Lack of Efficacy of Prophylactic Application of Antibiotic-Loaded Bone Cement for Prevention of Infection in Primary Total Knee Arthroplasty: Results of a Meta-Analysis

Abstract

Background:

Deep incisional surgical site infection (SSI) is a devastating and costly complication of primary total knee arthroplasty (TKA). The effectiveness of antibiotic-loaded bone cement (ALBC) in preventing these infections remains controversial.

Methods:

A meta-analysis was conducted to assess the efficacy of ALBC in preventing deep infection in primary TKA after a detailed and systematic search of the PubMed, Embase, CNKI, and Cochrane databases had been performed to identify appropriate comparative trials on the prophylactic use of ALBC in primary TKA.

Results:

Five comparative trials were included. In total, 3,461 patients (ALBC group) received ALBC, whereas 3,176 patients (non-antibiotic-loaded cement; NALBC group) did not. The incidence of deep incisional SSI in the ALBC group was 1.32% (n=46) whereas the incidence in the NALBC group was 1.89% (n=60), figures which are not significantly different. No adverse events associated with ALBC were reported in any studies.

Conclusion:

Statistical analysis did not reveal a significantly different incidence of deep or superficial SSI in patients receiving and not receiving antibiotic-loaded cement. The prophylactic application of ALBC thus did not show efficacy in primary TKA. More large-sample studies are required to confirm this finding.

Deep incisional surgical site infection (SSI) is one of the most devastating and costly complications of total knee arthroplasty (TKA) [1,2]. More deep incisional SSIs are observed after TK than after total hip arthroplasty (THA) [3,4]. With the use of prophylactic antibiotics, laminar airflow, and other precautions, the incidence of incisional SSI has been reduced to 1%–3% [1,5,6]. However, these infections remain important, because once they appear, patients experience many adverse events, such as pain, osteomyelitis, infection of the prosthesis, osteoporosis, and soft tissue loss, all of which increase the difficulty of revision of the TKA and entail a substantial cost [7,8].

How to prevent deep incisional SSI in TKA is always a substantial concern. Some surgeons use antibiotic-loaded bone cement (ALBC) in an attempt to prevent infection However, the efficacy of this measure remains controversial [1,9 –12], so a meta-analysis was performed to determine the effect of prophylactic use of ALBC in primary TKA.

Materials and Methods

Identification and Selection of Studies

We performed a literature search using the PubMed (MEDLINE), Embase, and CNKI databases and the Cochrane Central Register of Controlled Trials to identify all articles published between 1966 and 2014 that evaluated the clinical outcome of ALBC use in primary TKA. Comparative studies of primary TKA alone were included; re-operations were not considered. The key terms were “total knee arthroplasty/replacement,” “bone cement,” “antibiotic prophylaxis,” “prosthesis-related infection,” and “antibiotic-loaded bone cement.” A literature search was taken for each author of identified studies to locate other relevant studies. Each study and previous review was examined manually to find further studies on similar topics. As we did not include unpublished research, publication bias could not be avoided.

In consideration of the selection bias, the criteria for inclusion were as follows: English- and Chinese-language papers and neither a history of knee infection nor other knee surgery associated with any of these patients. Although randomized controlled trials (RCTs) may be preferable in meta-analysis, number of such suitable studies was small, so reports were also considered suitable if they described comparative trials between antibiotic-loaded and non-antibiotic cement in primary TKA provided their sample size was more than 100 subjects and their main outcome was the incidence of deep incisional SSI after primary TKA. Infections had to be confirmed by laboratory measures such as the erythrocyte-sedimentation rate, C-reactive protein concentration, radiologic examination, bacterial culture of joint fluid, and signs and symptoms such as purulent drainage from the incision, incisional dehiscence, fever (>38°C), and localized pain or tenderness. Three authors made independent assessments of the quality of the studies before they were accepted for inclusion. After all suitable studies were chosen, data were extracted independently by the three authors.

Data Analysis

Although strict inclusion criteria were used, some aspects of the studies differed, such as the surgical technique, type of implant, and use of systemic antibiotics and their dosages. Therefore, a random-effects model was used for the meta-analysis. All analysis was performed by Review Manager (RevMan) 5.0 (Cochrane Informatics & Knowledge Management, Oxford, U.K.). Relative risk (RR) was used to express the value of antibiotic cement in preventing deep and superficial incisional SSI. The results were shown as forest plots. We used 95% confidence intervals (CI) for each study. In our plots, values <1 indicate ALBC is effective in reducing the rate of infection after primary TKA, whereas values >1 indicate non-antibiotic-loaded bone cement (NALBC) is more effective. In the plots, the statistical significance was set at p<0.05 when the 95% CI did not include 1.0.

Results

A total of 258 potential studies were identified (104 from PubMed, 132 from EmBase, 22 from CNKI, and none from the Cochrane databases). Of these, 185 were excluded on the basis of the titles alone, whereas 50 reports were excluded after review of the abstracts and 18 studies were excluded after detailed review of the full text, leaving five studies for inclusion in this meta-analysis (Fig. 1).

FIG. 1.

Flow diagram of study selection.

Table 1 summarizes the characteristics of the five studies, which were published between 2001 and 2013. These studies included three RCTs [14 –16], one retrospective comparative trial [17], and one prospective comparative trial [18]. A total of 6,637 cases were described in these papers and were included in the final analysis. We compared the incidence of deep incisional SSI in the ALBC and NALBC groups of the patients and also performed a subgroup analysis of the findings in the three RCTs [14 –16]. Another analysis was performed of superficial incisional SSIs.

Table 1.

Demographic Characteristics of Studies

Author	Year	Nation	Type	Group	NK	Male/Female	Mean Age (SD)	MF (Range)	DI	SI	DM	Infection (DM)	AEC
Chiu et al. [14]	2001	China	RCT	ALBC	41	28/13	72 (7.6)	50 (26–88)	0	1	41	0	0
				NALBC	37	24/13	69 (5.9)	50 (26–88)	5	1	37	5	0
Chiu et al. [15]	2002	China	RCT	ALBC	178	124/54	70 (7.7)	49 (26–80)	0	2	0	0	0
				NALBC	162	112/50	68 (6.9)	49 (26–80)	5	2	0	0	0
Gandhi et al. [18]	2009	Canada	PRO	ALBC	814	285/529	65.1 (15.4)	12	18	NA	NA	NA	0
				NALBC	811	268/543	67.2 (10.8)	12	25	NA	NA	NA	0
Zhang et al. [17]	2012	China	RE	ALBC	945	414/531	70.2 (7.6)	>24	8	NA	284	NA	NA
				NALBC	701	350/351	70 (7.9)	>24	5	NA	203	NA	NA
Hinarejos et al. [16]	2013	Spain	RCT	ALBC	1,483	346/1,137	75.8 (7.44)	12	20	27	245	NA	0
				NALBC	1,465	353/1,112	76.0 (7.22)	12	20	18	259	NA	0

AEC=adverse effect of cement; ALBC=antibiotic-loaded bone cement; DI=deep incisional surgical site infection; DM=diabetes mellitus; MF=mean follow-up (mos); NA=not applicable; NALBC=non-antibiotic-loaded bone cement; NK=Number of knees; PRO=prospective trial; RCT=randomized controlled trial; RE=retrospective trial; SD=standard deviation; SI=superficial infection.

Efficacy in Avoiding Deep Incisional SSI

First, we examined the incidence of deep incisional SSI after primary TKA (Fig. 2). Although the overall RR showed no significant difference in the first two studies (Fig. 2), the overall results suggested that prophylactic application of ALBC in primary TKA did not decrease the incidence of deep incisional SSI compared with NALBC (RR=0.75; 95% CI 0.43–1.33; p=0.33; I²=34%; Fig. 2). The results of the subgroup analysis of the RCTs also showed no significant reduction in the incidence of deep incisional SSI with ALBC (RR=0.28; 95% CI 0.04–1.25; P=0.22; I²=65%; Fig. 3).

FIG. 2.

Forest plot of deep incisional surgical site infection after primary total knee replacement.

FIG. 3.

Forest plot of incisional surgical site infection after primary total knee replacement. Data from three randomized studies.

Efficacy in Avoiding Superficial Incisional SSIs

Three studies [14 –16] were relevant to the analysis of superficial infection. Prophylactic application of ALBC was not associated with a significant reduction in the incidence of these infections (RR=1.40; 95% CI 0.08–2.43; p=0.24; I²=0; Fig. 4).

FIG. 4.

Forest plot of superficial incisional surgical site infections after primary total knee replacements.

Discussion

Antibiotic-loaded bone cement has been used in orthopaedic surgery for more than 40 years and has been popular in primary TKA. Indeed, some surgeons regard it as routine in such procedures [7]. Efficacy has been demonstrated in primary total hip arthroplasty and revision procedures [19 –22], but it is still unclear whether ALBC is efficacious in primary TKA.

This meta-analysis covered all suitable published papers, including three RCTs [14 –16] and two comparative studies [17, 18]. Two small-sample RCTs showed a significant effect of ALBC in preventing deep infection in primary TKA, but the three other studies did not. However, we cannot conclude that ALBC is not efficacious because the difference between the two groups was small and the patients may have been too few for meaningful analysis. A retrospective cohort studied by Namba et al. [13] containing 22,889 cases showed that the results in the NALBC patients were better than those in patients receiving ALBC. However, the difference in the sample sizes in the two groups was large, and the selection bias was substantial, so that paper was not included in this analysis. Bohm et al., in their latest retrospective case-control study [23], showed no significant difference between the groups in the incidence of deep infection. Superficial incisional SSI after primary TKA was examined in three RCTs, and no significant difference was observed.

No adverse event after the application of ALBC was reported in any of the studies we analyzed. For many years, antibiotics such as gentamicin and tobramycin have been the most common antibiotic additives to bone cement [17]. Many papers reported that the proportion of Staphylococcus aureus infections has decreased, but the proportion of coagulase-negative staphylococci causing infection was higher [24 –26]. The effectiveness of gentamicin and tobramycin has been reduced greatly in recent years by mutations causing resistance [25], which may be a reason for the lack of efficacy of ALBC. Two in vitro studies suggested that about 8% of the antibiotic in ALBC is released quickly after surgery, and the protracted low-dose release thereafter may cause lack of efficacy and contribute to the problem of antibiotic resistance [27,28].

Some studies have indeed reported the appearance of bacterial resistance after prophylactic use of ALBC in primary TKA. Randelli et al. [29] deemed that prophylactic use of ALBC was a safe tactic, and Sader et al. reported that Sweden, which used ALBC in TKA and THA for many years, had the lowest rates of methicillin-resistant S. aureus and the lowest incidence of carbapenem resistance in the European Union [30]. Hansen et al. likewise reported that no direct evidence suggested that ALBC could lead to resistance [31]. On the other hand, Josefsson et al., through biopsy and bacterial cultures of infection sites, found that 88% of infected patients (30/34) who had received gentamicin-loaded cement in primary joint arthroplasty harbored at least one gentamicin-resistant isolate [32].

Deep incisional SSI after TKA is a costly complication [7]. Jiranek et al. [9] said that every 40 g of ALBC cost USD284–349. However, those authors mentioned that if the incidence of deep incisional SSI was reduced from 1.5% to 0.3% after using ALBC in primary TKA, such use would be cost-neutral. Gutowski et al. [33] also reported that medical costs increase with the use of ALBC.

To our knowledge, this is the first meta-analysis of the efficacy of prophylactic application of antibiotic-loaded bone cement in primary TKA, and there were several shortcomings. The sample size was small, as was the number of RCTs. Inclusion of non-randomized studies increased the heterogeneity of the population. Cement and antibiotic types were not standardized. Finally, some ALBC-related aspects were not scrutinized, such as the potential of ALBC to cause systemic toxicity.

In our meta-analysis, no significant decrease in the infection rate was observed when ALBC was used in primary TKA. Few adverse events were reported, but the cost increased. We conclude that the prophylactic application of ALBC did not demonstrate efficacy in primary TKA. More studies of larger numbers of patients are required to confirm or refute this conclusion.

Author Disclosure Statement

No external funding was provided for this study.

References

Bourne

. Prophylactic use of antibiotic bone cement: An emerging standard—in the affirmative. J Arthroplast, 2004; 19:69–72.

Joseph

, Chen

, Di Cesare

. Use of antibiotic-impregnated cement in total joint arthroplasty. J Am Acad Orthop Surg, 2003; 11:38–47.

Davies

, Harris

. Effect of hand mixing tobramycin on the fatigue strength of Simplex P. J Biomed Mater Res, 1991; 25:1409–1414.

Masri

, Duncan

, Beauchamp

. Long-term elution of antibiotics from bone-cement: An in vivo study using the prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) system. J Arthroplast, 1998; 13:331–338.

Rorabeck

. Session IV: Salvage of the infected total knee replacement. Infection: The problem. Clin Orthop Related Res, 2002; 18:113–115.

Peersman

, Laskin

, Davis

, Peterson

. Infection in total knee replacement: A retrospective review of 6489 total knee replacements. Clin Orthop Rel Res, 2001;(392):15–23.

Dunbar

. Antibiotic bone cements: Their use in routine primary total joint arthroplasty is justified. Orthopedics, 2009; 32 doi: 10.3928/01477447-20090728-20.

Department of Orthopedics, Lund University Hospital. The Swedish Knee Arthroplasty Annual Report 2008. Lund, Sweden. University of Lund. 2008.

Jiranek

, Hanssen

, Greenwald

. Antibiotic-loaded bone cement for infection prophylaxis in total joint replacement. J Bone Joint Surg, 2006; 88-A:2487–2500.

10.

Kurtz

, Lau

, Schmier

, et al. Nationwide infection burden in revision hip and knee arthroplasty. Trans Orthop Res Soc, 2006; 31:179.

11.

Heck

, Rosenberg

, Schink-Ascani

, et al. Use of antibiotic-impregnated cement during hip and knee arthroplasty in the United States. J Arthroplast, 1995; 10:470–475.

12.

Hanssen

. Prophylactic use of antibiotic bone cement: An emerging standard—in opposition. J Arthroplast, 2004; 19:73–77.

13.

Namba

, Chen

, Paxton

, et al. Outcomes of routine use of antibiotic-loaded cement in primary total knee arthroplasty. J Arthroplast, 2009; 24:44–47.

14.

Chiu

, Lin

, Chen

, et al. Cefuroxime-impregnated cement at primary total knee arthroplasty in diabetes mellitus: A prospective, randomised study. J Bone Joint Surg, 2001; 83-B:691–695.

15.

Chiu

, Chen

, Lin

, Lo

. Cefuroxime-impregnated cement in primary total knee arthroplasty: A prospective, randomized study of three hundred and forty knees. J Bone Joint Surg, 2002; 84-A:759–762.

16.

Hinarejos

, Guirro

, Leal

, et al. The use of erythromycin and colistin-loaded cement in total knee arthroplasty does not reduce the incidence of infection: A prospective randomized study in 3000 knees. J Bone Joint Surg, 2013; 95-A:769–774.

17.

Zhang

, Wu

, Fu

, et al. A retrospective cohort study on prophylactic use of antibiotic-loaded bone cement in primary total knee arthroplasty. Chin J Joint Surg, 2012; 6:842–847.

18.

Gandhi

, Razak

, Pathy

, et al. Antibiotic bone cement and the incidence of deep infection after total knee arthroplasty. J Arthroplast, 2009; 24:1015–1018.

19.

Malchau

, Herberts

, Eisler

, et al. The Swedish Total Hip Replacement Register. J Bone Joint Surg, 2002; 84-A(Suppl 2):2–20.

20.

Engesaeter

, Espehaug

, Lie

, et al. Does cement increase the risk of infection in primary total hip arthroplasty? Revision rates in 56,275 cemented and uncemented primary THAs followed for 0–16 years in the Norwegian Arthroplasty Register. Acta Orthop, 2006; 77:351–358.

21.

Parvizi

, Saleh

, Ragland

, et al. Efficacy of antibiotic-impregnated cement in total hip replacement. Acta Orthopaed, 2008; 79:335–341.

22.

Herberts

, Malchau

. Long-term registration has improved the quality of hip replacement: A review of the Swedish THR Register comparing 160,000 cases. Acta Orthopaed Scand, 2000; 71:111–121.

23.

Bohm

, Zhu

, Gu

, et al. Does adding antibiotics to cement reduce the need for early revision in total knee arthroplasty?. Clin Orthop Rel Res, 2014;(472):162–168.

24.

Nickinson

, Board

, Gambhir

, et al. The microbiology of the infected knee arthroplasty. Int Orthop, 2010; 34:505–510.

25.

Stefansdottir

, Johansson

, Knutson

, et al. Microbiology of the infected knee arthroplasty: Report from the Swedish Knee Arthroplasty Register on 426 surgically revised cases. Scand J Infect Dis, 2009; 41:831–840.

26.

Stefansdottir

, Johansson

, Lidgren

, et al. Bacterial colonization and resistance patterns in 133 patients undergoing a primary hip- or knee replacement in Southern Sweden. Acta Orthop, 2013; 84:87–91.

27.

Dunne

, Hill

, McAfee

, et al. In vitro study of the efficacy of acrylic bone cement loaded with supplementary amounts of gentamicin: Effect on mechanical properties, antibiotic release, and biofilm formation. Acta Orthop, 2007; 78:774.

28.

Van de Belt

, Neut

, Schenk

, et al. Gentamicin release from polymethylmethacrylate bone cements and Staphylococcus aureus biofilm formation. Acta Orthop Scand, 2000; 71:625.

29.

Randelli

, Evola

, Cabitza

, et al. Prophylactic use of antibiotic-loaded bone cement in primary total knee replacement. Knee Surg Sports Traumatol Arthrosc, 2010; 18:181.

30.

Sader

, Fritsche

, Stillwell

, Jones

. 10 years of surveillance of bloodstream infections in European medical centres by the SENTRY Antimicrobial Surveillance Program (1997–2006). Presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases. Munich, Germany. March 31–April 3, 2007.

31.

Hansen

, Adeli

, Kenyon

, Parvizi

. Routine use of antibiotic laden bone cement for primary total knee arthroplasty: Impact on infecting microbial patterns and resistance profiles. J Arthroplast, 2014; 29:1123–1127.

32.

Josefsson

, Kolmert

. Prophylaxis with systematic antibiotics versus gentamicin bone cement in total hip arthroplasty: A ten-year survey of 1,688 hips. Clin Orthop Relat Res, 1993;(292):210.

33.

Gutowski

, Zmistowski

, Clyde

, Parvizi

. The economics of using prophylactic antibiotic-loaded bone cement in total knee replacement. J Bone Joint Surg, 2014; 96-B:65–69.