S ince Brånemark defined osseointegration

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1 IMPLANT DENTISTRY / VOLUME 0, NUMBER Postoperative Infections After Dental Implant Placement: Prevalence, Clinical Features, and Treatment Octavi Camps-Font, DDS,* Rui Figueiredo, DDS, MS, PhD, Eduard Valmaseda-Castellón, DDS, MS, PhD, and Cosme Gay-Escoda, MD, DDS, MS, PhD S ince Brånemark defined osseointegration in the mid-1960s, 1 oral rehabilitation has dramatically changed because of the introduction of dental implants. Although the survival rate of osseointegrated implants is high, 2 both short- and long-term complications may occur. 3,4 Postoperative wound infections are one of the major concerns for patients and surgeons, as they might hamper osseointegration and lead to an early implant failure. 5,6 Two recently published metaanalyses have shown that the prophylactic use of antibiotics seems to decrease the implant failure rate. 7,8 However, these agents did not seem to significantly reduce the incidence of postoperative infections. 7,8 Although some data have been published on this subject, 9 14 very few papers focus on determining the clinical *Fellow of the Master degree program in Oral Surgery and Implantology, Faculty of Dentistry, University of Barcelona, Barcelona, Spain. Associate Professor of Oral Surgery and Professor of the Master degree program of Oral Surgery and Implantology, Faculty of Dentistry, University of Barcelona; Researcher of the IDIBELL institute, Barcelona, Spain. Professor of Oral Surgery, Director of the Master degree program of Oral Surgery and Implantology, Faculty of Dentistry, University of Barcelona; Researcher of the IDIBELL institute, Barcelona, Spain. Chairman and Professor of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Barcelona; Coordinating investigator of the IDIBELL institute, Head of the Oral and Maxillofacial Surgery Department, Teknon Medical Center, Barcelona, Spain. Reprint requests and correspondence to: Rui Figueiredo, DDS, MS, PhD, University of Barcelona, Campus de Bellvitge, Facultat d Odontologia, C/Feixa Llarga, s/n, Pavelló Govern, 2ª planta, L Hospitalet de Llobregat, Barcelona, Spain, Phone: , rui@ruibf.com ISSN /15/ Implant Dentistry Volume 0 Number 0 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: /ID Purpose: To determine the prevalence and describe the clinical features and treatment of patients with early infections after implant placement. Materials and Methods: A retrospective cohort study was performed. Postoperative infections were defined as the presence of purulent drainage and/or increasing pain and swelling in the operated area before prosthetic loading. Patient-based infection prevalences and 95% confidence intervals for implant were determined. Patients who healed, were followed up to determine implant survival and success rates. Results: Three hundred thirtyseven participants (1273 implants) were included. Twenty-two postoperative infections were recorded (6.5% of the patients and 1.7% of the implants). These complications characteristics, risk factors, and treatment for patients afflicted with postoperative infections after dental implant treatment. Therefore, the aims of this study were to determine the prevalence and describe the main clinical features and treatment of patients who have developed early infections after dental implant placement. MATERIALS AND METHODS A retrospective cohort study comprising a total of 474 outpatients (1625 were usually diagnosed within the first month, and in 17 cases (77.3%) surgical treatment was performed because of antibiotic therapy failure. Twelve implants (54.6%) in 12 patients (54.6%) failed before prosthetic loading. The survival and success rates of the infected loaded implants were 80% and 50%, respectively, with a mean follow-up of 42.9 months (SD of 10.2 months). Conclusion: Four to 10% of patients receiving dental implants develop postoperative infections. This complication is important because applied treatments are usually ineffective and two-thirds of the infected implants fail, most before prosthetic loading. (Implant Dent 2015;0:1 7) Key Words: dental implant, postoperative wound infection, complication implants), who were consecutively treated between February 2009 and October 2012 in the Oral Surgery and Implantology Unit of the School of Dentistry in the University of Barcelona, was performed. The study design followed the STROBE guidelines for cohort studies. 15 The study protocol was approved by the Ethical Committee for Clinical Research (CEIC) of the Dental Hospital in the University of Barcelona. At the time of implant surgery, all patients presented an American Society

2 2 POSTOPERATIVE INFECTIONS IN IMPLANTS CAMPS-FONT ET AL of Anesthetist health status score not higher than 3. Patients with active periodontal disease had been previously treated according to the American Academy of Periodontology guidelines. 16 Patients with either incomplete clinical records or with dental implants placed in previous failure sites were excluded from the analysis. The authors also excluded patients who required guided bone regeneration procedures or those with nonconventional prosthetic loading (at least 3 months, for the mandible, and 4 months, for the maxilla, after implant placement were required). Patients who overcame the postoperative infection were recalled for a follow-up visit to determine implant survival and success rates according to Albrektsson et al 17 criteria. Surgical Procedure Implants were placed under local anesthesia, generally with articaine in a 4% solution of epinephrine 1:100,000 (Artinibsa; Inibsa Dental, Lliçà de Vall, Spain) by third-year fellows of the Master degree program in Oral Surgery and Implantology. A midcrestal incision was made and full-thickness flaps were elevated to expose the alveolar ridge. Implant sites were prepared using drills of increasing diameters, under constant irrigation with sterile saline, according to the manufacturers recommendations. Functional and esthetic requirements were taken into account to determine the inclination of the implants in mesiodistal and buccolingual directions. The flaps were usually repositioned with 4/0 polyamide sutures (Supramid; Aragó, Barcelona, Spain). The suture was removed 7 to 15 days after surgery. After the operation, an antibiotic (usually 750 mg amoxicillin, p.o. every 8 hours for 7 days), a nonsteroidal antiinflammatory drug (usually 600 mg ibuprofen, p.o. every 8 hours for 4 5 days [Algiasdin; Esteve, Barcelona, Spain]), an analgesic (usually 1 g paracetamol, p.o. every 8 hours for 3 4days [Gelocatil; Gelos, Barcelona, Spain]), and a mouthrinse (15 ml of 0.12% chlorhexidine digluconate every 12 hours for 15 days [Clorhexidina Lacer; Lacer, Barcelona, Spain]) were prescribed. Fig. 1. Flow-chart diagram of participants of this article, which reports the number of individuals at each stage of the study. This diagram explains as to how many subjects were excluded or lost during the study and for what reason. In this figure, the data are presented using patients (right side) and dental implants (left side) as the study unit. Postoperative instructions and use of prescribed drugs were explained and handed out in a paper sheet that was given to the patient. Patients compliance was not specifically assessed. Postoperative infections were defined as the presence of a purulent drainage and/or increasing pain and swelling in the operated area before prosthetic loading. Implants with mobility or impaired osseointegration before prosthetic abutment placement were classified as early failures. 18 Table 1. Main Demographic Characteristics of Infected Patients Case Age (y) Gender Systemic Pathology Data Sampling All clinical records were examined by the same researcher (O.C.-F.), who also collected the following data on patients with postoperative infections: (1) time elapsed from implant placement to infection; (2) clinical signs and symptoms; (3) age; (4) gender; (5) Smoking (Cigarettes per Day) Periodontal Disease 1 65 Female H No Yes 2 78 Male None No No 3 46 Male None No No 4 43 Male None.10 Yes 5 65 Female H No Yes 6 57 Male None No Yes 7 55 Male None No Yes 8 69 Male H No Yes 9 49 Male None No Yes Male H.10 Yes Female H No Yes Male H.10 Yes Male None No No Female H No Yes Female None No Yes Male None 1 10 Yes Female None No No Male None.10 Yes Female H No Yes Male H No No Female H and D No Yes Male None 1 10 No Most patients were 45 years or older, nonsmokers, with previous history of periodontitis and without significant systemic pathologies. D, diabetes; H, hypertension.

3 IMPLANT DENTISTRY / VOLUME 0, NUMBER presence of systemic diseases (diabetes, hypertension); (6) smoking habit (nonsmoker, 1 10 cigarettes per day, or more than 10 cigarettes per day); (7) periodontal disease (healthy or periodontally compromised); (8) implant manufacturer; (9) prosthetic connection (external or internal); (10) surface (according to implant manufacturer); (11) collar surface (considered smooth when at least 0.5 mm of the coronal portion of the implant had a polished or machined surface); (12) location (maxilla or mandible); (13) position (anterior or posterior); (14) protocol for implant placement, according to classification of Hämmerle et al 19 ; (15) primary stability (considered achieved when insertion torque was above 15 Ncm); (16) submerged or nonsubmerged healing; (17) surgeon who performed the operation and the postoperative appointments; (18) use of antibiotics or antibacterial mouthrinses after surgery; (19) specifictreatment for the postoperative infection; and (20) resolution and date of the last follow-up. Statistical Analysis The sample size was calculated to estimate the population prevalence of postoperative infections, with 2.5% precision and 95% confidence interval (CI). To this effect, postoperative infections prevalence was estimated a priori to affect 6% of the patients. A 30% overestimation was considered to compensate the expected number of excluded patients. Thus, a sample size of 452 patients was required. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS; IBM Corp., Armonk, NY). The normality of scale variables (patient age, time elapsed from implant placement to infection onset, and follow-up period) was explored using the Shapiro Wilks test. Wherever the normality was rejected, the interquartile range and median were calculated. Wherever the distribution was compatible with normality, the mean and SD were used. A nonparametric Mann Whitney U test was used to determine the relation between the postoperative infection onset and early implant failure. In contrast, a Fisher exact test was performed to detect whether the implant collar characteristics were associated with early failures. Ninety-five percent CI of implant- and patient-based prevalences of postoperative infections were calculated. The level of significance was set at P, RESULTS One thousand two hundred seventy-three implants were placed in 337 patients who fulfilled the inclusion criteria (Fig. 1). Twenty-two postoperative infections (22 patients) were recorded. The patient- and implant-based prevalences were 6.5% (95% CI: 4.4% to 9.7%) and 1.7% (95% CI: 1.2% to 2.6%), respectively. The mean age of patients (14 male and 8 female patients) with postoperative infections was 58.2 years (SD ¼ 9.4 years). Sixteen patients (72.7%) were nonsmokers, 2 (9.1%) smoked fewer than 10 cigarettes per day, and 4 patients (18.2%) were heavy smokers. Table 2. Main Surgical Characteristics of Infected Patients Case Implant Manufacturer Connection Body Surface Collar Surface Location Position Implant Placement Timing* Primary Stability Submerged Healing 1 Nobel Biocare External TiUnite Rough Maxilla Anterior 3 Yes Yes 2 Nobel Biocare External TiUnite Rough Mandible Anterior 4 Yes Yes 3 Nobel Biocare External TiUnite Rough Maxilla Posterior 4 No Yes 4 Nobel Biocare External TiUnite Rough Mandible Posterior 4 Yes Yes 5 Phibo External Avantblast Smooth Maxilla Posterior 4 Yes Yes 6 Nobel Biocare External TiUnite Rough Mandible Posterior 4 Yes Yes 7 Nobel Biocare External TiUnite Rough Maxilla Anterior 4 Yes Yes 8 Phibo External Avantblast Smooth Mandible Posterior 4 Yes Yes 9 Nobel Biocare External TiUnite Rough Mandible Anterior 4 Yes Yes 10 Phibo External Avantblast Smooth Mandible Posterior 4 Yes Yes 11 Nobel Biocare External TiUnite Rough Maxilla Anterior 3 No Yes 12 Nobel Biocare External TiUnite Rough Maxilla Anterior 4 Yes Yes 13 Astra Tech Internal OsseoSpeed Rough Maxilla Anterior 4 Yes No 14 Phibo External Avantblast Smooth Mandible Posterior 4 Yes No 15 Nobel Biocare External TiUnite Rough Mandible Posterior 4 Yes No 16 Astra Tech Internal OsseoSpeed Rough Mandible Posterior 4 Yes Yes 17 Phibo External Avantblast Smooth Mandible Anterior 4 Yes Yes 18 Phibo External Avantblast Smooth Maxilla Anterior 4 Yes Yes 19 Nobel Biocare External TiUnite Smooth Mandible Posterior 4 Yes Yes 20 Straumann Internal SLA Smooth Mandible Anterior 2 Yes No 21 Phibo External Avantblast Smooth Mandible Posterior 4 Yes Yes 22 Astra Tech Internal OsseoSpeed Rough Mandible Posterior 3 Yes Yes *According to Hammerle et al 19 : type 1, immediate; type 2, 4 to 8 weeks; type 3, 12 to 16 weeks; and type 4,.16 weeks. Note that only 4 patients had 1-stage implant placement (unsubmerged healing).

4 4 POSTOPERATIVE INFECTIONS IN IMPLANTS CAMPS-FONT ET AL Fifteen patients (68.2%) had a history of periodontitis. Tables 1 and 2 show the main demographic and surgical variables of the sample. The median time elapsed from implant placement to postoperative infection was 28 days (interquartile range ¼ 38.3; range: days). The time elapsed between implant placement and infection diagnosis did not seem to significantly increase the risk of an early implant failure (U ¼ 52.5; P ¼ 0.65). After infection onset, additional pharmacological treatment was prescribed in all cases. The most commonly prescribed drug was 875 mg amoxicillin and 125 mg potassium clavulanate (Augmentine 875/125; GlaxoSmithKline, Madrid, Spain), although other antibiotics were also used (Table 3). Patients were also instructed to perform mouthrinses with 0.12% chlorhexidine digluconate at every 12 hours for 15 days. When the initial antibacterial treatment did not resolve the infection, a surgical procedure, which consisted of implant, second-stage surgery (when the implant was submerged), or mechanical debridement with plastic curettes, was performed (17 cases; 77.3%) (Table 3). In the remaining 5 cases (22.7%), a second antibiotic treatment was prescribed. Amoxicillin with clavulanate was initially administered in 12 patients, but all of them required further surgical treatment. Clindamycin seemed to perform slightly better, as 2 of the 4 patients were successfully managed when this antibiotic was initially prescribed. Furthermore, 4 of the 5 patients, who did not require any surgical therapy to solve the postoperative infection, had been adequately treated with clindamycin (Table 3). Twelve infected implants (54.6%) in 12 patients (54.6%) failed before prosthetic loading. Bone-level implants had more failures (8 out of 13 implants; 61.5%) when compared with smoothcollar fixtures (4 out of 9 implants; 44.4%) (P ¼ 0.66). The surface did not seem as a relevant risk factor for implant loss after infection, because the TiUnite (6 cases; 54.6%), Avantblast (4 cases; 57.1%) and OsseoSpeed Table 3. Clinical Features and Performed Treatment in Patients With Postoperative Infections After Dental Implant Placement Case Time Elapsed (d) Suppuration Pain Antibiotics Used Antibiotic Treatment (d) Surgical Procedures Treatment That Resolved Infection Follow-Up After Loading (mo) 1 52 Yes No C 21 No C Yes Yes C 7 Implant Implant d No Yes C 28 2nd stage Surgery and C Yes No CP 10 Debridement Implant d 5 51 Yes No AC 7 2nd stage Surgery and AC Yes No AC, AZ 15 2nd stage Surgery and AZ Yes Yes AC 7 Implant Implant d No Yes A, C 15 No C Implant after 32 mo 9 43 No Yes AC 7 Implant Implant d Yes Yes C 7 No C Yes No AC, C 14 No C Yes Yes AC 15 Debridement Implant d Yes No A 8 Implant Implant d Yes No AC 7 Debridement Implant d Yes Yes A 8 No A Yes No AC 7 Implant Implant d Yes No AC 14 Debridement Surgery and AC Yes No A, M, AC 24 Debridement Surgery and AC Implant after 17 mo No Yes AC, C 14 Implant Implant d No Yes A 7 Implant Implant d Yes No AC 7 Debridement Implant d Yes Yes AC 10 Implant Implant d Note that more than half of the patients needed implant to solve this complication. A, amoxicillin; AP, amoxicillin and potassium clavulanate; AZ, Azithromycin (Zitromax, Pfizer; Madrid, Spain), 500 mg, every 24 hours for 3 days; C, clindamycin (Dalacin, Pfizer; Madrid, Spain), 300 mg, every 6 hours for 7 days; CP, ciprofloxacin (Ciprofloxacino Pharma; Madrid, Spain), 500 mg, every 12 hours for 7 days; M, metronidazole (Flagyl, Sanofi; Barcelona, Spain), 500 mg, every 8 hours for 7days.

5 IMPLANT DENTISTRY / VOLUME 0, NUMBER Table 4. Main Characteristics of the Previously Published Papers on Postoperative Infections After Dental Implant Placement No. of Implants No. of Patients No. of Infections Patient-Based Prevalence (%) 95% CI (Lower Upper Limit) (%) Implant-Based Prevalence (%) 95% CI (Lower Upper Limit) (%) Gynther et al 9 Abu-Ta a et al 10 Esposito et al 11 Anitua et al 12 Esposito et al 13 Caiazzo d 0 d et al 14 Present study There is a great disparity of patient-based prevalences, with values ranging from 0% to 11.5%. (2 cases; 66.7%) had similar survival rates. The loaded implants had survival and success rates of 80% and 50%, respectively, with a mean follow-up period of 42.9 months (SD ¼ 10.2 months). Table 3 describes some of the clinical features and treatment outcomes of the infected patients. DISCUSSION According to this study, postoperative infections after implant placement can affect up to 2.4% of the implants. However, this low percentage might be misleading because this complication can affect almost 10% of patients, if we consider the upper limit of 95% CI. Another extremely important fact is that two-thirds of the infected implants failed (most before prosthetic loading). Although the prevalence of postoperative infections when systemic antibiotics are administered varies considerably across the published studies, Esposito et al 7 found a weighted rate of 5.9% (95% CI: 3.8% to 7.9%). These numbers are quite similar to the ones reported in this study. In contrast, reports with small samples, 10,12,14 unclear diagnostic criteria, different research designs, and diverse demographic characteristics have shown disperse infection rates (Table 4). A single preoperative administration of antibiotics seems to reduce the failure rate of dental implants placed in ordinary conditions. Surprisingly, it has been suggested that the prescription of these drugs has no effect in the prevention of postoperative infections. In fact, a recent meta-analysis reported no statistical significant differences regarding infection prevalence when antibiotics were administered (5.9% vs 7.0%. P ¼ 0.39). 7 Although the preoperative administration of antibiotics seems to be recommended, there is still a lack of information regarding the most suitable antibiotic regimen in implant dentistry. In this report, antibiotics were only prescribed in the postoperative period, and the results of our cohort were quite similar compared to the samples that received preoperative medication. One of the major limitations of our study is related with its retrospective nature. Although this design might have slightly compromised the accuracy of the data, it allowed to include a large number of patients. Indeed, to our knowledge, this is one of the largest samples published on this topic. Another drawback of several papers published on this subject is related to the criteria used to define infection, which is mostly based on clinical observations. Some methods, such as the measurement of acute-phase protein levels could contribute to detect infections in a more objective way. 20 Most studies report a significantly higher prevalence of implant failures before prosthetic loading, when postoperative infections occur during the osseointegration period In fact, according to Esposito et al, 13 patients taking antibiotics, who developed this complication, had 80-times more risk of having an early implant failure (odds ratio ¼ 81.7; 95% CI: ; P, 0.001). 13 These authors also found that 3 quarters of these infections occurred within 2 weeks after the operation. In our sample, nearly two-thirds of the patients developed infection during the first month after surgery. However, it has to be emphasized that infection was later diagnosed in 4 cases, 3 to 4 months after operation. Some papers have stated that the time elapsed between the surgical procedure and infection onset could be a relevant prognosis factor, as early signs may seriously compromise the bone healing process. 18 Our results show that late onset postoperative infections (1 month after placement) are difficult to treat, as 66% of implants with this complication failed. The lack of soft tissue integrity during the healing phase of a 2-stage submerged implant, can lead to bone loss. In theory, the presence of bone defects, because of insufficient biological width, might be a risk factor for implant failure and periimplant infections. 21 In this report, unintentional exposure of the cover screw during the healing period could not be assessed due to the lack of data in the clinical records. An important variable that should be investigated in the future is the use

6 6 POSTOPERATIVE INFECTIONS IN IMPLANTS CAMPS-FONT ET AL and duration of chlorhexidine mouthrinses. In this study, all patients followed the same recommendations (postoperative chlorhexidine mouthrinses for 15 days), and therefore no comparison could be made. Although most of the infected patients in our report were nonsmokers, the lack of a control group, does not allow us to rule out smoking as a risk factor. In fact, other articles published by our department found an association between tobacco and higher failure rates, complications, and periimplant diseases. 22,23 The authors decided not to include patients who required simultaneous bone augmentation procedures because this can be an important confounding variable, as these procedures can increase the risk of infection, especially when wound dehiscence occurs. Although the influence of surgeons experience on implant survival is controversial, 24 some authors have shown higher complication rates when surgeons with limited experience perform operations. 25 The fact that all dentists were master degree residents could partially explain the high prevalence reported. Generally, rough implant surfaces enhance initial adhesion, attachment, and colonization of bacteria and influence plaque formation. Consequently, these surfaces might favor the onset and progression of the periimplant diseases more than smoother implant surfaces. 26,27 Accordingly, our results suggest that implants with smooth-surface collar fixtures had a better prognosis after conservative treatment of postoperative infections. In fact, these implants had a 1.4 times higher probability of overcoming infections when compared to rough-surfaced collar fixtures. However, probably due to the limited number of cases included in our study, no significant differences were observed. Future research on this topic is needed to clarify if this variable influences the incidence and the prognosis of this complication. It is known that biomaterial-based infections are extremely resistant to antibiotics and frequently persist until the implanted device is removed. 28,29 In this report, the prescribed antibiotics had very disappointing results, especially amoxicillin with clavulanate. Indeed, 17 out of 22 (77.3%) patients had to be surgically retreated because of antibiotic therapy failure. This stresses the importance to perform a study with the aim of identifying the bacteria involved and its susceptibility to commonly used antibiotics to determine the most adequate drug to treat such infections. A more effective therapeutic approach can eventually lead to improvement in the survival and success rates of these implants. Dental implants are considered a safe and predictable treatment method with both high survival and success rates. 2,30 Nevertheless, a postoperative infection might jeopardize the longterm treatment outcome as only 50% of the loaded implants fulfilled the Albrektsson et al success criteria. 19 Future research should be focused on the possible relationship between postoperative infections during the osseointegration period and the prevalence of periimplant diseases after prosthetic loading. CONCLUSIONS Four to 10% of patients receiving dental implants develop postoperative infections. This complication is important because applied treatments are usually ineffective, and two-thirds of the infected implants fail, most before prosthetic loading. DISCLOSURE The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article. This study was performed by the Dental and Maxillofacial Pathology and Therapeutic research group of the IDIBELL Institute. APPROVAL The study protocol was approved by the Ethical Committee for Clinical Research (CEIC) of the Dental Hospital in the University of Barcelona. REFERENCES 1. Brånemark PI, Breine U, Adell R, et al. Intra-osseous anchorage of dental prostheses. I. Experimental studies. Scand J Plast Reconstr Surg. 1969;3: Albrektsson T, Donos N; Working Group 1. Implant survival and complications. The Third EAO consensus conference Clin Oral Implants Res. 2012;6:S63 S Mir-Mari J, Mir-Orfila P, Figueiredo R, et al. Prevalence of peri-implant diseases. A cross-sectional study based on a private practice environment. J Clin Periodontol. 2012;39: 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. 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