## 4 Discussion
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 [PERSON] 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 \begin{table}
\begin{tabular}{c c c} \hline \hline \multirow{2}{*}{**Classification**} & \multirow{2}{*}{**Organism**} & \multicolumn{2}{c}{**Mean Minimal Inhibitory Concentration (\(\mathbf{\mu}\)g/mL)**} \\ \hline \multirow{4}{*}{Gram-positive bacteria} & _Staphylococcus aureus_ & 1.6 \\  & _Streptococcus pyogenes_ & 0.39 \\  & _Streptococcus pneumoniae_ & 0.2 \\  & Viridans group streptococci & 0.39 \\ \hline \multirow{4}{*}{Gram-negative bacteria} & _Neisseria gonorrhoeae_ & 0.39 \\  & _Neisseria meningitidis_ & 1.6 \\  & _Haemophilus influenzae_ & 1.6 \\  & _Legionella pneumophila_ & 1.0 \\  & _Bacteroides fragilis_ & 0.1–8 \\ \hline \multirow{4}{*}{Mycoplasma/chlamydia} & _Mycoplasma pneumoniae_ & 1.6 \\  & _Ureaplasma urealyticum_ & 0.13 \\ \cline{1-1}  & _Chlamydia_ spp. & 0.02 \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Antibiotic sensitivities of doxycycline [19]. 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. Conceptualization, S.C. and L.F.; methodology, S.C.; validation, S.C., L.A., and L.F.; resources, L.F.; data curation, S.C.; writing--original draft preparation, S.C., A.V., and L.T. ; writing--review and editing, S.C., A.V., and L.T. ; supervision, L.F. All authors have read and agreed to the published version of the manuscript. This research received no external funding.