Microbiological Concepts of the Infected Total Knee Arthroplasty

© Springer International Publishing AG 2018
E. Carlos Rodríguez-Merchán and Sam Oussedik (eds.)The Infected Total Knee Arthroplastydoi.org/10.1007/978-3-319-66730-0_2

2. Microbiological Concepts of the Infected Total Knee Arthroplasty

E. Carlos Rodríguez-Merchán  and Alexander D. Liddle 

Department of Orthopaedic Surgery, “La Paz” University Hospital-IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain

University College London Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex, HA7 4LP, UK



E. Carlos Rodríguez-Merchán (Corresponding author)


Alexander D. Liddle


The microbiology of the infected joint replacement is now well established. Causative organisms are generally gram positive, principally staphylococci and streptococci, but many organisms may cause periprosthetic joint infection (PJI), particularly in the presence of immunosuppression. Infections following total knee arthroplasty (TKA) are difficult to treat due to the formation of biofilms, which protect the causative bacteria from antibiotics and host defenses. Adequate prevention, diagnosis, and management schemes for biofilm-based PJIs are still lacking. The current approach to biofilms centers on prevention, with the use of local and systemic antibiotics. Future strategies for the prevention and treatment of biofilms include the use of surface coatings (including surface-tethered antibiotics and metal oxide nanoparticle coatings) and disruption of the established biofilm by mechanical or pharmacological means.

Total knee arthroplastyInfectionIncidenceMicrobiological conceptsBiofilm

2.1 Introduction

Periprosthetic joint infection (PJI) is a challenging problem as a result of the adaptations made by the causative bacteria to avoid destruction by the host organism, in particular the formation of biofilms [1]. The common causative bacteria in PJI have a high attraction for adhering to the components of joint replacement, including cobalt-chromium, titanium, polyethylene, and polymethyl methacrylate (PMMA) cement, and tend to be strong formers of biofilms.

In this chapter, we discuss the microbiology of the infected total knee arthroplasty (TKA), focusing on the nature of bacterial biofilms and the current and future strategies for their detection, prevention, and treatment.

2.2 Microbiology of the Infected Total Knee Arthroplasty (TKA)

2.2.1 Common Causative Agents of Infection Following TKA

Most prosthetic joint infections are caused by gram-positive bacteria, predominantly staphylococci [2]. In Nickinson et al.’s study of 121 patients undergoing revision TKA for infection over 15 years, coagulase-negative Staphylococcus and Staphylococcus aureus accounted for 62% of organisms cultured [3]. Holleyman et al. cross-referenced data on septic revisions from the National Joint Registry for England and Wales with microbiology data held by Public Health England [4]. They reported on 275 patients; again, staphylococci were the commonest organisms, and gram-positive organisms accounted for 241 of 275 patients (88% of the total).

Matthews et al. published a review of the literature regarding prosthetic joint infection (both hip and knee), reporting the relative frequency of bacteria in PJI reported by previous studies [5]. They estimated the rate of infection with coagulase-negative staphylococci at between 13 and 37%; Staphylococcus aureus accounted for 20–62%, Streptococcus between 4 and 27%, enterococci between 6 and 13%, and other gram positives between 6 and 20%. Gram negatives were rare, with enteric gram negatives accounting for 2–15% and pseudomonas being present in 1–4% of samples. No pathogen was identified in up to a quarter of PJIs reported in this review. More recently, Benito et al. reported on the microbiological diagnosis of 2288 cases over 15 years (again, both the hip and knee), in which gram-positive cocci were present in 78% of infections, gram-negative organisms were present in 28%, and anaerobes were present in 7% [2].

Methicillin-resistant Staphylococcus aureus (MRSA) presents a particular problem. It is harder to eradicate and associated with inferior outcomes compared to sensitive bacteria in terms of function and rate of reoperation [6]. The rate of MRSA bacteremia and surgical site infection increased markedly during the 1990s and early 2000s [7]. Benito et al. report that the rate of MRSA PJI increased over the first decade of this century but appears to be declining [2]. The rate of MRSA increased from less than 5% in 2003–2004 to 9.5% in 2009–2010 but fell to 7.6% in 2011–2012. This mirrors the rate of MRSA isolation overall in epidemiological datasets which have fallen as awareness has increased and programs have been introduced to screen, isolate, and treat patients who carry MRSA (see Chap. 6) [8, 9].

2.2.2 Rare and Atypical Agents of Infection Following TKA

Many other bacterial and fungal species have been reported to cause PJI in very small numbers. Most are only evidenced by case reports and are extremely rare. Rare causative agents have been described in cases involving contact with cats and dogs, vigorous dental flossing, and intravesical bacillus Calmette-Guerin [1013]. Some organisms have particular implications—for instance, isolation of Streptococcus bovis/Streptococcus equinus species can suggest the presence of undiagnosed colonic malignancy [14]. Surgeons should be vigilant when patients present in the setting of immunosuppression where unusual organisms may present [15].

Mycobacterium tuberculosis is a rare cause of prosthetic joint infection. In 2013 Kim et al. reported a systematic review on Mycobacterium tuberculosis infections [16]. Only 15 patients were identified from 13 studies. Tuberculosis was confirmed in all cases by histological examination and positive culture or histochemical stain/PCR. Treatment consisted of antituberculosis medication therapy (AMT) only in two patients, AMT plus debridement and retention of the arthroplasty in five patients, and AMT plus removal/exchange of the arthroplasty in eight patients. Three patients in the cohort died; results were favorable in the surviving patients.

Fungal PJI is a rare but devastating complication following TKA. In a systematic review, Jakobs et al. found that Candida spp. accounted for about 80% (36 out of 45 cases) of fungal PJIs and was therefore the most frequently reported pathogen [17]. Cobo et al. performed a literature review and identified 73 cases of Candida PJI [18]. Of the 73 cases, 50 had a documented cause of immunosuppression; most were treated with medication and surgery, most commonly two-stage revision. Cure was obtained in three quarters of patients, but 32 of the 73 cases had to undergo definitive excision arthroplasty. Antifungals were used for long durations—courses lasted from 6 weeks to over 1 year.

2.3 Delivery of Antimicrobial Agents

In PJI, antimicrobials may be delivered systemically, either orally or intravenously, or directly via antibiotic-eluting cement or cement spacers or via intra-articular catheter.

Intravenous antibiotics demonstrate good systemic bioavailability, and the use of standard doses of cephalosporins results in therapeutic concentrations within the knee joint [19, 20]. Antibiotic-containing bone cement has been used for many years and is both effective and cost-effective in the prevention of PJI [21]. When used as a spacer in two-stage revisions, it has been shown to continue eluting antibiotics to an effective local dose over 6 weeks following implantation and, provided a sufficient dose is used, may be effective at a mean of up to 4 months following implantation [22, 23].

Whiteside et al. have described the use of intra-articular infusion for the delivery of antibiotics in revision hip and knee replacement [24]. They describe a protocol involving single-stage revision with the insertion of intra-articular Hickman lines to deliver a once daily infusion of antibiotics for up to 6 weeks. After an initial loading dose, no intravenous antibiotics are given; their pharmacokinetic study has demonstrated maintenance of therapeutic local levels of antibiotic with minimal systemic absorption. Excellent results are reported, even in difficult groups such as those with previous failed two-stage revisions and resistant organisms [24].

2.4 The Biofilm

The main challenge to the prevention and treatment of PJI is the behavior of causative bacteria in the presence of implants. Bacteria, either introduced at the time of surgery or by later hematogenous spread, adhere to the surface of the implant and form a complex glycocalyx known as a biofilm [25, 26]. The biofilm protects the bacteria from the antibiotics which are effective against them in the planktonic form. As a result, our principal pharmacological strategies for treatment of bacterial infection are ineffective; our efforts instead focus on prevention of biofilm formation by reducing the number of bacteria present in the surgical field (see Chap. 4) and by treating the planktonic form of bacteria before they are able to adhere to the implant—this forms the basis of antibiotic prophylaxis regimens (covered in more detail in Chap. 5).

The first stage of biofilm formation is adhesion; planktonic bacteria produce adhesins which allow them to bond to the surface of the implant, after which the bacteria divide and start to secrete the complex combination of proteins, polysaccharides, and phospholipids which form the acellular structure of the biofilm; these are known as extracellular polymeric substances or EPS [27]. The structure of the biofilm confers protection, nutrition, and communication, through a process known as quorum sensing [28]. This communication can involve the control of the population of bacteria and the transmission of plasmids to spread antibiotic resistance within the population of bacteria within the biofilm.

In a biofilm, bacteria comprise 10% of the overall mass, and EPS comprises 90%. The bacteria can be a single species or multiple species can exist within the same biofilm [28]. The precise contents of the EPS vary from species to species and are poorly understood [29]. Components include polysaccharides (which are involved in adhesion, aggregation, and protection of bacteria), enzymes (which are involved in turnover of the biofilm and degradation of structural biofilm components, either to liberate bacteria to create new biofilms or to provide nutrition to bacteria within the existing biofilm), extracellular deoxyribonucleic acid (DNA), lipids (which contribute to adhesion), and biosurfactants. The largest component of the EPS is water, which is retained due to the hydrophilic components of the EPS, allowing bacteria to survive in otherwise inhospitable conditions.

2.5 Targets for the Prevention and Treatment of Biofilms

Recent research has focused on the detection of biofilms, the prevention of biofilm formation, and the disruption of biofilms which are present.

2.5.1 Improvements in Detection of Biofilms

Bacteria are generally detected and characterized on the basis of culture growth; however, bacteria in biofilm form are difficult to culture and diagnosis may be elusive. Suda et al. reported a moderate increase in yields of bacteria from PJI using the polymerase chain reaction (PCR) for bacterial ribonucleic acid (RNA), although other authors have debated the usefulness of this technology [30, 31]. Sonication of implants is performed with the aim of liberating bacteria from the biofilm into their planktonic form to allow a higher yield from culture [32]. Other methods for detection include fluorescence in situ hybridization (FISH) and DNA microarrays [33, 34].

An emerging field is the use of imaging technology to detect biofilms on orthopedic implants. Stoodley has used confocal laser scanning microscopy to image the biofilm in a retrieved specimen; others have examined biofilms using scanning electron microscopy [35, 36].

2.5.2 Prevention of Biofilm Formation

While the use of antibiotic-eluting cement is an established and evidence-based implant-based approach to the prevention of biofilm formation [37], there is increasing evidence that strategies based on the surface properties of implants may have a role to play in preventing biofilm formation. Surface properties of implants affect the ability of bacteria to adhere and form biofilms [38]. There is some evidence from basic science studies that current implant materials such as vitamin E—impregnated polyethylene and ceramic—may confer a degree of protection against biofilm formation, but studies are contradictory and clinical evidence is lacking [3942].

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Mar 10, 2018 | Posted by in ORTHOPEDIC | Comments Off on Microbiological Concepts of the Infected Total Knee Arthroplasty
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