story of medicine
but the strategy to target individual periopathogens,
such as P. gingivalis, is complicated because the
organism is difficult to eliminate completely. Besides
having pathogenic effects, even at low abundance,
P. gingivalis is able to survive inside epithelial cells,
well protected from antibiotics and thus is a source
for recrudescence of infection (54, 107). Moreover,
overuse of these drugs has contributed to the emer-
gence of resistant microorganisms, which has become
a major public health problem (6, 14, 26). Studies
have revealed a major reservoir of antibiotic-resis-
tance genes in the human microbiome (62). There-
fore, some existing antibiotic treatments may lead to
lethal treatment failures. If the use of antibiotics is
the treatment of choice, then there is an urgent need
to discover a new generation of antibiotics (123).
As polymicrobial diseases in general are difficult to
treat with antibiotics, Guo et al. (82) suggested the
potential of using targeted antimicrobials to modu-
late the microbiome. In a recent study of the cario-
genic Streptococcus mutans group, removal could be
achieved within an in vitro oral multispecies setting
using a synthetic antimicrobial peptide: C16G2. In
addition, a drastic reconstruction of the multispecies
communities was observed following treatment.
Another recent study, by Wu et al. (232), revealed the
identity of major genetic components involved in
mediating the coaggregation of Candida albicans and
F. nucleatum under planktonic conditions, whereas
mutation of FLO9 in C. albicans and radD in F. nu-
cleatum rendered the mutants defective in inter-
species binding. These observations of cellular
components mediating co-adherence may be impor-
Adjunctive antibiotic/antimicrobial therapy in periodontitis
tant for developing new therapies for disrupting inter-
actions between major oral pathogens.
Host-modulation strategies involving anti-inflam-
matory strategies are another approach to inhibit
destructive inflammation by antimicrobial effects
through limiting inflammatory exudate-derived nutri-
ents or blocking immune-evasion pathways. Studies
on resolvins (64, 88, 188, 234) have shown that stimu-
lating resolution pathways goes a long way to restor-
ing tissue homeostasis and periodontal healing.
Addressing the underlying inflammatory imbalance
by harnessing the body’s own immunoregulatory
mechanisms through the recruitment of regulatory
T-cells may reveal another possibility for the treat-
ment of periodontal disease. A recent study has
shown that this can be accomplished by the sustained
release of small quantities of the chemokine CCL22
from a point source. Administration of these regula-
tory T-cell-recruiting treatments to the gingiva of
mice and dogs reduced the clinical scores of peri-
odontitis as well as hard- and soft-tissue destruction
(67). By enhancing protective innate immunity in
ways that counteract chemokine paralysis, toll-like
receptor-4 antagonism (128) or human antimicrobial
peptides (47) are considered to be very promising
templates for the development of new clinical strate-
gies in immunology and cancer research without
compromising the host.
As an alternate strategy to antibiotic treatment,
manipulation of the microbiome through probiotics
and/or genetic modification of bacteria through syn-
thetic biology represent promising newer antimicro-
bial approaches. Probiotics containing Lactobacillus,
Bifidobacterium and Saccharomyces are available for
treatment of traveler’s diarrhea and antibiotic-
induced diarrhea. Synthetic biology has already
proved successful in applications for influenza vac-
cine production and makes it possible to develop
modified species that can be introduced into the
human body and monitored. Probiotic or engineered
strains can be improved for efficiency, altering path-
ways that may result in increased production of vita-
mins or the delivery of bioactive agents. These
modified species include yeasts, small eukaryotes or
bacteria that produce bioactive compounds at dis-
ease sites whilst also acting as a delivery system. They
could also be used to produce synthetic natural-pro-
duct medicines (222). In addition, synthetic virus bac-
teriophages may be designed to modulate
populations of bacteria that have negative effects on
human health (33). It is almost certain that there will
further developments in microbial replacement ther-
apies and host-modulation strategies. However, as
103
Jepsen & Jepsen
Fig. 7. Magnitude of the periodontal benefits of using systemic antibiotic adjuncts to the treatment of periodontitis vs.
health risks to society and the world’s ecosystems. In periodontics, antibiotics should only be used as a last resort (Cour-
tesy: G. Armitage).
new therapies are introduced to restore a health-
associated homeostasis between the periodontal
microbiota and the host, diagnostic tests will be
required to assess treatment outcomes.
Summary and conclusion
A large number of randomized clinical trials and sys-
tematic reviews have clearly established that adjunc-
tive systemic antibiotics, combined with mechanical
debridement, offer clinical improvements additional
to those obtained with scaling and root planing alone.
These effects are more pronounced in aggressive peri-
odontitis compared with chronic periodontitis and in
initially deep pockets, whereas only limited additional
improvements can be expected for moderately deep
sites. The marginal clinical benefit of 0.3 mm of addi-
tional pocket reduction and 0.2 mm of additional
clinical attachment gain in patients with moderate
disease has to be balanced against possible severe
risks (Fig. 7), such as microbiologically adverse effects
and increase in bacterial resistance. The effects of the
adjunctive local administration of antimicrobials
have also been very well documented in several sys-
tematic reviews. Overall, in persistent or recurrent
localized deep sites, antibiotic application by sus-
tained local-delivery devices may offer a benefit of an
104
additional 0.4 mm in pocket depth reduction and
0.3 mm in clinical attachment level gain.
In conclusion, the slight additional benefits of
adjunctive antimicrobials, which have been shown
for moderate forms of periodontitis, have to be bal-
anced against their side effects, and therefore their
prescription should be limited as much as possible.
Therapists should be careful not to underestimate the
effect of proper mechanical debridement and modifi-
cation of behavioral risk factors. The patient’s overall
risk for periodontitis must be considered, and excep-
tions that may indicate antibiotic treatments include
cases of early-onset disease if the periodontal infec-
tion needs to be rapidly suppressed, localized deep
sites with persistent or recurrent disease and patients
with uncontrolled diabetes. However, these patients
should ideally be treated in the practice setting of a
specialist.
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