As the number of total hip prosthesis (THP) surgeries have increased around the world, the number of patients had to undergo a revision surgery have also increased, regardless of the cause. While the periprosthetic joint infection (PJI) in primary total hip prosthesis surgeries is the third-often (15%) unsuccessful result observed, the rate of PJIs in the cases of revision surgeries is the most common result. The incidence rate of infection is 1% in the UK; 2.2% in the US. The rate of deep infection in the total hip prosthesis revision surgeries is 12%, 14.5%, and 12.9% in the UK, Canada and Switzerland, respectively.
Double-Phase Revision in the Treatment of Infected Total Hip Prosthesis
Despite being among the rarest of complications, the infection observed post-total hip prosthesis surgeries are both difficult and expensive to deal with. The treatment should be planned considering the infection type, implants, host bone status, and disease-related factors. In their study, Kurt, et. al have reported that the cost of infected total hip prosthesis treatments is 1.76 times higher than the cost of non-infected total hip prosthesis treatments. In another study, the cost of septic total hip prosthesis revision treatment has been estimated 2.8 times higher compared to aseptic revision treatment, and 4.8 higher than the primary total hip prosthesis.
Classification of the Double-Phase Revision
The longevity of the period between the first surgery and the identification of the infection symptoms is significant for planning of the treatment. The classification made by Filtzgerald, et. al have been modified by Toms, et. al. The fourth phase have been defined by Tsukayama, et. al (see Chart 1).Chart 1. Classification of the periprosthetic joint infection during the period between the first surgery and the infection beginning
| Phase 1 | Infections observed within the six weeks after the first surgery (acute infections) |
| Phase 2 | Late findings of the chronical infection independent of the post-surgery period |
| Phase 3 | Sudden infections occurred on a functional, painless hip (typically begins from another focus in a hematogenous way) |
| Phase 4 | During the revision emergence of positive cultures in patients not showing infection symptoms |
Chart 2. Reported incidents of common PJI organisms per country
| UK | Australia | Germany | US | |
| Organism | (%) | (%) | (%) | (%) |
| Methicillin-sensitive S. aureus | 44 | 30 | 13 | 31 |
| Coagulase-negative S. aureus | 47 | 45 | 39.3 | 20.2 |
| Methicillin-resistant S. aureus | 8 | 45 | 48.1 | 12.1 |
| Polymicrobial infection | 47 | 36 | – | – |
| Anaerobic organisms | 7 | 1.7 | 9 | 0.9 |
| Culture-negative infections | – | – | 16.1 | 15.8 |
Diagnosis of Double-Phase Revision
In the infected total hip prosthesis, the types of staphylococcus are the most commonly isolated microorganisms. However, the types of isolated bacteria and the antibiotic-resistance may vary depending on the region, which makes it difficult to adopt a universal treatment protocol. According to the countries’ national arthroplasty records, the incidence of coagulase-negative staphylococcus has increased, while the incidence of gram-negative bacteria has decreased (see Chart 2). It is difficult to treat the cases involving high-resistant microorganisms, such as methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermis, (MRSE), and vancomycin-resistant enterococcus (VRE). While the the S. aureus types show a methicillin resistance of 30-35%, their cephalosporin resistance is only 5%. It is also reported that the methicillin resistance of S. epidermis is 30-41%, the vancomycin resistance of enterococcus is 30%. As is the case with all foreign elements contained in the body, a biofilm layer is created by the colonized microorganism in the case of total hip prosthesis. The bacteria contained in this biofilm layer demonstrate an organized structure. The formation of the biofilm layer over the implant may begin in a span of minutes. This biofilm layer consists of glycocholic matrix in which the bacteria begin a stable growing phase. The bacteria organize here and act like a multicellular organism. Biofilm creates a significant problem in the PJI treatment. Firstly, the cellular defense and the antibiotic treatment becomes ineffective. The reason for this ineffectiveness is the fact that antibiotic effectiveness decreases since biofilm layer provides a physical cover for the bacteria which reproduce slowly within the biofilm. Secondly, the particles moving away from the biofilm layer spread the bacteria to the surrounding tissues, which transmits the infection.
For the purposes of PJI, no test ensures 100% sensitivity and authenticity (see Chart 3). In order to reach an accurate diagnosis, clinical suspicion, careful physical examination, laboratory tests and radiologic tests are required. Isolation of the factor from the joint is not considered as the “golden standard.” Instead, PJI is diagnosed according to the criteria developed by Musculoskeletal Infection Society, revised by International Consensus Meeting on PJI and approved by Center for Disease Control. Thus, at least one of the following criteria must be met:
1. Isolation of the two different cultures sampled by periprosthetic tissue or liquids by the same microorganism.
2. The entrance of the sinus related with the implant.
3. Existence of at least three minor criteria below:
a- Increased Serum C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
b- Increased number of white blood cells in the synovia or ++ change in the synovial liquid leucocyte esterase (LE) strip test.
c- Increased rate of polymorphonuclear neutrophil (PMN) in the synovial liquid
d- Identification of more than five (PMN) in at least five regions (400 times magnified) in the histopathological examination of the periprosthetic tissue.
e- Reproduction of a culture sampled from the periprosthetic tissue or liquid.
The minimum limits of the criteria above are summarized in the Chart 4 below:
Chart 3. Sensitivity and authenticity levels of the tests used for PJI diagnosis (25-31)
| Test | Sensitivity (%) | Authenticity (%) |
| CRP | 96 | 92 |
| ESR | 82 | 85 |
| ESR and CRP | 96 | 56 |
| IL-6 | 95-100 | 87-95 |
| Leucocyte Count (synovial liquid) | 89 | 85 |
| Neutrophil Count (%) (synovial liquid) | 80 | 94 |
| IL-6 (synovial liquid) | 87 | 89-100 |
| CRP (synovial liquid) | 97 | 90-100 |
| a-defensin (synovial liquid) | 100 | 95-100 |
| Bone scintigraphy | 33 | 86 |
| Leucocyte marked scintigraphy | 77 | 88 |
| Hip aspiration | 86 | 94 |
| Gram staining | 19 | 98 |
| Tissue biopsy | 94 | 97 |
| Frozen examination | 80 | 94 |
| CRP: C-reactive protein; ESR: Erythrocyte Sedimentation Rate; IL-6: Interleukin-6 |
Chart 4. Minimum limits of the minor criteria in PJI diagnosis
| Acute | Chronic | |
| ESR | – | >30 mm/hour |
| CRP | >100 mg/L | >10 mg/L |
| Synovia leucocyte | >1000 cell/mL | >3000 cell/mL |
| Synovia PMN | >90% | >80% |
| Synovia LE | ++ | ++ |
The studies are ongoing on the biomarkers for the PJI diagnosis. Leucocyte esterase is an enzyme released by the active neutrophils in the case of infection. LE levels may be identified with a simple urine strip test performed on the synovial liquid. If the result is (++) the test is considered positive. A positive result is assumed as an equivalent of synovial leucocyte count and is classified among the minor criteria. LE test is a simple, cheap, fast and effective test. There is a high correlation between ESR, CRP, synovia WBC count, synovia PMN % and LE test. Another biomarker subject of ongoing studies is alpha defensin (a-defensin). Released from the neutrophilia in the synovial liquid, a-defensin shows an antimicrobic effect by hanging on the cellular wall of the pathogen organism. It’s level in the synovial liquid is identified with an immunoassay test, in which levels over 5.2 mg/L are considered positive. The test results are not affected by the antibiotics treatment or systematic inflammatory diseases. It’s sensitivity and authenticity are close to 100%. It is believed that a-defensin will be an important marker of PJI diagnosis in the future, together with the Synovial CRP.
Double-Layer Revision Treatment Among the treatment options of PJI cases emerged post-hip prosthesis surgery are; antibiotics repression, surgical debridement, single-phase revision, double-phase revision and resection arthroplasty/amputation.
Antibiotics Suppression
Antibiotics Suppression without surgical intervention can be considered as an option only in the patients ineligible to surgical intervention due to associated diseases, patients refusing the surgical treatment, in cases where surgery is technically not possible and where the infection can be suppressed through non-toxic oral antibiotics. The main purpose here is not to eradicate but suppress the infection. Regardless of how much the infection is repressed with medication treatment, how much pain reduction is observed in the patient, the functional cases in the long term is much worse than patients underwent the revision surgery.
Protection of Debridement and Implants
In the case of acute PJI emerging post-total hip prosthesis surgery, several conditions should be simultaneously ensured to protect the implants by performing a debridement and to change the mobile particles. First, the infection must have begin in an acute way (Phase I or Phase III); the implants must be stable; the integrity of the soft tissues must have not damaged; and the active microorganism must have no resistance against the antibiotics permeating through the biofilm (i.e. rifampicin, ciprofloxacin, phosphomycine). Following the arthrotomy, broad synovectomy, radical debridement, irrigation and changing of the mobile particles must be performed in the treatment. The rate of re-infection has been reported at 18%, 29% and 74% by the experienced physicians. Especially if the antibiotics-resistance is higher, the risk of re-infection will be higher, too.
Single-Phase Revision Lately the single-phase revision surgery has been gaining interest, especially in Europe, due to the lower costs, better functional results and patient satisfaction the procedure offers. There are several studies reporting the success rate between 75% and 100%. However, if the case has underwent two single-phase revision surgeries in the past and suffered from relapse, or the case shows the systems of systematic sepsis, or the active microorganism has not been isolated, or the case involves high-resistant infection, such as polymicrobial and/or MRSA, or the patient has any severe soft tissue disorder, the case is considered contraindicated. All prosthesis material will be removed during the surgery. The implantation will be re-applied once the infected soft tissues are cleared. The removed implants by sampling new cultures during the surgery will be sent to sonication. Antibiotics treatment will be continued for three months.
Double-Phase Revision
The double-phase revision is regarded as the most effective method and golden standard for PJI treatment by several centers in North Amerika and other regions. While the rate of success is between 86% and 96%, the rate of long-term success is 90% with Prosthesis of Antibiotic Loaded Acrylic Cement – PROSTALAC spacer according to 12 years of monitoring studies. During the surgery, all implants are removed, all infected tissues are debrided, culture is sampled, and the antibiotic loaded spacer is applied. The second phase begins six-to-twelve weeks after, in which implants are re-applied. During the waiting period in between, the patient is put on an antibiotic treatment for six weeks. At the end of six weeks, the patient is monitored without antibiotics for two weeks, during which CRP and ESR levels are closely monitored. If the patient has higher inflammatory markers, and shows infection symptoms, puncture is considered as an option. The ideal waiting period is between 10 and 12 weeks.
The period of the antibiotics treatment is a subject of ongoing discussions. While there are some studies suggesting there is no difference between long term and short term antibiotics treatment, several other studies have reported that the parental antibiotics treatment should be continued for six weeks during the waiting period before the second phase. In the case of double-phase revision surgeries, conditions such as soft tissue disorders, surgery-related functional loss, higher rates of mortality and morbidity due to the toxicity caused by the long-term antibiotics treatment are more common. Although this issue may be related to the patients’ accompanying diseases or their fight against more complex infections. Following the debridement procedure in the antibiotic spaces are applied to the patients in the first phase. Thus, the emergence of excessive scar tissue is prevented and the joint stability, as well as the soft tissue balance is ensured. The patient satisfaction is higher with this procedure since it allows early mobilization and provides an easier rehabilitation. Additionally, the surgical approach is easier in the second operation. In general practice, the spacers contain higher levels of antibiotics, which facilitates concentration of a higher dosage than that is possible with intravenous way. There are two types of spaces; static and dynamic. The static type prevents joint movement; which develops bone loss, muscle atrophy, and arthrofibrosis. On the other hand, the dynamic type spacers allow joint movement, leading to fewer bone loss and scar, which makes the second phase surgery easier. Although the patient satisfaction in dynamic spacers is higher, they may cause complications such as fracture or dislocation.
There are two types of dynamic spacers; ready-made and prepared during the surgery. The antibiotic concentration is higher in the cement (>1 gr/per bag). Generally, vancomycin, teicoplanin, and gentamicin or tobramycin are used for this purpose. The time of the second phase surgery is also a separate topic of discussion. For re-application of the implants, all laboratory findings, radiologic and clinical findings must be available. The ESR and CRP levels should be closely monitored on a weekly basis during the antibiotic treatment. The results should decrease gradually and return to normal levels eventually. However, the inflammatory markers may be insufficient in detecting the eradication of the infection. Another significant factor is that the area surrounding the scar should not be dry nor hyperemic. At the end of the treatment the ESR and CRP levels are confirmed to be stable around normal values for two weeks, during which antibiotics treatment should be paused. Thereafter, the second phase may be planned. If the CRP levels continue to remain high, the potential causes other than infection may be investigated. Typically, the cause of high CRP levels is inflammatory arthritis. If the patient does not suffer from hip pain and the high level of CRP can be associated with any cause other than an infection, the patient should be provided with the appropriate treatment and the second phase should begin only after CRP levels return to normal values. If CRP levels remain high despite the treatment, six more weeks of antibiotics treatment should be prescribed. If CRP levels fail to return normal values after the second six-week period, or in case of any infection symptom, the first phase should be re-performed. If the symptoms persist, or in case of any resistant infection that cannot be treated, the spacers will be removed, and Girdlestone arthroplasty will be performed on the patient. Generally, the spacers are removed in the second phase, and then, uncemented total hip prosthesis revision procedure is performed on the patient. In case of detecting macroscopic infection findings, the first phase should be re-applied. Patient’s tissues and liquid cultures are sampled, and the removed spacers are sent to culture and sonication. If cultures are found to be negative after the second phase, the patient will be prescribed oral antibiotics; in case of reproduction in the cultures, the intravenous antibiotic treatment should be continued.
Discussion
Several methods have been defined in the hip PJI treatment. Since each patient and each case of infected total hip prosthesis is different, the treatment should be identified according to the patients’ needs. The most important part of the treatment is the proper depredation of the infected tissues and isolation of the active cause before the infectious diseases physician can begin the proper treatment. The eradication of the infection is not possible unless the debridement is adequate. In the cases of acute infections, debridement is considered as an option if the components are stable. If the active cause has been isolated and the patient show no soft tissue problem, single-phase revision surgery may be considered as an option. Double-phase revision surgery is viewed as the golden standard in the treatment of hip PJI. In their study, Oussedik, et. al performed single-phase revision surgery on 12 out of the total 52 patients; while performing double-phase revision surgery on the remaining 39. No infection was observed on patients who underwent a single-phase revision surgery, whereas infection was observed in two cases of double-phase revision surgeries. The functional results and patient satisfaction were found significant among the group. However, among the group of patients underwent a double-phase surgery were infected due to either causes of virulence or polymicrobial infections. Since both groups were not equivalent in this study, they cannot be measured against one another, which makes it impossible to reach a definite conclusion. On this subject, two compilations have been published recently. According to one compilation, Beswick, et. al detected re-infection rate of 8.6% among 1225 patients treated with the single-phase revision; whereas, they observed re-infection rate of 10.2% among 1188 patients treated with double-phase revision. According to the other compilation, on the other hand, Leonar, et. al assessed the eradication of infection as well as functional results, and found the re-infection rate in the single-phase and the double-phase revision surgeries at 16.8% and 10.6%, respectively. In terms of functionality, no significant difference was detected in either group. The authors of both studies, however, have stated that the general quality of the studies was low, that randomization was not performed, that the results were incomparable due to the differences in definitions and methodologies. Also, too few studies included the assessment of the clinical results. According to the study conducted by Engesæeter, et. al based on the arthroplasty records of Norway, the relative risk of re-infection in patients treated with a single-phase revision surgery was compared with the patients treated with a double-phase revision surgery. As a result of this study, the risk of revision for any reason was found 1.4 times higher; whereas, the risk of revision due to an infection was found 2 times higher. In conclusion, there is no consensus about an ideal treatment for the cases of PJI. The single-phase revision may be applied on the group of patients meeting certain criteria; however, the long-term results are unknown. The double-phase revision is the most-preferred treatment option today. There are several studies demonstrating the positive long-term functional results and successful infection eradication in the revision surgeries performed by using dynamic spacers. Especially in the cases of polymicrobial infections, resistant active causes, contraindication of the single-phase revision, the only available treatment option is double-phase revision surgery.