Antibiotic-loaded cement spacer for treatment of Klebsiella infected total hip and knee arthroplasty

Background/Aim. Infection following total hip arthroplasty (THA) or total knee arthoplasty (TKA) may have devastating consequences. Some bacterial strains are often encountered as agents of these infections, others occur less frequently but are sometimes burdened with more severe complications. Klebsiella spp. are uncommon causes of THA or TKA infection. The aim of this study was to identify an effective treatment algorithm for multidrug resistant Klebsiella spp. caused THA or TKA infections. Methods. During the 3-year period, from January 1 2009 to December 31 2011, we registered and treated 5 patients with THA or TKA multidrug resistant Klebsiella spp. caused infection. All the patients were primarily operated in other institutions, and were admitted in our clinic after the onset of infection symptoms. In three of the cases Klebsiella infection was complicated by additional infection (Staphyloccocus aureus, Pseudomonas aeruginosa and Serratia marscescens). In 3 of the cases we performed revision arthroplasty after double exchange of antibiotic-loaded articulating cement spacer, and in 2 of the cases the standard two-stage revision approach with one antibiotic cement spacer exchange was applied. Results. The mean length of follow-up after reimplantation surgery was 17.1 months (range 2–31 months). One patient died 2 months after the final reimplantation procedure. The initial Klebsiella infection was eradicated in all the patients. At the end follow-up after definitive reimplantation, the patients had no clinical, laboratory or microbiological parameters positive for active infection. Conclusion. According to our experience with multidrug-resistant Klebsiella TKA/THA infections, two-stage approach, in some cases with double articulating cement spacer exchange prior to definitive reimplantation, is the most effective treatment option.


Introduction
Infection following total hip arthroplasty (THA) or total knee arthroplasty (TKA) may have devastating consequences for the patient.The incidence of infection associated with THA or TKA in many studies has been reported to range from less than 1% in general population to almost 4% in patient groups with comorbidities such as rheumatoid arthritis, that increase risk of infection [1][2][3] .Some bacterial strains are often encountered as agents of these infections, others occur less frequently but are sometimes burdened with more severe complications.
Bacteria belonging to the genus Klebsiella frequently cause human nosocomial infections.Klebsiella spp.are gram-negative, nonmotile, usually encapsulated rod-shaped bacteria, belonging to the family Enterobacteriaceae 4,5 .These bacteria produce lysine decarboxylase but not ornithine decarboxylase and are generally positive in the Voges-Proskauer test.Members of the Enterobacteriaceae family are generally facultatively anaerobic, and range from 0.3 to 1.0 mm in width and 0.6 to 6.0 mm in length 5 .Klebsiella spp.often occur in mucoid colonies 4,5 .The principal pathogenic reservoirs for transmission of Klebsiella are the gastrointestinal tract and the hands of hospital personnel.In particular, Klebsiella pneumonia, the medically most important Klebsiella species, accounts for a notable proportion of hospital-acquired urinary tract infections, pneumonia, septicemias, and soft tissue infections.It is estimated that Klebsiella spp.cause 8% of all nosocomial bacterial infections in the United States and in Europe 6 .Fortunately Klebsiella spp.are not common infective agents in TKA or THA infections, with a relatively small number of reports on the subject of Klebsiella periprosthetic infection in the literature 7,8 .
Two-stage reimplantation with antibiotic loaded cement spacers and 4-6 weeks of antibiotic treatment remains the most successful procedure for infection resolution.In most of the series success rates are up to 95 % 9,10 .In cases of persistent multidrug-resistant (MDR) Klebsiella spp.infection there is a limited role for one-stage exchange and even two-stage reimplantation may not warrant eradication 11 .In some cases additional unconventional steps may be required for successful treatment.
The aim of this study was to identify an effective treatment algorithm for multidrug resistant Klebsiella-caused THA or TKA infections.

Methods
All investigations were conducted in conformity with ethical principles of research, and informed consent for participation in the study was obtained.
Since January 2009 to January 2012 we registered and treated 5 patients with THA or TKA multidrug-resistant Klebsiella-caused infection.All the patients were primarily operated in other institutions, and were admitted in our clinic after the onset of infection symptoms.The hospital records, operative notes, medications, laboratory reports, microbiological analysis data with antibiograms, and follow-up re-ports were reviewed.Collected data included patient age, gender, comorbidities, dates, initial arthroplasty procedure and subsequent reimplantation procedures, culture results with antibiograms, type of spacer, antibiotic combination mixed in the cement, iv and oral antibiotic therapy with the duration of antibiotic therapy.
There is the established protocol for the diagnosis and management of infected THA and TKA in our institution.It starts with preoperative clinical and laboratory evaluation.Aspiration is routinely performed if a patient was without antibiotics for at least 14 days prior to aspiration.If the results a positive for infection a patient is admitted and scheduled for surgery.All the patients in this series were initially planned for two-stage rearthroplasty.Preoperative and postoperative laboratory evaluation consisted of complete blood count, urine, biochemical analyzes, C-reactive protein, erythrocyte sedimentation rate, fibrinogen, and in some cases interleukin-6 was obtained.Intravenous (iv) antibiotic therapy was started after intraoperative cultures and tissue samples were obtained.In the first stage extraction of THA or TKA implants and debridement were performed followed by implantation of antibiotic loaded cement spacer (Figure 1).In all the cases we used Refobacin ® Revision (Biomet) bone cement containing a combination of two antibiotics: 1.0 g gentamicin and 1.0 g clindamycin per 40 g of bone cement.In one case where cultures, in addition to Klebsiela spp.were positive for Staphyloccocus aureus we intraoperatively added 2 g of vancomycin per 40 g of bone cement.In all the cases StageOne (Biomet) knee or hip spacer molds were used to make articulating spacer molds.After spacer placement no drains were used.Postoperatively, all the patients were regularly monitored by the infectious disease specialist, iv and afterwards oral antibiotic regimen was based upon pathogen sensitivity profile obtained from intraoperative cultures.Postoperatively, it consisted of combination of iv antibiotics in two cases, in other two cases iv meropenem 1 g every 8 h for two weeks, and in one case imipenem/cilastatin 0.5 g every 6 h for two weeks was applied.All patients underwent regular controls of renal, hepatic and hematologic parameters during iv antibiotic therapy.Iv antibiotic therapy, was modified during treatment according to suggestions of infectious diseases specialist, but in all cases after spacer implantation duration of iv antibiotics lasted less than four weeks, and oral administration of antibiotics was continued afterwards.According to preoperative clinical, laboratory and intraoperative findings, second stage procedure with removal of articulating spaces had two possible outcomes, ther final reimplantation of definitive prosthesis or three stage procedure with extraction of previous spacer, additional debridement and reimplantation of new knee or hip articulating spacer, and conditionally the 3-stage procedure with definitive reimplantation.
Klebsiella infections of THA and TKA in this study were found to be eradicated when at the end of a 12-month follow-up period after definitive reimplantation, the patients had no clinical, laboratory nor microbiological parameters positive for active infection.

Results
During a 3-year period, from January 1, 2009 to December 31, 2011, we registered and treated 5 patients with THA or TKA multidrug-resistant Klebsiella-caused infection.All the patients in the series had microbiologically confirmed Klebsiella prosthetic joint infection.During the treatment in 3 cases there were other pathogens isolated.All the patients were female, the mean age at the time of diagnosis of infection was 67.4 years (Table 1).
In 3 of the cases we performed 3-stage revision arthroplasty (double exchange of articulating cement spacer prior to reimplantation with definitive prosthesis), and in 2 cases 2-stage revision artheroplasty.The mean length of follow-up after the reimplantation surgery was 17.1 months (range 2 to 31 months); one patient died two months after the final reimplantation procedure.There were 3 infected THA and 2 TKA.The average time after primary arthroplasty and onset of infection symptoms was 28 days in the cases of THA and 39 days in the TKA cases.All the patients in the series had microbiologically confirmed Klebsiella prosthetic joint infection.In 2 of the cases of infected THA and in one case of infected TKA preoperative aspiration was positive for Klebsiella, and in other cases Klebsiella was isolated from intraoperatively obtained cultures and tissue samples.
During the treatment in 3 cases Klebsiella infection was additionally complicated by an infection with another bacteria.Two cases of Klebsiella infected total hips treated with double exchange of articulating spacer were complicated with additional pathogen, in one case during the first spacer exchange procedure Pseudomonas aeruginosa was obtained from intraoperative cultures, and in the other case Staphyloccocus aureus was found postoperatively in aspirations after first spacer implantation.One case of infected TKA was also treated with double spacer exchange, Serratia marscescens was isolated from knee aspirations after the first spacer exchange procedure.Adjustments in antibiotic therapy in these cases were made according to the resistance of Klebsiella and concomitant bacteria by an infectious diseases specialist.One patient in the series with Klebsiella infected THA, 72 years old, was admitted to our hospital with evident signs of sepsis, severe anaemia and hepatorenal failure.This patient had cementless THA, at another institution, after femoral neck fracture, 5 weeks prior to admission in our hospital.Prior to sepsis development the patient was treated for two weeks with oral antibiotics at another outpatient clinic and was referred to our hospital when clinical and laboratory findings indicated sever deterioration.Besides obesity and high blood pressure before the primary arthroplasty the patient had no other comorbidities.This patient underwent 2stage revision surgery, after first stage procedure and articulating spacer implantation there were significant positive improvements in the patient status.Hepatorenal failure persisted and required regular consults with nephrology and infectious diseases specialists.Eleven weeks after spacer implantation and subsidence of infection signs second stage procedure, cemented THA was perfomed.Initially early postoperatively patient was stable and recovering without complications.But one month after reimplantation cardiac and renal insufficiency developed, and the patient died 8 weeks after the reimplantation procedure.Considering reimplantation THA, at the time of death the patient was clinically, laboratory and microbiologically infection free.
One patient in the series, 59 years old, had bilateral simultaneous TKA, during primary arthroplasty procedure right knee was done first, and there was Klebsiella pneumoniae infection of the right TKA, the left knee was infection free.The onset of infection signs was 6 weeks after primary arthroplasty.This patient was treated with double spacer exchange.The first spacer was removed after 8 weeks, and the second one after 3 months.Serratia marscescens was isolated from knee aspirations after the first spacer exchange procedure.Antibiotic therapy was altered according to antibiograms by an infectious disease specialist.
In four of the cases end-stage procedures were performed as cemented total hip or knee arthroplasty, Refobacin ® Revision (Biomet) bone cement was used in all the cases.In one case a hybrid total hip was definitive implant.
All the patients were allowed immediate full weight bearing.We did not note spacer fractures in any of the cases.In one case of Klebsiella THA infection after first stage exchange 4 weeks postoperatively hip spacer dislocation was noted (Figure 2).
The average time between removal of primary implants and definitive reimplantation was 6.8 months (range 2-15 months).
The initial Klebsiella infection was eradicated in all the patients, at the end follow-up after definitive reimplantation, patients had no clinical, laboratory or microbiological parameters positive for active infection.Clinically, at the last follow-up, except for the patient who died, in both cases of revision TKA knee, society functional score 12 improved from 30 to 90, and in cases of revision THA, Harris hip score 13 improved from 57.15 to 89.7.
We have noted the effects of articulating spacer cement abrasion phenomena (Figure 3.) and in each case thorough debridement and copious irrigation was perfomed during each step of the treatment.

Discussion
The purpose of this study was to identify an algorithm of treatment of multidrug-resistant Klebsiella-caused THA/TKA infections.Klebsiella infections of TKA/THA are relatively rare [7][8][9] , but can be very difficult to treat and sometimes can lead to sepsis, multiorgan failure and ultimately have fatal outcome.
There are few factors that additionally complicate treatment.Klebsiella infections of TKA/THAs can be complicated by an additional bacterial infection.Polymicrobial arthroplasty infections were seen in 6 of 10 knee arthroplasty patients; these infections involved a mixture of Grampositive and Gram-negative species, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus species, Escherichia coli, and Enterobacter cloacae 7,[14][15][16][17][18][19][20] .In our series in three cases Klebsiella arthroplasty infection was additionally complicated by an infection with another bacteria (Staphyloccocus aureus, Pseudomonas aeruginosa and Serratia marscescens were identified).
In addition to the multiresistant ability, Klebsiella pneumoniae has several adhesive factors, such as type 1 and type 3 pili, which help bacteria to adhere to abiotic or biological surfaces.The adherence of Klebsiella pneumoniae to cardiac valve prostheses, catheters of urinary tracts, intestinal cells, and bladder epithelial cells has been previously reported 21 .
Two-stage treatment is currently the most common approach for management of an infected joint prosthesis, static antibiotic-impregnated cement spacers have traditionally been used, increasingly, however, mobile or articulating spacers are being utilized [22][23][24] .Although comparisons in the literature of static and articulating spacers have shown average eradication rates of approximately 90% and 92%, respectively 25 , articulating spacers have some potential advantages, including more effective maintenance of the joint space and prevention of soft tissue contracture, facilitation of local antibiotic delivery, early mobilization, full or in some cases limited weight bearing, and possible reduction in bone loss.
In all cases we used antibiotic-loaded cement articulating hip and knee spacers.In our series of Klebsiella infected TKA/THA simplex two stage revision was not always sufficient option, and in some cases repetition of articulating antibiotic cement spacer prior to final reathroplasty was required for eradication of infection.
We used the term 3-stage reimplantation for the procedures of repetition of antibiotic cement spacer prior to reimplantation of definitive prosthesis.In the literature generally accepted understanding of 2-stage reimplantation concept, as it was firstly described by Insall et al. 26 and further promoted by other authors 14, 17, 27, points to the procedures where the stage one is the operation with removal of infected implants and application of cement spacer, after a certain period of time followed by the stage two, spacer removal and definitive prosthesis implantation.Some authors consider as 2-stage reimplantation procedures even cases where two cement spacers exchanges occur before definitive rearthroplasty 7 .It could be that in situations where spacer elution time has subsided, but infection signs are still present and there are clear indications for one more spacer repetition, a more appropriate term is 3-stage reimplantation.This slight change in arthroplasty terminology could contribute to better recognition and follow-up of persistent periprosthetic joints infections caused by MDR bacteria treated by double cement spacer exchange.
Fink et al. 28 noted that articulating spacers used in 2stage revision surgery of infected prostheses have the potential to abrade and subsequently induce third-body wear of the new prosthesis.Given the presence of abrasion debris, they recommend total synovectomy and extensive lavage during the second-stage reimplantation surgery to minimize the number of abraded particles and any retained bacteria.
Spacer fractures were reported 29,30 but we had no fractured cemented spacer in the series.
Our study has some limitations.The major deficiencies are a small number of patients, and its retrospective design.Larger series and prospective research may be needed to provide adequate predictions for the appropriate treatment modality.The small number of patients, and heterogeneity of the series prevent us from making a definitive recommendation of which primary treatment is required for eradication of infection and restitution of function.

Conclusion
In our limited experience with multidrug-resistant Klebsiella total knee arthroplasty and total hip arthroplasty infections, we consider that 2-stage and 3-stage revisions (double articulating cement spacer exchange prior to definitive reimplantation) are the most effective treatment options.