risk factors for mixed genus infection in 579 primary hip ...introduction: the management of...

Risk Factors for Mixed Genus Infection in 579 Primary Hip and Knee Arthroplasties Revised for Periprosthetic Infection: A Study Using the National Joint Registry Dataset

Review Article

Recent Advances in Arthroplasty © All rights are reserved by Paul Baker

ISSN 2576-6716

*Address for Correspondence: Mr Paul Baker, James Cook University Hospital, Marton Rd, Middlesbrough, UK, Tel: 01642 854479; E-Mail: [email protected]

Received: May 16, 2017; Accepted: June 16, 2017; Published: June 19, 2017

Introduction Periprosthetic joint infection (PJI) is reported in up to 3% of

patients following primary joint hip and knee arthroplasty [1-8]. Both surgical and medical management of such cases is met with considerable cost and patient morbidity [9, 10]. Previous work has confirmed that if a single organism is isolated this is likely to be from the Staphylococcusgenus [4, 11-14]. However, in up to 20% of cases, a mixed genus colony may be implicated as the causative focus [11, 12, 15].

Mixed genus peri-prosthetic infections represent an additional clinical challenge and they are more expensive to treat [16]. Manage-

ment is more likely to be met with failure of eradication and poorer clinical outcomes [17-19]. Additionally, mixed genus infection has the potential to increase the required spectrum of antimicrobial therapy therefore inadvertently leading to generation of multi resistant subcolonies, iatrogenic drug related morbidity and super infection. Given these risks, it is important to understand the clinical patterns of mixed genus periprosthetic infection and the pathobiology of this type of infection. Stratification of infection type at an early stage with targeted appropriate therapeutic measures can only lead to improved clinical outcomes and allows consideration of a single stage revision surgery [20].

This study examined the differing combinations of organisms from review of a centralized national database with particular referen-ce to mixed genus infection documented after tissue analysis from revision hip and knee arthroplasty. This allowed for determination of the key factors linked to such when compared to single genus infecti-on. Finally, a comparison was made between those factors that distin-guished propensity for mixed genus infection cbetween chip and knee

Richard Holleyman1, David Deehan2, Andre Charlett3, Kate Gould4, Paul Baker5*

1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.2Department of Trauma and Orthopaedics, Freeman Hospital, Newcastle upon Tyne, UK.3Centre for Infectious Disease Surveillance and Control, Public Health England, London, UK.4Newcastle Public Health Laboratory, Public Health England, Freeman Hospital, Newcastle upon Tyne, UK.5Department of Trauma and Orthopaedics, James Cook University Hospital, Middlesbrough, UK.

AbstractIntroduction: The management of periprosthetic joint infection is complex and costly. This study describes the epidemiology and risk factors associated with the development of polymicrobial periprosthetic joint infection following primary hip and knee arthro-plasty using linked national datasets.

Materials and Methods: Retrospective analysis of culture positive primary hip and knee replacements revised for periprosthetic infection. Microbiological samples including information about infecting organism and associated sensitivities for each patient were identified within a national microbiological culture database held by Public Health England (PHE). This information was then linked to surgical data held by the National Joint Registry (NJR) for England and Wales using unique identifiers.

Results: Intra-operative culture results were identified for 579 patients within the PHE database. Infections were divided into those where a single microorganism genus was isolated (n=477, 82%) and those where mixed genera were isolated (n=102, 18%). Binary logistic regression was used to identify predictors of mixed genus infection. Staphylococcus species were grown in 75% of all patients with mixed genus infections. Increased patient body mass index (BMI) was significantly associated with increased risk of mixed genus infection (odds ratio 1.06, 95%CI 1.01 to 1.11 (p = 0.01)). This effect was more marked in patients who had undergone knee arthroplasty.

Conclusions: Patients with high BMI are at increased risk of mixed genus periprosthetic infection. Appreciation of this risk may allow initiation of targeted appropriate prophylactic and therapeutic measures such as the use of additional prophylactic antibiotics or high dosage antibiotic loaded cement in patients with high BMI at time of primary surgery.

Keywords: Arthroplasty; Infection; Revision; Mixed genus; Polymicrobial; Organism

Recent Adv Arthroplast, 2017 Volume 1(1): 9 - 15

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ure as well as implant details for these procedures. For identif-ied cases, this information was identified from the NJR dataset for each primary and revision procedure.

Linkage & Study Cohort

Microbiological data from PHE was linked to the NJR database using patient NHS number. For each linked case, we verified that a) the culture specimens within the PHE database had a sample date on the same day, or the day after revision procedure and b) the revision case within the NJR was undertaken for an indication of ‘infection’.

The NJR allows the surgeon to record the clinical indication for revision contemporaneously at the time of surgery. The NJR data collection form does not, however, record if tissue specimens were sent or if infection was later confirmed by microbiological testing. The completion of the form is therefore based on the presumption of infection based on pre-operative clinical, radiological, biochemical and microbiological assessment. We therefore worked both forwards from the NJR dataset and backwards from the PHE dataset to achieve a dataset of complete patient and surgical data linked at the individ-ual level to tissue microbiological data. This allowed us to examine comprehensively the patient, surgical and microbiological character-istics of mixed genus infection. Using a methodology we identified 705 cultures in a series of 579 arthroplasties revised for infection (primary hip: n=248 (43%), primary knee: n=331 (57%). Data at microorganism species level was not consistently recorded by all contributing laboratories. We therefore focused our analysis at the genus level in order to reduce any potential reporting bias. Cases were divided into single genus (n=477, 82%) and mixed genus (n=102, 18%) infections.

Data linkage was achieved directly between Public Health England and the NJR. As such, the research team as part of this analysis held no patient sensitive information (NHS number); this study was therefore classed as a service evaluation and ethical appro-val was not required. After methodological review by Public Health England’s confidentiality advisory group, section 251 endorsement was not required.

Holleyman R, Deehan D, Charlotte A, Gould K, Baker P.Risk Factors for Mixed Genus Infection in 579 Primary Hip and Knee Arthroplasties Revised for Periprosthetic Infection: A Study Using the National Joint Registry Dataset. Recent Adv Arthroplast. 2017; 1(1): 9-15.

Specimen Code

Bone Tissue Synovial Fluid "Pus (source unknown) Prosthesis Joint FLUID - Not otherwise specified Hip Knee

arthroplasty. The null hypotheses were that there would be no relati-onship between increased risk of mixed genus infection and patient or surgical factors.

Materials & Methods

This study was conducted as a retrospective analysis of patients with positive deep cultures taken from either the hip and knee joint during revision of a primary arthroplasty performed for an indication of periprosthetic infection.Patients were initially identified within a national microbiological culture data base held by Public Health England (PHE) and then linked to data from the National Joint Regi-stry (NJR) for England and Wales using their unique NHS number.

Microbiology Dataset Public Health England (PHE) is responsible for the surveillance

of UK national data concerning clinically important infections. The Second Generation Surveillance System (SGSS) is a voluntary labora-tory reporting system containing both the Communicable Disease Reporting (CDR) and antimicrobial susceptibility testing (AmSurv) databases. All clinically significant isolates from sterile sites such as blood, CSF, joint fluids, bone, pleural and pericardial fluids, heart valves, and abscesses in the brain, liver and spleen should be repo-rted. Laboratories are expected to report each week and preliminary reports (with the exception of mycobacteria) should to be received by PHE within 14 days of the specimen date in at least 90% of reports. Currently the CDR database contains reports of over 30 million infe-ctions. The AmSurv database contains the results of all antimic-robial susceptibility tests performed on an isolate and currently contains over 60 million individual drug-bug results. Within both databases, cultures with no growth are not recorded. The SGSS dataset was queried for all cultures with a specimen code likely to be arising from a prosthetic hip or knee joint between 2003 and 2014. Specimen codes chosen for inclusion are listed in table 1.

Table 1: Specimen codes used to identify probable joint cultures from Public Health England microbiology dataset

National Joint Registry Dataset The National Joint Registry (NJR) has prospectively collected

information concerning primary and revision hip and knee arthropl-asty procedures performed in England and Wales since April 2003 and in Northern Ireland since February 2013. We followed the NJRs standard processes for research to request access to link the cases identified within the PHE database. The NJR data collection forms also collect information on patient demographics (age, gender, Ame-rican Association of Anaesthesiologists grade (ASA) and Body Mass Index (BMI)), date of primary/revision surgery) in addition to surg-ical information pertaining to both the primary and revision proced-

Statistical Analysis The null hypothesis was that there would be no differences in

patient and primary implant characteristics when comparing cases of single genus vs. mixed genus infection. Binary logistic regression was employed in univariate and multivariate analyses to identify signif-icant predictors of mixed genus infection. A p value of <0.05 was deemed to be statistically significant. Age was modelled as both a continuous variable and in groups broadly divided into quintiles (rounded to nearest whole years). BMI (which as available for 322 (56%) of patients) was modeled as both a continuous and as a categ-orical variable grouped according to World Health Organisation classifications.

ResultsOrganism Combinations Two hundred and twenty eight (228) culture results were recor-

ded in 102 patients with mixed genus infection. Combinations of two different microorganism genera were implicated in 82 cases (80%), combinations of three microorganism genera in 16 cases (16%) and four microorganism genera in 4 cases (4%). Staphylococcus species with mixed genus infections. The most common combinations of microorganism genera and their relative frequencies are described in Table 2.


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*Address for Correspondence:Leandro Bueno Bergantin,Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo– SP, Brazil, CEP: 04039-032. Fax: 1-913-588-0681;E-mail: [email protected]


Table 2: Description of the most common combinations of microorganism genera implicated in mixed genus infections. ‘All Other’ included all patients with a unique organism combination that occurred in only one case.

Microorganism Combination Number of Patients %

STAPHYLOCOCCUS + STREPTOCOCCUS 22 22%

STAPHYLOCOCCUS + ENTEROCOCCUS 8 8%

STAPHYLOCOCCUS + ESCHERICHIA 5 5%

STAPHYLOCOCCUS + CORYNEBACTERIUM 4 4%

STAPHYLOCOCCUS + PROPIONIBACTERIUM 4 4%

STAPHYLOCOCCUS + PROTEUS 4 4%

STAPHYLOCOCCUS + BACILLUS 3 3%

MICROCOCCUS + STREPTOCOCCUS 2 2%

STAPHYLOCOCCUS + PSEUDOMONAS 2 2%

STAPHYLOCOCCUS + STREPTOCOCCUS + DIPHTHEROIDS 2 2%

STAPHYLOCOCCUS + ENTEROCOCCUS + DIPHTHEROIDS 2 2%

ALL OTHER UNIQUE COMBINATIONS 44 43%

TOTAL 102

Univariate Analysis

The only patient factor that was associated with an increased risk of developing a mixed genus infection was increasing patient BMI (odds ratio 1.06, 95%CI 1.01 – 1.11 (p = 0.01)) [Table 3]. Similarly, patients in high BMI categories (30-40kg/m2 and >40kg/m2) were sig-nificantly more likely to suffer mixed genus infections when compared to patients with a ‘normal’ BMI (25-30kg/m2) (odds ratio 2.05, 95%CI 1.05 to 4.00 (p=0.04) and 2.82, 95%CI 1.06 to 7.49 (p=0.04) respectiv-ely). Whilst not statistically significant, there was a trend towards increased risk of mixed genus infection in patients who underwent the primary procedure for an indication of previous or acute trauma when compared to patients whose primary indication for surgery was a diagnosis of osteoarthritis (odds ratio 2.69, 95%CI 0.88 – 8.20 (p = 0.08)).

Multivariate Analyses After the influence of all variables were considered, high patient

BMI remained the only patient or surgical factor significantly associa-ted with increased of risk of mixed genus infection(odds ratio for BMI 30-40kg/m2 vs BMI 25-30 kg/m2 = 2.36, 95%CI 1.18 to 4.75 (p=0.02)and for BMI>40 kg/m2 vs BMI 25-30 kg/m2= 3.16, 95%CI 1.13 – 8.89(p= 0.03)) [Table 2]. Multivariate analysis of hip and knee data revealedthis trend was much stronger for knee arthroplasty (odds ratio for BMI>40kg/m2 vs BMI 25-30 kg/m2= 4.46, 95%CI 1.12 – 17.79 (p = 0.03)than hip arthroplasty where the effect of BMI was not significant[Figure 1 & Table 4].

Discussion This principal finding of this work is that increased patient body

mass index (BMI) was significantly associated with increased risk of mixed genus pathology identified from microbiological tissue specim-ens retrieved at first-time revision of primary hip and knee arthropl-asty for infection. Patients with a BMI of greater than 30 kg/m2 at time of surgery in whom infection was present were twice as likely to have a

mixed genus infection. This effect was more marked in patients who had undergone knee arthroplasty. In patients with a confirmed mixed genus infection, the most frequently observed pathogen combination was Staphylococcus with Streptococcus species.

Mixed genus infections were evident in 18% of the studied population. Direct comparison of incidence with the literature is difficult given its relative scarcity and the differences in reporting nomination of data as polymicrobial vs. mixed genus. Adjusting for the fact that some studies include ‘culture-negative’ cases in their incidence calculations reported incidence ranges from 7% to 39% [13, 14, 22-24]. Whilst also being more challenging to treat pharmacolog-ically, there is data to suggest that polymicrobial infection may be associated with poorer clinical outcome compared to pure coagulase-negative or staphylococcal infections [25].

Our study found that a high patient BMI to be associated with a significantly increased risk development of mixed genus PJI. There are a number of possible explanations for this finding. Firstly, increa-sed BMI will lead to a greater potential space within the adipose layer in which haematomas and seromas may collect in addition to local fat necrosis which may all act as a culture medium for bacterial growth. Secondly, BMI may be a surrogate marker for co-morbidities that predispose to infection such as diabetes. Finally, larger body mass equates to a larger volume of drug distribution and thus potentially lower peak concentrations of antibiotics delivered if standard prophy-lactic doses are employed [26]. Our study found a strong association towards increased risk of mixed genus infection in patients who underwent primary arthroplasty for indication of previous or acute trauma. Whilst this was not statistically significant, numbers in this group were small and greater numbers may yield a significant result. There are very few studies examining risk factors for development of polymicrobial PJI. Marculescu et al. performed a retrospective inves-tigation into risk factors of development of polymicrobial PJI [15]. They identified several predictive factors including presence of drainage, soft tissue defect or wound dehiscence and age greater than


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VARIABLE

n Mixed Genus n (%)

Univariate Analysis Multivariate Analysis

Odds Ratio 95% CI p value Odds Ratio 95% CI p value

Age (Years) 1·01 0·99 - 1·04 0·19 - Age Group (Years) <60 106 18 (17%) Reference - Reference - 60 to 67 133 22 (17%) 0·97 0·49 - 1·92 0·93 0·99 0·48 - 2·01 0·97 67 to 72 120 16 (13%) 0·75 0·36 - 1·56 0·44 0·78 0·36 - 1·68 0·52 72 to 77 107 23 (21%) 1·34 0·67 - 2·66 0·40 1·55 0·75 - 3·20 0·24 >77 113 23 (20%) 1·25 0·63 - 2·47 0·52 1·53 0·73 - 3·20 0·26

Gender Male 339 55 (16%) Reference - Reference - Female 240 47 (20%) 1·26 0·82 - 1·93 0·30 1·21 0·77 - 1·91 0·41

ASA Grade ASA 1 79 13 (16%) Reference - Reference - ASA 2 383 67 (17%) 1·08 0·56 - 2·06 0·82 0·94 0·48 - 1·87 0·87 ASA 3/4 117 22 (19%) 1·18 0·55 - 2·50 0·67 0·89 0·40 - 2·00 0·78

BMI (kg/m2) 1·06** 1·01 - 1·11 0·01 - BMI Group (kg/m2) <25 24 4 (17%) 1·48 0·45 - 4·92 0·52 1·31 0·38 - 4·54 0·67 25 to 30 126 15 (12%) Reference - Reference - 30 to 40 143 31 (22%) 2·05** 1·05 - 4·00 0·04 2·36** 1·18 - 4·75 0·02 >40 29 8 (28%) 2·82** 1·06 - 7·49 0·04 3·16** 1·13 - 8·89 0·03 Unrecorded 257 44 (17%) 1·53 0·81 - 2·87 0·19 1·55 0·81 - 2·96 0·19

Primary Indication Osteoarthritis 537 92 (17%) Reference - Reference - RA/Inflammatory Arthritis

11 4 (36%) 2·76 0·79 - 9·64 0·11 2·80 0·77 - 10·18 0·12

Trauma/Previous Trauma

14 5 (36%) 2·69* 0·88 - 8·20 0·08 2·98* 0·92 - 9·65 0·07

Other 17 1 (6%) 0·30 0·04 - 2·31 0·25 0·31 0·04 - 2·43 0·26

Fixation Cemented 393 68 (17%) Reference - Reference - Uncemented 119 20 (17%) 0·97 0·56 - 1·67 0·90 1·10 0·54 - 2·28 0·79 Hybrid 49 11 (22%) 1·38 0·67 - 2·84 0·38 1·55 0·64 - 3·75 0·33 Unrecorded 18 3 (17%) 0·96 0·27 - 3·39 0·94 1·01 0·24 - 4·19 0·99

Joint Replacement Hip 248 46 (19%) Reference - Reference - Knee 331 56 (17%) 0·89 0·58 - 1·37 0·61 0·95 0·51 - 1·76 0·87

Table 3: Binary logistic regression analysis identifying predictors of mixed genus infection. (*** p<0.01, ** p<0.05, * p<0.1).



65 years. Peel et al. identified antibiotic prophylaxis spectra without activity against subsequently isolated organisms and rheumatoid arthr-itis as independent risk factors for polymicrobial infection [24]. They also observed an association between rheumatoid arthritis and infect-ions due to Gram-negative organisms. To the best of the authors’ knowledge, there are no existing studies confirming BMI as a risk factor for mixed genus infection. However, increased BMI has been shown to be a significant risk factor for treatment failure after debrid-ement and prosthesis retention for PJI [27]. Aside from infection, body mass index has been shown to be an important determinant of patient outcome, with increased obesity being associated with reduced patient satisfaction following knee replacement despite significantly improved functional outcome scores [28-30].

VARIABLE

Multivariate Knee Multivariate Hip

n Mixed Genus n (%)

Odds Ratio 95% CI

p value

n Mixed Genus n (%)

Odds Ratio 95% CI p

value

BMI (kg/m2) - - 1·08*** 1·02 - 1·15 0·01 - - 1·02 0·95 - 1·10 0·51 BMI Group (kg/m2) <25 12 1 (8%) 0·62 0·07 - 5·59 0·67 12 3 (25%) 2·33 0·41 - 13·31 0·34 25 to 30 79 9 (11%) Reference - 47 6 (13%) Reference - 30 to 40 89 19 (21%) 2·29* 0·94 - 5·58 0·07 54 12 (22%) 2·66 0·82 - 8·64 0·10 >40 14 5 (36%) 4·46** 1·12 - 17·79 0·03 15 3 (20%) 2·02 0·38 - 10·81 0·41

Unrecorded 137 22 (16%) 1·48 0·63 - 3·48 0·36 120

22 (18%) 1·68 0·58 - 4·83 0·34

Total 331 56 (17%) 248 46 (19%)

Figure 1: Single vs. mixed genus infections by joint and BMI Group. (n = 322)


Table 4: Results of multivariate analysis of hip and knee data. All other variables in the multivariate model were not statistically significant and not listed (*** p<0.01, ** p<0.05, * p<0.1). All variable included in previous analyses were included in the full multivariate models for hip and knee. BMI data only shown for clarity.

Considered separately, this study found BMI was a strongly predictive factor in the development of mixed genus PJI in knee arthroplasties but not hip arthroplasties. The knee is a more superficial joint, as such contiguous spread of superficial infections may easily reach the knee joint after passing through the retinacular layer. Conversely, the prost-hetic hip-joint is protected by several thick layers following surgical closure which include capsule and fascial layers. Such a hypothesis would be in agreement with the association between polymicrobial infection and superficial wound problems reported by Marculescu et al [15].

The incidence of polymicrobial PJI and its association with BMI should be discussed during the pre-operative counselling and consent



1. Choong PFM, Dowsey MM, Carr D, Daffy J and Stanley P. Risk factors associated with acute hip prosthetic joint infections and outcome of treatment with a rifampi-nbased regimen. Acta Orthop. 2007; 78:755–765. [Crossref]

2. Bozic KJ, Kurtz SM, Lau E, Ong K, Chiu V, Vail TP, et al . The Epidemiology of Revision Total Knee Arthroplasty in the United States. Clin Orthop Relat Res. 2010; 468:45–51. [Crossref]

3. Jämsen E, Huhtala H, Puolakka T and Moilanen T. Risk factors for infection after knee arthroplasty. A register-based analysis of 43,149 cases. J Bone Joint Surg Am. 2009; 91:38–47. [Crossref]

consent process. Patients should be encouraged to lose weight prior to surgery to reduce the risks associated with an elevated BMI. Patients with BMI 30 kg/m2 should be warned of the sequelae of polymicro-bial infection and its association with poorer implant survival and functional outcomes [25]. The findings of this study suggest a role for stratified or extended antibiotic prophylaxis in certain groups at ‘high risk’ of polymicrobial PJI. Extended gram-negative antibiotic prophy-laxis is reported to reduce surgical site infections in hip replacement patients [31], but has not yet been utilised routinely in knee replacem-ent patients. One potential avenue for further research would be the study of alternative treatment algorithms for antibiotic prophylaxis based on local flora and resistance patterns but also stratified based on risk factors such as BMI.

There are several limitations to this study. Unfortunately, BMI was not recorded for all patients in the National Joint Registry cohort (n=322 [56%]). We therefore chose to consider BMI as both a conti-nuous variable, with regression models including only those cases with a recorded BMI, and also as a categorical variable, with all cases considered through the use of an 'unrecorded' category (n=257, [44%]). Findings are presented preferentially to favour the categorical analysis for this reason. It was reassuring to observe that the relation-ship between BMI and mixed genus infection was similar within these models with increasing BMI associated with a greater risk of mixed genus infection. In addition, those categorised as ‘unrecorded’ BMI showed no significant difference in their risk of development of mixed genus PJI compared to the reference 'normal' BMI group. Previous studies have noted that patients with BMI data recorded in the NJR differ from those without BMI data recorded in terms of surgical characteristics (including hospital type, lead surgeon grade, and implant characteristics) but are similar in terms of demographic features [21]. We were unable to include information on hospital type and surgeon grade within our analyses and we had limited implant data. It is conceivable that the type of hospital and/or surgeon grade could influence the type of infection and these associations warrant further investigation should this data become available. Finally, this study’s designation of an infection as ‘mixed genus’ should be distin-guished from ‘polymicrobial’ infection. For clarity, a ‘single genus’ infection in the present study would include a both Staphylococcus aureus pure growth or, for example, a mixed growth but comprising only staphylococci e.g. Staphylococcus aureus and Staphylococcus epidermidis; such a combination may be classified as ‘polymicrobial’ in other studies.

In conclusion, this examination of over 500 microbiologically confirmed PJIs demonstrates that approximately a fifth of cases are infected with multiple organisms and that, within the knee arthropl-asty group, increasing body mass index is a significant predictor for the development mixed genus infection. Appreciation of the incide-nce and risk factors for mixed genus infection increases awareness of this potentially catastrophic complication and allows targeted appro-priate therapeutic measures to be instituted at an early stage.

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