Local and Systemic Antibiotics in Peri-Implantitis Management: An Umbrella Review

The present umbrella review aimed to characterize the type and regimen of antibiotics administered locally and/or systemically, alone or in combination with surgical and nonsurgical treatments, for peri-implantitis and to evaluate and compare the associated clinical, radiographic, and crevicular peri-implant outcomes. The secondary objective was to determine the most effective antibiotic type, route of administration, regimen, and protocols (antibiotics alone or in combination with other approaches) for treating peri-implantitis. The study protocol, which was developed in advance under the PRISMA statement, was registered at PROSPERO (CRD42022373957). BioMed Central, Scopus, MEDLINE/PubMed, the Cochrane Library databases, and the PROSPERO registry were searched for systematic reviews through 15 November 2022. Of the 708 records found, seven reviews were included; three were judged of a critically low and four of low quality through the AMSTAR 2 tool. Locally administered antibiotics alone or as an adjunct to surgical or nonsurgical treatments for peri-implantitis showed favorable outcomes, albeit with limited evidence. The administration of systemically-delivered antibiotics in combination with nonsurgical or surgical treatments remained questionable. Local plus systemic antibiotics have not been shown to have durable efficacy. Due to the heterogeneity of reported antibiotic types, routes, regimens, and protocols, no definitive conclusions could be drawn regarding the most effective antibiotic use in treating peri-implantitis.


Introduction
Dental implants have become one of the most reliable therapeutic options to replace missing teeth. As a result, a significant increase in the number of dental implants placed annually, on the one hand, and in the number of cases diagnosed with peri-implantitis, on the other hand, has been observed worldwide [1,2].
The 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions defined peri-implantitis as a pathological condition occurring in the tissues surrounding dental implants characterized by signs of inflammation of the outer tissues and progressive bone loss [3][4][5][6][7][8].
Abrasive air powder, metallic or non-metallic curettes (the latter made of carbon or plastic, reinforced or not with resin), with an ultrasonic scaler with a metal or plastic tip [14,15] provide nonsurgical mechanical biofilm control. In addition, implantoplasty is performed to reduce the roughness of dental implant surfaces and, in turn, bacterial adhesion [15]. Further physical methods, such as phototherapy and laser therapy, e.g., with out date restriction until 15 November 2022, using keywords and Boolean operators as follows: ("peri-implantitis" OR "peri-implant dis-ease" OR "dental implant" OR "implant loss") AND ("local antibiotic" OR "local antibiotics" OR "general antibiotic" OR "general antibiotics" OR "antibiotic therapy" OR antibiotics OR antimicrobial OR "peri-implant mucositis").
The following filters were applied: "review (English)" and "refine": "review (English)" in the Scopus database; "systematic review (English)" in the MEDLINE/PubMed database; "keywords" in the Cochrane Library; no filters were used in the BioMed Central database or the PROSPERO registry.

Study Selection and Eligibility Criteria
Collected citations were recorded, duplicates were eliminated via the reference management tool EndnoteTM (Clarivate), and the remaining systematic review titles (with or without meta-analysis) were screened by the three independent reviewers (FDS, FDA, MPDP), who then screened relevant abstracts.
The full texts of these potentially eligible title-abstracts were obtained, contacting the study authors if full texts were unavailable, and were independently reviewed by the same authors (FDS, FDA, MPDP). Any differences of opinion were clarified by consultation, and in case of doubt, another author (FG) was consulted. No manual search was carried out from the reference lists of included articles.
Inclusion criteria: no restrictions were applied on publication date, the number of studies, and study design included in each systematic review; age, gender, and characteristics of the participants; the number of dental implants and type of prosthetic restorations; type and regimen of antibiotics administered locally and/or systemically, alone or in combination with other (nonsurgical or surgical) peri-implantitis treatment.
Exclusion criteria: non-English language studies and self-reported peri-implant status were excluded.

Data Extraction and Collection
Data were extracted independently and in duplicate by two authors (F.D.A., M.P.D.P.) using a standardized data extraction form developed based on the models recommended for intervention reviews of RCTs and non-RCTs [29] before data extraction; a third author (F.D.S.) was consulted in case of disagreement.
Of each systematic review (with or without meta-analysis) included in the present umbrella review, data illustrated in Table 1 were recorded.

Data Synthesis
A narrative synthesis of the data regarding the population studied, intervention(s), and outcomes was performed.
Data from the included studies were qualitatively synthesized: • to characterize the type and regimen of antibiotics administered locally and/or systemically alone or in combination with other (surgical or nonsurgical) peri-implantitis treatments and comparisons; • to assess clinical, radiographic, and crevicular peri-implant outcomes according to the type and regimen of locally-and/or systemically-delivered antibiotics administered alone or in combination with other (surgical or nonsurgical) peri-implantitis provided; • to compare clinical, radiographic, and crevicular peri-implant outcomes after administration of locally-and/or systemically-administered antibiotics alone or in combination with other (surgical or nonsurgical) peri-implantitis vs. placebo and to each other.

Quality Assessment
The quality assessment of the systematic reviews included in this umbrella review was performed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool, accessed online (https://amstar.ca) on 16 November 2022, evaluating for quality the systematic reviews with or without meta-analysis [30].

Study Selection
A total of 708 records were identified from the electronic search, specifically 64 from BioMed Central, 216 from Scopus, 252 from MEDLINE/PubMed, five from the Cochrane library databases, and 171 from the PROSPERO register.
In total, 330 duplicates were eliminated, and 378 title-abstracts were screened. Of these 378 title-abstracts, 17 abstracts were relevant and compliant with the eligibility criteria of the present systematic review.

Study Characteristics
The total number of subjects involved was 1575 with 2262 implants. However, three studies [44,46,47] did not report the sample size or the number of implants. In no case was the gender ratio or mean age of participants or the number, location, characteristics, and survival of implants affected by peri-implantitis reported.
The characteristics and outcomes from included studies are synthesized in Table 3. Table 3. Characteristics and outcomes from included studies. Source: first author, year, reference, journal of publication, meta-analysis, funding, and study quality (if any). Studies reported the systematic reviews included in the present umbrella review: design and number; population sample size (n.), mean age (y.o.), and gender ratio (M/F); dental implant number, position, and survival. Type, route of administration, regimen, and duration of locally-and/or systemically-delivered antibiotics alone or in combination with other (surgical or nonsurgical) peri-implantitis treatment. Clinical, radiographic, and crevicular peri-implant outcomes (statistically significant). Conclusions.

Study Characteristics
The total number of subjects involved was 1575 with 2262 implants. However, three studies [44,46,47] did not report the sample size or the number of implants. In no case was the gender ratio or mean age of participants or the number, location, characteristics, and survival of implants affected by peri-implantitis reported.

Local and Systemic Antibiotics in Peri-Implantitis Management
Locally-delivered antibiotics for treating peri-implantitis were administered alone and in combination with other nonsurgical and surgical interventions and systemic ones.
No data were available about the characteristics of systemic antibiotic therapy alone in treating peri-implantitis from included studies.

Locally-Delivered Antibiotics Alone and in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
Three systematic reviews [41,42,46] described findings from studies with local antibiotic administration combined or not to other peri-implant treatments.
Local tetracycline hydrochloride delivery by monolithic ethylene vinyl acetate fiber (for one time of antibiotic with a duration of 10 days) + rubber cup polishing + SRP, doxycycline "Atridox" subgingivally for one time + SRP and irrigation with 0.2% CHX, and minocycline "Periocline" subgingivally + OFD at 1, 3, and 6 months were found to positively affect PPD and BoP up to 12 months after therapy [43].
Local doxycycline hyclate 8.5% "Atridox" applied through a syringe with a blunt cannula in the peri-implant sulcus + SRP determined a more significant improvement in CAL and PPD values compared to mechanical debridement at 4 months follow-up [46].

Systemically-Delivered Antibiotics in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
Four systematic reviews [43][44][45]47] reported results from systemically-delivered antibiotics, which were always used in combination with other interventions in treating peri-implantitis.
Several drug regimens were recorded for amoxicillin ( as well as for other antibiotic combinations (e.g., clindamycin + metronidazole + azithromycin + tetracicline for 4 weeks and metronidazole + amoxicillin + ciprofloxacin + sulfonamide + trimethroprim + metronidazole for 2 weeks), overall highlighting that systemic antibiotics should be carefully evaluated in peri-implantitis management considering the risk of antibiotic resistance [45].
The association of amoxicillin and metronidazole in combination with ultrasonic debridement (500 mg/8 h + 500 mg/24 h for 7 d), scaling and root planing (375 mg/8 h for 7 d + 250 mg/8 h for 7 d; 500 mg/8 h + 400 mg/24 h for 7 d), as well as the administration of clarithromycin in combination with the antimicrobial photodynamic therapy (500 mg/24 h for 3 d) significantly reduced BoP, CAL, and PPD [47]. Table 6 synthesizes the characteristics of systemically-delivered antibiotics combined with other interventions in the treatment of peri-implantitis.

Locally-Plus Systemically-Delivered Antibiotics in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
Two systematic reviews [39,43] reported peri-implant outcomes after local plus systemic antibiotics administration alone or combined with other interventions in treating peri-implantitis.

Discussion
The treatment of peri-implantitis, which aims to reduce the microbial load, decontaminate the dental implant surface, and eliminate peri-implant mucosal inflammation, thereby preserving the peri-implant bone, can be divided into nonsurgical approaches using mechanical instrumentation, antibiotics, antiseptics, and chemical or laser decontamination of the dental implant surface and surgical approaches such as air powder abrasion, resective, or regenerative procedures [48][49][50][51][52].
Nonsurgical treatment of peri-implantitis aims to reduce inflammation by controlling biofilm [50]. Mechanical therapy includes using resin, carbon, or titanium cuvettes, specialized ultrasonic instruments, rubber bowls/polishing brushes, and air-powder devices [50]. However, nonsurgical mechanical debridement alone is ineffective for the long-term treatment of peri-implantitis [50]. Adjunctive antiseptic agents such as chlorhexidine improve clinical parameters but only for six months or less [50].
Surgical treatment of peri-implantitis is required when PPD and bone resorption have progressed or persist in removing biofilm and creating a surface that allows reosteointegration through a full-thickness flap [50]. Accordingly, in conjunction with openaccess flaps, mechanical debridement and adjuvants, such as saline, abrasive pumice, citric acid, chlorhexidine, and hydrogen peroxide, are used [50]. The open approach and the morphology of the residual bone determine the choice of surgical intervention and whether a resective or regenerative approach is opted for [53].
Given these considerations and the fact that peri-implantitis is maintained by microorganisms [48], it is legitimate to ask whether systemic and/or local antibiotics are effective in treating peri-implantitis [42]. Accordingly, concomitant antibiotics, including minocycline and doxycycline hyclate, have improved gingival inflammation and probing depths [50]. However, further studies are needed to verify their long-term efficacy.
Therefore, the present umbrella review aimed to characterize the type and regimen of antibiotics administered locally and/or systemically, alone or in combination with surgical and nonsurgical treatments for peri-implantitis, and to evaluate and compare the associated clinical, radiographic, and crevicular peri-implant outcomes. The secondary objective was to determine the most effective antibiotic type, route of administration, regimen, and protocols (antibiotics alone or in combination with other approaches) for treating peri-implantitis.

Locally-Delivered Antibiotics Alone and in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
The efficacy of locally-delivered antibiotics alone on periodontal parameters, especially PPD, BoP, and plaque index (PI), was investigated in three studies [41,42,46] with contrasting results, probably due to the different interventions and control groups in each of the three studies [41,42,46].
Indeed, only one study [41] found an improvement in PPD and BoP after using local antibiotics compared with the control group. Toledano et al. [41] demonstrated that the local use of antibiotics in peri-implantitis patients positively affected the reduction of PPD and BoP. Specifically, the likelihood of bleeding on probing was halved when antibiotics were applied topically, and on average, a 0.30 mm reduction in PPD was observed when topically administered antibiotics were used [41]. However, peri-implant parameters in subjects under minocycline [41] were not significantly different from those using chlorhexidine [42]. Similarly, metronidazole was reported to be associated with both improvements in periimplant conditions [41] and implant failure in the studies by Esposito et al. [46].
Four studies investigated the efficacy of local antibiotics in combination with nonsurgical and surgical treatment of peri-implantitis. Except for one study in which implant failure was recorded [46], the various combinations of tetracyclines (doxycycline or minocycline) with nonsurgical treatments (such as scaling and root planing and photodynamic therapy) or surgical flap incision always resulted in improvement of peri-implant BoP and PPD [42,43,47], even at a follow-up of 12 months [43]. Clinical attachment loss (CAL) [47] and gingival index (GI) and PI also improved in some cases [43].
Accordingly, Passarelli et al. [42] found an improvement in PPD and BoP when local antibiotics were combined with nonsurgical treatment compared with nonsurgical treatment alone [42].
Tetracyclines were the most commonly administered antibiotics [41,42], especially doxycycline and minocycline, which are also the most commonly used in treating periodontal infections (Rodrigues, 2004), followed by metronidazole, which showed a positive effect either if used alone in comparison with photodynamic therapy [42] or in combination with amoxicillin and scaling and root planing [47].

Systemically-Delivered Antibiotics in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
Systemically-delivered antibiotics have always been evaluated in combination with other interventions, likely because antibiotic stewardship advises against prescribing antibiotics unless they are indispensable and their efficacy is supported by evidence to combat antimicrobial resistance [20,22].
A total of four studies evaluating the efficacy of systemic antibiotics in combination with nonsurgical and surgical treatment for peri-implantitis were presently retrieved.
Different associations of amoxicillin and metronidazole at variable doses and durations were administered in combination with nonsurgical (such as scaling and root planing, nonsurgical debridement) and surgical treatments with implant debridement and showed improvement in PPD and BoP in only two studies [43,47]. Conversely, Toledano-Osorio et al. [45] showed that systemically-delivered administered antibiotics did not significantly improve BoP and PPD, although improvements in CAL, suppuration, recession, and total bacterial count were described in patients with peri-implantitis [45]. Similarly, Oen et al. [44] found no improvement in PPD when systemic antibiotics were combined with surgical procedures.
Consequently, combining systemically-administered antibiotics with nonsurgical and surgical treatments for peri-implantitis remains controversial in the current state of knowledge. However, there is some evidence to support their use in recurrent and refractory peri-implantitis cases [35].

Efficacy of Locally-Plus Systemically-Delivered Antibiotics in Combination with Nonsurgical and Surgical Treatment of Peri-Implantitis
The efficacy of locally-plus systemically-delivered antibiotics in combination with nonsurgical and surgical treatment was investigated in two studies [39,43].
Wang et al. [43] concluded that using local plus systemic antibiotics in combination with other peri-implantitis treatments had a beneficial effect and significantly improved PPD values [43]. However, the authors suggested that such a positive result could also be attributable to the combination of local and systemic administration of antibiotics with open flap debridement and scaling and root planing [43].
Esposito et al. [39] also reported the concomitant use of systemic and local amoxicillin, with no significant improvement in PPD, CAL, and REC from baseline at 2-year follow-up. Therefore, despite the limited data, local plus systemic administration of amoxicillin may have no durable efficacy.

Local and Systemic Antibiotics in Peri-Implantitis Management: Clinical Considerations
Nonsurgical treatments such as mechanical debridement and oral hygiene instructions effectively managed peri-implant mucositis and reduced but did not eliminate the inflammatory signs and symptoms of peri-implantitis [42,[54][55][56]. In the latter case, the surgical treatment allows direct decontamination of the dental implant surface and complete removal of the inflammatory granulation tissue [55].
Chemical biofilm control and locally-and systemically-delivered antibiotics administration have been proposed to improve nonsurgical and surgical treatment outcomes.
In particular, although supported by mild evidence, locally-delivered antibiotics used as an adjunct to nonsurgical mechanical debridement produced favorable results. In addition, local antibiotics, in combination with other surgical interventions, also showed modest clinical improvements in peri-implant parameters. Because adequate drug concentration at the site of infection is required for a sufficient time to eliminate the pathogens [57], various drug carriers have been developed to improve outcomes associated with locallydelivered antibiotics.
Conversely, systemically-delivered antibiotics had no significant effect on the treatment of peri-implantitis, either in combination with nonsurgical or surgical treatments [43][44][45]47]. As there is currently no clear indication for the use of systemically-delivered antibiotics for treating peri-implantitis, their administration should be evaluated even more cautiously, given the ever-growing phenomenon of antimicrobial resistance [45].
In fact, dentists are responsible for 10% of all antibiotic prescriptions [58], and antimicrobial resistance is mainly caused by the overuse and misuse of antibiotics [59], leading to an increased risk of complications and mortality and a more complex resolution of infectious diseases [20,22,60]. In this perspective, alternative techniques to avoid or reduce antimicrobial administration have been introduced as an adjunct to nonsurgical and surgical treatment of peri-implantitis, such as photodynamic therapy (aPDT). Specifically, Zhao et al. [47] reported promising results after aPDT comparable to those of antibiotic administration, although stating that further studies are needed to evaluate the efficacy of aPDT as an alternative to antibiotics [47].
Due to the variability of antibiotic types, routes of administration, dosages, and combinations with other nonsurgical and surgical interventions, the most effective antibiotic type, route of administration, regimen, and protocol (antibiotics alone or in combination with other approaches) for the management of peri-implantitis could not be determined from the currently retrieved data for either locally-or systemically-delivered antibiotics.
Moreover, given the conflicting results and following antibiotic stewardship to combat antimicrobial resistance [20,22,[60][61][62], it may be concluded that the prescription of systemically-delivered antibiotics should be discouraged, and the use of locally-delivered ones should be cautiously evaluated based on a case-and site-specific benefit-risk assessment.
Further research on the type of antibiotic, route of administration, therapeutic regimen, and protocols (antibiotics alone or in combination with other approaches) for managing peri-implantitis is still needed to demonstrate the most effective antibiotic therapy and to limit the risks resulting from inappropriate antibiotic therapy.
Given the heterogeneous data on antibiotic type, routes of administrations, therapeutic regimens, duration, and combination with other interventions, the incomplete data on periimplant outcomes, and those missing on dental implants' number, location, characteristics, and survival, no meta-analysis could be conducted. Findings from the presently included systematic reviews revealed contrasting and inconclusive results concerning the effectiveness of systemically-and locally-delivered antibiotics in peri-implantitis management. As a result, the ideal antibiotic type, route of administration, regimen, and protocols (antibiotics alone or in combination with other approaches) in peri-implantitis management could not be determined.
In addition, some studies, such as those by Renvert et al. and Cha et al. [63,64], were included in multiple systematic reviews, and all included reviews were classified as of low [41,[43][44][45] or critically low quality [42,46,47]. Consequently, the need for future investigations with higher evidence levels, such as randomized controlled trials, with defined antibiotic therapeutic regimens and protocols, methodically recorded peri-implant outcomes, and at least > 3 years of follow-up [44] are needed. Moreover, the need for caseand site-specific indication of antibiotic administration and benefit-risk assessment should be provided.
However, the present umbrella review may be the first to collectively evaluate the effectiveness and the proposed regimens and protocols of local and/or systemic antibi-otic administration alone and in combination with other nonsurgical or surgical periimplantitis treatments.

Conclusions
Seven systematic reviews were included in the present umbrella review; three were classified as critically low quality and four as low quality using the AMSTAR 2 tool.
Locally-delivered antibiotics administered alone or as an adjunct to surgical or nonsurgical treatments for peri-implantitis showed favorable results, albeit with limited evidence. The administration of systemically-delivered antibiotics in combination with nonsurgical or surgical treatments remained questionable. Local plus systemic antibiotics have not been shown to have durable efficacy.
Because of the heterogeneity of reported antibiotic types, routes, regimens, and administration protocols, no definitive conclusions could be drawn regarding the most effective antibiotic use in managing peri-implantitis. However, given the phenomenon of antimicrobial resistance, the prescription of systemically-delivered antibiotics should be discouraged, and locally-delivered ones should be used with caution based on a case-and site-specific benefit-risk assessment.
Further research is needed on antibiotics' type, route of administration, therapeutic regimen, and protocols (antibiotics alone or in combination with other approaches) for managing peri-implantitis, pointing out the case-and site-specific indications and the most effective antibiotic therapy, concurrently limiting the risks of inappropriate antibiotic use.