antibiotics

Review
Local/Topical Antibiotics for Peri-Implantitis Treatment:
A Systematic Review
Pier Carmine Passarelli 1 , Andrea Netti 1, *, Michele Antonio Lopez 2 , Eleonora Favetti Giaquinto 1 ,
Giuseppe De Rosa 1 , Gianmarco Aureli 1 , Alina Bodnarenko 3 , Piero Papi 4 , Anna Starzyńska 3 ,
Giorgio Pompa 4 and Antonio D’Addona 1

1 Department of Head and Neck and Sensory Organs, Division of Oral Surgery and Implantology, Institute of
Clinical Dentistry, Gemelli Foundation for the University Policlinic, Catholic University of the “Sacred Heart”,
00168 Rome, Italy; piercarmine.passarelli@unicatt.it (P.C.P.); Eleonora.favetti@gmail.com (E.F.G.);
giuseppederosa1410@gmail.com (G.D.R.); gianmarco.aureli@gmail.com (G.A.);
Antonio.daddona@policlinicogemelli.it (A.D.)
2 Unit of Otolaryngology, University Campus Bio-Medico, 00128 Rome, Italy; micheleantonio.lopez@gmail.com
3 Department of Oral Surgery, Medical University of Gdańsk, 7 D˛ebinki Street, 80-211 Gdańsk, Poland;
a.bodnarenko@gumed.edu.pl (A.B.); anna.starzynska@gumed.edu.pl (A.S.)
4 Department of Oral and Maxillofacial Sciences, Policlinico Umberto I, “Sapienza” University of Rome,
00161 Rome, Italy; Piero.papi@uniroma1.it (P.P.); giorgio.pompa@uniroma1.it (G.P.)
* Correspondence: a.netti84@live.it; Tel./Fax: +39-06-3015-4079

Abstract: Most studies indicate that the mechanical removal of the bacterial biofilm from the implant
surface is the central goal of peri-implantitis therapy. However, controversial results in the treat-



ment of peri-implantitis have led to the consideration of additional strategies that include surgical


approaches and chemical adjuvants. Local/topical antibiotics, such as minocycline, azithromycin,
Citation: Passarelli, P.C.; Netti, A.;
tetracycline, amoxicillin, doxycycline, and metronidazole, may improve the efficacy of the definitive
Lopez, M.A.; Giaquinto, E.F.; De Rosa,
treatment of the disease, but the lack of conclusive findings prevents their use in clinical practice.
G.; Aureli, G.; Bodnarenko, A.; Papi,
This systematic review aimed to evaluate the effect of local/topical antibiotics for peri-implantitis
P.; Starzyńska, A.; Pompa, G.; et al.
Local/Topical Antibiotics for
treatment. Randomised controlled studies (RCT) on patients with peri-implantitis and comparing
Peri-Implantitis Treatment: A the efficacy of local/topical antibiotics vs. placebo or mechanical debridement were included. A
Systematic Review. Antibiotics 2021, systematic search strategy was carried out using three registered databases (PubMed, Web of Science,
10, 1298. https://doi.org/10.3390/ and Scopus). RoB2 was used to assess risk of bias. Five RCTs were identified (n = 250 patients
antibiotics10111298 and 333 implants). Contrast results emerged among the included studies, and a high heterogeneity
level was observed. Risk of bias revealed some concerns for three studies out of five, while one
Academic Editor: Nicholas Dixon study was judged at high risk. Only one study analysed the limitations of its findings. Overall, local
antibiotic use can be considered a valid approach in the treatment of peri-implantitis. Therefore,
Received: 20 August 2021
future long-term clinical trials with standardised protocols and antibiotics with similar biological
Accepted: 22 October 2021
activity profiles should be tested to achieve a valid and definitive conclusion.
Published: 25 October 2021

Keywords: chemical adjuvants; peri-implantitis; peri-implant mucositis; local antibiotics; minocycline;

Publisher’s Note: MDPI stays neutral
clinical practice guidelines
with regard to jurisdictional claims in
published maps and institutional affil-
iations.

1. Introduction
Peri-implantitis and peri-implant mucositis are included within the peri-implant
Copyright: © 2021 by the authors.
disease concept [1]. Peri-implantitis prevalence has been observed in 19.83% of subjects
Licensee MDPI, Basel, Switzerland.
and 9.25% of implant sites, while 46.83% of subjects and 29.48% of implants develop
This article is an open access article
peri-implant mucositis [2].
distributed under the terms and Peri-implantitis is a progressive and irreversible disease of implant-surrounding
conditions of the Creative Commons hard and soft tissues, associated with progressive bone loss, bone resorption, decreased
Attribution (CC BY) license (https:// osseointegration, increased pocket formation, and purulence [2,3]. Peri-implant mucositis
creativecommons.org/licenses/by/ refers to a reversible inflammatory process in the soft tissues and connective tissues adjacent
4.0/). to the implant [4].

Antibiotics 2021, 10, 1298. https://doi.org/10.3390/antibiotics10111298 https://www.mdpi.com/journal/antibiotics

Antibiotics 2021, 10, 1298 2 of 15

Although smoking, poor plaque control, absence of keratinised mucosa, excess cement,
diabetes, and other systemic conditions have been identified as risk factors related to peri-
implantitis [5], dental plaque or biofilm are considered the principal etiological factors
in periodontal disease [6]. Furthermore, analysing the aetiology, pathophysiology, risk
assessment, and therapy of peri-implantitis, many studies have observed a strong level of
similarity between the two pathologies and suggested similar therapeutic approaches [7,8].
To date, the etiological studies of peri-implant diseases are limited, especially if com-
pared to periodontal diseases [4,8]. Many etiological factors [5,9,10] and causative organ-
isms (e.g., Prevotella intermedia, Tannerella forsytbia, Eikenella corrodens, Filifactor alocis, and
Aggregatibacter actinomycetemcomitans) [1,4,8,9,11] of periodontal disease may also be identi-
fied in the onset of peri-implantitis [12]. According to two recent studies, peri-implantitis is
the result of the action of several different species of bacteria, including Tannerella forsytbia
and Porpbyromonas gingivalis [2,5]. A systematic and meta-analysis review analysing the
peri-implantitis lesions and associated bacteria and comparing the results with a control
group of individuals with healthy implants demonstrated a higher prevalence of Prevotella
intermedia, Tannerella forsytbia, and Aggregatibacter actinomycetemcomitans [11]. The histologi-
cal data obtained from human biopsy specimens identified polymorphonuclear leukocytes,
plasma cells, macrophages, and lymphocytes in the connective tissue around the implant
with peri-implant inflammation [13].
Consequently, peri-implantitis highly depends on the imbalance of host–microbiome
periodontal homeostasis as it occurs in periodontal disease, in which susceptible hosts
facilitate dysbiosis and the development of plaque biofilm-associated microbial commu-
nities that consist of pathobionts and keystone pathogens [9]. Concomitantly with the
host’s response, their synergistic virulence causes destructive inflammation. Through
the facilitation of dysbiosis and bone loss through inflammation, systemic complications
are observed together with tooth and implant loss [5,9,10]. Conversely, variations in the
number of pathogen species populations within the plaque biofilm and oral microbiome
trigger the host’s immunological reaction, facilitating periodontitis and peri-implantitis
less often [14].
Most of the published peri-implantitis therapeutic strategies are founded on peri-
odontitis treatment strategies: the colonisation of pathogens on the implant and dental
surfaces has a common pathophysiology involving the microbial film, as in the periodontal
disease [14]. Therefore, treatment in peri-implantitis aims to reduce the pathogen load
by shifting the bacteria’s biofilm composition. The volume of plaque biofilm is reduced
through mechanical instrumentation with air powder abrasive, metal curettes, non-metal
curettes (carbon, plastic, resin-reinforced, and resin-un-reinforced), an ultrasonic scaler
with a metal or plastic tip, and implantoplasty, which, by reducing the roughness of the
implant surfaces, reduces plaque adherence [15]. In addition to having quantitative efficacy
in the overall volume of the biofilm, this reduction represents, from an etiological point of
view, a qualitative variation in the biofilm composition [16,17].
The therapeutic gold standard for peri-implantitis is dynamic, comprising mechanical
instrumentation, regular periodontal supportive maintenance therapy, and home care. For
the control of peri-implantitis, mechanical debridement alone has failed to thoroughly
remove bacterial biofilms due to their location and accessibility; therefore, a single therapy
can be unreliable in disease control [8,15]. Furthermore, mechanical debridement alone is
insufficient for immunocompromised patients, especially those with altered immune capac-
ity. The Cumulative Interceptive Supportive Therapy (CIST) protocol appears to be a viable
alternative in the approach to peri-implant disease, depending on the severity grade [3],
given that the reduction of peri-implant inflammation and ideally peri-implant tissue
regeneration is the central therapeutic goal. CIST protocol is based on regular recalls of the
implanted patient and repeated assessments of plaque, bleeding, suppuration, pockets, and
radiological evidence of bone loss. Local/topical and systemic antibiotic administration
represents a fundamental step to avoid or delay regenerative or resective surgery [18].
In 2004, it was modified and called the AKUT-concept, divided into four stages: stage A
 pockets, and radiological evidence of bone loss. Local/topical and systemic antibiotic ad-
ministration represents a fundamental step to avoid or delay regenerative or resective
Antibiotics 2021, 10, 1298 surgery [18]. In 2004, it was modified and called the AKUT-concept, divided into3four of 15
stages: stage A (pocket depth (PD) < 3 mm, plaque, and/or bleeding on probing (BOP))
involves mechanical cleaning, polishing, and oral hygiene instructions; stage B (PD 4–5
mm and no bone loss) involves adding antiseptic regimens (e.g., chlorhexidine) to the
(pocket depth (PD) < 3 mm, plaque, and/or bleeding on probing (BOP)) involves mechani-
stage A treatment; stage C (PD > 5 mm, radiological bone loss (RBL) < 2 mm) involves
cal cleaning, polishing, and oral hygiene instructions; stage B (PD 4–5 mm and no bone loss)
adding microbiological testing and local/topical or systemic antibiotic therapy to the stage
involves adding antiseptic regimens (e.g., chlorhexidine) to the stage A treatment; stage C
B treatment; and, finally, stage D (PD > 5 mm and RBL > 2mm) involves regenerative or
(PD > 5 mm, radiological bone loss (RBL) < 2 mm) involves adding microbiological testing
resective surgical treatment [19].
and local/topical or systemic antibiotic therapy to the stage B treatment; and, finally, stage
Therefore, adjunct methods involving chemical methods, such as hydrogen peroxide,
D (PD > 5 mm and RBL > 2 mm) involves regenerative or resective surgical treatment [19].
tetracycline, saline-soaked
Therefore, cottoninvolving
adjunct methods pellets, citric acid, and
chemical chlorhexidine,
methods, have been
such as hydrogen proven
peroxide,
fundamental in the treatment
tetracycline, saline-soaked of peri-implantitis
cotton [15],and
pellets, citric acid, together with other
chlorhexidine, adjuvant
have meth-
been proven
ods including phototherapy and laser therapy, such as a continuous carbon dioxide
fundamental in the treatment of peri-implantitis [15], together with other adjuvant methods laser
[20,21].
including phototherapy and laser therapy, such as a continuous carbon dioxide laser [20,21].
The
The need
need for
for surgery
surgery decreases
decreases in
in peri-implantitis
peri-implantitis withwith anti-infective
anti-infective chemotherapy
chemotherapy
and
and mechanical debridement. A meta-analysis concluded that the
mechanical debridement. A meta-analysis concluded that the effective management
effective management
of
of peri-implantitis
peri-implantitis improves
improves the
the retention
retention of
of dentition
dentition throughout
throughout thethe lifetime
lifetime [22].
[22]. Man-
Man-
agement of plaque biofilm in peri-implant mucositis makes it reversible.
agement of plaque biofilm in peri-implant mucositis makes it reversible. However, this However, this
approach could be revealed to be insufficient in more severe cases, and other
approach could be revealed to be insufficient in more severe cases, and other nonsurgical nonsurgical
procedures
procedures or surgery become
or surgery become treatments
treatments ofof choice
choice [16]
[16] (Schemes
(Schemes 11 and
and 2).
2).

Scheme 1. Non-surgical treatment methods of peri-Implantitis and peri-Implant mucositis. Legend: AMOX:
AMOX: amoxicillin,
amoxicillin,
CA: citric acid, CHX: chlorhexidine, CPFX: ciprofloxacin, DOX: doxycycline, HP: hydrogen peroxide, MIN: minocycline,
minocycline,
MTZ: metronidazole, PA:
PA: phosphoric
phosphoric acid,
acid, TET:
TET:tetracycline.
tetracycline.

Lan et al. introduced personalised alginate rings/poly-caprolactone loaded with

metronidazole to ensure the constant release of the drug to maintain an appropriate
concentration effective for the elimination of colonising bacterial biofilms. The study
reported that the above method potentially minimises the development of a bacterial
biofilm and, therefore, the therapy is applicable for the prevention of peri-implantitis [23].
In the treatment of peri-implantitis, it is becoming a standard practice to administer
antibiotics and/or antiseptics locally to individuals with the disease, especially in moderate-
to severe-progression PD [24]. To achieve a continuous release of antibiotics and sustain
the required levels of antibiotics at the infected sites, controlled-release devices, includ-
ing microcapsules, polymeric fibres, chips, and gels, have been proposed [25,26]. These
 Antibiotics 2021, 10, 1298 4 of 15

kinds of devices allow the use of several antibiotics, such as metronidazole, minocycline,
doxycycline, and tetracycline, and have been shown to ensure a steady, elevated antibiotic
agent concentration in the periodontal pocket (gingival crevicular fluid) for an extended
Antibiotics 2021, 10, x FOR PEER REVIEW before removal or antibiotic agent degradation [27]. For example, after 7–14 days,
period 4 of 1
tetracycline fibre devices should be removed, whereas doxycycline polymer devices and
minocycline microspheres require no removal since they are biodegradable [27,28].

Scheme2.2.Surgical
Scheme Surgical treatment
treatment methods
methods of peri-implantitis.
of peri-implantitis.

Different forms of tetracycline for local delivery are available and have been tested
Lan et al. introduced personalised alginate rings/poly-caprolactone loaded with met
on periodontitis, such as nano-particles [29], fibres [30–32], and ointment [29]. The use of
ronidazole to ensure
tetracycline fibres the constant
as an adjunct release
to scaling of the
and root drug to
planning maintain
resulted an appropriate
in periodontal health concen
tration effective
improvement and,for the elimination
therefore, is a reliableoftreatment
colonising
[33].bacterial biofilms.ofThe
The combination study
scaling andreported
thatplanning
root the above method
with potentially
tetracycline fibres isminimises the development
a more effective of a bacterial
therapeutic approach biofilm and
than scaling
therefore,
and the therapy
root planning is applicable
alone when for the prevention
clinical parameters of peri-implantitis
such as clinical attachment level[23].
(CAL)
and PD In are
theconsidered
treatment[31].
of peri-implantitis, it is becoming a standard practice to administe
In the clinical context,
antibiotics and/or antiseptics local/topical
locally antibiotic adjuncts
to individuals in the
with themechanical treatment of
disease, especially in moder
peri-implantitis have always been applied [15] without being supported by firm recom-
ate- to severe-progression PD [24]. To achieve a continuous release of antibiotics and sus
mendations and guidelines. Therefore, this review aimed to evaluate the effect of local
tain the required levels of antibiotics at the infected sites, controlled-release devices, in
antibiotics on peri-implantitis in reducing peri-implantitis signs.
cluding microcapsules, polymeric fibres, chips, and gels, have been proposed [25,26]
These
2. kinds of devices allow the use of several antibiotics, such as metronidazole, mino
Methods
cycline, doxycycline,
The materials and tetracycline,
and methods were basedand have
on the been (Preferred
PRISMA shown toReporting
ensure a Items
steady,
forelevated
antibiotic Reviews
Systematic agent concentration in theguidelines
and Meta-Analysis) periodontal [34].pocket (gingival
A search strategy crevicular
was carriedfluid)
out for an
on PubMed,
extended Embase,
period and Web
before of Science
removal from January
or antibiotic agent todegradation
September 2021, without
[27]. time
For example, afte
and language restrictions.
7–14 days, tetracycline fibre devices should be removed, whereas doxycycline polyme
The components of the PICOS question were as follows: (Patients) patients with
devices and minocycline microspheres require no removal since they are biodegradabl
periimplantitis; (Intervention) local antibiotics, topical antibiotics, or antibacterial agents;
[27,28].
(Comparison) mechanical debridement alone or placebo procedure; (Outcome) clinical and
Different outcome;
microbiological forms of (Study
tetracycline
Design)for local delivery are available and have been tested
RCT.
on periodontitis,
The keywords used in this search were: [29],
such as nano-particles fibres [30–32],
(peri-implantitis) ANDand ointmentOR
(antibiotics [29]. The use o
local
tetracycline
antibiotics ORfibres as an
topical adjunct toGrey
antibiotics). scaling and root
literature wasplanning
searchedresulted
using theinOpen
periodontal
Grey health
improvement
database and, therefore,
(www.opengrey.eu, is a reliable
accessed treatment
on 13 September [33].
2021) The
with thecombination of scaling and
same search strategy
used for the other
root planning with tetracycline
databases. Additionally,
fibres isseveral
a morejournals were
effective hand-searched
therapeutic manually.
approach than scaling
and root planning alone when clinical parameters such as clinical attachment level (CAL
and PD are considered [31].
In the clinical context, local/topical antibiotic adjuncts in the mechanical treatment o
peri-implantitis have always been applied [15] without being supported by firm recom
Antibiotics 2021, 10, 1298 5 of 15

The first (title/abstract screening) and second (full-text assessment) steps of the search
process were performed by two independent reviewers (P.C.P. and A.N.), and any disagree-
ment was discussed until a decision was made by consensus.

2.1. Study Selection

The complete list of articles obtained through the search was scrutinised to remove du-
plicates and select the potentially relevant articles based on the title to answer the research
question. Subsequently, abstract screening was performed as well. The eligible studies were
independently selected by two reviewers (P.C.P. and A.N.). From the remaining potentially
relevant articles, those that met the inclusion and exclusion criteria were selected through
full-text reading. The reasons for exclusion were recorded.
The subsequent article selection was independently made by two authors (P.C.P. and
A.N.). When there was disagreement, a third experienced reviewer (M.A.L.) was consulted
to achieve a consensus.

2.2. Inclusion/Exclusion Criteria

The inclusion criteria were as follows: (i) studies conducted on patients with peri-
implantitis defined as bleeding and/or suppuration on probing, peri-implant PD ≥ 4
or 5 mm; (ii) studies comparing the efficacy of local/topical antibiotics vs. placebo or
mechanical debridement; (iii) randomised controlled studies (single- or double-blinding).

2.3. Data Extraction

Two reviewers (P.C.P. and A.N.) independently extracted the data from the full texts
of the studies that fulfilled the inclusion criteria. Disagreements were resolved through
team discussions. The primary outcomes analysed in this review were BOP, probing pocket
(PPD), PD. In addition, microbiological analysis, plaque index (PI), and gingival index (GI)
were also reviewed as secondary outcomes.
Data extraction was organised in tables that included the following information:
• Study characteristics: name of the first author, year, country, disease (peri-implantitis
or peri-implant mucositis), study design, blinding, type of intervention (surgical vs.
non-surgical), follow-up;
• Participant characteristics: implant numbers/subjects, inclusion criteria;
• Treatment and control groups characteristics;
• Primary and secondary outcomes;
• Results

2.4. Risk of Bias

The quality of each RCT was independently assessed according to the Cochrane
Risk of Bias Tool (RoB2) by two reviewers. Five domains of bias (i.e., randomisation
process, deviations from intended interventions, missing outcome data, measurement of
the outcome, and selection of the reported results) were evaluated and reported. The
Cochrane Handbook for Systematic Reviews of Interventions [35] was used. A judgement
of “high” indicated a high risk of bias, “low” indicated a low risk of bias, and “some
concerns” indicated the presence of bias due to lack of information or uncertainty about the
potential for bias. The studies were categorised as having a low or high risk of bias or some
concerns. Any discrepancy in the assessment of RoB2 was discussed to attain a consensus.

3. Results
3.1. Study Selection
A flow diagram of the search strategy results is presented in Scheme 3. After the
removal of 12 duplicates, a total of 88 articles were obtained. From these 88 articles,
74 studies were excluded after reading their titles and abstracts. Finally, 14 studies were
selected for full-text reading. Of these 14 studies, two studies were not RCTs, and seven
Antibiotics 2021, 10, 1298 6 of 15

studies used systemic antibiotics. Therefore, a total of five studies were included in the
review [28,36–39].

Scheme 3. PRISMA 2020 flow diagram—Source: http://www.prisma-statement.org, accessed on

13 September 2021. * Total number of records across all databases was reported.

3.2. Risk of Bias

The overall risk of bias assessment of the included studies is presented in Scheme 4.
We judged one study at low risk of bias [38]. Three studies were considered with some risk
of bias because people delivering the intervention were aware of participants’ assigned
intervention during the trial, and no appropriate analyses were carried out to estimate
the effect of assignment to intervention [36,37,39]. Finally, one study [28] was judged at
high risk of bias because, although the participants were randomised, more implants were
allocated to the test treatment.
 The overall risk of bias assessment of the included studies is presented in Scheme 4.
We judged one study at low risk of bias [38]. Three studies were considered with some
risk of bias because people delivering the intervention were aware of participants’ as-
signed intervention during the trial, and no appropriate analyses were carried out to esti-
Antibiotics 2021, 10, 1298 mate the effect of assignment to intervention [36,37,39]. Finally, one study [28] was judged
7 of 15
at high risk of bias because, although the participants were randomised, more implants
were allocated to the test treatment.

Reference Experimental Comparator Outcome Weight D1 D2 D3 D4 D5 Overall

BUCHTER (2004) 8.5% DOXYCYCLINE HYCLATE + SUBGINGIVAL LOCAL DEBRIDEMENT SUBGINGIVAL LOCAL DEBRIDEMENT BOP, CAL, PD
1 + ! + + ! ! + Low risk

RENVERT (2006) MYNOCYCLINE CHLORHEXIDINE BOP/SOP, 1 +

PI, PD, BACTERIA ! + + + ! ! Some concerns

RENVERT (2008) MINOCYCLINE MICROSPHERES CHLORHEXIDINE BOP/SOP, 1 +

LPS, PD, BACTERIA ! + - + - - High risk

CHA (2019) LOCAL MINOCYCLINE + SURGICAL TREATMENT PLACEBO OINTMENT + SURGICAL TREATMENT BOP/SOP, 1
PI, PPD + + + + + +

PARK (2021) MINOCYCLINE (WITH AND WITHOUT METRONIDAZOLE) + NON-SURGICAL TREATMENT SURGICAL TREATMENT BOP, PI, PPD, + !
1 Pus Suppuration, + + + ! D1 Randomisation process

D2 Deviations from the intended interventions

D3 Missing outcome data

D4 Measurement of the outcome

D5 Selection of the reported result

Scheme 4.
Scheme Risk of
4. Risk of bias.
bias.
3.3. Study Characteristics
3.3. Study Characteristics
We
Weprovide
provideaadescriptive
descriptivesummary
summaryofofthe theinformation
informationon onparticipants,
participants,treatments,
treatments,and
comparisons in Table 1. We included a total of five RCTs: two
and comparisons in Table 1. We included a total of five RCTs: two carried out carried out in Korea [37,38],
in Korea
two in Sweden [28,36], and one in Germany
[37,38], two in Sweden [28,36], and one in Germany [39]. [39].
One
One study
study included
included moremore thanthan100100participants
participants[37],
[37], while
while thethe remaining
remaining fourfour
in- in-
cluded less than 50 patients [28,36,38,39]. The median follow-up was
cluded less than 50 patients [28,36,38,39]. The median follow-up was six months (IQR: 4– six months (IQR:
4–12 months). Four studies used minocycline local/topical antibiotics
12 months). Four studies used minocycline local/topical antibiotics [28,36–38], while only [28,36–38], while
only one study
one study used used doxycycline
doxycycline [39].
[39]. All All studies
studies reported reported BOP, suppuration
BOP, suppuration on probing,
on probing, PPD,
PPD,
and PDandasPD theasprimary
the primary outcomes.
outcomes. Clinical
Clinical and microbiological
and microbiological measurements
measurements were per-were
performed
formed in four in four studies
studies [28,36–38].
[28,36–38]. Participants
Participants were recruited
were recruited from departments
from departments of perio- of
periodontology
dontology [37,38] [37,38] and dental
and dental schoolschool
[28,36].[28,36].
One studyOnedid
study
notdid not specify
specify a settinga[39].
setting [39].
The
The five studiesincluded
five studies includeda total
a total of 250
of 250 patients
patients andimplants.
and 333 333 implants. Four com-
Four studies studies
compared
pared the the efficacy
efficacy of local/topical
of local/topical antibiotics
antibiotics with mechanical
with mechanical debridement
debridement or scaling
or scaling and
and
rootroot planning
planning without
without surgical
surgical treatment
treatment [28,36,37,39],
[28,36,37,39], while
while oneone
studystudy
used used a surgical
a surgical
approach[38].
approach [38].Two
Twostudies
studiescompared
comparedminocycline
minocyclinemicrospheres
microspheres with
with 0.1
0.1 mL
mLchlorhexidine
chlorhexi-
dine gel 1% [28,36], one study compared minocycline ointment
gel 1% [28,36], one study compared minocycline ointment with placebo ointment with placebo ointment[38],
[38], while the remaining two studies compared, respectively, doxycycline
while the remaining two studies compared, respectively, doxycycline and minocycline, and minocy-this
cline, this last used alone or with metronidazole, without adding additional
last used alone or with metronidazole, without adding additional treatments in the control treatments in
the control
group [37,39]. group [37,39].

3.4.Doxycycline
3.4. Doxycycline Efficacy
Onlyone
Only one study
study investigated
investigated the theeffectiveness
effectivenessofofthe
thelocal application
local application of doxycycline
of doxycycline
related to usual treatment: Butcher et al. compared the effect of 8.5%
related to usual treatment: Butcher et al. compared the effect of 8.5% doxycycline doxycycline and noand
additional treatment in a sample of 28 patients and 48 implants
no additional treatment in a sample of 28 patients and 48 implants (treatment (treatment group: 14 group:
pa-
tients; control group: 14 patients). After executing removal prosthetic
14 patients; control group: 14 patients). After executing removal prosthetic restoration,restoration, abut-
ment sterilisation,
abutment irrigation
sterilisation, with 0.2%
irrigation with of chlorhexidine,
0.2% and implant
of chlorhexidine, scaling, scaling,
and implant local deb-
local
ridement together with 8.5% doxycycline hyclate (treatment group)
debridement together with 8.5% doxycycline hyclate (treatment group) was compared was compared with
locallocal
with subgingival debridement.
subgingival debridement.After After
four months, statistically
four months, significant
statistically differences
significant be-
differences
tween groups emerged for the attachment level changes, BOP and
between groups emerged for the attachment level changes, BOP and PD, showing a more PD, showing a more
substantialimprovement
substantial improvement in in the
thegroup
grouptreated
treatedwith
withdoxycycline
doxycycline than in in
than thethe
control group
control group
(p < 0.05) [39].
(p < 0.05) [39].

3.5. Minocycline Efficacy

Four studies analysed the effectiveness of minocycline in reducing peri-implantitis signs.
Two studies (n = 62 patients, 125 implants, treatment group: 33 patients/73 implants; control
group: 29 patients/52 implants) compared the submucosal administration of minocycline
microspheres and 0.1 mL chlorhexidine gel 1%. Statistically significant improvements in
all clinical and microbiological outcomes within both groups (p < 0.001) after 12 months
emerged. Nevertheless, both studies failed to observe statistically significant differences
between groups at the end of the planned follow-up period [28,36]. Furthermore, no
significant differences emerged between the two groups in the mean total number of
bacteria in both studies.
Antibiotics 2021, 10, 1298 8 of 15

Table 1. Included studies.

Number Pz and
Author Country Setting Clinical Characteristics Surgical/Non-Surgical Treatment TG CG FU (Months) Main Findings
Imp

TG: CAL: 5.32 ± 0.33, 4.17 ± 0.30 (p < 0.001); PD: 5.64 ± 0.32,
Removal prosthetic
28 pz Chronic peri-implantitis PD > 5 mm; 4.49 ± 0.29 (p < 0.001); BOP: 0.54 ± 0.07, 0.27 ± 0.06 (p = 0.001)
restoration + abutment
Buchter et al. 48 imp bone defects exceeding 50% of the CG: CAL: 5.51 ± 0.27, 5.18 ± 0.33 (p < 0.001); PD: 5.68 ± 0.28,
Germany NR Non-surgical sterilised + 0.2% CHX 8.5% DOX No additional treatment 4
(2004) [39] TG: 14 pz length of the implant on 5.4 ± 0.34 (p < 0.001); BOP: 0.63 ± 0.06, 0.50 ± 0.07 (p = 0.001)
irrigation + implant
CG: 14 pz radiographs Difference between groups: CAL: p = 0.024, PD: p = 0.046,
scaling
BOP: p = 0.01

TG: PI (%): 50 ± 25, 27 ± 24; BOP/BOS (%): 88 ± 12, 71 ± 22

PD (mm) 3.9 ± 0.7, 3.6 ± 0.6
CG: PI (%): 60 ± 49, 27 ± 45; BOP/BOS (%): 89.2 ± 17.2, 63.5 ± 19.1;
PD (mm) 3.87 ± 1.16, 3.72 ± 1.02.
30 pz BOP or pus + PD ≥ 4 mm + Comparison between groups at six months: PI (p > 0.05), BOP/SOP
OHI + supra and sub Submucosal Submucosal
Renvert et al. 30 imp Kristianstad presence of putative pathogenic (p ≤ 0.01 all four sites/implants, p > 0.05 deepest site/implant), PD
Sweden Non-surgical mucosa scaling + rubber administration of MIN administration of 0.1 mL 12
(2006) [36] TG: 16 pz University bacteria + loss of bone ≤ 3 threads (p ≤ 0.001). Comparisons between groups at 12 months: PI (p > 0.05),
cup polish microspheres CHX gel 1%
CG: 14 pz on radiographs BOP/SOP (p > 0.05 all four sites/implants, p ≤ 0.05 deepest
site/implant), PD (p ≤ 0.001 all four site/implants, p ≤ 0.01 deepest
site/implant).
No statistical significance emerged between the two antimicrobials
for any bacteria at any time point.

Treatment group: LPS (%): 50 ± 50, 22 ± 42; BOP/BOS (%):

86.5 ± 20.1, 48.1 ± 20.7; PD (mm) 3.85 ± 1.04, 3.55 ± 0.98; Control
group: LPS (%): 60 ± 49, 27 ± 45; BOP/BOS (%): 89.2 ± 17.2,
32 pz PD ≥ 4 mm + BOP and/pr pus +
63.5 ± 19.1; PD (mm) 3.87 ± 1.16, 3.72 ± 1.02.
Renvert et al. 95 imp Kristianstad radiographic bone loss ≤ 3 threads
Sweden Non-surgical NR MIN microspheres 0.1 mL 1% CHX gel 12 Comparison between groups at six months: LPS (p = 0.003);
(2008) [28] TG: 17 pz/57 imp University + occurrence of anaerobic bacteria +
PD (p > 0.05), BOP/SOP (p < 0.001). Comparisons between groups at
CG: 15 pz/38 imp presence of one or more bacteria
12 months: LPS (p > 0.05); PD (p > 0.05), BOP/SOP (p < 0.001).
No statistically significant differences in the mean total numbers of
bacteria between and within groups after 12 months.

PPD: TG: 3.58 ± 2.32; CG: 2.45 ± 2.13; p = 0.094.

46 pz BOP: TG: 0.58 ± 0.50; CG: 0.32 ± 0.57; p = 0.102.
Local MIN (10 mg of
Cha et al. 46 imp Department of Peri-implant bone loss > 2 mm; PI: TG: 0.12 ± 0.90; CG: 0.23 ± 1.07; p = 0.728.
South Korea Surgical treatment Surgical treatment minocycline in 0.5 g of PBO OIN 6
(2019) [38] TG: 24 pz Periodontology PPD > 5 mm; concomitant BOP GI: TG: 0.96 ± 0.86; CG: 0.41 ± 0.85; p = 0.035.
OIN)
CG: 22 pz Number of red-complex bacteria decreased in both groups, without
statistically significant differences between groups.

MM: PPD −2.71 ± 1.90; BOP: −0.66 ± 0.53; Pus Suppuration:

−0.18 ± 0.39; PI: −0.71 ± 0.80.
MC: PPD −2.51 ± 1.82; BOP: −0.59 ± 0.50; Pus Suppuration:
114 pz −0.31 ± 0.46; PI: −0.54 ± 0.76.
Implant inserted at least 1 year
114 imp MD + MTZ-MIN OIN NTS: PPD −2.03 ± 1.38; BOP: −0.38 ± 0.49; Pus Suppuration:
Park et al. Department of previously; PPD ≥ 5 mm; presence OH + non-surgical
Korea MM: 38 pz Non-surgical (MM); MD + MIN OIN MD 4 −0.32 ± 0.53; PI: −0.35 ± 0.89. Statistically significant differences
(2021) [37] Periodontology of BOP, SoP, and peri-implant bone debridement
MC: 39 pz (MC) were found for PPD and BOP between MM and NTS (p = 0.0023,
loss in a periapical radiograph
NST: 37 pz p = 0.0381). After 12 weeks, significant decreases in the counts of P.
gingivalis, T. forsythia, T. denticola, P. intermedia, C. rectus, and F.
nucleatum in MM and MC group. In the NST group, decrease only
for P. gingivalis

Legend: BOP: bleeding on probing; CAL: clinical attachment level; CG: control group; CHX: chlorhexidine; DOX: doxycycline; FU: follow-up; imp: implants; MC: mechanical debridement + minocycline
ointment; MD: mechanical debridement; MIN: minocycline; MM: mechanical debridement + minocycline–metronidazole ointment; MTZ: metronidazole; OH: oral hygiene; OHI: oral hygiene instructions; OIN:
ointment; PBO: placebo; PD: pocket depth; PI: plaque index; PPD: probing pocket depth; SOP: suppuration on probing; TG: treatment group; pz: patients; RCT: randomised clinical trial.
Antibiotics 2021, 10, 1298 9 of 15

In 2019, Cha et al. investigated the effectiveness of 10 mg of local minocycline in

0.5 g of ointment in a sample of 46 patients/46 implants, comparing results with those
observed in a placebo group, treated with a placebo ointment, and using the same modality
of administration already used in the treatment group. In both groups, surgical treatment
was performed. After 6 months, at the deepest site, a statistically significant improvement
emerged only for the gingival index (treatment: 0.96 ± 0.86, control: 0.41 ± 0.85, p = 0.035),
while the mean at four sites showed a statistically significant difference between groups for
PPD (treatment: 2.68 ± 1.73; control: 1.55 ± 1.86, p = 0.039) and GI (treatment: 0.83 ± 0.60;
control: 0.40 ± 0.68, p = 0.026). The number of red-complex bacteria decreased in both
groups [38].
Recently, Park et al., in a randomised double-blind three-arm clinical trial, compared
the effectiveness of mechanical debridement (identified as group NST) alone, mechanical
debridement combined with minocycline ointment (identified as group MC), or combined
with minocycline–metrodinazole ointment (identified as group MM). After 4 months,
statistically significant differences emerged between the MM group and the NTS group for
PPD (MM: −2.71 ± 1.90; NTS: −2.03 ± 1.38, p = 0.0023) and BOP (MM: −0.66 ± 0.53; NTS:
−0.38 ± 0.49, p = 0.0381). Bacteria counts of P. gingivalis, T. forsythia, T. denticola, P. intermedia,
C. rectus, and F. nucleatum showed a significant decrease in the MM and MC groups. In the
NTS group, a significant decrease was observed only for P. gingivalis [37].

4. Discussion
The pathophysiology underlying the development of peri-implantitis involves pathogenic
microorganisms. Therefore, the proposed treatment modality should minimise the micro-
bial load, decontaminate the surface of the implant, and eliminate peri-implant mucosal
inflammation. This approach would be critical in preserving the bone structure supporting
the implant and initiating the regeneration of the bone lost during the disease process.
Although mechanical debridement and oral health instructions have been demon-
strated to effectively minimise inflammatory signs and symptoms, current findings can
be considered inconclusive. On the one hand, many studies have employed antiseptics,
systemic or local antimicrobial therapies, and regenerative therapies as adjunctive to me-
chanical decontamination; on the other hand, in non-surgical peri-implantitis treatment, the
use of mechanical debridement alone could be ineffective [8,40]. Therefore, non-surgical
approaches should be limited to peri-implant mucositis management as, in cases of bone
loss characteristic of peri-implantitis, the therapy fails to resolve lesions secondary to the
inflammatory process.
Therefore, surgery is recommended to allow direct decontamination of the implant
surface and complete granulation tissue removal [40]. However, non-univocal findings
have emerged: success rates of surgical treatments vary among studies from 79%, with
a decrease to 63% after 5 years [41], to 23% [42]. Chemical adjuvants and mechanical
debridement followed by systemic antibiotics are adjunctive to the surgical approaches
to enhance therapeutic effects. In this case, the use of different chemical adjunctive peri-
implantitis treatments failed to establish a single recommended protocol [8,40,43].
Therefore, determining new non-surgical and surgical approaches using local/topical
antibiotics may represent a fundamental approach to control peri-implantitis.
The use of local/topical antibiotics as an adjunctive therapy of mechanical debride-
ment has reported favourable but mild evidence. Therefore, we had hypothesised that
local/topical antibiotics could significantly improve clinical peri-implant disease compared
to mechanical debridement or scaling root planning and could enhance the efficacy of the
surgical approach. Antimicrobial agents applied locally during periodontal surgical treat-
ment may improve the outcomes and minimise the manifestations of peri-implantitis [44].
To focus better on the topic of this systematic review, only RCT studies, without regard to
surgical or non-surgical approach, and which compared local antibiotic application with
mechanical debridement, scaling and root planning, or placebo ointment, were included to
Antibiotics 2021, 10, 1298 10 of 15

reduce the overestimation of the actual local/topical antibiotics effectiveness. The findings
of this systematic review failed to demonstrate the superiority of local/topical antibiotics.
Minocycline reduces inflammatory cytokines, producing significant decreases in
PD and BOP, although repeated applications are needed to maintain the therapeutic re-
sults [28,36–38], increasing the risk for bacterial resistance [45]. When used in combination
with metronidazole, minocycline showed efficient antimicrobial action [37]. Combining the
evidence of different included studies about the efficacy of minocycline, we hypothesised
that these results should not be considered the direct effect of minocycline but the effect
of metronidazole, which had already shown a positive antimicrobial effect against a wide
range of microorganisms [46].
Minocycline added as an ointment in the surgical approach did not show significant
improvements compared to placebo ointment [38]: although a strong and significant
reduction was noted within the treatment group, the lack of a statistically significant
difference between treatment and placebo ointment applications should be explained as
the result of an ineffective action of antibiotic treatment.
The topical application of tetracycline has been reported to produce remarkably
positive effects on clinical parameters such as CAL, sulcular bleeding index (SBI), and
PD [47]. Furthermore, using local/topical antibiotics at the surgical site could decrease the
inflammation following the placement of an implant [48].
Mombelli et al. [30] reported improvements in the clinical and microbiological param-
eters in the therapeutic management of peri-implantitis using tetracycline applied topically.
Erythromycin eye ointment and minocycline ointment were administered at the surgical
implant site topically. Both ointments produced comparable results regarding the healing
process, particularly in the early stage [48].
Only one study analysed the effect of doxycycline in reducing peri-implantitis symp-
toms [39]: the findings of this included study appeared encouraging. Doxyclycline is a
second-generation semisynthetic derivative of tetracycline, with efficacious antimicrobial
action [46] in periodontitis therapy [49]. Similarly to minocycline, doxycycline effectively
reduces the depth of pockets and has strong antimicrobial activity against Prevotella inter-
media/nigrescens, Fusobacterium sp., Bacteroides forsythus, and Campylobacter rectus [30].
An innovative gel composed of doxycycline and metronidazole compared to CBB and
planktonic species showed promising results in an in vitro study. For 13 days, the positive
effect continued, and the authors reported that the application of the new gel could be
discussed in cases of peri-implantitis [50]. Furthermore, Madi et al. (2018) demonstrated
that nano-doxycycline gel combined with scaling and root planning produced significant
anti-inflammatory effects [51].
Then, despite marked improvements in all peri-implantitis symptoms (e.g., BOP, PPD,
GI, and PI) in the group treated with L/T antibiotics, the evidence failed to reveal any
remarkable differences between the control and test groups for all microbiological and
clinical parameters.
Comparing the findings of this review with those observed in observational studies,
many contrasting results emerged too. Schenk et al. and Hallstrom et al., administering, re-
spectively, 43% tetracycline fibres as adjunctive therapy to mechanical debridement for ten
days and mechanical debridement (rubber polishing + titanium curettes) + oral health in-
structions + systemic azithromycin (4 days), failed to demonstrate any significant difference
between the treatment and control group without local antibiotic treatment [52,53]. Con-
trarily, Schwartz et al. reported a considerable improvement in clinical and radiographic
parameters when combining non-surgical peri-implantitis treatment with chlorhexidine
irrigation and minocycline applied locally [54]. Promising results were also confirmed by
Heo et al., who demonstrated that the use of a simple non-surgical approach combining
intrasulcular chlorhexidine and the local delivery of minocycline improved clinical and
radiographic parameters [54]. According to Heitz-Mayfield, significant improvements in
clinical and microbiologic parameters were achieved at 3 months in treating peri-implantitis
using the local application of minocycline microspheres as part of the CIST protocol [55].
Antibiotics 2021, 10, 1298 11 of 15

From our findings, local antibiotic applications could reduce PD, but their efficacy appears
limited to a short period.
In some case series and case reports, many encouraging results also emerged. Mensi et al.
reported improvements in PPD and BOP using a Multiple Anti-Infective Non-Surgical
Treatment (MAINST) protocol that consisted of two treatments, each executed in two
consecutive weeks, based on air polishing, ultrasonic, manual debridement, chlorhexidine
rinse, and a final pocket filling with doxycycline gel 14% (Ligosan® Kulzer Gmbh, Hanau,
Germany) [56]. The same results were also reported in Moura et al. and Diachova et al.,
where improvements in PD [57,58] and BOP [58] were registered after using local doxy-
cycline. These findings confirmed Butcher et al. (2004), who demonstrated a significant
improvement in peri-implant disease after applying doxycycline as a local antibiotic [39].
The contrasting findings that emerged could be explained by the difficulty of lo-
cal/topical antibiotics to arrive at a high concentration on the implant surface. This
difficulty could discourage clinicians from adopting local/topical antibiotics. To achieve
a high concentration of local/topical antibiotics, clinicians are required to increase the
total amount of local/topical antibiotics, consequently increasing the risk of antimicrobial
resistance and adverse effects [20].
The synthesis of the current data indicated that peri-implant mucositis non-surgical
treatment, concerning PD and BOP scores, does not favour local/topical antibiotics or
local antiseptic treatment as a combination with mechanical detoxification alone [59,60].
These findings were confirmed in a recent systematic review, which also demonstrated that
the adjunctive treatment fails to facilitate the effectiveness of plaque removal in reducing
PD (such as air abrasive device, systemic and local/topical antibiotics) and BOP (such
as septic or systemic/local antibiotics) scores at the sites with peri-implant mucositis [5].
Contrarily, for non-surgical peri-implantitis treatment, the BOP scores favoured either
local antibiotics [28,30,36,39,45,56,61–64] adjunctive therapy or alternative plaque control
measures [63] over respective control therapeutic managements. Therefore, from the
above evidence, local/topical antibiotics as an adjunctive treatment are more effective in
peri-implantitis than peri-implant mucositis.
Regarding the microbiological outcome, all included studies demonstrated a reduction
in bacteria, although without statistically significant differences between treatment and
control groups. Only Park et al. showed the more robust activity of local minocycline
in reducing P. gingivalis, T. forsythia, T. denticola, P. intermedia, C. rectus, and F. nucleatum
after 12 weeks of treatment. This result is encouraging, but it is not enough: contaminated
implant surfaces represent a reservoir of peri pathogens in both healthy and diseased
implants, as a result of the “circular model” of bacterial contamination [65,66].
Comparing our findings with the current literature, moderately significant results
were demonstrated in a recent systematic review and meta-analysis that investigated
the efficacy of local antibiotic administration in reducing PPD and BOP using a different
approach than ours [67]. After the screening of an initial 95 articles and including different
study designs (i.e., RCTs, case series, cohort, and case–control studies) and different control
groups (e.g., photochemotherapy), the authors concluded that local antibiotics reduce PPD
and BOP in comparison to the control group without local antibiotics, but a high level of
heterogeneity was highlighted as a study limitation that could have reduced the quality of
the encountered evidence [67].
A high level of heterogeneity was observed among the included studies, mainly due
to the surgical or non-surgical approach, materials employed, operators, local antibiotic
dosage and delivery, different control groups, study protocol, and microbiological out-
comes. These factors reduced the quality of the evidence. Even in those studies which
used the same local antibiotics, i.e., minocycline, differences in follow-up hampered a
valid comparison [28,36–38]. None of the included studies reported adverse effects after
local antibiotic administration. The incidence of side effects should be verified in future
studies. To date, we know that adverse effects were demonstrated after systemic antibiotic
Antibiotics 2021, 10, 1298 12 of 15

administration in periodontitis (e.g., gastrointestinal disorders, allergic reaction, headache,

or fever) [68].
The limitations of this review could be addressed as follows. First, only five RCTs
were eligible for this review and the risk of bias was not assessed because only two of
the included were almost recent and therefore conducted according to the CONSORT
guidelines. Secondly, the multiplicity of antibiotics prevents us from determining an actual
clinical effect, given a different host response. Finally, diverse follow-up periods, implant
types, locations, outcomes, and diagnostic criteria determined high heterogeneity among
studies, which prevents definitive conclusions from being made.
Future clinical trials are suggested in order to compare the effect of different lo-
cal/topical antibiotics in the presence of diverse microbiological factors and immunological
parameters. Moreover, accurate comparisons of the antibiotics’ impact with similar biologi-
cal activity profiles could provide a validated and conclusive protocol.

5. Conclusions
In conclusion, the extensive use of implants raises the question of future peri-implant
diseases. Unfortunately, there are very few existing studies that report on etiological peri-
implantitis treatment in isolation. However, enough current studies have proven that in
peri-implantitis treatment, the elimination of the bacterial biofilm from the implant surface
either through surgical or non-surgical access should be supplemented by chemical adjunct
therapeutic approaches through surgical access. Unfortunately, to date, few existing studies
also compare the efficiency of different types of chemical treatments as adjuncts to peri-
implantitis management. Therefore, it is impossible to establish a firm recommendation of
the chemical adjunct that should be used for peri-implantitis management. To the best of
our knowledge, this work is the first literature review focused on local/topical antibiotics.
However, the administration of local/topical antibiotics has been shown to have
positive clinical outcomes in peri-implantitis. Nevertheless, a protocol with strong scientific
evidence cannot be derived from the studies conducted to date. Therefore, more studies
with homogeneous designs and longer follow-up are desirable considering the lack of a
definable gold-standard treatment to date.

Author Contributions: Conceptualisation, A.N., P.C.P. and M.A.L.; methodology, A.N., P.C.P. and
M.A.L.; validation, P.C.P., M.A.L. and A.S.; formal analysis, A.B. and A.S.; investigation, A.N., P.C.P.,
M.A.L., G.A. and G.D.R.; resources, A.N., P.C.P., A.S. and A.D.; data curation, A.N., P.C.P., G.A. and
E.F.G.; writing—original draft preparation, P.C.P. and A.N.; writing—review and editing, A.N., P.C.P.,
A.B. and G.D.R.; visualisation, E.F.G., A.N., M.A.L., G.P. and P.P.; supervision, P.C.P., A.D., P.P. and
G.P.; project administration, P.C.P., A.D., A.S., G.P. and P.P. All authors have read and agreed to the
published version of the manuscript.
Funding: This review received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Pjetursson, B.E.; Tan, K.; Lang, N.P.; Bragger, U.; Egger, M.; Zwahlen, M. A systematic review of the survival and complication
rates of fixed partial dentures (FPDs) after an observation period of at least 5 years. Clin. Oral Implants Res. 2004, 15, 625–642.
[CrossRef]
2. Lee, C.T.; Huang, Y.W.; Zhu, L.; Weltman, R. Prevalences of peri-implantitis and peri-implant mucositis: Systematic review and
meta-analysis. J. Dent. 2017, 62, 1–12. [CrossRef]
3. Smeets, R.; Henningsen, A.; Jung, O.; Heiland, M.; Hammacher, C.; Stein, J.M. Definition, etiology, prevention and treatment of
peri-implantitis—A review. Head Face Med. 2014, 10, 34. [CrossRef] [PubMed]
Antibiotics 2021, 10, 1298 13 of 15

4. Berglundh, T.; Persson, L.; Klinge, B. A systematic review of the incidence of biological and technical complications in implant
dentistry reported in prospective longitudinal studies of at least 5 years. J. Clin. Periodontol. 2002, 29 (Suppl. 3), 197–212;
[CrossRef]
5. Schwarz, F.; Derks, J.; Monje, A.; Wang, H.L. Peri-implantitis. J. Periodontol. 2018, 89 (Suppl. 1), S267–S290. [CrossRef]
6. Berglundh, T.; Armitage, G.; Araujo, M.G.; Avila-Ortiz, G.; Blanco, J.; Camargo, P.M.; Chen, S.; Cochran, D.; Derks, J.; Figuero, E.;
et al. Peri-implant diseases and conditions: Consensus report of workgroup 4 of the 2017 World Workshop on the Classification
of Periodontal and Peri-Implant Diseases and Conditions. J. Clin. Periodontol. 2018, 45 (Suppl. 20), S286–S291. [CrossRef]
7. Heitz-Mayfield, L.J.; Lang, N.P. Comparative biology of chronic and aggressive periodontitis vs. peri-implantitis. Periodontol.
2000 2010, 53, 167–181. [CrossRef]
8. Heitz-Mayfield, L.J.; Mombelli, A. The therapy of peri-implantitis: A systematic review. Int. J. Oral Maxillofac. Implant. 2014, 29,
325–345. [CrossRef]
9. Teughels, W.; van Assche, N.; Sliepen, I.; Quirynen, M. Effect of material characteristics and/or surface topography on biofilm
development. Clin. Oral Implant. Res. 2006, 17 (Suppl. 2), 68–81. [CrossRef] [PubMed]
10. Heitz-Mayfield, L.J. Peri-implant diseases: Diagnosis and risk indicators. J. Clin. Periodontol. 2008, 35, 292–304. [CrossRef]
[PubMed]
11. Sahrmann, P.; Gilli, F.; Wiedemeier, D.B.; Attin, T.; Schmidlin, P.R.; Karygianni, L. The Microbiome of Peri-Implantitis: A
Systematic Review and Meta-Analysis. Microorganisms 2020, 8, 661. [CrossRef]
12. Hultin, M.; Gustafsson, A.; Hallstrom, H.; Johansson, L.A.; Ekfeldt, A.; Klinge, B. Microbiological findings and host response in
patients with peri-implantitis. Clin. Oral Implant. Res. 2002, 13, 349–358. [CrossRef]
13. Renvert, S.; Polyzois, I. Treatment of pathologic peri-implant pockets. Periodontol. 2000 2018, 76, 180–190. [CrossRef] [PubMed]
14. Hajishengallis, G. Immunomicrobial pathogenesis of periodontitis: Keystones, pathobionts, and host response. Trends Immunol.
2014, 35, 3–11. [CrossRef] [PubMed]
15. Valderrama, P.; Blansett, J.A.; Gonzalez, M.G.; Cantu, M.G.; Wilson, T.G. Detoxification of Implant Surfaces Affected by Peri-
Implant Disease: An Overview of Non-surgical Methods. Open Dent. J. 2014, 8, 77–84. [CrossRef] [PubMed]
16. Casado, P.L.; Otazu, I.B.; Balduino, A.; de Mello, W.; Barboza, E.P.; Duarte, M.E. Identification of periodontal pathogens in healthy
periimplant sites. Implant. Dent. 2011, 20, 226–235. [CrossRef] [PubMed]
17. Ebadian, A.R.; Kadkhodazadeh, M.; Zarnegarnia, P.; Dahlen, G. Bacterial analysis of peri-implantitis and chronic periodontitis in
Iranian subjects. Acta Med. Iran. 2012, 50, 486–492.
18. Lang, N.P.; Mombelli, A.; Tonetti, M.S.; Bragger, U.; Hammerle, C.H. Clinical trials on therapies for peri-implant infections. Ann.
Periodontol. 1997, 2, 343–356. [CrossRef]
19. Lang, N.P.; Berglundh, T.; Heitz-Mayfield, L.J.; Pjetursson, B.E.; Salvi, G.E.; Sanz, M. Consensus statements and recommended
clinical procedures regarding implant survival and complications. Int. J. Oral Maxillofac. Implant. 2004, 19, 150–154.
20. Zhao, Y.; Pu, R.; Qian, Y.; Shi, J.; Si, M. Antimicrobial photodynamic therapy versus antibiotics as an adjunct in the treatment
of periodontitis and peri-implantitis: A systematic review and meta-analysis. Photodiagn. Photodyn. Ther. 2021, 34, 102231.
[CrossRef]
21. Natto, Z.S.; Aladmawy, M.; Levi, P.A., Jr.; Wang, H.L. Comparison of the efficacy of different types of lasers for the treatment of
peri-implantitis: A systematic review. Int. J. Oral Maxillofac. Implant. 2015, 30, 338–345. [CrossRef] [PubMed]
22. Filoche, S.; Wong, L.; Sissons, C.H. Oral biofilms: Emerging concepts in microbial ecology. J. Dent. Res. 2010, 89, 8–18. [CrossRef]
[PubMed]
23. Lan, S.F.; Kehinde, T.; Zhang, X.; Khajotia, S.; Schmidtke, D.W.; Starly, B. Controlled release of metronidazole from composite
poly-epsilon-caprolactone/alginate (PCL/alginate) rings for dental implants. Dent. Mater. 2013, 29, 656–665. [CrossRef]
24. Kotsovilis, S.; Karoussis, I.K.; Trianti, M.; Fourmousis, I. Therapy of peri-implantitis: A systematic review. J. Clin. Periodontol.
2008, 35, 621–629. [CrossRef] [PubMed]
25. Garrett, S.; Adams, D.F.; Bogle, G.; Donly, K.; Drisko, C.H.; Hallmon, W.W.; Hancock, E.B.; Hanes, P.; Hawley, C.E.; Johnson,
L.; et al. The effect of locally delivered controlled-release doxycycline or scaling and root planing on periodontal maintenance
patients over 9 months. J. Periodontol. 2000, 71, 22–30. [CrossRef]
26. Schwarz, F.; Schmucker, A.; Becker, J. Efficacy of alternative or adjunctive measures to conventional treatment of peri-implant
mucositis and peri-implantitis: A systematic review and meta-analysis. Int. J. Implant. Dent. 2015, 1, 22. [CrossRef] [PubMed]
27. Killoy, W.J. Chemical treatment of periodontitis: Local delivery of antimicrobials. Int. Dent. J. 1998, 48, 305–315. [CrossRef]
28. Renvert, S.; Lessem, J.; Dahlen, G.; Renvert, H.; Lindahl, C. Mechanical and repeated antimicrobial therapy using a local drug
delivery system in the treatment of peri-implantitis: A randomized clinical trial. J. Periodontol. 2008, 79, 836–844. [CrossRef]
29. Da Rocha, H.A.; Silva, C.F.; Santiago, F.L.; Martins, L.G.; Dias, P.C.; de Magalhães, D. Local Drug Delivery Systems in the
Treatment of Periodontitis: A Literature Review. J. Int. Acad. Periodontol. 2015, 17, 82–90.
30. Mombelli, A.; Feloutzis, A.; Bragger, U.; Lang, N.P. Treatment of peri-implantitis by local delivery of tetracycline. Clinical,
microbiological and radiological results. Clin. Oral Implant. Res. 2001, 12, 287–294. [CrossRef]
31. Sinha, S.; Kumar, S.; Dagli, N.; Dagli, R.J. Effect of tetracycline HCl in the treatment of chronic periodontitis—A clinical study. J.
Int. Soc. Prev. Community Dent. 2014, 4, 149–153. [CrossRef]
32. Boyeena, L.; Koduganti, R.R.; Panthula, V.R.; Jammula, S.P. Comparison of efficacy of probiotics versus tetracycline fibers as
adjuvants to scaling and root planing. J. Indian Soc. Periodontol. 2019, 23, 539–544. [CrossRef]
Antibiotics 2021, 10, 1298 14 of 15

33. Dang, A.B.; Chaubey, K.K.; Thakur, R.K.; Mohan, R.; Chowdhary, Z.; Tripathi, R. Comparative evaluation of efficacy of three
treatment modalities—Tetracycline fibers, scaling and root planing, and combination therapy: A clinical study. J. Indian Soc.
Periodontol. 2016, 20, 608–613. [CrossRef] [PubMed]
34. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and
meta-analyses: The PRISMA statement. BMJ 2009, 339, b2535. [CrossRef]
35. Higgins, J.P.; Altman, D.G.; Gotzsche, P.C.; Juni, P.; Moher, D.; Oxman, A.D.; Savovic, J.; Schulz, K.F.; Weeks, L.; Sterne, J.A.; et al.
The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011, 343, d5928. [CrossRef] [PubMed]
36. Renvert, S.; Lessem, J.; Dahlen, G.; Lindahl, C.; Svensson, M. Topical minocycline microspheres versus topical chlorhexidine gel
as an adjunct to mechanical debridement of incipient peri-implant infections: A randomized clinical trial. J. Clin. Periodontol.
2006, 33, 362–369. [CrossRef] [PubMed]
37. Park, S.H.; Song, Y.W.; Cha, J.K.; Lee, J.S.; Kim, Y.T.; Shin, H.S.; Lee, D.W.; Lee, J.H.; Kim, C.S. Adjunctive use of metronidazole-
minocycline ointment in the nonsurgical treatment of peri-implantitis: A multicenter randomized controlled trial. Clin. Implant.
Dent. Relat. Res. 2021, 23, 543–554. [CrossRef]
38. Cha, J.K.; Lee, J.S.; Kim, C.S. Surgical Therapy of Peri-Implantitis with Local Minocycline: A 6-Month Randomized Controlled
Clinical Trial. J. Dent. Res. 2019, 98, 288–295. [CrossRef] [PubMed]
39. Buchter, A.; Meyer, U.; Kruse-Losler, B.; Joos, U.; Kleinheinz, J. Sustained release of doxycycline for the treatment of peri-
implantitis: Randomised controlled trial. Br. J. Oral Maxillofac. Surg. 2004, 42, 439–444. [CrossRef] [PubMed]
40. Figuero, E.; Graziani, F.; Sanz, I.; Herrera, D.; Sanz, M. Management of peri-implant mucositis and peri-implantitis. Periodontol.
2000 2014, 66, 255–273. [CrossRef]
41. Heitz-Mayfield, L.J.A.; Salvi, G.E.; Mombelli, A.; Loup, P.J.; Heitz, F.; Kruger, E.; Lang, N.P. Supportive peri-implant therapy
following anti-infective surgical peri-implantitis treatment: 5-year survival and success. Clin. Oral Implant. Res. 2018, 29, 1–6.
[CrossRef]
42. Jepsen, K.; Jepsen, S.; Laine, M.L.; Anssari Moin, D.; Pilloni, A.; Zeza, B.; Sanz, M.; Ortiz-Vigon, A.; Roos-Jansaker, A.M.;
Renvert, S. Reconstruction of Peri-implant Osseous Defects: A Multicenter Randomized Trial. J. Dent. Res. 2016, 95, 58–66.
[CrossRef] [PubMed]
43. Strooker, H.; Rohn, S.; van Winkelhoff, A.J. Clinical and microbiologic effects of chemical versus mechanical cleansing in
professional supportive implant therapy. Int. J. Oral Maxillofac. Implant. 1998, 13, 845–850.
44. Paquette, D.W.; Ryan, M.E.; Wilder, R.S. Locally delivered antimicrobials: Clinical evidence and relevance. J. Dent. Hyg. 2008, 82
(Suppl. 3), 10–15.
45. Bassetti, M.; Schar, D.; Wicki, B.; Eick, S.; Ramseier, C.A.; Arweiler, N.B.; Sculean, A.; Salvi, G.E. Anti-infective therapy of
peri-implantitis with adjunctive local drug delivery or photodynamic therapy: 12-month outcomes of a randomized controlled
clinical trial. Clin. Oral Implant. Res. 2014, 25, 279–287. [CrossRef]
46. Tan, O.L.; Safii, S.H.; Razali, M. Commercial Local Pharmacotherapeutics and Adjunctive Agents for Nonsurgical Treatment of
Periodontitis: A Contemporary Review of Clinical Efficacies and Challenges. Antibiotics 2019, 9, 11. [CrossRef] [PubMed]
47. Nadig, P.S.; Shah, M.A. Tetracycline as local drug delivery in treatment of chronic periodontitis: A systematic review and
meta-analysis. J. Indian Soc. Periodontol. 2016, 20, 576–583. [CrossRef]
48. Xu, L.; Wang, Y.; Nguyen, V.T.; Chen, J. Effects of Topical Antibiotic Prophylaxis on Wound Healing After Flapless Implant
Surgery: A Pilot Study. J. Periodontol. 2016, 87, 275–280. [CrossRef] [PubMed]
49. Herrera, D.; Matesanz, P.; Martin, C.; Oud, V.; Feres, M.; Teughels, W. Adjunctive effect of locally delivered antimicrobials in
periodontitis therapy: A systematic review and meta-analysis. J. Clin. Periodontol. 2020, 47 (Suppl. 22), 239–256. [CrossRef]
[PubMed]
50. Nastri, L.; de Rosa, A.; de Gregorio, V.; Grassia, V.; Donnarumma, G. A New Controlled-Release Material Containing Metronida-
zole and Doxycycline for the Treatment of Periodontal and Peri-Implant Diseases: Formulation and In Vitro Testing. Int. J. Dent.
2019, 2019, 9374607. [CrossRef] [PubMed]
51. Madi, M.; Pavlic, V.; Samy, W.; Alagl, A. The anti-inflammatory effect of locally delivered nano-doxycycline gel in therapy of
chronic periodontitis. Acta Odontol. Scand. 2018, 76, 71–76. [CrossRef] [PubMed]
52. Schenk, G.; Flemmig, T.F.; Betz, T.; Reuther, J.; Klaiber, B. Controlled local delivery of tetracycline HCl in the treatment of
periimplant mucosal hyperplasia and mucositis. A controlled case series. Clin. Oral Implant. Res. 1997, 8, 427–433. [CrossRef]
[PubMed]
53. Hallstrom, H.; Persson, G.R.; Lindgren, S.; Olofsson, M.; Renvert, S. Systemic antibiotics and debridement of peri-implant
mucositis. A randomized clinical trial. J. Clin. Periodontol. 2012, 39, 574–581. [CrossRef]
54. Heo, S.; Kim, H.J.; Joo, J.Y.; Lee, J.; Kim, S.J.; Choi, J. Simplified nonsurgical treatment of peri-implantitis using chlorhexidine and
minocycline hydrochloride. J. Periodontal Implant Sci. 2018, 48, 326–333. [CrossRef] [PubMed]
55. Heitz-Mayfield, L.J.; Lang, N.P. Antimicrobial treatment of peri-implant diseases. Int. J. Oral Maxillofac. Implant. 2004, 19, 128–139.
56. Mensi, M.; Scotti, E.; Calza, S.; Pilloni, A.; Grusovin, M.G.; Mongardini, C. A new multiple anti-infective non-surgical therapy in
the treatment of peri-implantitis: A case series. Minerva Stomatol. 2017, 66, 255–266. [CrossRef]
57. Moura, L.A.; Oliveira Giorgetti Bossolan, A.P.; de Rezende Duek, E.A.; Sallum, E.A.; Nociti, F.H., Jr.; Casati, M.Z.; Sallum, A.W.
Treatment of peri-implantitis using nonsurgical debridement with bioresorbable nanospheres for controlled release of doxycycline:
Case report. Compend. Contin. Educ. Dent. 2012, 33, E145–E149.
Antibiotics 2021, 10, 1298 15 of 15

58. Diachkova, E.; Corbella, S.; Taschieri, S.; Tarasenko, S. Nonsurgical Treatment of Peri-Implantitis: Case Series. Dent. J. 2020, 8, 78.
[CrossRef]
59. Thone-Muhling, M.; Swierkot, K.; Nonnenmacher, C.; Mutters, R.; Flores-de-Jacoby, L.; Mengel, R. Comparison of two full-mouth
approaches in the treatment of peri-implant mucositis: A pilot study. Clin. Oral Implant. Res. 2010, 21, 504–512. [CrossRef]
60. Porras, R.; Anderson, G.B.; Caffesse, R.; Narendran, S.; Trejo, P.M. Clinical response to 2 different therapeutic regimens to treat
peri-implant mucositis. J. Periodontol. 2002, 73, 1118–1125. [CrossRef]
61. Schar, D.; Ramseier, C.A.; Eick, S.; Arweiler, N.B.; Sculean, A.; Salvi, G.E. Anti-infective therapy of peri-implantitis with adjunctive
local drug delivery or photodynamic therapy: Six-month outcomes of a prospective randomized clinical trial. Clin. Oral Implant.
Res. 2013, 24, 104–110. [CrossRef]
62. Salvi, G.E.; Persson, G.R.; Heitz-Mayfield, L.J.; Frei, M.; Lang, N.P. Adjunctive local antibiotic therapy in the treatment of
peri-implantitis II: Clinical and radiographic outcomes. Clin. Oral Implant. Res. 2007, 18, 281–285. [CrossRef] [PubMed]
63. Tang, Z.; Cao, C.; Sha, Y.; Lin, Y.; Wang, X. Effects of non-surgical treatment modalities on peri-implantitis. Zhonghua Kou Qiang Yi
Xue Za Zhi 2002, 37, 173–175.
64. Paul, T.P.; Emmatty, R.; Pulikkottil, J.J.; Rahman, A.A.; Kumar, S.A.; George, N. Comparative Evaluation of Sustained Release
Collagen Device Containing 5% Metronidazole (Metrogene) along With and Without Scaling and Root Planing at Regular
Intervals with Treatment of Chronic Periodontitis: A Case Control Study. J. Int. Oral Health 2015, 7, 18–22.
65. Canullo, L.; Penarrocha-Oltra, D.; Soldini, C.; Mazzocco, F.; Penarrocha, M.; Covani, U. Microbiological assessment of the
implant-abutment interface in different connections: Cross-sectional study after 5 years of functional loading. Clin. Oral Implant.
Res. 2015, 26, 426–434. [CrossRef]
66. Canullo, L.; Penarrocha-Oltra, D.; Covani, U.; Rossetti, P.H. Microbiologic and Clinical Findings of Implants in Healthy Condition
and with Peri-Implantitis. Int. J. Oral Maxillofac. Implant. 2015, 30, 834–842. [CrossRef] [PubMed]
67. Toledano, M.; Osorio, M.T.; Vallecillo-Rivas, M.; Toledano-Osorio, M.; Rodriguez-Archilla, A.; Toledano, R.; Osorio, R. Efficacy of
local antibiotic therapy in the treatment of peri-implantitis: A systematic review and meta-analysis. J. Dent. 2021, 113, 103790.
[CrossRef]
68. Smiley, C.J.; Tracy, S.L.; Abt, E.; Michalowicz, B.S.; John, M.T.; Gunsolley, J.; Cobb, C.M.; Rossmann, J.; Harrel, S.K.; Forrest, J.L.;
et al. Systematic review and meta-analysis on the nonsurgical treatment of chronic periodontitis by means of scaling and root
planing with or without adjuncts. J. Am. Dent. Assoc. 2015, 146, 508–524. [CrossRef] [PubMed]