Evaluaon of the eﬀect of Levoﬂoxacin and Cefalexin derivave anbiocs on Implant Osseointegraon in rat bia Evaluación del efecto de los anbiócos derivados de levoﬂoxacino y cefalexina sobre la osteointegración de implantes en bia de rata *Corresponding Author: mtanrisever@ﬁrat.edu.tr Revista Cienﬁca, FCV-LUZ / Vol. XXXV Recibido: 16/04/2025 Aceptado:31/05/2025 Publicado: 06/07/2025 hps://doi.org/10.52973/rcfcv-e35650 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 6 Revista Cienﬁca, FCV-LUZ / Vol. XXXV hps://doi.org/10.52973/rcfcv-e35679 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico ABSTRACT Osseointegraon refers to the process where an implant ﬁrmly and funconally bonds with the bone, establishing a stable union capable of bearing loads without any relave movement between the implant and the surrounding bone ssue. Post- surgery infecons that may develop in the surgical area can negavely aﬀect osseointegraon, pung the success of the implant at risk. The objecve of this research was to evaluate the impact of anbiocs derived from levoﬂoxacin and cephalexin on the osseointegraon of implants in the bias of rats. A total of 21 female Sprague Dawley rats were ulized, randomly divided into three equal groups of seven rats each. Titanium implants measuring 2.5 mm in diameter and 4 mm in length were inserted into cavies created in the corcocancellous bone of the metaphyseal region of the right bias of all animals. In the implant control group (n=7), no addional procedures were performed throughout the two- week experimental period. Subjects in the implant levoﬂoxacin group (n=7) received subcutaneous injecons of levoﬂoxacin at a dose of 25 mg/kg, administered three mes weekly for two weeks. Similarly, rats in the implant cephalexin group (n=7) were given subcutaneous injecons of cephalexin at a dosage of 20 mg/kg, three mes per week for two weeks. Two weeks aﬅer the operaon, the implant samples in the bias of the rats were subjected to biomechanical analysis using a digital torque device in order to evaluate the osseointegraon process. As a result, it was observed that levoﬂoxacin and cephalexin-derived anbiocs had a negave eﬀect on implant osseointegraon in the bias of rats. Key words: Levoﬂoxacin; Cephalexin; osseointegraon, rat RESUMEN La osteointegracion es el proceso mediante el cual, un implante se integra estructural y funcionalmente con el hueso, preparándose para soportar cargas y formando una conexión sólida sin movimiento entre el implante y el hueso. Las infecciones posquirúrgicas que pueden desarrollarse en la zona quirúrgica pueden afectar negavamente este proceso, poniendo en riesgo el éxito del implante. Este estudio tuvo como objevo invesgar el efecto de la levoﬂoxacina y los anbiócos derivados de la cefalexina en la osteointegración de implantes en bias de rata. Se ulizaron 21 ratas hembra Sprague Dawley, divididas en tres grupos de siete ratas cada uno. Se colocaron implantes de tanio de 2,5 mm de diámetro y 4 mm de longitud en las cavidades abiertas en el hueso corcoesponjoso de la porción metaﬁsaria de la bia derecha de todos los sujetos. No se realizó ninguna otra intervención durante el período experimental de dos semanas en el grupo control con implantes (n=7). Los sujetos del grupo con implante de levoﬂoxacino (n=7) recibieron una inyección subcutánea de 25 mg/kg de levoﬂoxacino tres veces por semana durante dos semanas. Las ratas del grupo con implante de cefalexina (n=7) recibieron una inyección subcutánea de 20 mg/kg de cefalexina tres veces por semana durante dos semanas. Dos semanas después de la operación, las muestras de implantes en las bias de las ratas se someeron a un análisis biomecánico mediante un disposivo de torsión digital para evaluar el proceso de osteointegración. Como resultado, se observó que el levoﬂoxacino y los anbiócos derivados de la cefalexina tuvieron un efecto negavo en la osteointegración de los implantes en las bias de las ratas. Palabras clave: Levoﬂoxacino; Cefalexina; osteointegración; rata Umit Koray Can 1 , Murat Tanrisever 2 * , Burak Dagtekin 3 , Pinar Pak 3 , Erhan Cahit Ozcan 4 , Ozmen Istek 5 , Serkan Dundar 3α ¹ Turkish Jockey Club Elazig Racecourse Horse Hospital, Elazig, Turkiye ²Firat University, Faculty of Veterinary Medicine, Department of Surgery, Elazig, Turkiye ³Firat University, Faculty of Dentistry, Department of Peridontology, Elazig, Turkiye α Firat University, Institute of Sciences, Department of Statistics, Doctorate Student ⁴Firat University, Faculty of Medicine, Department of Esthetic, Plastic and Reconstructive Surgery, Elazig, Turkiye ⁵Mus Alparslan University, Faculty of Health Medicine, Department of Nursing, Mus, Turkiye

Revista Cienﬁca, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Dental implants are synthec tooth roots inserted into the jawbone to provide support and stabilizaon for dental prosthecs such as crowns, bridges, or dentures. Today, paent sasfacon has increased signiﬁcantly thanks to the predictability, stability, comfort, aesthec results and funconality of implants. Therefore, the areas of use of dental implants have expanded considerably. In clinical applicaons, they are preferred in various cases such as paents who are parally or completely edentulous, those who have suﬀered trauma, congenital anomalies or defects in the maxillofacial region. However, the success of implants depends on comprehensive preoperave planning and appropriate paent selecon, where factors such as the paent’s bone quality, oral hygiene and systemic health status are carefully evaluated. While dental implants present numerous beneﬁts, they may not be appropriate for all individuals, parcularly those with medical condions or lifestyle factors that could elevate the risk of implant failure [1 , 2 , 3]. The process of an implant directly and funconally integrang with the bone, becoming ready to bear loads and creang a solid connecon between the implant and the bone without any movement is called “osseointegraon” [4 , 5]. This process is crical for the long-term success of the implant. However, infecons that may develop in the surgical site aﬅer surgery can negavely aﬀect osseointegraon and jeopardize the success of the implant. Infecons may cause signiﬁcant complicaons, beginning with localized symptoms like pain and swelling, progressing to bone loss, and potenally resulng in the total failure of the surgical procedure. During the infecon process, increased levels of pro-inﬂammatory cytokines and chemokines can prevent new bone formaon [6 ,7]. In addion, increased bioﬁlm accumulaon can cause more serious infecon condions such as osteomyelis [6]. Therefore, the use of anmicrobial treatments is of great importance to prevent postoperave wound infecons. Such treatments support the osseointegraon process by reducing the risk of infecon and increase the chances of implant success [7]. Bone healing is a mulfaceted biological process that occurs in three stages: inﬂammaon, repair, and late remodeling. The inﬂammatory stage typically concludes within one week, while the remodeling phase commences around the third week. These stages are governed by intricate molecular-level mechanisms [8 , 9]. Bone ssue healing and successful osseointegraon of implants are crical issues in modern orthopedic and dental surgery. Osseointegraon refers to the formaon of a funconal and structural bond between the implant surface and the adjacent bone ssue, a process that is heavily aﬀected by bone metabolism, cellular dynamics, and various environmental factors. Factors aﬀecng implant success include surgical technique, implant surface properes, paent factors, and systemic drug use. In parcular, the eﬀects of systemically administered drugs on bone metabolism and implant osseointegraon have become a focus of increasing interest in recent years [10]. Several approaches, including the administraon of growth factors and pharmaceucals as well as the use of electrical smulaon, have been explored for their potenal to enhance and expedite bone healing. [10]. Studies have shown that certain drugs, especially some types of anbiocs, can slow down or negavely aﬀect the bone healing process. If such drugs are detected and not used, bone healing can be expected to occur completely [11]. The selected anbioc should eﬀecvely target the bacteria most commonly responsible for causing infecons. In most cases, postoperave infecons are caused by microorganisms that originate from the surgical site. For example, infecons following oral surgery are usually caused by bacteria found in the body’s natural ﬂora, such as aerobic Gram-posive cocci (such as streptococci), anaerobic Gram-posive cocci (such as peptococci), and anaerobic Gram-negave bacilli (such as bacteroids). Although oral infecons are polymicrobial, with anaerobic bacteria outnumbering aerobic bacteria by roughly 2:1, studies have shown that the growth of anaerobic bacteria depends on the presence of aerobic bacteria. In the inial phases of oral infecons, aerobic streptococci are typically found, which facilitate the development of an environment conducive to the proliferaon of anaerobic bacteria. As a result, an opmal anbioc should be eﬀecve against both aerobic and anaerobic microorganisms [12]. Anbiocs are widely used to reduce the risk of postoperave infecon. However, there are concerns that some anbiocs may have adverse eﬀects on bone ssue. It has been reported that ﬂuoroquinolone anbiocs (such as Levoﬂoxacin) in parcular may delay bone healing by suppressing the proliferaon and diﬀerenaon of bone cells and may negavely aﬀect implant osseointegraon. In contrast, cephalosporin anbiocs (such as Cephalexin) are thought to have less adverse eﬀects on bone ssue. Therefore, comparing the eﬀects of anbiocs used for postoperave infecon prophylaxis on bone healing and implant success is an important clinical queson [13]. Levoﬂoxacin is a third-generaon ﬂuoroquinolone anbioc with a broad spectrum of acvity, eﬀecve against both Gram- posive and Gram-negave aerobic bacteria, as well as certain anaerobic bacteria. It exerts its bactericidal acon by blocking bacterial DNA replicaon. When administered orally, it is quickly absorbed and has a half-life of about 6 to 8 hours. It is mainly eliminated through urine, eﬀecvely reaches bone ssue, and is commonly chosen for the treatment of condions such as osteomyelis, acute sinusis, urinary tract infecons, and acute bronchis [12 , 13]. Cephalexin is a ﬁrst-generaon cephalosporin anbioc that is widely used in the treatment of various bacterial infecons. It is eﬀecve against both Gram-posive and Gram-negave bacteria, working by inhibing bacterial cell wall synthesis. This anbioc is commonly prescribed, parcularly following maxillofacial surgical procedures [11], 14 , 15]. The aim of this study was to compare the eﬀects of systemically administered levoﬂoxacin and cephalexin anbiocs on the osseointegraon of tanium implants placed in the bia bone of rats. 2 of 6

Levoﬂoxacin, cefalexin and implant osseointegraon / Pekince et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico MATERIALS AND METHODS Animal and study design This research was carried out at the Firat University Experimental Research Center, with approval granted by the Firat University Animal Experimentaon Local Ethics Commiee (Approval Number: 21839, Date: 02.02.2024). The principles outlined in the Declaraon of Helsinki were rigorously adhered to throughout the experimental procedures. For the standardizaon of this animal study, 21 female Spraque Dawley rats that were determined to be in the same estrus period aﬅer vaginal swabs were included in the study due to the possibility that female hormones could aﬀect bone healing. The rats were obtained from the Firat University Experimental Research Center. The rats were housed in plasc cages, with the room temperature consistently maintained at 22 °C each day. Throughout the experimental period, the rats were maintained on a 12-hour light and 12-hour dark cycle. They were given free access to food and water. Cavies were created in the corcocancellous bone of the metaphyseal region of the right bias of the rats. Titanium implants, measuring 2.5 mm in diameter and 4 mm in length, were inserted into the cavies. The animals were allocated into three equal groups, with each group consisng of seven rats. Implant control group (n=7): In this group, 2.5 mm in diameter and 4 mm in length bone cavies were created in the corcocancellous bone of the metaphyseal area of the right bias of the subjects under serum cooling. Titanium implants of the same dimensions (2.5 mm diameter and 4 mm length) were then inserted into these cavies. No other intervenon was performed during the two- week experimental period. Implant levoﬂoxacin group (n=7): In this group, 2.5 mm diameter and 4 mm long bone cavies were opened in the corcocancellous bone ssue of the metaphyseal part of the right bia bones of the subjects under serum cooling, and tanium implants of the same size (2.5 mm diameter and 4 mm length) were placed in these cavies. During the two-week experimental me, 25 mg/kg levoﬂoxacin was injected subcutaneously three mes a week, including the day of surgical procedures. Implant cephalexin group (n=7): In this group, bone cavies of 2.5 mm in diameter and 4 mm in length were opened in the corcocancellous bone ssue of the metaphyseal part of the right bia bones of the subjects under serum cooling and tanium implants of the same dimensions (2.5 mm in diameter and 4 mm in length) were placed in these cavies. During the two-week experimental me, 2 mg/kg cephalexin was injected subcutaneously three mes a week, including the day of surgical procedures. All the rats were sacriﬁced at the end of the experimental setup. Surgical procedure General anesthesia was provided by intraperitoneal injecon of 10 mg/kg Xylazine and 50 mg/kg Ketamine [1]. Subsequently, 0.5 mL of arcaine with 1:200,000 epinephrine was administered to the surgical site for local anesthesia and to control bleeding. Aﬅer anesthesia and shaving, the relevant legs of the rats were disinfected with povidone-iodine (FIG. 1). FIGURE 1. Preoperave preparaon of the surgical site in a rat for tanium implant placement in the bia bone An incision about 2 cm long was made using a number 22 scalpel, maintaining contact with the crestal bone of the bia. The soﬅ ssues and periosteum were removed using a periosteal elevator and the bia bone was reached (FIG. 2). FIGURE 2. Corco cancellous region of the bia where the implant will be applied aﬅer cung the skin and the subcutaneous connecve ssue 3 of 6

Revista Cienﬁca, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Bone cavies measuring 2.5 mm in diameter and 4 mm in length were created under serum cooling, and tanium implants of idencal dimensions (2.5 mm diameter and 4 mm length) were inserted into these cavies (FIG. 3). Once the implants were posioned, the surgical site was closed using 5-0 absorbable sutures. All subjects who underwent surgery received 1 mg/kg of tramadol hydrochloride intramuscularly for pain management on the day of the operaon and for the subsequent three days. Following euthanasia, the implants along with the surrounding bone ssues were dissected from the soﬅ ssues and preserved in formaldehyde. All surgical intervenons were carried out by the same surgeon. Biomechanical analysis Two weeks aﬅer the operaon, implant samples from the rats’ bias were taken by removing the bia as a block to evaluate the osseointegraon process. The bia blocks with implants were prepared for biomechanical analysis. The samples were promptly assessed to avoid dehydraon and subsequently stored in a 10% buﬀered formalin soluon. All implants were secured onto polymethylmethacrylate blocks. A rachet (Implance; Istanbul, Turkiye) was ulized to assess the torque of the implants, and a gradually increasing removal force was applied counterclockwise using a digital torque meter (Mark 10, USA). The procedure was stopped once the dental implant began to rotate within the bone socket. The maximum torque value (N/cm) was automacally recorded by the digital torque device at the inial moment of implant rotaon within the socket. Stascal analysis Descripve stascs such as standard deviaon and median are given in the data included in the study. Kolmogorov- Smirnov and Shapiro Wilk tests were performed to determine the normality of the data. As the normality assumpons were sasﬁed, One-Way ANOVA was employed to compare all groups. A stascal signiﬁcance level of P<0.05 was considered in the analyses. Stascal analyses were conducted using the SPSS 21 soﬅware (Stascal Package for the Social Sciences; SPSS Inc., Chicago, IL). FIGURE 3. Aﬅer a hole is opened in the bone using a drill, the implant is placed in this hole RESULTS AND DISCUSSION In the comparison of bone implant fusion values with One Way ANOVA test, a stascally signiﬁcant diﬀerence was observed between the biomechanical bone implant connecon (BIC) (N/ cm) levels of the groups (P<0.05). The BIC value of Levoﬂoxacin and Cephalexin applicaon was found to be signiﬁcantly lower than the control applicaons (P<0.05) (TABLE I). 4 of 6 TABLE I. Biomechanic bone implant connecon (BIC) (N/cm) levels of the groups Groups N Mean (N/cm) (BIC) Std. Deviaon P* Control 7 12,24 2,27 <0,05 Levoﬂoxacin a1 7 8,50 1,50 Cephalexin a2 7 8,36 1,22 *One Way Anova (P=0,001). a1, a2 : Stascally signiﬁcantly diﬀerent compared with control. a1 : 0,002 a2 : 0,001. ( a1, a2 : Tukey HSD Test) The BIC values of Levoﬂoxacin a1 and Cephalexin a2 groups are stascally signiﬁcantly diﬀerent compared to the control group. Levoﬂoxacin a1: P=0.002 and Cephalexin a2: P=0.001 indicate that these groups showed a signiﬁcant diﬀerence compared to the control group. Since both P values are less than 0.05, these diﬀerences are stascally signiﬁcant. The ﬁndings show that these anbiocs signiﬁcantly aﬀect the osseointegraon process. In parcular, biomechanical connecon strength (BIC) values revealed that anbioc use altered the healing process at the bone-implant interface. Numerous studies in the literature invesgate the impact of anbiocs on bone metabolism and implant osseointegraon. In studies conducted by Golestani et al. [16] and Perry et al. [11], it was reported that ﬂuoroquinolones group anbiocs (including levoﬂoxacin) inhibit osteoblast acvity and negavely aﬀected bone formaon aﬅer fracture healing in rat bias.

Levoﬂoxacin, cefalexin and implant osseointegraon / Pekince et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Holtom et al. [17] reported that in their study Cephalosporin group anbiocs (including Cephalexin) slowed inhibitory eﬀects on the proliferaon of osteoblasts. These ﬁndings are consistent with the low BIC values observed in the levoﬂoxacin and cephalexin groups in this study. In this study, BIC values were found to be signiﬁcantly lower in the levoﬂoxacin group compared to the control group (P=0.002). This situaon can be explained by the hypothesis that ﬂuoroquinolones may inhibit bone cell proliferaon and matrix synthesis. A similar trend was observed in the cephalexin group, where BIC values were found to be signiﬁcantly lower in this group compared to the control group (P=0.001). These results support the potenal negave eﬀects of cephalosporins on bone healing. Biomechanical analyses showed that new bone formaon at the bone-implant interface was less in the levoﬂoxacin and cephalexin groups compared to the control group. These ﬁndings are in line with a study conducted by Zhang et al. [18]. In their experimental study on fractures of the rat bia, Huddleston et al. [19] reported in their study that levoﬂoxacin and ciproﬂoxacin inhibited chondrocyte proliferaon, signiﬁcantly reduced callus formaon at the fracture site, and hindered complete fracture healing. The study further indicated that these anbiocs delayed osseointegraon by slowing the bone remodeling process.”. In addion, only two diﬀerent anbioc groups were examined in the study, and the eﬀects of other anbiocs were not evaluated. Therefore, studies examining a wider range of anbiocs are needed. CONCLUSION This study shows that Levoﬂoxacin and Cephalexin derivave anbiocs negavely aﬀect implant osseointegraon in rat bias. These ﬁndings emphasize that cauon should be exercised in the selecon of anbiocs aﬅer implant surgery and that potenal eﬀects on bone healing should be considered. Future studies may reveal the mechanisms of these eﬀects in more detail. AKCNOWLEDGEMENT The authors wish to thanks Implance Dental Implant System, AGS Medical Corporaon, Istanbul, Turkiye. Conﬂict of interests The authors have no conﬂict of interests to declare concerning the authorship or publicaon of this arcle. Funding There were no speciﬁc sources of funding for this research. BIBLIOGRAPHIC REFERENCES [1] Ozcan EC, Sokmen K, Karasu N, Bal A, Tanrisever M, Istek O, Kirtay M, Bozoglan A, Dundar S. Biomechanical Evaluaon of the Osseointegraon Levels of Implants Placed Simultaneously With Tibia, Femur, and Jaw Allogeneic Bone Graﬅs. J. Craniofac. Surg. [Internet]. 2025; 36(1):323-327. doi: hps://doi.org/pszs [2] Gómez-deDiego R, Mang-de la Rosa MR, Romero-Pérez MJ, Cutando-Soriano A, López-Valverde-Centeno A. 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