The Application of Local Doxycycline Gel for the Nonsurgical Treatment of Peri-Implant Diseases: A Systematic Review of the Literature

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The application of local doxycycline gel for the nonsurgical treatment of peri-implantitis showed promising results, although further scientific validation is needed.

Abstract

Doxycycline is an antibiotic belonging to the tetracycline family. Although systematic reviews do not recommend the local administration of antibiotics in association with mechanical instrumentation for the treatment of peri-implant diseases, none of these studies refer to the use of locally derived doxycycline. The aim of this systematic review is to evaluate the efficacy of the local application of doxycycline gel in the treatment of peri-implant diseases. The protocol of the review was submitted in PROSPERO. The manuscript was organized and prepared following the PRISMA guidelines and the systematic review was conducted according to the Cochrane Handbook for Systematic Review of Interventions—Second Edition. MEDLINE through OVID interface, EMBASE and Cochrane Central were interrogated for article research. The OpenGrey search engine was used for grey literature. Three articles were included in the review, involving 69 patients and 123 implants. None of these studies reported adverse events or complications during the observation period. In conclusion, the evidence about the local administration of doxycycline is not enough to provide a clinical recommendation; however, the results of the study and the biological plausibility of the potential advantages of the use of such antibiotics for the treatment of peri-implant diseases should stimulate further research.

1. Introduction

Peri-implant diseases are defined as inflammatory pathosis of the implant-surrounding tissues with an infectious origin, whose exacerbation follows the dysbiosis and impairment of the host immune response [1]. It can be distinguished into two different forms of peri-implant diseases: peri-implant mucositis, which is an inflammation of soft tissues around dental implants, and peri-implantitis, which is an irreversible inflammatory condition affecting both soft and hard (bone) implant-surrounding tissues, causing marginal bone loss if not treated [2].

The recently published European Federation of Periodontology (EFP) guidelines for the prevention and treatment of peri-implants clearly distinguish different phases for approaching the management of peri-implantitis [3]. The nonsurgical steps for the treatment of peri-implantitis should always include instructions and motivation for the patient for establishing and maintaining adequate oral hygiene, and the supramarginal and submarginal removal of dental biofilm through appropriate treatment protocols [3]. After this phase, a re-evaluation visit is fundamental for deciding whether the case should proceed with the surgical phase of treatment, if the endpoints of the nonsurgical treatment are not matched [3]. Currently, the local administration of antibiotics is not recommended, as associated with mechanical instrumentation for the treatment of periodontal diseases, based on systematic reviews of the literature [4,5]. Interestingly, none of the studies used for providing such a recommendation were about the use of locally derived doxycycline. Doxycycline is an antibiotic belonging to the tetracycline family that may inhibit bacterial growth by acting through the inhibition of the protein synthesis of the bacteria. It is widely used for treating infections of the respiratory tract and of the urinary tract, and to treat oral infectious diseases [6].

Local applications of doxycycline could be considered for the treatment of periodontal diseases as an adjunct to nonsurgical mechanical instrumentation, as reported in a systematic review used for the implementation of the European Federation of Periodontology Guidelines [7]. Locally delivered tetracycline was also used for the treatment of peri-implantitis associated with surgical procedure, as described in the study by Mercado et al., published in 2018, in which the application of doxycycline was performed in conjunction with the enamel matrix derivative and regenerative procedures [8]. In the cited study, the authors observed a significant improvement, on average, in all clinical and radiographic parameters. Another published case reported the use of a bioresorbable polymer that can release doxycycline over time, in conjunction with autogenous bone for the treatment of peri-implantitis [9].

Regarding the use of the local administration of doxycycline for the treatment of peri-implant diseases, due to the lack of scientific evidence on the topic, and considering the risk of inducing bacterial resistance in patients with peri-implantitis [10], there is a need, in the opinion of the authors, for a scientific appraisal of the efficacy of such a treatment approach. In particular, the scientific literature does not provide, to our knowledge, a review about the efficacy/effectiveness of the local application of such an antibiotic, providing data about the scientific robustness of its use.

For this reason, the aim of the present systematic review of the literature is to evaluate the efficacy of the local application of doxycycline gel as a monotherapy or in conjunction with another treatment as compared, if possible, with other treatment strategies when used for the treatment of peri-implant diseases and conditions.

2. Materials and Methods

The protocol of the present review of the literature was submitted in PROSPERO before the systematic search, obtaining the registration number CRD42025643727. The manuscript was organized and prepared following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines as published in 2020 [11] and the systematic review was carried out by following the instructions and the indications of the Cochrane Handbook for Systematic Review of Interventions—Second Edition [12].

The main purpose of the present systematic review was to answer the following question, presented following the PICO framework: considering in vivo studies on human subjects (P), what is the efficacy of the local application of doxycycline gel as monotherapy or in conjunction with another treatment (I) as compared, if possible, with other treatment strategies (C) when used for the treatment of peri-implant diseases and conditions, as measured through the evaluation of clinical and microbiological outcomes (O)?

2.1. Eligibility Criteria

For the purposes of the study, based on the research question, these are the inclusion criteria to be followed:

• In vivo studies on humans, any design, excluding case reports;
• Studies describing the local application of doxycycline gel as monotherapy or in conjunction with other therapies;
• Studies describing the local application of doxycycline gel for the nonsurgical treatment of peri-implant diseases, such as peri-implantitis or peri-implant mucositis;
• English, German, Italian, French, or Spanish language;
• Any follow-up.

2.2. Search Strategy

The following electronic sources were interrogated for potentially relevant articles: MEDLINE through Ovid interface, EMBASE, and Cochrane Central. The full search strategy is presented in Appendix A. Grey literature was also searched through the OpenGrey search engine. Clinical trials registers (ClinicalTrials.gov and EU Clinical Trials Register) were also searched and carefully screened. The authors performed a manual search of the reference lists of all included papers and of all the issues published from 2000 to 2024 of the following relevant journals: Clinical Implant Dentistry and Related Research, Clinical Oral Investigations, Clinical Oral Implants Research, Journal of Clinical Periodontology, Journal of Periodontology, Journal of Dentistry, Journal of Dental Research, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral Implantology, International Journal of Periodontics and Restorative Dentistry, and Journal of Oral Implantology.

The last electronic search was performed on 31 October 2024.

2.3. Selection Process

Two authors (AV and LT) retrieved, from the included papers, the following information: authors’ names, year of publication, country, setting, study type, number of subjects treated, characteristics of the population, description of the techniques, follow-up duration, radiographic, clinical, and patient-reported outcomes at any follow-up, adverse events, and complications (type and time they occurred). In the case of missing information, the authors of the papers were contacted by email to provide missing data.

2.4. Risk of Bias and Quality of Evidence Appraisal

For randomized (or nonrandomized) controlled clinical trials, the risk of bias was evaluated through the RoB 2.0 tool. A study was judged at high risk of bias if at least one of the domains presented high risk of bias or if more than two domains presented some concerns about risk of bias; the study was considered at low risk if all domains were at low risk of bias; and in any other cases, the study was judged to have some concerns about risk of bias. For other study types, the appropriate tool was adopted (Newcastle–Ottawa Scale for single-arm studies).

The quality of evidence was evaluated by using the GRADE approach.

2.5. Data Synthesis and Analysis

It was planned to perform a quantitative analysis and meta-analysis of the results of the included studies. Due to the paucity of the available research and to the heterogeneity of the study types, of the settings, of the treatments adopted, and of the criteria adopted, the authors performed just a qualitative appraisal of the existing evidence on the topic by considering the studies singularly.

3. Results

The systematic search of the literature retrieved a total of 55 articles. After the removal of duplicates and abstract and title selection, only three articles satisfied all inclusion criteria and were included in the present review (Figure 1).

The general characteristics of the studies are presented in

Table 1. General characteristics of the included studies [9,13,14].

Study Authors	Year	Objective	Sample	Methodology	Probe	Follow-Up	Group 1	Group 2	Results	Conclusions	Limitations
Büchter et al. [9]	2004	Compare mechanical debridement with and without doxycycline (Atridox™ 1) application for peri-implantitis treatment	28 patients (48 peri-implant defects)	Control group: mechanical debridement with plastic hand instruments	PCP 11 periodontal probe (Hu-Friedy, Chicago, IL, USA), 3–3–2–3 mm calibration, 0.4 mm diameter	18 weeks	Mechanical debridement with plastic hand instruments	Mechanical debridement + controlled-release topical doxycycline (Atridox™ 1, 8.5% doxycycline), one application	Greater reduction in PPD (1.15 mm vs. 0.56 mm) and BOP (0.27 vs. 0.13) in doxycycline group compared to debridement alone	Treatment with debridement and doxycycline showed better results than debridement alone	Limited duration (18 weeks), small sample size
Mensi et al. [13]	2017	Evaluate the efficacy of a non-surgical protocol (MAINST) for acute peri-implantitis	15 patients (27 implants)	MAINST: decontamination with air-polishing (erythritol and chlorhexidine) and 14% topical doxycycline application (Ligosan® 2)	PCP-UNC 15 periodontal probe (Hu-Friedy, Chicago, IL, USA)	12 months	MAINST protocol: Decontamination with erythritol powder and chlorhexidine, 14% topical doxycycline application (Ligosan® 2), one application	Not applicable	Significant reduction in BOP (from 98.5% to 4.5%) and PPD (from 7.89 mm to 3.16 mm) between baseline and 12 months	MAINST protocol effective up to 12 months with significant reduction in clinical parameters	Absence of control group, small sample size
Latronico et al. [14]	2022	Evaluate the efficacy of a non-surgical protocol for peri-implantitis using 14% doxycycline gel (Ligosan® 2)	26 patients (49 implants)	Supra/subgingival debridement with dedicated tools, biofilm removal, doxycycline gel application (Ligosan® 2)	Not specified	12 months	Non-surgical treatment with debridement and 14% doxycycline (Ligosan® 2), one application	Not applicable	Average PPD reduction from 6.7 mm to 4.6 mm; BoP reduced from 100% to 29%	Protocol effective in reducing PPD and BoP, potentially lowering the need for surgery.	Small sample size, inability to evaluate the role of individual protocol components.

¹ Block Drug Corporation Inc., Jersey City, NJ USA. ² Kulzer GmbH, Hanau, Germany.

. One study was a well-designed randomized controlled clinical trial [9], while the others were single-arm prospective randomized studies [13,14]. The risk of bias was low for all included studies. A total of 69 patients, accounting for 124 implants, were treated by using a nonsurgical treatment protocol that included the use of local administration of doxycycline. In one study, the nonsurgical treatment was carried out by also using decontamination with an air-polishing device (erythritol and chlorhexidine) [14]. The follow-up was 18 weeks for one study [9] and 12 months for two studies [13,14].

The study by Buchter and coworkers on 28 subjects (48 defects with diagnosed peri-implantitis) [9] found that the test group (in which local doxycycline was used) reported better outcomes than the control group, with a significantly higher reduction in PPD (1.15 ± 0.23 mm versus 0.56 ± 0.30 mm) and BI over the observation period. No data were available about the resolution of peri-implantitis or about patient-reported outcomes. The study by Mensi et al. on 15 patients (27 peri-implant defects), published in 2017, combined doxycycline and air-polishing (MAINST protocol), reporting a very significant decrease in PPD (from 7.89 mm to 3.16 mm on average) and in BoP% (from 98.5% to 4.5%) [14]. Interestingly, similar results were found by Latronico and coworkers in 2022, on a cohort of 26 patients (49 peri-implant defects) with a decrease in PPD over time that reduced the need for further surgical treatment [13].

None of the studies reported adverse events or complications during the observation period.

On the basis of the available results from the included studies, the quality of the available evidence was very low, due to heterogeneity and to the low number of papers available.

4. Discussion

The present research into the literature aimed at systematically reviewing the existing literature about the use of local doxycycline as an adjunct to standard nonsurgical treatment for the management of peri-implantitis. The lack of comparability among the included studies (also due to the heterogeneity in study protocols) and the absence of a higher number of RCTs prevented the authors from performing a quantitative synthesis of the available data. However, on the basis of the available results, it can be stated that the local application of doxycycline may be considered as a promising treatment option in the nonsurgical phase of management of peri-implantitis, although a larger amount of confirmative research is needed to give more strength to the recommendation.

The results of the review should be read in the light of previously published literature also about the use of this antibiotic for treating periodontal disease, to weigh their external validity.

The pivotal review of the literature published by Herrera and coworkers in 2020 [7] analyzed data from three studies that used local doxycycline for treating periodontal pockets in a total of 232 patients. In the meta-analysis, the test group resulted in a significantly higher PPD reduction than control group, with 0.283 mm on average after 6 to 12 months, and higher CAL gain of 0.408 mm in the same follow-up period. Two of the included studies revealed a significant improvement in the periodontal parameters [15,16], and one of the studies explored the treatment of furcation defects during the supportive periodontal care [16]. One of the studies included in the meta-analysis did not find any significant difference between the test and control group, failing to find any adjunctive effect of using local doxycycline applications [17,18].

In the study by Klein et al., the behavior of tetracyclines is described, with a particular focus on several molecules within this antibiotic class, including doxycycline. Although the article does not specifically address the effect of doxycycline on bacterial biofilm in the oral cavity, a key factor in peri-implant diseases, it provides the mean minimal inhibitory concentration (MIC) of doxycycline against the pathogens most sensitive to this molecule (see

Table 2. Antibiotic sensitivities of doxycycline [19].

Classification	Organism	Mean Minimal Inhibitory Concentration (µg/mL)
Gram-positive bacteria	Staphylococcus aureus	1.6
	Streptococcus pyogenes	0.39
	Streptococcus pneumoniae	0.2
	Viridans group streptococci	0.39
Gram-negative bacteria	Neisseria gonorrhoeae	0.39
	Neisseria meningitidis	1.6
	Haemophilus influenzae	1.6
	Legionella pneumophila	1.0
	Bacteroides fragilis	0.1–8
Mycoplasma/chlamydia	Mycoplasma pneumoniae	1.6
	Ureaplasma urealyticum	0.13
	Chlamydia spp.	0.02

) [19].

The recently published study by Aimetti and coworkers investigated the influence of locally delivered doxycycline on the inflammatory status of periodontal intrabony defects before periodontal regeneration [20]. The authors could demonstrate that the number of sites presenting bleeding at the end of the nonsurgical phase was significantly lower in the test sites than in control ones and that there was a significant decrease, more evident in the test group, of several inflammatory cytokines, such as IL-1b, MMP-8, and MMP-9, that are very often correlated with the presence of periodontal inflammation [20]. Such an improvement resulted in better soft tissue healing outcomes two weeks after surgeries.

In the study published in 2020, Lecio and coworkers treated a sample made exclusively of type-2 diabetics with periodontal disease with nonsurgical subgingival instrumentation and adjunctive 20% doxycycline [21]. In this particular cohort, the experimental group showed higher improvements in BoP, PPD, and CAL in the short term as compared to control group. Moreover, confirming the results obtained by Aimetti et al., the group treated with adjunctive doxycycline presented a significant reduction in periodontal pathogens and inflammatory cytokines. Interestingly, the level of HbA1c decreased more in the treatment group [21].

Considering the studies included in the present review on peri-implant defects, the results obtained, although applied in a slightly different clinical condition, were comparable to those obtained in the previously cited papers on periodontal defects, since both peri-implantitis and periodontitis presented a similar (not identical) inflammatory pattern [22,23].

A further confirmation of the results from the included studies may come from the consideration of several case reports published on the topic but not included in the present research. The case report by Neely and colleagues combined both mechanical debridement with a titanium brush and the application of local doxycycline, after a surgical approach, reporting the resolution of peri-implantitis after 5 years [24]. Other case reports focused on the nonsurgical treatment of peri-implantitis by using a combination of doxycycline application and nonsurgical submucosal debridement [25,26]. In general, the effects of the local antibiotic are expressed through its ability to disinfect the implant surface, as was described in several in vitro studies [27,28]. It is notable that, although all the authors reported a significant ability to reduce the contamination of titanium surfaces, all chemical agents, when applied on implant surfaces in in vivo conditions, may potentially cause a cytotoxic effect [27]. In the studies we included in the present research, we found no evidence of unexpected complications or of any harmful side effects in the treated subjects, thus supporting the clinical use of local doxycycline.

The validity of the results we obtained from the analysis of the literature has been limited by several factors that should be discussed and evaluated. First, the absence of a sufficient number of comparative studies (RCTs) to perform a meta-analysis may represent a limit in the evaluation of the external validity of the results, since just a qualitative appraisal was performed and, in general, the evidence on the topic is sparse. However, we should consider that, even considering the above-mentioned limitation, highlighting the presence of a lack of evidence in this field may help to promote more studies on this specific topic [12]. Moreover, although just three studies were available, it can be noted that the results they provided were coherent across the difference research, both in magnitude and in direction. Another limitation is represented by the heterogeneity of the studies, in terms of clinical setting, inclusions criteria, protocol adopted, and success criteria.

While considering the limitations that have emerged, it can be concluded, on the basis of the present systematic review of the literature, that the level of evidence about the use of a local administration of doxycycline is not enough to provide a clinical recommendation. However, the results of the included studies are coherent and, in general, they showed a positive effect of the application of the product. Thus, the biological plausibility of the potential advantages of the use of such an antibiotic for the treatment of peri-implant disease should stimulate further research in this specific field.