Aseptic loosening is the leading cause of revision after THA . It is well recognized that occult infection is the underlying cause of some of these presumed aseptic revisions [4, 12, 14, 20], because some prosthetic joint infections (PJIs) can remain subclinical for years and may present with component instability and pain without other clinical signs of infection. A missed PJI diagnosis could be of great consequence, because the opportunity for appropriate antibiotic treatment may be missed in patients whose hip was presumed to be free from infection and so débridement may have been sparse or implants may have been retained. Intraoperative cultures, as proposed by Kamme and Lindberg , remain an important method for diagnosing PJI and are recommended routinely in all THA revision surgery . Up to 10% of presumed aseptic revision THAs or TKAs have been reported with positive bacterial cultures, some of which were proven to be PJI [7, 20].
The current consensus is that if two of five intraoperative cultures show growth of the same bacteria, that is evidence of PJI, whereas one positive culture or mixed growth of different bacteria generally is considered to be of questionable clinical relevance in the setting of clinically aseptic revision [1, 13, 15, 22]. A recent study has shown increased risk of implant failure within 2 years of presumed aseptic TKA revisions with cultures with two or more of the same bacteria. However, this could not be demonstrated in THA . The risk of a rerevision after a presumed aseptic revision of THA with unexpected positive intraoperative cultures remains unclear.
Therefore, we asked: (1) What is the clinical importance of bacterial growth in intraoperative tissue cultures taken during first-time revision of a clinically aseptic THA in terms of all-cause rerevision and rerevision for PJI specifically? (2) Is there a difference in outpatient antibiotic treatment patterns that is dependent on the number of positive intraoperative cultures?
Patients and Methods
The present register study was based on longitudinal data from four validated Danish national clinical quality and administrative registers. The study was approved by the Danish Health and Medicines Authority (case number 3-3013-1664/1), the Danish Data Protection Agency (journal number 16/15215), and the Danish Clinical Registries (RKKP).
The Danish Civil Registration System (Centrale Person Register [CPR]) was established in 1968 and contains information on all people living in Denmark, including immigrants. All 5.7 million Danish citizens are assigned a unique and unchangeable personal identification number known as the CPR number at birth or on immigration . Among other information, the register contains a person’s name, sex, date of birth, and vital status and enables unambiguous linkage between registers at the individual level and complete followup, because the prevalence of individuals lost to followup is only 0.3% . The CPR number is recorded for all healthcare contacts, including hospital admissions and outpatient clinic visits provided by the National Health Service .
The Danish Hip Arthroplasty Register (DHR) is a clinical quality database that gathers data from all THAs performed in Denmark, including both primary and revision THAs . Reporting is compulsory for both public and private hospitals, resulting in high completeness, which was 97.5% for primary THAs and 94.5% for revisions in 2016 . The register’s data have previously been validated and loss to emigration is low . The indication for revision surgery is reported by the surgeon according to classification in the DHR: aseptic loosening of the femur and/or the acetabular component; dislocation, deep infection; fracture of the femur; and other less frequent indications with or without exchange of implant components. The surgeon commonly defines aseptic loosening as a revision without clinical, radiologic, or serologic evidence of PJI. Reporting is done immediately after surgery. Thus, culture samples taken during surgery are usually not used for classification. Surgeon classification indicates that all procedures reported as aseptic loosening were clinically aseptic revision surgery.
Data were obtained on request for all THAs (identified by CPR number and side) that had been registered with a revision resulting from aseptic loosening. The data were acquired on May 17, 2017, after the monthly register update.
The Danish Microbiology Database (MiBa) was established in January 2010 and gathers microbiology reports from all departments of clinical microbiology in Denmark. All intraoperative tissue samples collected at Danish orthopaedic departments are analyzed at the nearest department of clinical microbiology in the same health region, and an electronic copy of the report is automatically sent to the MiBa. All requests and reports are kept using the CPR number as a patient identifier . The register data have been validated previously . The data were acquired on request based on the CPR numbers of the included cohort.
The Danish National Prescription Registry contains individual-level data on prescriptions redeemed by Danish residents at public pharmacies since 2003. The register records the CPR number, prescribed drug identifier (Anatomical Therapeutic Chemical classification system [ATC]), date of prescription redemption, and pack size, among other variables. The indication for prescription is not recorded. The Danish National Prescription Registry has a high degree of completeness and validity; thus, it is extensively used in pharmacoepidemiologic research, including antibiotic use . In this study, we used the register to examine outpatient antibiotic treatment patterns. Data were acquired on request based on the CPR numbers of the included cohort.
We examined the DHR for all reports of first-time revision surgery, which were recorded in the register as being the result of aseptic loosening of any prosthesis component from January 1, 2010, to May 15, 2016, excluding revisions performed as a result of other indications such as dislocation, fractures, and PJI (Fig. 1). Hip identification was obtained by combining the patient-unique CPR number with operated side and including both THAs if the patient had been revised bilaterally.
THAs were excluded if there were errors in registering the CPR number, operated side, operation date, operation classification, or patient vital status (Fig. 1).
We identified 10,365 THAs from the DHR registered as revised resulting from aseptic loosening, of which 2305 were first-time aseptic revisions in 2243 patients performed within the study period (Fig. 1). The mean age was 73.4 ± 11.1 years; 56% of patients were women. The cohort was predominantly partial component revisions (67%) (Table 1).
DHR data on first-time clinically aseptic revisions and rerevision were linked using the CPR number, operation side, and operation date. DHR data were then linked with MiBa data containing national microbiologic results from growth of intraoperative cultures (Fig. 1). The study period was chosen to correspond with the introduction of the MiBa database on January 1, 2010, which maximized the sample size when the two databases were combined.
We defined unexpected positive intraoperative cultures as the presence of one or more positive cultures in a revision that the surgeon had defined as aseptic and reported to the DHR as such. First-time aseptic revisions were stratified according to the number of unexpected positive intraoperative cultures of the same bacterial genus, creating the following groups: culture-negative (reference population); one positive culture (this group included multiple positive cultures growing different bacteria [mixed growth]); and two or more positive cultures with the same bacteria. If no culture data were available, the revision was regarded as culture-negative. This classification was chosen because it reflects commonly used cutoffs in clinical decision-making.
Data on intraoperative cultures were obtained for 2090 of 2305 (91%) of first-time revisions. Of these first-time clinically aseptic revisions, 1855 (89%) had five samples collected, whereas 1938 revisions (93%) had between three and five samples collected as recommended by the Musculoskeletal Infection Society .
Of the 2305 revisions reported as aseptic, 282 (12%) had bacterial growth in the intraoperative cultures. Of these, 170 (60%) had one positive culture (157) or had mixed bacterial growth (13). One hundred twelve revisions (40%) had two or more positive cultures growing the same bacteria (Table 2).
The dominant bacteria in the presumed aseptic first-time revisions were recorded. This was defined as the most prevalent bacteria in the cultures, and in the case of different bacteria of equal prevalence, we recorded the bacteria most clinically relevant to PJI. Revisions with more than one bacterial genus grown from cultures were recorded as mixed-growth revisions.
Among all culture-positive revisions, coagulase-negative Staphylococcus was the dominant bacteria in 189 revisions (67%) followed by Propionibacterium species in 30 revisions (11%) and Staphylococcus aureus in 12 revisions (4%). This pattern was also present in revisions with one positive culture or mixed growth, coagulase-negative Staphylococcus being the dominant bacteria in 121 revisions (71%) (Table 2).
All first-time revisions were followed until rerevision, death, emigration, or end of the followup period, which was defined as 1 year. A 1-year followup period was chosen, because the majority of rerevisions resulting from PJI occur within the first year (approximately 80%-90%) . Rerevision and rerevision cause were identified in the DHR. We defined revision as any subsequent procedure on the hip with component change, component removal, or débridement of the tissue surrounding the prosthesis. Cause for rerevision was classified in accordance with a previously validated definition of PJI, combining DHR and MiBa data . Revision was considered to be the result of PJI if three or more intraoperative samples with the same virulent or opportunistic bacteria were identified from the revision or if PJI was registered as the indication for revision in the DHR. Revision was classified as aseptic if no growth was present in any of five or more intraoperative cultures, regardless of the indication registered in the DHR. Data on intraoperative cultures were obtained for 82% of rerevisions. Rerevisions with no culture data available were regarded as culture-negative.
A rerevision was performed for 163 (7%) of the 2305 first-time clinically aseptic revisions within 1 year, whereas 87 patients (4%) died in the followup period without rerevision. None in the cohort emigrated during the 1-year followup period. In rerevisions, PJI was diagnosed in 43 patients (26%) (Fig. 1). Of the 163 THAs that were rerevised, 116 (71%) received a partial revision, whereas 47 (29%) were completely revised at their first-time revision. This representation of partially revised THAs among the rerevised THAs was not different from the overall cohort.
The DHR data were linked with the Danish National Prescription Registry at the individual level and reviewed for any antibiotic prescriptions (ATC category J01) redeemed within a 6-week period of the initial revision date. We recorded whether patients had been prescribed outpatient antibiotic treatment within this period, assuming that the patient had redeemed the prescribed medication. The prescribed drug was also recorded.
Within 6 weeks of surgery, 585 patients (25.4%) received an antibiotic prescription, of which 380 (16.5%) had possible relevance to PJI treatment.
The primary outcome was risk of rerevision resulting from all causes within 1 year of first-time revision, including rerevisions resulting from PJI. The secondary outcome was risk of rerevision resulting from PJI alone. The relative risk for rerevision was estimated with the subdistribution hazard ratio with culture-negative first-time revisions as the reference .
The relative risk for rerevision resulting from all causes was analyzed, treating death as a competing risk. The relative risk for rerevision resulting from PJI was analyzed, treating death and rerevisions resulting from other causes as competing risks. The proportional hazard assumption was assessed with the log–log plot and was not violated. We also calculated the cumulative incidence of outcome events in the groups; however, our outcomes were only analyzed using the subdistribution hazard ratio.
In our results, we report p values to describe whether the difference between groups is statistically significant. We also report the hazard rate ratio, hereafter referred to as the relative risk, to describe the magnitude of the difference. The relative risk is reported with 95% confidence interval; we remind readers that with this statistical approach, differences between groups can be statistically significant in some instances where the confidence intervals are overlapping.
The chi-square test was used to analyze the prevalence of patients with an antibiotic prescription including all antibiotics. This prevalence was subanalyzed, including only antibiotics relevant to PJI treatment in accordance with international literature and consensus [22, 26]. In our cohort, we identified dicloxacillin, flucloxacillin, phenoxymethylpenicillin, and amoxicillin.
We regarded a statistically significant difference as a p value < 0.05.
Risk of Rerevision
The risk of all-cause rerevision was greater among first-time revisions with one positive culture, but not in the two or more positive culture group. In first-time revisions with one positive culture, the relative risk (RR) for all-cause rerevision was increased to 1.73 (95% confidence interval [CI], 1.07–2.80; p = 0.020) compared with the culture-negative revisions (Table 3). First-time revisions with two or more positive cultures did not have an increased risk of all-cause rerevision (RR, 1.52; 95% CI, 0.82–2.80; p = 0.180) compared with the culture-negative revisions.
First-time revisions in the one positive culture group also had a higher risk of rerevision for PJI specifically, but this was not the case in the two or more positive group. Revisions with one positive culture had a RR of 2.63 (95% CI, 1.16–5.96; p = 0.020) (Fig. 2). Additionally, when analyzing the revisions in the one positive culture group, excluding mixed-growth revisions, the RR for rerevision resulting from PJI remained increased to 2.44 (95% CI, 1.02–5.84; p = 0.045) compared with culture-negative revisions.
In revisions with two or more positive cultures growing the same bacteria, the RR for rerevision for PJI was 2.28 (95% CI, 0.81–6.43; p = 0.120).
All THAs in the one positive culture group that went on to be rerevised resulting from PJI had coagulase-negative Staphylococcus bacteria in the first-time revision.
Outpatient antibiotic prescription was more frequent after revisions in the two or more positive culture group when compared with the culture-negative revisions. This was the case with regard to both all antibiotic prescriptions (51% [57 of 112 ] versus 24% [486 of 2023]; odds ratio [95% CI], 3.28 [2.23-4.81]; p < 0.001) and PJI-relevant prescriptions (50 of 112 [45%] versus 353 of 2023 [17%]; odds ratio [95% CI] 3.82 [2.58-5.63]; p < 0.001) (Table 4). In contrast, revisions with one positive culture did not have more patients with an antibiotic prescription when compared with the culture-negative revisions for either antibiotics overall (42 of 170 [25%] versus 486 of 2023 [24%]; odds ratio [95% CI] 1.04 [0.72-1.49]; p = 0.840) or PJI-relevant drugs specifically (36 of 170 [21%] versus 353 of 2023 [17%]; odds ratio [95% CI] 1.27 [0.86-1.87]; p = 0.220).
Recognizing PJI in THA revisions is important to ensure appropriate patient care. Some THAs may be revised resulting from presumed aseptic loosening, but this diagnosis may be challenged by the presence of unexpected bacterial growth from intraoperative tissue samples. In revisions with ambiguous culture results such as one positive culture of several that were obtained during surgery, it can be difficult to choose the correct treatment for the patient; current consensus suggests that one positive culture is regarded as clinically irrelevant . We examined 2305 clinically aseptic first-time revisions for presumed aseptic loosening and found an increased risk of all-cause rerevision and rerevision for PJI alone within the first year in THA revisions with unexpected growth in one culture or mixed bacterial growth from several cultures when compared with culture-negative THA revisions. These patients were not more likely to receive outpatient antibiotic treatment than the patients with culture-negative THA revisions, suggesting that the positive growth was regarded as sample contamination and therefore believed not to be clinically relevant. The THAs with one positive culture that went on to be rerevised all had growth of coagulase-negative Staphylococcus in the samples of the first-time revision, a common skin bacterium that could easily be mistaken for sample contamination.
This study had several limitations. First, registry data are prone to miscoding and missing data; however, the DHR has been validated, finding completeness of both primary and revision surgery is very high (95%-98%) . Our study design was based on multiple databases, which all have been validated and have a high degree of completeness. Although the validity of the PJI diagnosis in the DHR has been reported to be poor, combining DHR and MiBa data increases the sensitivity to 90% and the specificity to 100% . The combination of databases for improved PJI identification is key in addressing the limitations of a register study and was made possible by the unambiguous person identifier that is the CPR number. Misclassification of PJI as aseptic in rerevisions may still have occurred, however, leading us to include all-cause rerevision among the study outcomes. In this study, 43 of 2305 first-time revisions underwent rerevision resulting from PJI within the first year. This incidence may potentially be higher, because our definition of PJI only has a sensitivity of 90%. However, because this underestimation was consistent across our three groups (culture-negative, one positive culture, and two or more positive cultures), it should not affect our estimation of the RR or our conclusions. Nonetheless, it is a limitation of our study, because we only based our definition of PJI on surgeon evaluation and intraoperative cultures and did not include other criteria for infection. Likewise, the surgeon reported first-time revisions as aseptic loosening to the DHR based on clinical judgment and usually did not include the results of sample cultures. This may not fully satisfy the concept of aseptic loosing but reflects the conditions of clinical practice. Related to this, we remind readers that our study derives from a national register. Although it is likely that clinical practices may vary slightly among the reporting institutions and across the studied period, overall, we believe that our study has a high degree of generalizability, because it reflects common clinical practice across many institutions performed in everyday clinical scenarios.
Our primary outcome was assessed at 1 year to secure complete followup on the entire cohort while maximizing study power. Because this study evaluated the risk of rerevision from bacteria already present in the joint at the time of the first revision, we believe that 1 year is sufficient followup to capture the majority of revisions, because > 80% of PJIs have been shown to occur within the first year . Although some patients in our series may develop infections later, there is no particular reason to believe that there would be a between-group difference in this regard, and so we believe our results are robust despite the relatively short (1-year) surveillance period.
Microbiologic data were available for 91% of first-time revisions and 82% of rerevisions. The lack of microbiologic data in the other revisions likely was caused by several factors: the surgeon deciding not to obtain intraoperative cultures, deeming the revision to be clearly aseptic; the surgeon forgetting to obtain samples; or because the cultures were lost during sampling or cultivation. Deciding to regard missing microbiology data as culture-negative revisions may have influenced our analysis. However, this decision resulted in some revisions in which bacteria could have been present as being classified in the reference group (culture-negative group). This would lead to overestimation of the risk of rerevisions in the reference population. Therefore, if the estimated RR for the THAs with positive cultures compared with the culture-negative THAs is skewed, it is most likely underestimated. All included THAs were deemed clinically aseptic by the reporting surgeon. Later unexpected growth of the same bacteria in two or more positive cultures would reclassify the revisions as not an aseptic loosening revision. However, these revisions were confined to their own subgroup and did not influence the analysis of the other groups. Some definitions of PJI regard growth of high-virulence bacteria such as S. aureus in only one culture as evidence of infection. In our cohort, such revisions were rare (five of 170) and none of these were later revised as a result of PJI.
Another concern was that most culture-positive revisions had only one positive culture or mixed growth (one positive culture group, 60%). It can be argued that PJI risk may be higher in mixed-growth revisions. In our study, such revisions numbered only 13 (8%) of the 170 THAs, and the risk of rerevision resulting from PJI remained increased when these were removed from the analysis. We chose to group the mixed-growth revisions together with the group of one positive culture, because they are both considered non-PJI according to most definitions, including the Musculoskeletal Infection Society consensus , and instead regarded as likely sample contamination.
We calculated RR of rerevision using competing risk analysis, which assumes that all included observations are independent. This is not entirely fulfilled when including bilateral THA; however, this has little practical consequence when studying revision . In total, 62 patients had bilateral THA, of which only seven were rerevised on one side; none were bilaterally rerevised. Emigration was not a concern in this study because no patients in our cohort emigrated in the followup period.
We reviewed the Danish National Prescription Registry data for 6 weeks after first-time revision surgery. Patients were considered as having received antibiotic treatment if just one prescription had been made, regardless of timing, pack size, or other variables. It is not possible to be certain if the prescriptions were revision-related, but we performed a subanalysis focusing on antibiotics of potential relevance to PJI treatment. However, prescription of such antibiotics may also be the result of superficial surgical site infection or other reasons, which may explain why antibiotic prescriptions were given to the culture-negative patients. We have no reason to believe that such circumstances are more frequent in the culture-positive revisions. The registry records prescriptions when they are redeemed at a pharmacy. It is possible that some antibiotic prescriptions were not redeemed by the patient, leading to underestimations of the prevalence of antibiotic treatment. We believe this to be rare and should not differ between the study groups.
Risk of Repeat Revision After Unexpected Positive Cultures
Unexpected growth in one intraoperative culture, including mixed growth with different bacteria, was associated with increased risk of all-cause rerevision and rerevision for PJI alone in this cohort. The dominant bacteria overall and in revisions with one positive culture was coagulase-negative Staphylococcus, which is a well-known organism in PJI . Coagulase-negative Staphylococcus was also the predominant bacteria in THAs that went on to be rerevised. These findings indicate that some cases of unexpected bacterial growth should likely be regarded as clinically important and not merely as contamination, although they would not be regarded as PJI according to current guidelines [15, 26]. The cumulative incidence curves (Fig. 2) support this, showing the highest increase in rerevision risk in the first 3 months, which is a common period for PJI revision . It should be noted that although the 95% CIs of the cumulative incidence of the groups are overlapping, this does not imply a lack of statistical significance because they do not overlap the group means. The risk of rerevision in THAs with two or more cultures of the same bacteria was not increased, which was unexpected. One explanation may be that the patients with growth in more than one culture were treated with appropriate antibiotics for several weeks in accordance with the resistance pattern after first-time revision surgery in contrast to patients with only one positive culture who were treated as if they were culture-negative. These results highlight the need for more awareness and better strategies for treating patients with unexpected positive intraoperative cultures, including in revisions with only one positive culture or mixed growth. Such strategies likely include novel methods of microbiologic sampling and analysis such as sonication, improving the sensitivity to PJI and making more appropriate use of antibiotics possible . Innovations in preoperative diagnostics seem key for correct surgical planning, including appropriate débridement or a multiple-stage approach.
In our cohort, 12% of clinically aseptic revisions had positive cultures, which is in line with the study by Saleh et al. , who found positive tissue biopsy cultures in 10% of assumed aseptic THA and TKA revisions. Nine percent of patients with one positive culture, assumed to be contamination, were not treated with antibiotics, but were readmitted for PJI within 1 year; 22% of patients who had positive cultures (but PJI-negative according to Musculoskeletal Infection Society definitions ) and had been treated with antibiotics for 4 to 6 weeks were readmitted within a year as a result of PJI. This is in contrast to our study, which showed a competing risk-adjusted cumulative incidence for PJI revision of 4.1% in revisions with one positive culture or mixed growth. This difference may be explained by the use of culture-negative revisions as our reference population and the primary outcome being risk of rerevision, whereas Saleh et al. used readmission.
A more recent study by Jacobs et al.  found that 12% of revisions had growth of two or more of the same bacteria, regarded as unsuspected PJI. After 2 years of followup, no difference was seen in implant survival. Only 4.9% in our cohort had growth in two or more cultures with the same bacteria. Similar to Jacobs et al., we found no increased risk of rerevision for revisions with two or more positive cultures. This can be explained by a higher incidence of antibiotic treatment or a lack of statistical power.
Antibiotic Treatment After Positive Cultures
We found that outpatient antibiotic prescription was more frequent after revision in patients with two or more positive cultures when compared with the culture-negative revisions, both with respect to all antibiotic prescriptions and to PJI-relevant prescriptions. This was in contrast to revisions with one positive culture who were treated with antibiotics as if they were culture-negative. This suggests that the surgeon did not believe that one positive culture merited a clinical intervention. This finding is interesting because it highlights the lack of importance attributed to unexpected positive cultures, both with regard to one positive culture which seems to be considered merely contamination, but also revisions with two or more positive cultures. Fifty-one percent of these patients had outpatient antibiotic treatment prescribed, which seems low considering that these can be defined as PJI and antibiotic treatment for 4 to 6 weeks has been recommended for such infections .
The improved diagnosis of occult PJI in clinically aseptic THA is of great importance for future care of this large and growing patient group, where PJI is associated with increased morbidity, costs, and mortality . The frequent finding of unexpected growth in one culture was anticipated, but we found it surprising that it was associated with increased risk of subsequent revision within 1 year, as a result of both all causes and PJI. The predominant bacteria in first-time revisions with later rerevision was coagulase-negative Staphylococcus. This emphasizes that unexpected bacterial growth with common bacteria may have clinical importance, even if only one of five biopsy cultures is positive . This matter should be investigated further in future studies.
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