Changes in Antibiotic Susceptibility of Staphylococcus aureus ...

The Journal of Arthroplasty xxx (2018) 1e6

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Changes in Antibiotic Susceptibility of Staphylococcus aureus Between the Stages of 2-Stage Revision Arthroplasty Jaiben George, MBBS a, Jared M. Newman, MD a, Alison K. Klika, MS a, *, Evan M. Miller, BA a, Timothy L. Tan, MD b, Javad Parvizi, MD b, Carlos A. Higuera, MD a a b

Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio Department of Orthopaedic Surgery, Rothman Institute, Philadelphia, Pennsylvania

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 November 2017 Received in revised form 2 January 2018 Accepted 22 January 2018 Available online xxx

Background: Staphylococcus aureus is the predominant cause of periprosthetic joint infection (PJI) and can persist at the time of planned second stage of 2-stage revision arthroplasty, despite antibiotic cement spacer insertion and parenteral antibiotic therapy. Given the rapid emergence of antibiotic resistance, it is important to determine whether the antibiotic susceptibility of microorganisms changes between the stages of a 2-stage revision. Methods: A total of 1614 2-stage revision hip/knee arthroplasties performed for PJI at 2 academic institutions from 2000 to 2015 were identified. S aureus (methicillin susceptible and/or resistant) was isolated by culture in 402 (24.9%) cases during the first stage (resection arthroplasty). S aureus persisted and was cultured in 30 cases (knees ¼ 18, hips ¼ 12) during the second stage. Minimum inhibitory concentrations (MICs), demographics, antibiotic therapy, and surgical history were collected. The MICs at the time of the first-stage and second-stage surgeries were compared. Results: Nine (30%) revisions had an increase in vancomycin MIC. Six had an increase from 0.5 to 1 mg/mL, 2 had an increase from 0.5 to 2 mg/mL, and 1 had an increase from 1 to 2 mg/mL. All of the 9 revisions with an increase in vancomycin MIC had vancomycin in spacer. Conclusion: Increases in the MICs were observed for vancomycin, the antibiotic widely used in cement spacers, in about one-third of the revisions. Despite the small sample size, the data from this preliminary study raise concern about the potential for emergence of resistant organisms between the stages of a 2-stage revision. © 2018 Elsevier Inc. All rights reserved.

Keywords: periprosthetic joint infection persistent infection 2-stage revision antimicrobial resistance minimum inhibitory concentration

Periprosthetic joint infection (PJI) is a serious complication of total hip and knee arthroplasty with an overall incidence of approximately 1.5 infections per 1000 person-joint-years [1,2]. Currently, 2-stage revision arthroplasty, which involves the removal of prosthesis, and the implantation of a temporary antibiotic cement spacer, is the most widely used treatment for PJI [3,4]. In addition to the local delivery of the high dose of antibiotics, patients are administered parenteral antibiotic therapy for 6 to 8 weeks before attempting prosthesis reimplantation. Despite the

One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2018.01.056. * Reprint requests: Alison K. Klika, MS, Department of Orthopaedic Surgery, Cleveland Clinic e A41, 9500 Euclid Ave., Cleveland, OH 44195. https://doi.org/10.1016/j.arth.2018.01.056 0883-5403/© 2018 Elsevier Inc. All rights reserved.

delivery of both parenteral and high local concentrations of antibiotics, the 2-stage revision surgeries have a reported success rate approaching 70% to 80%, with some suggesting that success rates of these procedures are on the decline [5e10]. The majority of failed 2-stage revisions is thought to be due to the inability to eradicate the original infection before proceeding with the second-stage reimplantation [11,12]. Staphylococcus aureus (methicillin-susceptible S aureus [MSSA] or methicillin-resistant S aureus [MRSA]) is the predominant microbial species causing PJI and is responsible for approximately 50% to 60% of the culture-positive PJIs [1,2,13]. The microorganisms isolated at the time of the second-stage surgery may or may not be the same species initially responsible for the PJI. Isolation of the same species of microorganism is most likely due to persistence of the original pathogen, while a different species might be isolated if it was acquired during the interim period (ie, between the first-stage and second-stage surgeries), or went undetected during the

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J. George et al. / The Journal of Arthroplasty xxx (2018) 1e6

first-stage surgery. When the same species is isolated at the secondstage surgery, this may be related to its susceptibility to the antibiotics used in spacers and/or the antibiotic concentration that was delivered locally [14e17]. Previous studies have shown that spacers retain their eluting properties for long periods, suggesting that the latter (ie, susceptibility of these organisms to the antibiotics used in spacers) is the issue [14e17]. Furthermore, the antibiotic content of spacers usually differs from those administered systemically, which are based on the culture sensitivity [18]. This might expose the organisms to various concentrations of multiple antimicrobial agents, some of which may be subtherapeutic, thereby increasing the risk for emergence of resistant strains [19,20]. With an increased focus on antibiotic resistance, it is important to determine whether antibiotic spacers increase the minimum inhibitory concentrations (MICs) of microorganisms to the antibiotics that are commonly used in spacers, such as vancomycin [18,19]. Previous studies have examined the susceptibility patterns of microorganisms that cause PJI [21,22]. However, these studies were limited to those isolated at the time of first-stage surgery and did not evaluate the changes in the antibiotic susceptibility following the insertion of antibiotic spacers [21,22]. Therefore, we asked: (1) what proportion of the persistent S aureus shows an increase in the MIC of various antibiotics, especially vancomycin; and (2) what factors are associated with the increase in MICs? Methods This was a multicenter, retrospective study of patients who had a PJI caused by S aureus and underwent a 2-stage revision hip or knee arthroplasty between 2000 and 2015, but had persistence of S aureus at the time of their planned second-stage surgery. After obtaining approval from the institutional review boards, data, including microbiology information related to the MIC of organisms against various antibiotics at the time of first-stage and secondstage surgeries, were reviewed and collected from electronic medical records. Participants/Study Subjects A total of 1614 2-stage revision hip/knee arthroplasties performed at 2 large academic institutions were identified from the infection databases at these institutions. S aureus (MSSA or MRSA) was isolated at the time of antibiotic spacer insertion (first-stage surgery) in 402 (24.9%) cases. These revisions were screened to determine those in which S aureus persisted at the time of antibiotic spacer removal (ie, second-stage surgery), which identified 30 cases (knees ¼ 18, hips ¼ 12) to be included in the study cohort. During the first-stage revision surgery, all patients had their implants removed followed by irrigation and debridement. An antibiotic cement spacer was then implanted; the cement spacers were composed of tobramycin plus vancomycin (n ¼ 23), tobramycin alone (n ¼ 4), vancomycin alone (n ¼ 2), or tobramycin plus daptomycin (n ¼ 1). The second stage of the 2-stage revision was usually attempted after at least 6-8 weeks of parenteral antibiotic therapy, and an antibiotic holiday of approximately 2 weeks. The median duration between the first-stage and second-stage surgeries was 101 days (interquartile range, 73 to 137 days). The decision to reimplant or to perform a spacer exchange was made on the basis of clinical features, preoperative laboratory parameters, and intraoperative findings. At the planned second stage, a total of 4 revisions underwent reimplantation, whereas the remaining 26 revisions had a spacer exchange or a similar procedure due to concerns of persistent infection. The antibiotic selection was based on culture sensitivity reports and the respective institutions’

guidelines. All patients were initially on broad-spectrum antibiotics based on the recommendations of infectious disease specialist, and the regimen was altered in 17 patients after intraoperative culture results were obtained. In the remaining 13 patients, the same antibiotic was continued. Intravenous (IV) antibiotics used after first stage were vancomycin 15 mg/kg q12 h (n ¼ 12), daptomycin 6 mg/kg IV q24 h (n ¼ 11), cefazolin 1-2 g IV q8 h (n ¼ 4), nafcillin 1.52 g IV q4-6 h (n ¼ 1), ampicillin-sulbactam 3 g IV q6 h (n ¼ 1), and ceftaroline 200 mg IV q12 h (n ¼ 1). The dose of vancomycin was adjusted to maintain a trough level between 10-20 mg/L. In addition to the IV therapy, some patients also received oral antibiotics (rifampin ¼ 6, ciprofloxacin ¼ 2, doxycycline ¼ 1, metronidazole ¼ 1) based on the infectious disease specialists’ recommendations. Cultures were obtained preoperatively (synovial fluid) and intraoperatively (synovial fluid and multiple tissue specimens from different areas) based on the surgeons’ preferences. The median number of cultures taken at the first stage was 4 (range ¼ 2 to 8), while that at the second stage was 4 (range ¼ 1 to 10). We did not have any predefined number of positive cultures for a revision to be considered as truly infected. However, all the patients in the study had more than one positive cultures with S aureus at the first stage, and all expect 4 patients had more than one positive cultures with S aureus at the second stage. As S aureus is a virulent pathogen and is rarely considered to be a contaminant, we believe that it is reasonable to assume S aureus as a true pathogen even if only 1 culture was positive. Moreover, as patients who had a single positive culture at second stage had established infection with the same organism, this is unlikely to have been a contaminant. MICs, which are the lowest concentrations of antibiotics that prevent growth of the microorganisms, were obtained from laboratory reports [23]. The MIC values were reported over a predetermined range that was specific for each antibiotic, based on the Clinical and Laboratory Standards Institute susceptibility testing guidelines [24]. For example, the vancomycin MICs of susceptible S aureus are reported as 0.5 mg/mL, 1 mg/mL, or 2 mg/mL [25]. The MICs were tested using commercially available automated systems routinely used at the respective institutions (VITEK at institution 1 and Pheonix at institution 2); however, MIC measurements are expected to have a measurement error of 1 dilution [26]. The MICs of all antibiotics were not usually assessed for every specimen. The choice of antibiotics to be tested for each specimen was based on the laboratory guidelines at the 2 institutions. The MICs of the organisms isolated at the time of planned second-stage surgery were compared with the MICs of the corresponding first-stage surgery to see whether there was any increase in the MICs. All antibiotics whose MICs were recorded in the culture reports were analyzed. A comparison between the first-stage and second-stage surgery MICs was only possible when the MIC data were available for both specimens. With the exception of vancomycin and oxacillin, the MICs of other antibiotics were not routinely evaluated. The proportion of revisions in which there was an observed increase in the MICs was noted. To account for the lack of data in certain specimens, the number of revisions with complete data were used as the denominator when calculating proportions for different antibiotics (Table 1). Due to the limited sample size, only the factors (age, gender, body mass index (BMI), Charlson comorbidity score, joint type, culture results, and relevant surgical history including number of prior surgeries on the joint and previous spacer use) associated with increase in vancomycin MIC were evaluated. Fisher exact tests were used to detect differences between categorical variables, and Wilcoxon rank sum tests were used to compare continuous variables. The threshold for statistical significance for all analyses was set at less than 0.05. Statistical analysis was performed using R software (version 3.1.3, Vienna, Austria) [27].


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Table 1 The List of Antibiotics Which Showed an Increase in MIC After Insertion of Antibiotic Cement Spacer. Antibiotics

Data Available, Na

Revisions With an Increase in MIC, % (N)

Vancomycin Linezolid Daptomycin Oxacillin Tetracycline Gentamycin Penicillin G Erythromycin Clindamycin Rifampicin

30 8 13 30 28 19 11 21 19 25

30.0 25.0 23.1 13.3 10.7 10.5 9.1 5.5 5.3 4.0

(9) (2) (3) (4) (3) (2) (1) (1) (1) (1)

MIC, minimum inhibitory concentration. a Comparisons were possible only when MICs were reported for both the specimens (before and after spacer insertion).

Results In 43% (13/30) of the revisions, the MIC of at least 1 antibiotic was higher at the second-stage surgery. Vancomycin (30%; n ¼ 9/ 30), linezolid (25%; n ¼ 2/8), and daptomycin (23%; n ¼ 3/13) were the most common antibiotics to be affected by antibiotic cement spacer insertion (Table 1). Out of the 9 revisions that had an increase in vancomycin MIC, 6 had an increase in vancomyin MIC from 0.5 to 1 mg/mL, 2 had an increase from 0.5 to 2 mg/mL, and 1 had an increase from 1 to 2 mg/mL. All of the 9 revisions with an increase in vancomycin MIC had vancomycin in spacer (Table 2). There were a total of 25 revisions in which vancomycin was used in the spacer, and the vancomycin MIC distributions before and after the insertion of a spacer in these revisions are shown in Figure 1. Although a trend toward increased prevalence of high vancomycin MIC strains (MIC, 1-2 mg/mL) was observed after spacer insertion, with the given number of cases the difference did not reach statistical significance (P ¼ .396). MRSA was isolated from 22 cases (73%) at the first-stage surgery and 24 cases (80%) at the secondstage surgery. Among the 22 MRSA revisions, the MIC of at least 1 antibiotic was higher at the second-stage surgery in 7 (31.8%) revisions. Among the 8 MSSA revisions, the MIC of at least 1 antibiotic was higher at the second-stage surgery in 6 (75%) revisions. MSSA was more likely to have an increase in MIC compared to MRSA (P ¼ .04). Five (23%) of the MRSA revisions and 4 (50%) of the MSSA infections had an increase in vancomycin MIC (Table 3). In 6 (20%) revisions, S aureus developed resistance to at least 1 antibiotic after spacer insertion. Gentamycin (n ¼ 2), oxacillin (n ¼ 2), daptomycin (n ¼ 1), penicillin (n ¼ 1), rifampicin (n ¼ 1), tetracycline (n ¼ 1), and erythromycin (n ¼ 1) were the antibiotics that developed resistance after the spacer was inserted.

Antibiotics

Vancomycin þ Tobramycin, % (N ¼ 23)

Tobramycin, Vancomycin, Daptomycin þ % (N ¼ 4) % (N ¼ 2) Tobramycin, %(N ¼ 1)


39.1 28.6 25.0 13.0 9.1 13.3 0.0 6.3 7.1 5.0

0.0 0.0 0.0 25.0 0.0 0.0 33.3 0.0 0.0 0.0

(0/4) (0/1) (0/1) (1/4) (0/4) (0/3) (1/3) (0/3) (0/2) (0/3)

0.0 NA NA 0.0 0.0 NA 0.0 0.0 0.0 0.0

(0/2)

(0/2) (0/1) (0/1) (0/1) (0/2) (0/1)

MIC, minimum inhibitory concentration; NA, not available.

0.0 NA NA 0.0 100.0 0.0 0.0 0.0 100.0 0.0

An increased vancomycin MIC was associated with a lower BMI (26.5 kg/m2 ± 5.4 vs 35.6 kg/m2 ± 10.0, P ¼ .012). Revisions with an increase in vancomycin MIC were more likely to have a microorganism other than S aureus isolated at the time of second-stage surgery (44.4% vs 4.8%, P ¼ .019). However, no association was observed with respect to isolation of another organism at firststage surgery (P ¼ .287) (Table 4). No associations were observed with Charlson comorbidity index (P ¼ .396), duration of antibiotic spacer (P ¼ .684), or previous antibiotic spacer use (P ¼ 1). The 3 revisions which had an increase in daptomycin MIC also had a concomitant increase in vancomycin MIC (P ¼ .014). Discussion Antimicrobial resistance is a major global health concern [20]. With the increasing number of 2-stage revisions and less than ideal treatment success rates, it is important to know the changes in the MICs of antibiotics associated with microorganisms that persist despite antibiotic spacer insertion and parenteral antibiotic therapy. The results of the present study suggest that a large proportion of the persistent S aureus demonstrated an increase in MIC to at least 1 antibiotic with the increase in MIC being most commonly observed in vancomycin, which was the most common antibiotic used in the cement spacers and in parenteral therapy. There were several limitations to this study. The sample size of the study was small, which may have limited the ability to identify statistically significant associations. However, a large number of 2-stage revisions at 2 different institutions were screened, and the

Table 3 Proportion of MRSA (N ¼ 22) and MSSA (N ¼ 8) Revisions Showing an Increased MIC After Antibiotic Cement Spacer Insertion.

Table 2 Proportion of Revisions With an Increase in MIC, by Spacer Antibiotic.

(9/23) (2/7) (3/12) (3/23) (2/22) (2/15) (0/6) (1/16) (1/14) (1/20)

Fig. 1. Vancomycin MIC distribution of the isolates before and after spacer insertion (for patients with vancomycin in spacer, n ¼ 25). MIC, minimum inhibitory concentration.

(0/1)

(0/1) (1/1) (0/1) (0/1) (0/1) (1/1) (0/1)

Antibiotics

MRSA, % (N)

MSSA, % (N)


22.7 25.0 25.0 NA 15.0 6.3 0.0 6.7 7.7 4.8

50.0 NA 0.0 50.0 0.0 33.3 33.3 0.0 0.0 0.0

(5/22) (2/8) (3/12) (3/20) (1/16) (0/8) (1/15) (1/13) (1/21)

(4/8) (0/1) (4/8) (0/8) (1/3) (1/3) (0/6) (0/6) (0/4)

Linezolid MICs were not tested for MSSA. As all MRSA specimens were resistant to oxacillin, changes in MIC of oxacillin were not assessed. MRSA, methicillin-resistant S aureus; MSSA, methicillin-susceptible S aureus; MIC, minimum inhibitory concentration; NA, not applicable.

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Table 4 Characteristics of Patients With and Without an Increase in Vancomycin MIC. Variable

Increase in Vancomycin MIC (N ¼ 9)

No Increase in Vancomycin MIC (N ¼ 21)

P Value

Age, mean ± SD Female gender, n (%) Body mass index, mean ± SD Charlson score, mean ± SD Knees, n (%) MRSA, n (%) Previous spacer use, n (%) Number of previous surgeries, mean ± SD Vancomycin in spacer, n (%) IV vancomycin during interim, n (%) Duration of spacer, mean ± SD (d) Multiple organisms at first stage, n (%) Multiple organisms at second stage, n (%) Increase in daptomycin MIC, n (%)

65.9 ± 13.2 3 (33.3) 26.5 ± 5.4 3.1 ± 1.8 3 (33.3) 5 (55.6) 4 (44.4) 2.8 ± 2.5

62.7 ± 9.7 10 (47.6) 35.6 ± 10.0 3.7 ± 2.0 15 (71.4) 17 (81.0) 8 (38.1) 2.0 ± 2.2

.700 .691 .012 .396 .102 .195 1.000 .154

9 (100) 2 (22.2)

16 (76.2) 10 (47.6)

.286 .249

214 ± 233

114 ± 66

.684

4 (19.1)

.287

1 (4.8)

.019

0 (0)

.014

0 (0) 4 (44.4) 3 (75)

a

MIC, minimum inhibitory concentration; SD, standard deviation; MRSA, methicillinresistant S aureus; IV, intravenous. a Data were only available in 4 revisions.

low number indicates the rarity of persistence of the same microorganism. Although the rarity of persistence of infection in 2 stages is encouraging, it should be noted that antibiotic resistance is a very slow process, and even a single incidence of a multidrug-resistant organism can have serious consequences [28,29]. Although the multicenter nature of the study confers the external validity to this study, the inclusion of data from 2 different institutions could have led to variability in the protocols for surgery, antibiotic treatment, and laboratory testing. Moreover, even within 1 institution there might have been marked heterogeneity with respect to treatment protocols (antibiotic dose, antibiotic duration, type of cement, amount of cement, etc.) which affects the ability to make definitive conclusions from this study. However, such heterogeneity is expected in the treatment of a complex condition like PJI and is present in other similar studies on PJI patients [30,31]. The MIC values obtained in the present study were retrospectively obtained and not all specimens received MIC analysis for all of the antibiotics. However, to minimize the errors due to missing values, all proportions were calculated using the number of revisions with complete data as the denominator. As the study focused on changes in MICs, only the revisions in which S aureus was isolated at both the first-stage and second-stage surgeries were included. Revisions in which a different species was isolated at the time of second-stage surgery were not considered for this study, as there was no baseline MIC for comparison. Although coagulase-negative Staphylococcus species are also important pathogens responsible for PJI and can persist after antibiotic spacer insertion, the group is comprised of different Staphylococcus species, and it would have been difficult to distinguish them as persistent or a new species [13]. Future studies, however, may further help us understand the effects antibiotic spacers have on other microorganisms. Although direct comparisons of the MICs were made before and after spacer insertion, the MIC changes observed in this study may be unrelated to the antibiotic used in the patient and may be entirely due to random strainspecific changes in MIC which can even be bidirectional. Vancomycin was the predominant antibiotic that demonstrated an increase in MIC after the insertion of the antibiotic spacer. Vancomycin is commonly used in the cement spacers due to its elution properties and broad spectrum of activity [32e34].

Vancomycin is effective against MRSA which is one of the most common organisms causing PJI [35]. Since the initial detection of MRSA strains in 1960s, the incidence of MRSA infections has been on the rise leading to an increased use of vancomycin as a prophylactic and therapeutic agent [29]. Since 2002, there have been multiple reports of the isolation of vancomycin-resistant S aureus in United States, and combating vancomycin-resistant S aureus could potentially become a major public health concern [36,37]. According to the Centers for Disease Control and Prevention, S aureus is classified as vancomycin susceptible (MIC 2 mg/mL), vancomycin intermediate (MIC ¼ 4 to 8 mg/mL), and vancomycin resistant (MIC 16 mg/mL) [25]. The clinical relevance of subtle changes in MIC from 0.5 mg/mL to 1-2 mg/mL observed in this study is uncertain. Although previous studies have reported that vancomycin was less effective in treating patients with MRSA bacteremia when the isolates had a high vancomycin MIC (1-2 mg/mL compared to 0.5 mg/mL), it is possible that minor changes in MICs are within the margins of measurement errors [38e40]. Nevertheless, it is important to recognize that the microorganisms isolated at the second-stage surgery maintained their susceptibility to the antibiotics in the spacer, suggesting that poor elution of antibiotics from the spacer, the persistence of biofilm, or inadequate immune response of the patient might have contributed to the lack of infection eradication [41,42]. An increase in vancomycin MIC was associated with a lower BMI and simultaneous isolation of a different microorganism at the second-stage surgery. Although the antibiotic concentration in the spacer was expected to be similar for all patients, the total amount of antibiotics in the cement depends on the patient’s size, with more cement being used in those with a higher BMI. As the overall elution characteristics depend on both the concentration and the total amount of antibiotics in spacers, smaller amounts may result in suboptimal delivery of antibiotics when they are implanted in the joint for prolonged periods [41]. The simultaneous presence of multiple microorganisms could potentially result in the transfer of resistance genes from one species to another and may contribute to emergence of resistance [43,44]. The large number of polymicrobial infections at second stage raises the possibility that some organisms isolated at time of second stage might have been actually present at first stage, but were undetected. However, no association was observed when multiple microorganisms were present at the first-stage surgery, which may be due to the early recognition of multiple microorganisms and appropriate antibiotic therapy. Additionally, the increased vancomycin MIC was also associated with an increase in daptomycin MIC. The association between vancomycin MIC values and the MIC values of other anti-MRSA antibiotics, like daptomycin, has been previously reported [45,46]. Although this association is not completely understood, the emergence of daptomycin-resistant S aureus could be a serious problem because the use of daptomycin to treat PJIs has increased [47e49]. Although statistical significance could not be achieved, the use of vancomycin in spacers and a different antibiotic for parenteral therapy appeared to be associated with an increased MIC. Because the majority of the patients receive a vancomycin cement spacer, parenteral therapy with a different antibiotic may lead to subtherapeutic concentrations of vancomycin in the infected joint. This might also explain the fact that the changes in MIC were more common in MSSA, because MSSA PJIs are usually treated with parenteral beta lactam antibiotics, despite vancomycin being used in the spacer [13,18]. In an in vivo study by Brien et al [42], the hemovac fluid concentration of vancomycin was higher in patients who were treated with parenteral vancomycin compared to those who had vancomycin cement spacers, which suggests that both parenteral and local delivery of the same antibiotic may lead to optimal results.


In conclusion, the results of this preliminary study show that a considerable proportion of the persistent S aureus demonstrated an increased MIC of at least 1 antibiotic between the stages of a 2-stage exchange arthroplasty, although the clinical relevance of these minimal changes in the MICs needs to be further studied. Vancomycin was the most common antibiotic that showed an increased MIC. But the vancomycin MICs of persistent organisms were still in the susceptible range, and the increases were mostly by a factor of 1 dilution. With the serious consequences that may occur with the emergence of antibiotic resistance, and the increasing number of PJIs, further studies are required in order to better understand the changes in antibiotic susceptibility between the stages of 2-stage revision arthroplasty.

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