Infections associated with orthopaedic implants

           Infections associated with orthopaedic implants

               

                                                 Dr. KS Dhillon

Introduction

The use of implants in most of the orthopaedic procedures is common. The risk of infection can increase dramatically when implants are present in the body [1]. The overall surgical site infection rate following implant surgery is about 3% [2]. Since the number of these surgeries are increasing the number of infections is proportionally increasing.

In the United States, more than 4.4 million people have at least 1 internal fixation device and more than 1.3 million have an artificial joint [3].

In the last several decades sophisticated prevention strategies have been developed to lower the risk of infections in implant surgery. These include laminar airflow with ultraclean air [4], routine antimicrobial prophylaxis [5], short operating time, use of antibiotic-bonded cement [6], and antimicrobial coating [7,8].

The number of orthopedic device-related infections (ODRIs) per institution remains low. This scarcity of infections per institution is the main reason why the treatment of such an infection is poorly standardized. Randomized controlled clinical trials cannot be conducted in most institutions because of the low numbers of such cases. Therefore, many of the studies frequently lack appropriate statistical power because of low number of cases as well as due to the fact that many of the patients are lost to follow-up, changing residence, or dying of underlying diseases [9].

Currently, there are ample standard procedures for the identification of the microbes causing these infections [10]. There are, however, only a few diagnostic tools for rapid diagnosis of ODRIs with varying degrees of sensitivity and specificity available [11,12].

Pathogenesis Of ODRIs

Biofilm formation. 

An understanding of the pathogenesis of biofilm formation facilitates optimal diagnosis and treatment. The formation of biofilm also explains why signs and symptoms are relieved by short-term treatment with antimicrobial agents but reoccur immediately following the withdrawal of treatment [13]. 

Implants undergo physiological changes after they are implanted in the body. The earliest step is a contest between tissue cell integration and bacterial adhesion to the implant surface [14]. The body fluids immediately coat all surfaces of the implant with a layer of the host material, consisting mainly of serum proteins and platelets. Albumin is the major serum component. It is rapidly deposited on the implant and it prevents nonspecific neutrophil activation and deposition of matrix proteins on the surfaces [15]. 

Adhesins, such as fibronectin, fibrin, fibrinogen, collagen, vitronectin, laminin, thrombospondin, bone sialoprotein, elastin, and the matrix-binding protein mediate the adherence of Staphylococcus aureus to bioprosthetic materials. These host proteins promote the attachment of Staphylococcus aureus onto metallic or polymeric surfaces by specific receptors. The adherence progresses to aggregation of microorganisms on the surface of the foreign body, forming a biofilm. 

As the colonies increase in size, sessile bacteria at the periphery detach and disperse as planktonic bacteria. This process can lead to clinically overt infection. 

Costerton et al [16] have defined bacterial biofilms as “structured communities of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface.” Both types of surfaces are usually present in ODRIs. They are present on medical devices and sequestra of dead bone. Biofilms can resist cellular and humoral immune responses and grow slowly [17]. The biofilm bacteria are less susceptible to antimicrobial agents than their planktonic counterparts due to several established mechanisms. Clinically established mechanisms include slime production, adherence of bacteria, and slow rate of bacterial growth. The bacterias become sessile in the biofilm, and their phenotypic features change to a large extent. The two clinically important mechanisms that protect the bacteria are failure of antimicrobial agents to penetrate the biofilm and the stationary phase of growth. 

Some bacteria, such as Staph aureus, form small-colony variants that are characterized by reduced growth rate, diminished exoprotein production, decreased susceptibility to aminoglycosides, and also possible intracellular persistence [18]. Standard antibiotic therapy usually reverses signs and symptoms caused by planktonic bacteria released from the biofilm but fails to kill bacteria that are in the biofilm [16]. To successfully treat ODRIs with retention of the implant the treatment must be against both planktonic and sessile bacteria. The alternative is to kill planktonic bacteria with antimicrobial agents and remove the implants to get rid of sessile bacteria [16].

Slime production

Some microorganisms, such as coagulase-negative staphylococci (CNS),  P. aeruginosa, and Streptococcus mutans, develop slime, which is an amorphous extracellular glycocaliceal substance based on polysaccharides. Slime production is usually triggered by adherence of the bacteria to surfaces. Many strains of CNS have been found to exude slime. The slime extracted from CNS consists of 80% teichoic acid and 20% protein [19]. Glycocalix which is present on bacterial surfaces promotes intercellular adhesion, captures nutrients, and protects microorganisms from the deleterious effects of antimicrobial agents. 

The susceptibility of the microorganisms to antimicrobial agents can be altered by slime that has potent immunomodulatory properties. Slime can also decrease chemotaxis and opsonization of neutrophil granulocytes, increase degranulation, and block the penetration of antibiotics into the bacterial cell [20].

Mode of growth

Bacteria in a biofilm grow slowly. They do not grow exponentially. They exist in a slow-growing or starved state [16]. Studies in animal models confirm the slow-growing or starved state of bacterial growth for S. aureus and Escherichia coli. In ODRIs some cells are dormant or replicating slowly and, consequently, are not killed by antibiotics. 

Much higher concentrations of antibiotics are needed to kill stationary phase bacteria as compared to logarithmically growing bacteria [21,22]. 

Rifampin has been found to be highly effective against stationary-phase gram-positive cocci such as Staph aureus and Staphylococcus epidermidis. The Minimum Bactericidal Concentration (MBC) of rifampin determined for stationary-phase bacteria remained in a range achievable in serum and tissue with a standard dosage of rifampin. The MBCs of ciprofloxacin, on the other hand, increased 200 times when tested with stationary-phase S. epidermidis. Ciprofloxacin has been found to be highly efficacious against stationary-phase Salmonella Dublin and E. coli ATCC 25922. 

The reason why some antimicrobial agents perform better than others against stationary-phase bacteria is poorly understood. The efficacy of β-lactam antibiotics is reduced partly because of their primary mode of action. Their killing of bacteria by β-lactam antibiotics is growth-dependent, and, therefore, slow-growing bacteria in device-related infections are not affected. Slime production can also inhibit antimicrobial activity. Studies show that antimicrobial agents should be bactericidal against slow-growing bacteria for optimal effectiveness [21,23,24]. 

Nomenclature of orthopedic device-related infections

ODRIs can be divided into 3 categories, namely early postoperative infections, late chronic infections, and hematogenous infections.

Early postoperative infections

These infections occur in the immediate postoperative period. The patient usually presents with chills, fever, and sweating. Post-operative pain persists in the early postoperative period and does not decline as it does in noninfected patients. The wound is often tender, erythematous, swollen, and fluctuant. The distinction between a superficial infection and a deep infection around the implant is usually a diagnostic challenge. 

Empirical treatment with antibiotics is not recommended because antibiotics may mitigate signs or symptoms of infection but will ultimately result in chronic infection. Therefore, such patients usually require a rapid workup for suspected early infection and implant salvage may be done if the following criteria are met [25]:

• Acute infection with signs and symptoms of less than 14-28 days
• Implant stable with no signs of loosening
• Clearly established diagnosis by isolating a single microorganism
• Positive histopathologic result
• Pathogen susceptible to oral bactericidal drug
• Patient willing to undergo long term antimicrobial therapy

Late chronic infection

Chronic infections originate at the time of surgery and are caused by a very low inoculum or a low-virulence pathogen such as CNS. Low virulence pathogens delay the onset of clinically apparent infection and do not trigger symptoms of acute infection. The onset of this type of infection is usually between 16 months and 2 years [26]. The hallmark of such infections is a gradual deterioration of function and intensifying pain. Premature early loosening of the implant may be the only symptom of chronic infection in patients who have a joint prosthesis. In some cases, it may be difficult to differentiate between aseptic loosening of a prosthesis and low-grade chronic infection. Such infections usually respond poorly to treatment with antimicrobial agents with retention of the device, despite extensive debridement.

Hematogenous infection

In this type of infection, there is a sudden, rapid deterioration in the function of an implant that was functioning well for a long time following the surgery [26]. Almost exclusively this type of infection is seen in patients with joint prostheses. Most hematogenous infections are seen more than 2 years after the surgery. The patients present with signs and symptoms similar to early postoperative infection. Hematogenous seeding can be triggered by catheter-associated urinary tract infection, dental manipulations, urosepsis, and remote infections. Streptococci are most frequently isolated in this type of infection. Immunosuppressed and transplant patients are at risk for hematogenous seeding. 

Microorganisms In ODRIs

In patients with ODRIs, staphylococci are the most frequently encountered microorganisms isolated, accounting for about 50% of the cases [27]. Polymicrobial are seen in 14 to 19%, Gram-negative bacilli in 8 to 11%, streptococci 8 to 10%, anaerobes 6 to 10%, enterococci in 3%, and others in 10% of the cases.

Multiple specimens for culture should be taken from the infection site, and the samples should be put in transport media for anaerobic microorganisms. Results of multiple specimens will facilitate the interpretation of culture results. A single positive result may signify contamination, whereas the presence of an organism in all 3 specimens, indicates infection. 

Workup for Diagnosis

There are no preoperative tests that are consistently sensitive and specific for infection in patients who require a revision arthroplasty. Investigative test interpretation is easier for internal fixation devices than for joint prostheses. Diagnosis based solely on history and physical findings can prove to be inaccurate. A careful history and risk assessment is mandatory for all patients suspected to have ODRI. 

Several risk factors for the development of ODRI in patients with prosthetic joints have been established. The most important is postoperative surgical site infection [28] followed by a high NNIS (National Nosocomial Infections Surveillance) system score, systemic malignancy, and prior joint arthroplasty [29]. Knee arthroplasties have a higher risk of infection (2%) as compared to hip arthroplasties (1.3%) [30]. Revision arthroplasty is also associated with a higher risk of infection (9%) [31]. 

Pain at the site of implant is the only consistent clinical finding in ODRIs. The presence of a sinus tract communicating with the implant indicates the presence of infection. 

Blood test results, C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), x-rays, and bone scan results are usually highly variable. The sensitivity of standard microbiological cultures usually does not exceed 70% [32]. A combination of evaluation of clinical signs and symptoms, blood tests, radiography, bone scans, and a microbiological workup can usually provide an accurate diagnosis. 

The presence of a normal ESR and CRP level basically rules out the presence of ODRI. The CRP levels are always elevated following surgery but the levels should return to normal within 2–3 weeks [33]. 

The common workup for ODRI includes testing of WBC, ESR, CRP, plain radiographs, and multiple aspiration specimens for culture. Scintigraphy by means of a technetium scan, gallium citrate scan, or indium labeled leukocyte scan can be helpful in the diagnosis of ODRI. Intraoperative cultures should be combined with histopathology.

Clinical presentation

The clinical presentation of ODRIs is multifaceted and depends on:

(i) the preceding trauma and/or surgical procedures

(ii) the anatomical localization

(iii) the quality of bone and surrounding soft tissue

(iv) the time interval between microbial inoculation (trauma, surgery) and manifestation of infection

(v) the type of microorganism. 

Wound healing disturbances after internal fixation are highly suspicious of early infection. Early postoperative infection (less than 3 weeks) is characterized by erythema, local hyperthermia, a secreting wet wound, and protracted wound healing. The treatment of such infections includes debridement surgery which is both for diagnostic and therapeutic purposes. 

Delayed (3 to 10 weeks) or chronic (more than 10 weeks) infections are usually caused by low-virulence microorganisms such as coagulase-negative staphylococci. Such infections can also result from inadequate treatment of early infection. A short course of antibiotics without wound debridement can lead to a suppressed early infection which will reappear at a later date. Delayed and chronic infections present with persistent pain and signs of local inflammation, such as erythema, swelling, or intermittent drainage of pus from a sinus tract. Radiologically, there can be a pseudoarthrosis with bone sequestrum and soft-tissue calcification. 

Periprosthetic joint infection (PJI) can occur by seeding from the bloodstream by a systemic infection such as sepsis, skin and soft-tissue infection, pneumonia or enterocolitis, and also by contamination during implantation surgery.

The first symptom may be new-onset joint pain, initially without local inflammation. The most common causative agents are S. aureus, haemolytic streptococci, and Gram-negative bacilli. In exogenous staphylococcal infection, a temperature more than 38.3 °C is present in only about one-quarter of the patients, and the sepsis syndrome is present in less than 10% of the patients. In all patients with acute symptoms, regardless of the time after implantation of the orthopedic device, a prompt diagnostic work-up, and prompt treatment is required because the chance of retaining the implant is high if the duration of symptoms is short.

Chronic PJIs present with joint effusion, pain due to inflammation or implant loosening, local erythema and hyperthermia, and sometimes with recurrent or permanent sinus tracts. Routine follow-up markers such as C-reactive protein and/or erythrocyte sedimentation rate do not normalize after surgery and fluctuate within an elevated range.

Treatment

There are several established options for the treatment of ODRIs. The treatment depends on several factors such as [9]: 

• Type of infection (acute vs chronic)
• The isolated pathogen and its susceptibility pattern
• The fixation of the device
• The quality and availability of the bone stock
• The training and experience of the orthopedic surgeon and the infectious diseases physician. 

The treatment options for ODRIs include: 

• Debridement with retention of prosthesis and long term treatment with antibiotics
• Girdlestone arthroplasty
• One stage replacement with or without antimicrobial cement, and with long term antibiotics
• Two-stage replacement with or without antimicrobial cement and with long term antibiotics
• Suppressive antimicrobial therapy
• Arthrodesis
• Amputation

In patients with chronic infections, most authors recommend the removal of the device to eradicate the infection [34-37]. Patients with chronic infections usually do not respond to antimicrobial therapy alone and always implant removal is required [34,38]. A loose prosthesis always has to be removed. 

Early postoperative infection 

Treatment of early postoperative infections should be guided by an orthopedic surgeon and an infectious diseases physician who is trained in the management of ODRIs [39]. A thorough diagnostic workup should be carried out for patients presenting with fever, redness, pain, and drainage early after surgery and they should not be treated with antimicrobial agents before workup has been done. 

In patients with hematoma, extensive and meticulous debridement should be carried out and multiple biopsy samples should be taken from clinically infected tissue around the implant and multiple microbiological samples, including anaerobic cultures, should also be taken. Prophylactic antibiotics should be withheld until accurate specimens for histopathology and culture have been obtained [40]. This debridement must be done immediately following the onset of signs and symptoms of infection to prevent biofilm formation of the infecting pathogen which will lead to antibiotic resistance [13,16]. Preoperative aspiration may be an alternative, but such cultures are often falsely negative.

Patients who meet the criteria below are eligible for treatment with antimicrobial agents and salvage of the prosthesis or implant:

• Acute infection with signs and symptoms of equal to or less than 14 to 28 days
• Stable implant with no loosening
• Clearly established diagnosis by isolating a single organism from multiple cultures
• Positive histopathological results
• Pathogen susceptible to oral, preferably bacteriocidal, antimicrobial agent
• Antimicrobial with proven effectiveness
• Patient willing to undergo prolonged antimicrobial therapy

Initial treatment with antimicrobial agents is always given intravenously. There is no consensus as to how long antibiotics should be given intravenously. Most authors think that the minimum duration should be 2 weeks [23]. Tsukayama et al. [4] recommend 4 weeks and other authors [34] recommend 6 weeks of intravenous antibiotics. The treatment is then changed to oral medications for a minimum of 3 months for internal fixation devices and hip prostheses and for 6 months for total knee prostheses [23, 42,43,44]. 

The choice of antimicrobial therapy will depend on the pathogen isolated and its susceptibility pattern. The dosage of the antimicrobial agents should be as high as clinically possible. 

Rifampin has excellent efficacy against stationary-phase staphylococci and is orally well absorbed. Rifampin should always be included in the treatment regime of staphylococcal ODRIs if the strain is susceptible.

Rifampin monotherapy rapidly leads to the development of resistant strains. 

Therefore, rifampin must always be combined with another antimicrobial agent, preferably a quinolone. Quinolones are effective in preventing resistance to rifampin when given concurrently. The commonly used quinolones are ciprofloxacin or ofloxacin. 

The patient has to be closely monitored during treatment. The clinical signs and symptoms of infection should be recorded. The WBC count, CRP level, ESR, and, less frequently, radiographic examination has to be repeated. Treatment should be continued for a minimum of 3 months for total hip prostheses and internal fixation devices infections or for 6 months for total knee prostheses infections. The treatment should be continued for a maximum of 1 year if clinical or laboratory parameters have not normalized. The patient has to be followed up after completion of antimicrobial therapy so that failure of the treatment can be identified early.

About 80% of early infections will respond to such treatment. Patients with longer intervals from surgery to the onset of infection (1–3 months) might respond to such treatment if the pathogens are of low virulence, such as CNS or Propionibacterium species [35]. The failure rates, however, are likely to be higher compared with immediate removal of the implant and treatment with antimicrobial agents.

Chronic infection

The diagnosis of chronic infection can sometimes be difficult because of the lack of signs and symptoms. It can be difficult to differentiate between septic and aseptic loosening. Aspiration of the joint and a positive culture may help to differentiate between the two. The presence of a sinus tract communicating with the prosthesis or internal fixation device is usually  confirmatory of a chronic infection.

Infected fixation devices which serve no purpose are routinely removed at the time of debridement. Treatment of infected joint replacements calls for removal of the implant and a 1-stage or 2-stage revision arthroplasty. Infections due to CNS are usually treated with a 1-stage approach, if the quality of the bone stock is good [45,46]. Antibiotic-containing cement is commonly used. Ure et al. [46] found no significant difference between the failure rates after a 1-stage and a 2-stage approach. Infections due to low-virulence microorganisms are likely to be treated with a 1-stage approach. Most orthopedic surgeons prefer a 2-stage approach for purulent infections due to virulent organisms, such as methicillin-resistant S. aureus. Such cases are usually treated by removal of the implant, through debridement, and 2–6 weeks of iv antimicrobial therapy before a new implant is reinserted. Antimicrobial therapy should be discontinued before implantation of the new device and intraoperative cultures taken. After the histopathologic specimens have been taken, antimicrobial therapy should be started before inserting the new implant.

Positive cultures denote failure to eradicate the infection. The presence of microbials will influence treatment with antimicrobial agents in the postoperative period. Negative culture indicates successful treatment. This will allow shortening of the duration of treatment with antimicrobial agents after reimplantation. 

Patients who are not fit for surgery can be treated with suppressive antimicrobial therapy. 

Conclusion 

The treatment of ODRIs relies on an accurate classification, proper diagnosis, isolation of the microbials causing the infection, and finding their susceptibility pattern. 

Infected bone fixation devices which serve no further purpose are always removed at the time of debridement. Early postoperative infections of joint arthroplasties can be successfully treated with debridement and long-term antimicrobial therapy provided that the implant is stable and quality of bone stock is good. Early and rapid treatment after onset of infection is mandatory. Antimicrobial agents effective against the isolated pathogen must be available and the patient must be compliant and able to tolerate long-term antimicrobial therapy. 

In other patients with joint arthroplasty infections with virulent organisms a two stage arthroplasty with long term antibiotic therapy may be required. The morbidity and mortality is higher with the 2-stage approach.

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