Original Research Presoaking ACL Grafts in Vancomycin Decreases the Frequency of Postoperative Septic Arthritis A Cohort Study of 29,659 Patients, Systematic Review, and Meta-analysis From the SANTI Study Group Alessandro Carrozzo,*† MD, Adnan Saithna,‡ MD, FRCS(T&O), Alexandre Ferreira,† MD, Sylvain Guy,† MD, Lamine Chadli,† MD, Edoardo Monaco,§ MD, Daniel Pérez-Prieto,||{ MD, Yoann Bohu,#** MD, Thais Dutra Vieira,† MD, and Bertrand Sonnery-Cottet,† MD Investigation performed at Centre Orthopédique Santy, Lyon, France Background: Presoaking anterior cruciate ligament (ACL) grafts in vancomycin has been reported to reduce the occurrence of septic arthritis (SA). However, strong recommendations for its universal use have been precluded by concerns regarding the fragility of previous meta-analyses. Purpose: The primary objective was to investigate whether presoaking ACL grafts in vancomycin was associated with a reduction in the rate of SA in a large series of patients. The secondary objective was to perform an updated systematic review and meta- analysis to determine the efficacy of vancomycin in reducing the rate of SA. Study Design: Cohort study and systematic review; Level of evidence, 3. Methods: A retrospective analysis of patients who underwent primary ACL reconstruction (ACLR) at our institution was undertaken. Rates of postoperative SA were determined and analyzed according to whether patients had received grafts presoaked in vanco- mycin. A systematic review of the literature and meta-analysis was performed. Odds ratios (ORs) for the risk of SA were calculated according to the inverse variance approach. Results were presented using forest plots, funnel plots, and the fragility index. Results: A total of 5300 patients underwent primary ACLR during the study period. The rate of SA was 0.34% (11/3228) in the control group and 0.05% (1/2072) in the presoaked group. There was a 5-fold greater risk of SA in patients who did not receive grafts presoaked in vancomycin (OR, 5.13 [95% CI, 1.16-48.30]; P ¼ .04). Overall, 11 studies were included in the systematic review (29,659 ACLR procedures). The meta-analysis demonstrated a significantly greater risk of SA in those patients who did not receive grafts presoaked in vancomycin (OR, 14.39 [95% CI, 5.90-35.10]; fragility index ¼ 23). This finding held true for the subpopulation receiving hamstring tendon grafts (fragility index ¼ 16), but only a trend was demonstrated for bone–patellar ten- don–bone grafts. Conclusion: The meta-analysis demonstrated that presoaking ACL grafts in vancomycin was associated with significant reductions in the rates of SA when all graft types were analyzed together. This finding held true specifically for hamstring tendon autografts. The fragility index of these findings allows for a strong recommendation for the universal use of vancomycin presoaking. However, it should be noted that only a trend toward reduced SA rates was demonstrated with presoaking bone–patellar tendon– bone autografts in vancomycin. Keywords: knee; ligaments; ACL; anterior cruciate ligament reconstruction; septic arthritis; vancomycin Septic arthritis (SA) is an infrequent complication of ante- intravenous antibiotic prophylaxis.3,13,19,41 The current rior cruciate ligament (ACL) reconstruction (ACLR), with standard of care for the management of SA after ACLR an incidence ranging from 0.14% to 2.6%, despite the use of includes arthroscopic debridement, graft retention (with or without hardware removal), and antimicrobial treat- The Orthopaedic Journal of Sports Medicine, 10(2), 23259671211073928 ment. Although some authors 16,20 have reported good DOI: 10.1177/23259671211073928 results with such approaches, particularly with regards to ª The Author(s) 2022 their efficacy in eradicating infections, Presti et al 32 This open-access article is published and distributed under the Creative Commons Attribution - NonCommercial - No Derivatives License (https://creativecommons.org/ licenses/by-nc-nd/4.0/), which permits the noncommercial use, distribution, and reproduction of the article in any medium, provided the original author and source are credited. You may not alter, transform, or build upon this article without the permission of the Author(s). For article reuse guidelines, please visit SAGE’s website at http://www.sagepub.com/journals-permissions. 1 2 Carrozzo et al The Orthopaedic Journal of Sports Medicine cautioned that both arthrofibrosis and severe chondral to determine the efficacy of vancomycin in reducing the rate defects are observed frequently, even at short-term of SA and to report the fragility index of the findings. The follow-up. Additional potential complications include the hypothesis was that an updated meta-analysis with a very need for multiple reoperations, the need for the removal large study population would demonstrate that vancomycin of grafts and implants; prolonged duration of antimicrobial significantly reduces the risk of SA after ACLR and that the treatment and potentially devastating sequelae, including fragility index would give confidence in the findings and rapidly progressive chondrolysis. allow for firm recommendations for practice guidelines. In 2012, Vertullo et al45 reported that presoaking ACL hamstring tendon (HT) grafts in vancomycin (in combina- tion with routine intravenous antibiotic prophylaxis) was METHODS successful in reducing the rate of SA. Vancomycin appears to be an ideal drug to presoak the graft because of its low Cohort Study Design allergenicity, good heat stability, and safety for local use as well as the fact that it has bactericidal action against Institutional review board approval was granted for this most of the common pathogens isolated in ACLR infections study, and all participants gave valid consent to partici- such as Staphylococcus aureus and coagulase-negative pate. A retrospective analysis of prospectively collected staphylococci.15,26,27,29,31,37,40,47 Since the landmark publi- data from the SANTI Study Group Database was under- cation of Vertullo et al, 45 numerous groups have also taken. All patients who underwent primary ACLR per- reported that vancomycin presoaking could reduce the rate formed by the senior surgeon (B.S.-C.) between January of SA.2,5,10,21,23,24,26,27,29 However, it is important to note 2008 and September 2019 and had a minimum follow-up that despite this supporting evidence, important concerns of 12 months were considered for study eligibility. Patients exist, and this has limited the ability to make strong recom- were excluded if they had a history of ipsilateral knee inju- mendations for practice guidelines. ries or surgery; had a previous knee infection; sustained a Although several meta-analyses have confirmed an over- multiligamentous injury that required complex surgical all significant reduction in the rate of SA with vancomycin treatment; underwent other concomitant major procedures presoaking, they have been met with some skepticism (eg, osteotomy for coronal alignment correction or posterior because of concerns about the fragility of the findings. Fra- tibial slope correction); underwent reconstruction using an gility reflects the fact that a change in outcomes for a small allograft; had a known allergy to penicillin, cephalosporin, number of cases could significantly change the overall find- glycopeptide, or iodine; or had any history of diabetes or ings of the meta-analysis. This issue arises because of the immunosuppression. infrequency with which SA occurs and the resulting requirement for very large study populations to evaluate any intervention intended to reduce the risk. A further rea- Preoperative Infection Prophylaxis Protocol son that a blanket policy advocating for presoaking all grafts in vancomycin has not been recommended to date The same preoperative infection prophylaxis measures is because the majority of studies have focused on HT grafts were undertaken for all patients. The affected limb was and its efficacy has not been clearly demonstrated for other chemically epilated 1 week before surgery. The patients graft types. It appears that these unanswered questions took a shower using a povidone-iodine scrub brush 24 hours have resulted in a lack of widespread acceptance of vanco- before surgery. In the operating theater, a prophylactic mycin presoaking, with infrequent utilization reported in intravenous cefazolin bolus of 2 g was administered at the some countries.9,35,50 time of the induction of anesthesia, approximately 30 min- The primary objective of this study was to investigate utes before applying the pneumatic tourniquet. Next, the whether presoaking ACL grafts in vancomycin was associ- skin was precleaned via a brush application of alcoholic ated with a significant reduction in the rate of SA. The betadine. The surgeon subsequently performed a final secondary objectives were to perform an updated system- preparation, again using alcoholic betadine, before setting atic review and meta-analysis (including the current study) up sterile surgical drapes. Lastly, a stockinette and an *Address correspondence to Alessandro Carrozzo, MD, Centre Orthopédique Santy, 24 Avenue Paul Santy, 69008 Lyon, France (email: alessandrocarrozzo27@gmail.com) (Twitter: @ACarrozzoMD). † Centre Orthopédique Santy, Lyon, France. ‡ AZBSC Orthopedics, Scottsdale, Arizona, USA. § Orthopaedic and Trauma Surgery Unit, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy. || Department of Traumatology and Orthopaedic Surgery, Hospital del Mar, Autonomous University of Barcelona, Barcelona, Spain. { Catalan Institute of Traumatology and Sports Medicine, Dexeus University Hospital, Autonomous University of Barcelona, Barcelona, Spain. # Clinique du Sport, Paris, France. **Institut de l’Appareil Locomoteur Nollet, Paris, France. Final revision submitted November 9, 2021; accepted November 12, 2021. One or more of the authors has declared the following potential conflict of interest or source of funding: A.C. has received education support from Arthrex. E.M. and B.S.-C. have received consulting fees and royalties from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from the Scientific Committee of the GCS Ramsay Santé for Education and Research (reference No. COS- RGDS-2021-06-007-SONNERYCOTTET-B). The Orthopaedic Journal of Sports Medicine Vancomycin Presoaking of ACL Grafts 3 Ioban drape (3M) were applied. Postoperative antibiotics was created at the isometric point, slightly posterior and were not utilized. proximal to the lateral epicondyle. The ITB graft was then fixed within the socket using a bioabsorbable screw (Arthrex), with the knee placed in full extension and neu- Vancomycin Presoaking of Grafts and Group tral rotation. Allocation Combined ACLR þ ALL Reconstruction. Semitendin- Presoaking grafts in vancomycin was not utilized at our osus and gracilis tendons were harvested as described institution before July 2016. Therefore, all patients who above. A combined ACL þ ALL graft was prepared using underwent surgery before this date received intravenous a tripled semitendinosus tendon with an additional length antibiotic prophylaxis only and were allocated to the no of gracilis tendon sutured to it. The ACL portion of the graft vancomycin group. Patients undergoing surgery after this (3 parts semitendinosus and 1 part gracilis) was fixed on date received both intravenous antibiotics and grafts pre- both sides using bioabsorbable screws (Arthrex). The addi- soaked in vancomycin and were allocated to the vancomy- tional length of gracilis tendon that emerged from the fem- cin group. ACL grafts used for patients in the vancomycin oral tunnel, at the lateral cortex, formed the ALL portion of group were wrapped in gauze soaked in a 2.5-mg/mL van- the graft. This was passed under the ITB using a suture comycin solution (125 mg/50 mL) immediately after harvest grasper, then through a tunnel in the proximal tibia, and for approximately 10 minutes. back to the ALL origin, where it was tensioned and fixed with the knee in extension, completing double-strand ana- Surgical Techniques tomic ALL reconstruction.36 All procedures were performed with the patient under gen- Diagnosis and Management of Postoperative SA eral anesthesia and using a tourniquet. Bone–patellar ten- don–bone (BPTB), quadriceps tendon, or HT autografts The main outcome of interest was the occurrence of SA were utilized, and all tunnels were made using an within 12 months after ACLR. All patients with clinical outside-in technique. ACL grafts were fixed at 30 of knee symptoms suggestive of SA were admitted to the hospital flexion. Graft choices were based on patient factors and the urgently for physical examinations and laboratory tests evolving indications for performing a concomitant lateral (including C-reactive protein, erythrocyte sedimentation extra-articular procedure (either modified Lemaire lateral rate, and leukocyte count). The diagnosis of SA was clinical, extra-articular tenodesis [LET] or anterolateral ligament depending on the integration of history, examination, and [ALL] reconstruction) over the study period, including investigation findings. Clinical suspicion was based on younger age (<20 years), participation in pivoting sports, fever, rigor, knee pain, and loss of articular mobility. White high-demand athletes, high-grade pivot shift, lateral fem- cell count, erythrocyte sedimentation rate, and C-reactive oral notch sign, and Segond fractures. protein concentration were usually measured because, when raised, they aid in diagnosis and are useful to monitor ACLR With BPTB Graft. A 2-incision technique was responses to treatment. Patients who were suspected of used.12 BPTB grafts were harvested with a patellar bone having a deep infection underwent arthroscopic lavage plug (10  15 mm) and a tibial bone plug (9-11  25 mm). using 9 L of normal saline and careful debridement of Press-fit fixation was performed on the femoral side. Graft inflamed soft tissue. All knee compartments were fixation on the tibial side was performed using a bioabsorb- inspected, and graft integrity was assessed. Samples from able screw (Bio-Interference screw; Arthrex). intra-articular synovial fluid and debrided tissue were sent ACLR With HT Graft. The semitendinosus and gracilis for culture and antibiotic sensitivity. Postoperatively, tendons were harvested using an open-ended tendon strip- patients received empirical antibiotic therapy (intravenous per. The tibial insertion was preserved to improve fixation penicillin and gentamicin). This was subsequently adapted and vascularity.42 Tendons were quadrupled and then fixed according to bacterial identification and antibiotic sensitiv- using an interference screw and a cortical suspensory ities. Antibiotics were administered intravenously for device (TightRope; Arthrex). 3 days and then given orally for 6 weeks. ACLR With Quadriceps Tendon Graft. A 10 mm–wide quadriceps tendon graft was harvested with a patellar bone Systematic Review and Meta-analysis: Search plug (10  15 mm). The graft was routed proximally Strategy and Eligibility Criteria through the knee, with the bone plug placed on the tibial A systematic review of the literature relating to the influ- side. Fixation was performed using bioabsorbable screws on ence of presoaking ACL grafts on the rate of SA was per- both sides (Arthrex). formed according to PRISMA (Preferred Reporting Items Concomitant Modified Lemaire LET. A 1 cm–wide strip for Systematic Reviews and Meta-Analyses) guidelines. of the iliotibial band (ITB) was harvested up to 2 cm prox- The systematic review protocol was registered with the imal to the lateral epicondyle, keeping its tibial attachment PROSPERO database (registration No. CRD42020223628). to the Gerdy tubercle intact. The ITB graft was passed A literature search was performed using subject mapping beneath the fibular collateral ligament from distal to prox- and the following keywords: “anterior cruciate ligament” imal using a right-angled clamp. A 4.5 mm–diameter socket and “vancomycin” in combination with “septic arthritis” 4 Carrozzo et al The Orthopaedic Journal of Sports Medicine or “infection.” The search strategy was applied to the PubMed Eligible paents (N = 6398) and Embase databases by 2 investigators independently on • Underwent ACLR at our instuon, Excluded (n = 877) December 30, 2020 (A.C. and A.S.). January 2008 to September 2019 • Surgical treatment for Each article was reviewed for relevance, and the refer- • Minimum 12 months of follow-up mulligamentous injuries (107) ences of included articles were reviewed to identify further • History of previous ipsilateral knee injury or surgery (431) relevant studies. All comparative studies evaluating the • Concomitant major procedures (68) influence of vancomycin on the rates of SA after ACLR were • Use of allogra (53) included. Patients from our previously presented clinical • Allergy to penicillin, cephalosporin, Paents included glycopepdes, or iodine (184) series were included in the meta-analysis to increase the (n = 5521) • Diabetes or immunosuppression (34) sample size because of the rare nature of SA after ACLR. In addition, our population comprised a substantial number of Lost to follow-up (n = 221) patients who had undergone ACLR using a BPTB graft, which was an underrepresented group in the previously Final study populaon published work included in the meta-analysis. Studies were (n = 5300) only excluded if they were not published as a full article in a peer-reviewed journal, were duplicated or overlapped popu- lations with included studies, or were unavailable in the No vancomycin Vancomycin English language. Any disagreements between investiga- (n = 3228) (n = 2072) tors regarding study eligibility were resolved by the senior author (B.S.-C.). Figure 1. STROBE (Strengthening the Reporting of Observa- tional Studies in Epidemiology) flow diagram of the cohort Statistical Analysis study arm. ACLR, anterior cruciate ligament reconstruction. Calculations were made using SAS for Windows (Version 9.4; SAS Institute), with the level of statistical significance RESULTS set at P < .05. Descriptive data analysis was conducted depending on the nature of the considered criteria. For Results of Cohort Study quantitative data, this included the number of observed The study population comprised 5300 patients who under- (and missing, if any) values and the mean, SD, median, went primary ACLR during the study period: 3228 patients range and lower and upper quartiles. For qualitative data, (60.9%) in the no vancomycin group and 2072 patients this included the number of observed (and missing, if any) (39.1%) in the vancomycin group (Figure 1). Patients in the values and the number and percentage of patients per vancomycin group were significantly younger (age, 28.0 ± group. The characteristics of the studied population were 10.0 vs 29.3 ± 10.4 years, respectively; P ¼ .001); otherwise, described according to group allocation and the rate of SA there were no differences in preoperative patient character- reported. Because of the small number of infections, 95% istics between the groups. There were no differences CIs were calculated using the exact binomial method. between the no vancomycin and vancomycin groups regard- For the meta-analysis, data were extracted from ing the operating time (31.7 ± 16.4 vs 31.1 ± 15.9 minutes, included studies to determine the number of cases of SA respectively; P ¼ .788), but there was a significant differ- and the total number of patients in each group. Missing ence in the overall proportion that underwent a lateral SDs were determined according to the sample size and extra-articular procedure (either modified Lemaire LET means from reported P values.11 When the required data or ALL reconstruction) (35.5% vs 69.2%, respectively; P < were not available for extraction from published articles, .001). The population characteristics and details of graft they were requested directly from the corresponding choice (as well as extra-articular procedures) are reported author. Odds ratios (ORs) for the risk of SA in each group in Tables 1 and 2, respectively. were calculated according to the inverse variance approach. Heterogeneity across publications was assessed using I2 Occurrence of SA values, with moderate heterogeneity defined as I2 between 30% and 60%. A random-effects Mantel-Haenszel model Overall, 12 patients were diagnosed with SA during the was used to account for between-study variation. Results study period (0.23% [95% CI, 0.12%-0.40%]). There were were presented using forest plots, and 95% CIs were calcu- 11 infections that occurred in the no vancomycin group lated using the exact binomial method. Funnel plots were (0.34% [95% CI, 0.17%-0.61%]) and 1 in the vancomycin generated to assess bias due to small study effects.28 The group (0.05% [95% CI, 0.01%-0.27%]) (Table 4). The infec- fragility index, which describes the extent to which the tions were sustained by bacteria belonging to the Staphy- attribution of statistical significance is subject to random lococcus genus in 10 of 12 patients (83.3%). Patients who influences and indicates the number of patients whose did not receive grafts presoaked in vancomycin were at >5- results would have to change to alter the statistical inter- fold greater risk of SA compared with those who did (OR, pretation of the study, was determined using the R software 5.13 [95% CI, 1.16-48.30]; P ¼ .04). The characteristics of package. the infected patients are reported in Table 3. The Orthopaedic Journal of Sports Medicine Vancomycin Presoaking of ACL Grafts 5 TABLE 1 Patient Characteristicsa Total (n ¼ 5300) No Vancomycin (n ¼ 3228) Vancomycin (n ¼ 2072) P Value Age, y 28.8 ± 10.3 29.3 ± 10.4 28.0 ± 10.0 .001 Sex .319 Female 1454 (27.5) 904 (28.0) 559 (26.98) Male 3830 (72.5) 2324 (72.0) 1513 (73.02) Body mass index 23.9 ± 3.3 23.9 ± 3.3 24.0 ± 3.5 .341 Side .864 Right 2810 (53.2) 1722 (53.3) 1089 (52.99) Left 2475 (46.8) 1506 (46.7) 974 (47.01) a Data are reported as mean ± SD or n (%). Bolded P value indicates a statistically significant difference between groups (P < .05). TABLE 2 greater risk of SA after ACLR. This finding was demon- Surgical Procedure Characteristicsa strated in the cohort study and subsequently confirmed in the overall meta-analysis (OR, 14.39 [95% CI, 5.90-35.10]). Total No Vancomycin Vancomycin Although these findings are consistent with those of the (n ¼ 5300) (n ¼ 3228) (n ¼ 2072) previous literature, the very large study population allows Graft type for greater confidence in the findings than that conferred by BPTB 729 (13.8) 487 (15.1) 242 (11.7) previous smaller meta-analyses. This was best expressed HT 4510 (85.1) 2699 (83.6) 1811 (87.4) via the fragility index. In the current meta-analysis, a Quadriceps 61 (1.2) 42 (1.3) 19 (0.9) change in status of 23 patients (representing 16.2% of the tendon total number of SA events) was required for the study to Isolated ACLR 2720 (51.3) 2082 (64.5) 638 (30.8) lose statistical significance. Although there is no specific ACLR þ modified 203 (3.8) 150 (4.6) 53 (2.6) Lemaire LET fragility index that is considered acceptable, interpretation ACLR þ ALL 2376 (44.8) 996 (30.9) 1380 (66.6) is aided by considering that among statistically significant reconstruction meta-analyses from the Cochrane database, the median fragility index was found to be 12, and in 29% of meta- a Data are reported as n (%). ACLR, anterior cruciate ligament analyses, the overall fragility index was <5.1 Furthermore, reconstruction; ALL, anterolateral ligament; BPTB, bone–patellar 9% of meta-analyses would have become nonsignificant if tendon–bone; HT, hamstring tendon; LET, lateral extra-articular the event status was modified for <1% of the total number tenodesis. of events. On that basis, it is our opinion that the overall findings of this meta-analysis are robust. In the meta-analysis, we further sought to determine the Results of Literature Search and Meta-analysis efficacy of vancomycin presoaking specifically for the 2 The search strategy yielded 11 eligible studies,†† from which most popular graft choices in clinical practice. For HT auto- data were extracted and pooled alongside the current study grafts, which according to some authors are at a higher risk (Figure 2). The final population for the pooled data analysis of SA,17 a very large population was available for study, and comprised 29,659 patients. Table 4 shows the incidence of SA the meta-analysis demonstrated that the failure to utilize and the associated 95% CIs for all studies, including the cur- vancomycin presoaking resulted in a significantly greater rent study, and Table 5 shows the incidence of SA according to risk of SA (OR, 13.50 [95% CI, 4.03-45.21]). The fragility graft type. The meta-analysis demonstrated a significantly index for this finding was 16, and this allows for a strong greater risk of SA in those patients who did not receive grafts recommendation in favor of vancomycin presoaking for all presoaked in vancomycin (OR, 14.39 [95% CI, 5.90-35.10]) HT autografts. The same evaluation for BPTB grafts (Figure 3). The funnel plot analysis did not demonstrate showed no significant increase in the risk of SA when asymmetry (Figure 4). Analyses of the relative risk of SA after vancomycin presoaking was omitted (OR, 3.42 [95% CI, ACLR using HT and BPTB autografts in each included study 0.60-19.58]). However, this finding should be interpreted are reported in Figures 5 and 6, respectively. cautiously because the population available for study was relatively small (n ¼ 1618), and therefore, this part of the analysis was likely to have been underpowered. It is note- DISCUSSION worthy that no cases of SA occurred in those patients receiving a BPTB graft treated with vancomycin presoak- The main finding of this study was that not presoaking ACL ing (0/599) but that the rate of SA was 0.99% (7/1019) in the grafts in vancomycin was associated with a significantly control group. Although this trend was nonsignificant, it lends some support to a recommendation for presoaking †† References 2, 4, 5, 7, 10, 23, 27, 29, 39, 45, 46. of all ACL grafts in vancomycin, particularly given the 6 Carrozzo et al The Orthopaedic Journal of Sports Medicine TABLE 3 Characteristics of Patients Diagnosed With Septic Arthritis (n ¼ 12)a Lateral Time From Extra-articular Reconstruction to Patient Age, y Sex Graft Procedure Additional Procedures Bacterial Organism Infection, d 1 25 M BPTB No No SC 14 2 44 M HT Yes No SA 20 3 27 M BPTB Yes MM þ LM repair PBA 149 4 32 M HT Yes No SC 12 5 24 F HT Yes No SA 15 6 33 M HT Yes No SE 34 7 33 M HT Yes MM þ LM repair SM 10 8 37 M HT No MM repair þ LM meniscectomy SL, SC, SCA 15 9 24 M HT No No SA 60 10 28 F HT No No SA 20 11 18 M HT Yes MM repair SA 40 12b 27 M HT Yes No SC 13 a BPTB, bone–patellar tendon–bone; F, female; HT, hamstring tendon; LM, lateral meniscus; M, male; MM, medial meniscus; PBA, Propionibacterium acnes; SA, Staphylococcus aureus; SC, Staphylococcus caprae; SCA, Staphylococcus capitis; SE, Staphylococcus epider- midis; SL, Staphylococcus lugdunensis; SM, Serratia marcescens. b Patient 12 was in the vancomycin group. result in a relatively benign course. This message has per- Records retrieved through haps been reinforced by a previous systematic review in database search which Makhni et al18 concluded that outcomes in patients Idenficaon (N=284) after SA are broadly comparable to those in patients in whom an infection does not develop (including range of motion, residual instability, Lysholm score, and return to Records aer duplicates preinjury levels of activity). However, pooling studies with removed inconsistent reporting, a short-term follow-up, and conflict- (n = 240) ing findings may have resulted in a lack of clarity regarding the severity and spectrum of morbidity. It is therefore Screening important to highlight that several authors have reported Titles and/or abstracts Records excluded (n = 226) • Editorials (4) inferior outcomes after SA compared with those in patients screened in whom an infection did not develop and furthermore that • In vitro studies (17) (n = 240) • Nonrelated studies (205) resultant limitations can be severe.16,20,37,40,43 Waterman et al48 reported on 31 (of a series of 9511 ACLR procedures) cases of SA from the military health care system. At a mean Eligibility Full-text arcles excluded Full-text arcles assessed for ineligible design (n = 3) follow-up of 26.9 months, only 33.3% of those who under- for eligibility • Editorial (1) went graft resection and 54.5% of those who underwent (n = 14) • In vitro study (1) graft retention were able to return to military function . • Overlapping cohorts (1) Significant risk factors for the inability to return to duty included symptomatic postinfection arthritis and arthrofi- Included Studies included in brosis. These risk factors appear to be surprisingly common qualitave and quantave after SA, with Presti et al32 reporting high rates of arthro- synthesis (meta-analysis) fibrosis (81%) and severe chondral defects (63%) at a mean (n = 11) follow-up of 56 months. Although very long-term studies are sparse, Schub et al 38 reported the outcomes of 4 Figure 2. PRISMA (Preferred Reporting Items for Systematic patients with a mean follow-up of 17.9 years. The authors Reviews and Meta-Analyses) flow diagram of the systematic reported that all patients had a Kellgren-Lawrence arthri- review and meta-analysis arm. tis severity grade of at least 3 (in at least 1 compartment). They also reported diminished long-term subjective and functional outcomes compared with historical reports of significant overall reduction in the rate of SA when all graft uncomplicated cases and attributed these inferior outcomes types were grouped together. to advanced arthritis. These findings serve to highlight that It is our opinion that there have been several previous the sequelae of SA are considerable and that the condition barriers to the widespread adoption of presoaking all ACL is associated with significant morbidity. grafts in vancomycin. One of these is perhaps a misconcep- Further barriers to the widespread use of vancomycin tion that early arthroscopic washout and graft retention presoaking were highlighted by a 2021 survey of ACL study The Orthopaedic Journal of Sports Medicine Vancomycin Presoaking of ACL Grafts 7 TABLE 4 SA Incidence and Antibiotic Prophylaxis Protocolsa No. of Patients Total No. of SA Incidence With SA Patients (95% CI), % Vancomycin Presoaking Protocol Current study Vancomycin wrapping: 2.5 mg/mL (10-15 min). IV antibiotic preoperative Overall 12 5300 0.23 (0.12-0.40) prophylaxis: 2 g of cefazolin. No vancomycin 11 3228 0.34 (0.17-0.61) Vancomycin 1 2072 0.05 (0.00-0.27) Phegan29 (2016) Vancomycin wrapping: 5 mg/mL. IV antibiotic preoperative prophylaxis: Overall 4 1585 0.25 (0.07-0.64) 2 g of cefazolin. No vancomycin 4 285 1.40 (0.38-3.55) Vancomycin 0 1300 0.00 (0.00-0.28) Wan46 (2020) Vancomycin dipping (1 min) þ wrapping (15-20 min): 5 mg/mL. IV Overall 3 305 0.98 (0.20-2.85) antibiotic preoperative prophylaxis: 1 g of cefazolin. No vancomycin 3 185 1.62 (0.34-4.67) Vancomycin 0 120 0.00 (0.00-3.03) Pérez-Prieto27 (2016) Vancomycin dipping þ wrapping (10-15 min): 5 mg/mL. IV antibiotic Overall 15 1544 0.97 (0.54-1.60) preoperative prophylaxis: 2 g of cefazolin. No vancomycin 15 810 1.85 (1.04-3.04) Vancomycin 0 734 0.00 (0.00-0.50) Offerhaus23 (2019) Vancomycin dipping þ wrapping: 5 mg/mL. IV antibiotic preoperative Overall 22 1779 1.24 (0.78-1.87) prophylaxis: 2 g of cefazolin. No vancomycin 22 926 2.38 (1.49-3.58) Vancomycin 0 853 0.00 (0.00-0.43) Figueroa10 (2019) Vancomycin wrapping (15-20 min): 5 mg/mL. IV antibiotic preoperative Overall 4 490 0.82 (0.22-2.08) prophylaxis: 2 g of cefazolin. No vancomycin 4 230 1.74 (0.48-4.39) Vancomycin 0 260 0.00 (0.00-1.41) Banios2 (2021) Vancomycin wrapping: 5 mg/mL. IV antibiotic preoperative and Overall 7 1835 0.38 (0.15-0.78) postoperative prophylaxis. No vancomycin 7 1242 0.56 (0.23-1.16) Vancomycin 0 593 0.00 (0.00-0.62) Schuster39 (2020) Vancomycin wrapping: 5 mg/mL. IV antibiotic preoperative prophylaxis. Overall 35 10,516 0.33 (0.23-0.46) No vancomycin 35 8222 0.43 (0.30-0.59) Vancomycin 0 2294 0.00 (0.00-0.16) Bohu5 (2020) Vancomycin dipping (10 min): 5 mg/mL. IV antibiotic preoperative Overall 7 1674 0.42 (0.17-0.86) prophylaxis: 2 g of cefazolin. No vancomycin 7 1184 0.59 (0.24-1.21) Vancomycin 0 490 0.00 (0.00-0.75) Vertullo45 (2012) Vancomycin wrapping: 5 mg/mL. IV antibiotic preoperative prophylaxis: Overall 4 1155 0.35 (0.10-0.90) 2 g of cefazolin. No vancomycin 4 285 1.40 (0.38-3.55) Vancomycin 0 870 0.00 (0.00-0.42) Chaturvedi7 (2020) Vancomycin wrapping: 5 mg/mL. IV antibiotic preoperative prophylaxis: Overall 18 1836 0.98 (0.58-1.55) 2 g of cefazolin. No vancomycin 18 963 1.87 (1.11-2.94) Vancomycin 0 873 0.00 (0.00-0.42) Baron4 (2019) Vancomycin dipping (10 min) þ wrapping: 1 mg/mL. IV antibiotic Overall 11 1640 0.67 (0.34-1.20) preoperative prophylaxis: cefazolin. No vancomycin 10 842 1.19 (0.57-2.17) Vancomycin 1 798 0.13 (0.00-0.70) a IV, intravenous; SA, septic arthritis. group members. These included concerns regarding its limitations included questionable external validity, given cost-effectiveness, the effect on mechanical properties of the widely varying costs within the United States and the graft, and antibiotic resistance.50 Ruelos et al34 recently internationally. However, these findings are supported by demonstrated that vancomycin presoaking was highly cost- Offerhaus et al,23 who demonstrated cost-effectiveness in effective (assuming the following costs in US Dollars: van- the German health care system. Concerns about the effect comycin, $44; arthroscopic debridement and ACL graft of vancomycin on graft integrity are not supported by retention, $6424; ACL graft revision, $24,178), although Jacquet et al,14 who demonstrated no difference in the 8 Carrozzo et al The Orthopaedic Journal of Sports Medicine TABLE 5 SA Incidence According to Graft Type From Current Study and Included Studiesa Graft Type Without Vancomycin (n ¼ 18,402) With Vancomycin (n ¼ 11,257) Overall (n ¼ 29,659) BPTB 7/1019 (0.687) 0/599 (0.000) 7/1618 (0.433) HT 84/13,711 (0.613) 1/7926 (0.013) 85/21,637 (0.393) Other/not specified 49/3672 (1.334) 1/2736 (0.036) 50/6404 (0.781) Any 140/18,402 (0.761) 2/11,261 (0.018) 142/29,659 (0.479) a Data are reported as the ratio of SA per population. BPTB, bone–patellar tendon–bone; HT, hamstring tendon; SA, septic arthritis. Figure 3. Forest plot demonstrating the relative risk of septic arthritis (SA) after anterior cruciate ligament reconstruction using any type of graft in each included study and the pooled summary estimate. Sizes of data markers are proportional to the weight of each study. Horizontal bars represent the 95% CI of individual studies. Pooled analysis demonstrated that the failure to presoak grafts in vancomycin was associated with a significantly greater risk of SA (odds ratio [OR], 14.39 [95% CI, 5.90-35.10]). The fragility index was 23. Figure 4. Funnel plot demonstrating that the effect estimates derived from each of the included studies are symmetrical and scatter widely at the bottom. No publication bias was detected. Odds ratios >1 are in favor of the vancomycin group. The Orthopaedic Journal of Sports Medicine Vancomycin Presoaking of ACL Grafts 9 Figure 5. Forest plot demonstrating the relative risk of septic arthritis (SA) after anterior cruciate ligament reconstruction using hamstring tendon autografts in each included study and the pooled summary estimate. Sizes of data markers are proportional to the weight of each study. Horizontal bars represent the 95% CI of individual studies. Pooled analysis demonstrated that the failure to presoak grafts in vancomycin was associated with a significantly greater risk of SA (odds ratio [OR], 13.50 [95% CI, 4.03-45.21]). The fragility index was 16. Figure 6. Forest plot demonstrating the relative risk of septic arthritis (SA) after anterior cruciate ligament reconstruction using bone–patellar tendon–bone (BPTB) autografts in each included study and the pooled summary estimate. Sizes of data markers are proportional to the weight of each study. Horizontal bars represent the 95% CI of individual studies. Pooled analysis demonstrated that the failure to presoak grafts in vancomycin was associated with a nonsignificant trend toward a higher risk of SA (odds ratio [OR], 3.42 [95% CI, 0.60-19.58]). Three studies reporting the use of BPTB autografts were excluded because there were no events in either group or because the authors did not provide the necessary data.2,4,23 biomechanical properties of HT autografts treated with and institution, employing vancomycin at a 2.5-mg/mL concen- without vancomycin presoaking, or by Pérez-Prieto et al,25 tration, was established before there was a proliferation of who reported no difference in graft rupture rates in a small literature regarding this prophylactic wrap. This corre- comparative series. Still, Xiao et al49 examined the in vitro sponds to a lower concentration compared with that used toxicity of various doses of vancomycin on the patellar ten- in other studies but did not lead to a higher incidence of SA don, showing that even high concentrations (12.8 mg/mL) of than that in studies that used vancomycin at higher con- vancomycin, up to 6 hours of exposure, do not lead to cell centrations. Although concerns about antibiotic resistance death and toxicity to tenocytes. To our knowledge, there are more difficult to address, it seems that widespread were no cases of vancomycin resistance in this SA popula- global issues surrounding the use of antibiotics (including tion. The vancomycin presoaking protocol of our misuse, ease of availability, excessive use in the food chain, 10 Carrozzo et al The Orthopaedic Journal of Sports Medicine and lack of surveillance of resistance development8) are of CONCLUSION greater concern rather than specifically focused and appro- priately indicated prophylactic antibiotics for orthopaedic The meta-analysis demonstrated that presoaking ACL surgery. grafts in vancomycin was associated with significant reduc- In a recent editorial commentary, Vertullo44 addressed tions in the rates of SA when all graft types were analyzed whether vancomycin presoaking should become a universal together. This finding held true specifically for HT auto- recommendation for all ACL grafts. 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