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Abstract

Introduction:

Periprosthetic joint infection (PJI) is a terrible complication after hip arthroplasty. Clinical feature of culture-negative PJI (CN-PJI) has not been well studied till now. In our study, we retrospectively analyzed long-term clinical results after two-stage revision arthroplasty using an antibiotic-impregnated cement spacer for CN-PJI. The purpose of this study is to investigate the clinical features and prognosis of CN-PJI after hip arthroplasty and to compare these with those of culture-positive PJI (CP-PJI).

Methods:

We retrospectively reviewed 15 CN-PJI cases and 70 CP-PJI cases following hip arthroplasty. The average follow-up period was 7.4 years (5–11.7 years). The demographics, laboratory findings, the time interval between antibiotic-impregnated cement spacer insertion and revision arthroplasty, and recurrence of infection were analyzed.

Results:

The CN-PJI group showed a significantly higher incidence of prior antibiotic use (p = 0.004) and lower serum C-reactive protein (CRP) level (p = 0.001) than the CP-PJI group. Normalized time interval of CRP level in CN-PJI was shorter than that of CP-PJI group. The mean interval time for two-stage exchange arthroplasty was also significantly lower (p = 0.049) in the CN-PJI group than the CP-PJI group. There was no case of treatment failure or major complication in CN-PJI group.

Conclusion:

The CN-PJI group after total hip arthroplasty could be treated successfully by two-stage exchange arthroplasty without any complications. Clinical course and prognosis of CN-PJI group was also better compared with that of CP-PJI group. Therefore, culture negativity of PJI cannot be always a poor prognostic factor for the treatment.

Keywords

arthroplasty complication culture negative periprosthetic joint infection

Introduction

Periprosthetic joint infection (PJI) is a common indication for hip and knee revision surgery, constituting 15% of all revision hip and 25% of all revision knee procedures.¹ PJI is also one of the most terrible complications following total hip or knee arthroplasty, and the occurrence rate is reported to be 0.2–4.4% following total hip and knee arthroplasty.^1

–4 The most common pathogens of PJI are Staphylococcus aureus and coagulase-negative staphylococci.^5,6 However, preoperative or intraoperative culture could be negative for the identification of pathogens, and the rate of culture-negative PJI (CN-PJI) was 7–23% according to recent studies.^7

–11 Culture negativity makes it challenging to choose the appropriate antibiotics and determine proper time for revision surgery. However, clinical feature of CN-PJI has not been well studied. The purpose of this study is to investigate the clinical features and prognosis of CN-PJI after hip arthroplasty and to compare these with those of culture-positive PJI (CP-PJI).

Methods

We retrospectively identified 85 patients treated for PJI following hip revision arthroplasty at our hospital, from May 1996 to September 2015. There were 15 patients (17.6%) with CN-PJI and 70 patients (82.4%) with CP-PJI. The PJI diagnosis has been defined by the following criteria¹²: (1) There is a sinus tract communicating with the prosthesis or (2) a pathogen is isolated by culture from at least two separate tissues or fluid samples obtained from the affected prosthetic joint, or (3) if at least four of the following six criteria exist: (a) elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration, (b) elevated synovial leukocyte count, (c) elevated synovial neutrophil percentage (Polymorphonuclear neutrophil [PMN %]), (d) presence of purulence in the affected joint, (e) isolation of a microorganism in one culture of periprosthetic tissue or fluid, or (f) greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification.

When patients were referred to the emergency department or outpatient clinic, preoperative joint aspiration was performed to confirm the diagnosis. Broad-spectrum antibiotics (first-generation cephalosporin, cefazolin) were used empirically until the result of joint fluid culture was obtained in all cases (Figure 1). And then, periprosthetic tissues were taken for culture study from at least three different areas at the time of surgery. When the culture study showed negative result, cefazolin therapy was maintained. However, we decided to change to glycopeptide through the consultation with an infectious disease specialist, if the infection would not be controlled, such as sustained elevated ESR/CRP level, or local heating or redness persisted around the wound. When the culture study showed positive result, the antibiotics had been adjusted subsequently based on the sensitivities with maintaining cefazolin use or changing to glycopeptide in case of methicillin-resistant bacteria. Two-stage revision arthroplasty was performed in all cases because all patients had infective symptoms more than 4 weeks of symptoms. We conducted the two-stage revision arthroplasty using custom-made mobile articulating spacer made by used femoral stem coating with bone cement containing gentamycin and vancomycin (Figure 2). We performed the second-stage revision arthroplasty, after infection indicator was improved and normalized with ESR less than 22 mm/h, CRP less than 0.3 mg/dL, and WBC less than 10,000/μL.

Figure 1.

Diagram for the treatment of PJI. PJI: periprosthetic joint infection. EM: emergency department.

Figure 2.

Articulating spacer made using femoral stem coating with bone cement containing gentamycin and vancomycin.

All patients were followed up, and the mean follow-up period was 7.4 years (5–11.7 years). We analyzed serologic infective markers such as ESR and CRP from the time of diagnosis, and the time taken from admission date to two-stage exchange arthroplasty by estimation of normalized ESR and CRP level. Also, we compared the final clinical course and complications including recurrence of infection or death events between two groups. The protocol for this study was approved by the institutional review board of our hospital (number 2015-12-011).

We used various statistical tools to analyze CN-PJI and CP-PJI groups. Continuous variables not following a normal distribution were analyzed with the Mann–Whitney test, and the chi-square test was used to analyze prior antibiotic use. Using these two analytical tools, we compared the average and standard deviation between two groups. Statistical analysis was performed using SPSS program (version 19.0; IBM, Chicago, Illinois, USA).

Results

Demographic data with the patient’s age and comorbidities influence to infection showed no statistically different outcomes between two groups. Body temperature was higher in the CP-PJI group (p = 0.006), and higher incidence of prior antibiotics use showed a significantly in the CN-PJI group (p = 0.004) (Table 1).

Table 1.

The patients’ preoperative characteristics data of both groups.

Characteristics	CN-PJI (n = 15)	CP-PJI (n = 70)	p Value
Age (year)	66.67 ± 10.72	66.47 ± 12.23	0.836*
Comorbidities possible influence to infection (n)	7	23	0.310**
Body temperature (°C)	36.47 ± 0.31	36.91 ± 0.61	0.006*
Previous antibiotics (n)	13	31	0.004**

CN: culture negative; CP: culture positive; PJI: periprosthetic joint infection.

*Calculated by Mann–Whitney test for continuous variables.

**Calculated by chi-square test for categorical variables.

CRP level at the time of admission was significantly higher (p = 0.001) in CP-PJI group (6.55 ± 7.40 mg/dL) than in CN-PJI group (2.01 ± 1.00 mg/dL), and normalized time interval of CRP level in CP-PJI group and CN-PJI group was 49.81 ± 21.66 days and 38.27 ± 12.56 days, respectively (p = 0.051). ESR level at the time of admission was 62.36 ± 31.70 mm/h in CP-PJI group and 48.80 ± 21.47 mm/h in CN-PJI group (p = 0.156), and normalized time interval of ESR level in CP-PJI and CN-PJI groups was 42.47 ± 11.23 days and 30.40 ± 11.23 days, respectively (p = 0.054) (Table 2). Glycopeptide was administered intravenously at 48 patients (68.6%) in CP-PJI group and 14 patients (93.3%) in CN-PJI group (p = 0.059). They also had been initially administered by the first-generation cephalosporin.

Table 2.

Laboratory markers of both the groups.

Laboratory markers	CN-PJI (n = 15)	CP-PJI (n = 70)	p Value
WBC count	8986.0 ± 4912.72	11,300.0 ± 13,475.46	0.486*
Neutrophil (%)	69.25 ± 18.10	72.40 ± 11.41	0.568*
ANC	6939.60 ± 4994.66	5759.77 ± 3036.34	0.657*
CRP (mg/dL)	2.01 ± 1.00	6.55 ± 7.40	0.001*
ESR (mm/h)	48.80 ± 21.47	62.36 ± 31.70	0.156*
Normalization of CRP (days)	38.27 ± 12.56	49.81 ± 21.66	0.051*
Normalization of ESR (days)	30.40 ± 11.23	42.47 ± 23.04	0.054*

CN: culture negative; CP: culture positive; PJI: periprosthetic joint infection; WBC, white blood cell; ANC, absolute neutrophil count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

*Calculated by Mann–Whitney test for continuous variables.

The mean interval time for two-stage exchange arthroplasty was statistically significantly different between two groups: 53.9 ± 14.9 days in CP-PJI group and 46.4 ± 10.3 days in CN-PJI group (p = 0.049). Treatment failure was defined when there is recurrence of infection, limb amputation, and death after hospitalization. There was no case of treatment failure or major complication in CN-PJI group (Figure 3). In CP-PJI group, one case showed infection recurrence, one patient underwent girdle stone operation due to uncontrolled infection, and one patient expired due to sepsis related with PJI.

Figure 3.

Periprosthetic hip joint infection was treated by a two-stage reimplantation using cement articulating spacer. (a) A 70-year-old patient had undergone THA at local clinic 7 years ago. He had pain and redness around previous operation site; initial ESR and CRP was 32 mm/h and 3.5 mg/dL, respectively. (b) Two-stage revision surgery using cement spacer was performed. (c) There was no pain and radiologic finding of osteolysis, at the last follow-up 3 years after revision operation. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; THA: Total hip arthroplasty.

Discussion

Total hip and knee replacement increase quality of life and are very useful treatment options for those who suffer from severe arthritis. With increase in demand for total joint arthroplasty, there will a corresponding increase in the incidence of PJI. Infections are difficult to diagnose and once diagnosed, it is difficult to eradicate. PJI is one of the most common causes of implant failure and revision surgery, increasing the mortality rate in aged population.¹³ It is also challenging to make exact diagnosis and choose appropriate antibiotics when the culture results are negativity. The causes of culture negativity include unskillful culture techniques, atypical organisms cultured in specialized culture media, antibiotics use before sample collection (5), difficulty in the culture of anaerobic microorganisms, biofilm formation due to chronic infections, and differences in growth rate due to original nutritional status.¹⁴

Studies aiming to diagnose PJI using biochemical analysis method are undergoing recently.¹⁵ Jacovides et al. successfully identified pathogens from CN-PJI patients using polymerase chain reaction–based electron spray ionization time-of-flight mass spectrometry (ESI-TOF-MS) among 82 suspected PJIs.¹⁶ They concluded that the technique is useful not only in identifying organisms in cases of CN-PJI but also in revision arthroplasty cases suspected for infection.

One of the common causes of CN-PJI is previous antibiotic use, which has been reported by other papers.^5,8,17,18 According to Berbari et al. in a retrospective cohort study of 897 patients, the rate of CN-PJI was 60 patients (7%), and the ratio of antimicrobial therapy before diagnosis was high, which showed more favorable outcomes than those of CP-PJI group.⁵ Choi et al. concluded that the rate of previous antibiotic use was statistically significantly higher in CN-PJI group, which also showed a higher incidence of prior resection surgery, lower ESR level, and higher successful treatment rate compared to CP-PJI group (p = 0.006).⁸ Our medical center is a tertiary hospital, so most patients in this study were referred from outside hospitals, and the higher tendency of prior antibiotic use makes sense. Considerable number (86.7%) of CN-PJI group had antimicrobial therapy before hospitalization. We consider that culture test could be negative due to prior antibiotic use, reducing a virulence of infected bacteria. In this study, clinical course of CN-PJI group was better than that of CP-PJI group, and the treatment failure rate was lower in CN-PJI group. Although it is an accepted principle that antibiotics would not be applied until the identification of bacteria, empirical administration of antibiotics after joint aspiration could be advantageous option in the treatment of PJI.

First, we administered the first-generation cephalosporin empirically. But if infection had not been controlled after surgical treatment, antibiotics were replaced with glycopeptide by consulting the infectious disease department. Vancomycin is a glycopeptide antibiotic used for prophylaxis and treatment of PJIs in penicillin-allergic patients. Additionally, the American Academy of Orthopaedic Surgeons [orthopaedic organization] (AAOS) recommends it for treatment of Methicillin-Resistant Staphylococcus Aureus (MRSA)-colonized patients and MRSA outbreaks. Recent evidence suggests that vancomycin may play a role in the prophylaxis and treatment of MRSA-related PJIs after primary and revision arthroplasty surgery.^19
–21 It is disadvantaged, however, by its predominant intravenous use, and the risk of red man syndrome and ototoxicity requiring therapeutic drug monitoring. Additional resistance to vancomycin has been increasingly reported.²⁰

Hofmann et al. suggested that applying glycopeptide to 12 CN-PJI patients cannot lead to recurrence.²² Cuckler et al. also concluded that empirically used glycopeptide to 6 CN-PJI patients of 44 chronic infected Total knee arthroplasty (TKA) could induce no recurrence.²³ In this study, the administration rate of glycopeptide was higher in CN-PJI group compared to CP-PJI group, which could result in successful treatment without complications. High-quality prospective randomized trials dictating best antibiotic therapy for PJIs and surgical option are currently lacking, so application of glycopeptide to CN-PJI group needs more studies and discussion.

There are a few studies of optimal surgical treatment of CN-PJI. Berbari et al. reported that patients who underwent two-stage exchange arthroplasty among the three types of surgical treatment had a better outcome than patients who underwent other surgical therapy, and clinical outcome of CN-PJI group could be more favorable than that of CP-PJI group.⁵ Recently, Ilchmann et al. reported that single-stage revision had a high success rate in the treatment of PJI,²⁴ and hence it could be tried in the treatment of CN-PJI. Although single-stage exchange arthroplasty can be a good option in the treatment of CN-PJI, it may need more careful consideration. Our study had some limitations in that it is a retrospective study of a relatively small number of patients in a single institution.

Conclusions

The CN-PJI group after total hip arthroplasty could be treated successfully without any complications by two-stage exchange arthroplasty. Clinical course and prognosis of CN-PJI group was also better than that of CP-PJI group. Therefore, the culture negativity of PJI cannot be always a poor prognostic factor for treatment.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Inha University grant.

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Long-term clinical outcome of two-stage revision surgery for infected hip arthroplasty using cement spacer

Abstract

Introduction:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Results

Discussion

Conclusions

Footnotes

Declaration of conflicting interests

Funding

References