INFECTION

 Parvizi, J., et al.,  New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society.  Clin Orthop Relat Res, 2011.  469 (11): p. 2992-4.

Parvizi, J., et al., New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res, 2011. 469(11): p. 2992-4.

Prosthetic Joint Infection (PJI)

Prosthetic Joint Infection (PJI) is a cause of significant morbidity and mortality.  A lot of the preoperative patient optimization protocols (see preop optimization) are created to minimize infection risk, because of its correlation with obesity, diabetes, metabolic syndrome, malnutrition, smoking, and s.aureus colonization. PJI in THA (0.3 – 1.3%, and 3% in revision THA) is less common than TKA (1 – 2%, and 6% in revision TKA), yet both are important complication due to the significant associated morbidity.  PJI should always be a part of the differential diagnosis when evaluating postop patients for pain, loosening, instability or even periprosthetic fracture.  Many surgeons will culture every revision surgery.  Although others will argue, if you fix a periprosthetic fracture without other signs of infection, and then the cultures return positive, do you take that patient back for a re-revision?  Do you start them on IV antibiotics?  The practical aspects of evaluating an infection work up is complicated and is reviewed here.

What is a PJI? 

This seems obvious: the prosthesis is infected with a microorganism. Yet diagnosis of PJI is far more challenging in reality because positive cultures are not a reliable means of diagnosis, with reports suggesting that cultures are only 60% sensitive. There are many other complicating factors.  For example, what if you’re doing surgery and you see “gross purulence” around the implant, can’t you just say that its infected?  The answer is that “gross purulence” alone (with other tests negative) is not enough to diagnose an infection because many of the MoM soft tissue reactions appear very similar to “gross purulence” and osteolysis from poly wear can also appear as purulence, an thus will fool a surgeon’s into treating an infection. 

The Musculoskeletal Infection Society (MSIS) Diagnostic Criteria was developed to formalize the diagnosis process [1]. Yet controversy remains, even within this algorithm, specifically regarding what cutoffs should be used for certain lab values.  Remember that cutoff values are essentially a compromise between sensitivity and specificity and there are no absolutes.  Outliers exist.

Infection is diagnosed as 1 major criteria (either sinus tract or 2 cultures of the same bacteria), or 3 out of 4 minor criteria (elevated ESR/CRP, or WBC count or Leukocyte Esterase, or elevated PMN%, or one culture or positive histology)

WORK UP.

Identifying symptom duration and time from index procedure are two critical forks in the diagnostic and treatment pathways [2].  PJIs are best understood by separating them at these time points.  First see what category the patient get sectioned into and then work them up accordingly. For example, an early infection (surgery < 4 weeks prior) compared to a late infection, the CRP cut off jumps from 10 to 95 mg/L, while cell count jumps from 3,000 to 10,000, and PMN% increases from 60-70% to over 80%.  This is why it is critical to know the date of surgery before interpreting any results.

When patient presents with concern for infection, knee swelling, fevers, pain, erythema, drainage, etc.  The first step is to obtain blood work including ESR, CRP.  If inflammatory markers are elevated, then obtain aspiration.  If inflammatory markers are not elevated, but there is notable concern based on the h&p, then aspirate as well (remember the blood work is only about 90% sensitive).  In cases of acute onset of symptoms, it is believed that the bacteria is limited to the joint fluid, while chronic symptoms suggest the bacteria has had time to adhere to the prosthesis (biofilm) and invade the interface between bone and implant.

Acute Early.  Acute postoperative infection is onset of symptoms 4 weeks from the index procedure

-The distinction of an early infection is important because the cutoff values for many of the tests used to diagnose a PJI change in the early postoperative period.  Synovial leukocyte levels do not normalize for about 6 weeks, and therefore WBC cell counts for aspiration are elevated at baseline.  Furthermore, the systemic inflammatory markers are elevated.  It takes around 3 weeks for CRP to normalize, and over 6 months for ESR to normalize.

-Diagnostic values.  Elevated CRP in the early postoperative period is > 95 mg/mL.  Aspiration cell count over 27,800 and 89% PMN are considered elevated.  Although other studies suggest any cell count over 10,000 is elevated (this more sensitive number is more standard).  PMN > 90%.[3]

-Treatment see below.

Late. Onset of symptoms more than 4 weeks from the index procedure, and usually occurs years after surgery. These values can also be applied to patients with inflammatory arthritis.

Acute Late (Hematogenous).  This is acute onset (< 3 days) of symptoms long after the index procedure (> 3 weeks).Patients seen in the office after acute onset of symptoms need to be worked up quickly to maximize the benefit of surgical intervention if they are showing signs of PJI. Acute onset of symptoms suggest the bacteria has not formed a biofilm, although bacteria form the biofilm at different rates (with all bacteria forming biofilm by 4 weeks).

-Blood work: CRP > 10 mg/L, ESR > 30.

 -Aspiration: WBC count > 1,700; PMN > 80%

Chronic Late. This is gradual onset of symptoms (> 3 days), long after the index procedure (> 3 weeks).  In the case of chronic symptoms it is believed that bacteria has formed a biofilm (all bacteria form biofilm by 4 weeks).  Biofilm is a layer 15% cells and 85% glycocalyx (formal name: exopolysaccharide glyocalyx) that makes the infection 1,000 – 1.5k more resistant to antibiotics. Furthermore, there is no reliable way to remove biofilm once formed.  Thus, chronic infections require removal of the infected implants.

-Treatment see below.

-The ESR is an acceptable marker for late infections, however, it cannot be used in the immediate postop period (“acute early” infections) because ESR requires up to 6 months to return to normal.  It is therefore falsely elevated.  CRP in contrast returns to normal around 3 weeks, and can often be used in the decision making algorithm [4].

-Even in possible late PJI, the ESR is only a questionably valuable marker, and therefore, it must be positive in conjunction with the CRP to achieve a sensitivity and specificity over 90%.   [5]

-ESR and CRP levels are important precursors to joint aspiration for a few reasons.  ESR and CRP are highly sensitive and therefore, if they fall within a normal range, its ok to stop the work up for infection unless highly suspicious. There is the risk of introducing bacteria into a THA with aspiration and therefore, every patient with a fever and a THA should not get an aspiration.  Additionally, no test is perfect and some aspirations can be falsely positive.  However, aspirations that are preceded by inflammatory markers influences the positive predictive value and thus reduces the risk of unnecessary major surgery [6].

-What is a significant cell count upon aspiration? This remains controversial.  A WBC count suggestive of infection is considerably lower than for a native knee because there is less synovial lining for neutrophils to penetrate the joint.  Studies have suggested a cell count > 3,000 is indicative of a late infection [7]. Other studies suggest an even more sensitive cutoff of 1,700 cells, with anything over 65% PMNs [8].  These values however can only be used in late infections (> 6 weeks from index procedure) because synovial leukocyte levels do not normalize until then.  Therefore in Early infections the recommended cutoff is a cell count of 27,800, 89% PMN (and CRP > 95 mg/mL) [9]. 

- Notice that gram stain is not part of the MSIS criteria.  The sensitivity is too low to be helpful and should not be included in the work up [10].

-In cases of revision surgery, a single positive culture is insufficient to diagnose an infection.  These findings should be used in conjunction with other tests for diagnosis.

TREATMENT.

The goal of treatment is eradication.  This goal is challenging because bacteria form a biologic matrix around the hardware components that prevents antibiotics from reaching the bacteria.  The duration of infection (time since symptom onset) and type of bacteria both determine how advanced this glycocalyx matrix has become, and thus whether the components need to be removed.  The success of differing treatments depends on the type of bacteria and the duration of infection.  Lets look at treatment for each of PJI groups

Acute Early Infection

Consider I&D with poly exchange, followed by 6 weeks of IV antibiotics [11].  Studies suggest a 50% cure rate in the acute period.  However, there is a high failure rate with MRSA [12], reported around 85% failure, and therefore, 2-stage revision should be considered based on bacteria[13, 14].

Acute Hematogenous Infection

Approached the same as an acute early infection (due to similar impact of bacteria and timing on matrix formation). It is best to prevent late infections by giving antibiotics before dental procedures (although the correlation between dental work and acute hematogenous infection is unclear because the organisms cultured in the synovium are rarely the same ones commonly found in the mouth).  [15]

Chronic late infection.

2-Stage Exchange is the standard treatment.  The emphasis in the first stage is removing all infected material, performing an extensive debridement, opening the tibial and femoral canals, and placing an antibiotic spacer [16].  The second stage is implanting hardware that offers stable, functional knee.  The cure rate is about 80-95% (depending in part on the organism). 

STAGE ONE. Dr. Duncan performed a lot of the primary groundwork investigating the elution of antibiotics in cement [17-24]. Currently there is significant variability in the literature with regards to antibiotic spacer dosing, but these incremental changes derive from the initial work by Duncan et al.

 PROSTALAC Antibiotic-laden Cement Spacer after Stage 1.

PROSTALAC Antibiotic-laden Cement Spacer after Stage 1.

The antibiotic spacer contains variable types and amounts of antibiotic. 

The standard is 1-3 g of vancomycin and 1.2 g of tobramycin per package of cement.  The combination increases the rate of elution into the hip.  Thicker cement, like palacos, elutes the antibiotic more rapidly, and thus it creates a higher concentration of antibiotic in the joint, and also in the blood stream and it therefore must be monitored closely.  Simplex does not elute as well and therefore it can have higher concentration of abx without worrying about toxic levels (3 - 6 g of vancomycin). 

Spacers also come in two forms: static vs. dynamic. The more popular type is a dynamic spacer.  This has the advantage of allowing for weight bearing to reduce stiffness once replant occurs. A dynamic spacer is created by injecting antibiotic cement into a pre-contoured mould that surrounds a small metal stem to create the stem. To create the femoral head, the mould surrounds a trunnion. No shell or cup is created, its a “antibiotic hemiarthroplasty”. Once the cement hardens, you cut away the mould and put the stem and femoral head together.  Static spacers are created by placing a styman pin down the femoral canal, with a big glob of antibiotic cement at the hip joint.

The spacer remains in place for 6 - 8 weeks. 

STAGE TWO. Following Stage 1, the patient receives IV antibiotics for 6 weeks. Serial ESR/CRP is performed and should trend down (but often fails to normalize) [25].  A repeat knee aspiration is performed around 8 weeks (after 2 weeks off antibiotics), and a cell count of 3,000 should be utilized as a cutoff for response to intervention.  

1-Stage Exchange for chonic late infections is commonly used in Europe, but definitely not the standard in the United States.  In this technique, the components are explanted and a vigorous I&D is performed (read: significant tissue debridement, almost skeletonizing the remaining bone: collateral ligaments are often resected, and the revision TKA is a rotating hinge). The patient is then re-prepped, re-draped, and then new components are placed.  In these cases, the bacteria is always known preoperatively, its typically not performed for MRSA infections, and it is performed in generally healthier patients.

Avoid I&D alone due to high failure rate and damage to the soft tissue envelope which may risk outcomes for 2-stage [26].  This study either indicates that an I&D independently impedes recovery from further surgical procedures or it merely selects patients with a more virulent organism (already resistant to I&D) who are therefore more likely to fail 2-stage. 

The entire process of revision surgery with abx spacer, and final replant takes its toll on the patient.  Revision for TJA has higher mortality rate than other revisions [27].  Overall, the results for revision TJA for infection isn’t terrific, but functional spacers have improved results. [28] hips; and knees [29] [30]; [31] :[32]; [33]

Infections are clearly very challenging and thus the key is prevention.  Optimize patients.  Take precautions in the OR to minimize risk.  Give preoperative antibiotics.  Number needed to treat to prevent 1 infection is only about 50 patients. [34]. About 10% of Americans believe they are allergic to penicillin, while only 10% of those patients have any true reaction, and most can safely receive any beta-lactam antibiotic [35].  This is an important fact because Ancef (cefzolin) has a proven track record of offering good coverage [36]. Drug distribution in obese patients decreases due to the greater volume of tissue.  It may lead to unacceptably low blood levels, and thus doses should be increased in the obese patient.  High doses of ancef can be administered rapidly, however, vancomycin must be infused slowly (90 – 120 minutes) to avoid the potential complication of red man syndrome, and thus may complicate the timing of a surgical day.  The question of whether vancomycin should be used in high risk patients? 

What about other medications: Ceftaroline is a new cephalosporin antibiotic with the unique characteristic of covering both MRSA and methicillin-sensitive S aureus aggressively, as well as many common gastrointestinal gram-negative rods. It can be administered quickly, it has predictable pharmacology, and single doses are generally very well tolerated. This valuable drug is not currently indicated for surgical prophylaxis, and concerns for resistance with widespread use are warranted.

REFERENCES

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