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Fungi, Mycobacteria, Zoonotic and Other Organisms in Prosthetic Joint Infection

Marculescu, Camelia E, MD, MSCR*; Berbari, Elie F, MD; Cockerill, Franklin R III, MD; Osmon, Douglas R, MD, MPH

Section Editor(s): Garvin, Kevin MD, Guest Editor

Clinical Orthopaedics and Related Research®: October 2006 - Volume 451 - Issue - p 64-72
doi: 10.1097/01.blo.0000229337.21653.f2
SECTION I: SYMPOSIUM I: Papers Presented at the 2005 Meeting of the Musculoskeletal Infection Society
Free

A systematic review of the presentation and management of prosthetic joint infection (PJI) due to zoonotic microorganisms, fungi, mycobacteria and other unusual microorganisms is not available. We therefore sought to provide a resource for the practicing orthopaedic surgeon which will serve as a guide for making appropriate decisions in managing such rare, but potentially problematic conditions. We conducted a Medline search of all case reports of PJI due to these unusual microorganisms. Our review of the current literature showed the diagnosis of PJI due to zoonotic microorganisms, fungi, mycobacteria and other unusual microorganisms typically necessitates specialized diagnostic tests. Maintaining a high index of suspicion in diagnosis of such unusual microorganisms and requesting the appropriate laboratory tests at the time of surgical débridement is crucial for determining the microbiologic etiology of these infections. The appropriate medical and surgical management of such infections is complex and often requires the use of special antimicrobials with which the orthopaedist may not be familiar. Collaboration with an infectious disease specialist is advisable when treating these infections.

Level of Evidence: Therapeutic Study, Level V. See Guidelines for Authors for a complete description of levels of evidence.

From the *Medical University of South Carolina, Charleston, SC; and the †Mayo Clinic and Mayo College of Medicine, Rochester, MN.

Each author certifies that he or she has no commercial associations that may pose a conflict of interest with the submitted article.

Correspondence to: Camelia E. Marculescu, MD, Medical University of South Carolina, 100 Doughty Street, Suite 210, BA/IOP South, PO Box 250752, Charleston, SC 29425; Phone 843-792-4541; Fax: 843-792-6680; E-mail: marcule@musc.edu.

Unusual or fastidious microbes associated with prosthetic joint infection (PJI) have been rarely reported in the medical literature, but should be considered in the correct clinical and epidemiological setting. The presence of zoonotic, mycobacterial, fungal or other unusual microorganisms causing various infections is mentioned in book chapters,15,104 case reports or series,27,34,36,58,79 and review articles.17,20,21,43,98 These review articles and case series are focused on a description of various bone and joint or other infections caused by these unusual or fastidious microorganisms, and are in general without specific application to PJIs. Other book chapters104 briefly mention these unusual microorganisms as potential pathogens causing PJIs without exploring in depth the diagnostic or therapeutic modalities used in treatment. To our knowledge, a systematic review of the management of zoonotic, fungal, mycobacterial and other unusual PJIs is not available in the literature. This is important, since the inclusion of specialized culture media for the isolation of less frequently encountered organisms (eg, fungal, mycobacteria or Brucella spp) needs to be considered in recurrent PJI, when aerobic and anaerobic cultures are negative and/or patients are at risk for these infections based on their exposure history. Furthermore, the antimicrobial agents commonly used to treat PJIs are likely ineffective for these microorganisms.

In this report, we focused primarily on the epidemio-logical clues, clinical characteristics and management of PJIs due to zoonotic microorganisms, selected fungi and mycobacteria, Mycoplasma spp, Echinococcus spp and Tropheryma whipplei.

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MATERIALS AND METHODS

We conducted a Medline search for all case reports or case series published in the English and non-English literature of zoonotic, fungal, mycobacterial and other unusual microorganisms between 1966 and 2005. The primary author (CEM) also performed secondary searches of references from the articles identified through the Medline search. We included reports in this review if the diagnosis of PJI was made based on suggested criteria.89

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Zoonotic Bacteria

Brucella melitensis infection in humans is transmitted from animals through infected dairy products, nonpasteurized milk, by contact through a skin laceration or by inhalation. To date nine cases of Brucella PJI, four affecting a total hip arthroplasty (THA)56,86,121 and five affecting a total knee arthroplasty (TKA)1,70,87,121 have been reported. All patients consumed unpasteurized dairy products or had occupational exposure. Brucella PJI presents as an indolent infection. The median time from prosthesis implantation to diagnosis of PJI was 48 months (range, 2 months to 14 years). Local symptoms were present in six out of eight patients. Pain was present in all patients. Fever was present in 2 patients only. One patient had a sinus tract.1 The laboratory detection of Brucella sp requires culture of infected material using specialized media. As the organism may be difficult to detect in tissue samples by culture, isolation of Brucella sp from blood or urine cultures or a positive serology result, in the context of PJI, supports the diagnosis.

Management of Brucella osteomyelitis and PJI is controversial in regard to antimicrobial selection, duration of therapy and the role of surgery. Combination therapy with doxycycline and rifampin or doxycycline and streptomycin has been advocated.6,100,101 The optimal duration of treatment in the reported cases ranged from 6 weeks to 19 months in the current series. Malizos et al70 suggest longer duration of therapy of patients with joint implants even if the Brucella blood titers become negative, and believe the efficacy of the treatment should be monitored through serum and joint-aspirate Brucella titers. Monotherapy with fluoroquinolones and trimethoprimsulfamethoxazole is not recommended due to an unacceptably high risk rate of relapse.64 Complete eradication of the micro-organism is difficult to achieve, and relapse does occur, especially when the disease is caused by B. melitensis. The most frequent cause of relapse includes failure to complete treatment and unrecognized localized foci of infection.87 The relapse is confirmed by the isolation of brucellae from blood or other tissues of a patient with recurrent symptoms.

Two-stage exchange arthroplasty was performed in four cases. The optimal time to reimplantation is unknown, because there is no consistent test to ensure successful eradication. In three of the four cases treated with two-stage exchange arthroplasty, the average time to reimplantation was 6 weeks, similar to the time to reimplantation for PJI due to other microorganisms.121 Reimplantation was followed by combination antimicrobial therapy for 6 weeks. Prolonged antimicrobial therapy without resection of the prosthesis was successful in three cases. In these three cases, there was no loosening of the prosthesis.1,70,87 Treatment was administered until resolution of infection and sterilization of synovial fluid cultures. Failure of antimicrobial therapy was documented by Jones55 in one case ofB. abortus THA infection. The patient was subsequently treated with one-stage exchange arthroplasty followed by 1 year of combination antimicrobial therapy until negative serologic titers were reached. In one case, Brucella sp was cultured from tissue specimens at the time of revision of a THA for aseptic loosening. No additional surgical therapy was required, and the patient received vibramycin and rifampin for 5 months, with no evidence of infection after 4 years of followup.56 The duration of followup for all reported cases varied from 6 months to 4 years.

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Francisella tularensis (F. tularensis)

Francisella tularensis was recently described as a cause of chronic TKA infection in a 68-year-old man with rheumatoid arthritis treated with methotrexate (MTX).27 The patient had a history of wood tick bite prior to his original TKA. He presented 6 months after his TKA surgery with persistent, low-grade infection. It was presumed that asymptomatic lymphohematogenous seeding of F. tularensis was the likely mechanism of infection. As with Brucella spp, the laboratory diagnosis of F. tularensis PJI is achieved by culture of infected material on specialized media; in cases where synovial fluid, prosthetic material or periprosthetic material is negative by culture, detection of F. tularensis in culture from other body sites or detecting antibodies to F. tularensis in serum should support the diagnosis of F. tularensis PJI.

Antimicrobial susceptibility testing of F. tularensis is not usually performed in clinical microbiology laboratories because of safety concerns associated with these organisms. The microorganism is susceptible to fluoroquinolones, aminoglycosides and tetracyclines. Fluoroquinolones are effective in vitro and in vivo against F. tularensis. Rifampin has a relatively low minimum inhibitory concentration (MIC) against F. tularensis, but clinical experience is lacking. In the present case, the addition of rifampin to ciprofloxacin resulted in dramatic improvement of the symptoms. The patient was treated with a 4 month course of ciprofloxacin and rifampin. There was no evidence of recurrence of the infection after discontinuation of antimicrobial therapy.27

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Yersinia enterocolitica

To date only 2 cases of PJI due to Yersinia enterocolitica have been reported in the literature.51,85 This infection is primarily associated with gastrointestinal symptoms. Pigs and cattle are the primary reservoir of Yersinia enterocolitica.77 Both reported cases occurred in elderly patients and involved a TKA with associated hemarthrosis following anticoagulation. The presentation of infection was acute in one case and subacute for the other case. Both cases presented in the late postoperative period. Only one patient with diabetes mellitus who took iron supplements for anemia had diarrhea prior to the onset of symptoms. Iron supply associated with hemosiderin deposition due to hemarthrosis may be the main risk factor, at least in one case.51 The laboratory detection of Y. enterolitica is best achieved by culture on specialized media, especially if the specimen may be contaminated with other nonpathogens.

To date all serogroups have been reported susceptible to imipenem and aztreonam. Fluoroquinolones and broad-spectrum cephalosporins, often in combination with an aminoglycoside, have resulted in a successful outcome in patients with extra-intestinal Y. enterocolitica infection. Removal of the prosthesis was required in one case, followed by oral cefuroxime for 8 weeks.85 The other case was cured with oral ciprofloxacin for 6 weeks, but the duration of the followup was not reported.51 The optimal duration of treatment is unknown.

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Pasteurella multocida (P. multocida)

Pasteurella multocida infection most commonly localizes in skin and soft tissues. P. multocida, a small Gram-negative organism, is part of the normal mouth flora of many animals. Nineteen cases of PJI due to P. multocida have been reported to date. Most cases involve a TKA in immunocompromised patients (diabetes mellitus, rheumatoid arthritis, acute leukemia). Almost all patients presented with a history of animal bite or animal contact to the lower extremity containing the prosthetic joint. Two TKA infections were described after cat bites to the upper extremity.26,41,88 Cases of Pasteurella PJI transmitted by dog lick109 or close contact with a dog25 or in the absence of any close contact with a pet107 have been described. The majority (93%) of P. multocida PJI occurred in women. P. multocida PJI is usually an acute illness.5,44

Pasteurellae are generally susceptible to penicillin, macro-lides, tetracycline, and quinolones, and are resistant to clindamycin and amikacin. A few β-lactamase positive strains of P. multocida were reported; these were susceptible to the combination of a amoxicillin with clavulanic acid (ie, amoxicillinclavulanate).116 Case reports of P. multocida PJI were successfully treated with two-stage exchange,25,26,44,78,107,111 one-stage exchange5,18,78 or resection arthroplasty.41 The duration of antimicrobial therapy in these cases was variable, ranging from 3 to 10 weeks of parenteral therapy followed in some cases by 2 to 8 weeks of oral antimicrobial therapy.18,41,78 Success was also reported in cases where the infected prosthesis was retained using surgical débridement,7,102 aspiration,74 or antimicrobial therapy alone.42,71 On the other hand, several case reports of treatment failure occurred in patients treated with antimicrobial therapy with or without joint aspiration.88,109 Some authors believe patients with a total joint arthroplasty (TJA) should be instructed to take antimicrobial prophylaxis using amoxicillin-clavulanic acid (Augmentin®) following cat or dog bites, especially for those who are immunocompromised, to prevent hematogenous seeding of TJA.102 Most Pasteurella spp are easily cultivated using convention media and incubation conditions.

Infections caused by Campylobacter jejuni, coli, lari and fetus can be acquired via contact with domestic animals, chickens, seagulls, nonhuman primates, laboratory animals, and domestic pigs.105 Cases of THA and TKA PJI caused by C. jejuni,92 lari,122 fetus12,23,32,128 and upsaliensis53 have been reported. Six reported PJI cases due to Campylobacter spp occurred in immunocompromised patients: AIDS, cirrhosis and lymphoma,92 rheumatoid arthritis,12 leukemia23,128 and osteosarcoma.53 Werno et al122 recently described a fatal case of C. lari THA infection with bacteremia in an 81 year-old immunocompetent patient. Six out of the seven reported infections occurred in the late postoperative period. Six patients had an acute presentation with fever, joint pain or erythema. Four patients had a recent history of diarrhea.

C. jejuni has variable susceptibilities to a variety of antimicrobial agents, including macrolides, fluoroquinolones, aminoglycosides, chloramphenicol, nitrofurantoin and tetracycline.81 C. jejuni is resistant to trimethoprim and most β-lactam antibiotics,65 and is generally susceptible to erythromycin, with resistance rates of less than 5% (2% in United States).46 The prevalence of ciprofloxacin-resistance among Campylobacter spp increased from 13% in 1997 to 19% in 2001.46 Data from the National Antimicrobial Resistance Monitoring (NARMS) found resistance rates of 40% to tetracycline for Campylobacter jejuni strains in 2001.46 C. jejuni may also produce a β-lactamase that appears to be active against amoxicillin, ampicillin, and ticarcillin; this enzyme has been reported to be inhibited by clavulanic acid but not by sulbactam or tazobactam.63

Three reported cases were treated with débridement and retention of the prosthesis. One of these patients received 1 month of imipenem and gentamicin, followed by oral amoxicillin, with a good outcome.128 The second patient, who had C. lari bacteremia, died of septic complications.122 The third patient received 1 month of ceftriaxone, followed by 3 months of oral roxithromycin and remained free of recurrence of the THA PJI for 2 1½ years.23 One patient with bilateral TKA PJI was treated with two-stage exchange and had a successful outcome after 6 months of followup.32 Three other patients were managed with antimicrobial therapy without surgery. One of them received one month of chloramphenicol and died after 2 months of an unrelated cardiac cause.12 The second patient received 8 weeks of parenteral antimicrobials (main treatment erythromycin and ciprofloxacin), and had a good outcome at 6 months of followup.92 The third patient received ceftriaxone and roxithromycin for 4 weeks, followed by a 6-month course of amoxicillin and roxithromycin, with a good outcome after a 3 year followup.53 If Campylobacter spp are considered in the differential of infectious causes of PJI, specialized media and incubation conditions (microaerophilic environment and elevated temperature) are required to isolate these bacteria from clinical specimens.

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Fungi

Aspergillus fumigatus. To date, two cases have been reported. One patient was receiving steroids. The other patient had osteosarcoma treated with a hinged knee.13 Both cases were caused by Aspergillus fumigatus and involved a knee prosthesis. Both infections occurred in the late postoperative period, one case presented as an acute infection, and the second case as an asymptomatic popliteal cyst.

The in vitro susceptibility data were available for one case; A. fumigatus was susceptible to amphotericin B and was resistant to itraconazole and 5-fluorocytosine.8 For bone and joint infections caused by Aspergillus spp, surgical therapy, often in conjunction with systemic antifungal therapy is required. The role of a lipid formulation of amphotericin B is less studied in bone and joint infections caused by Aspergillus. There are reports of success and failure of liposomal amphotericin B in Aspergillus osteomyelitis.34,108 Itraconazole penetrates the bone well and has also been used successfully.28,29,45,91,95,106,123 Voriconazole seems to be a promising agent in management of Aspergillus osteomyelitis.108 Removal of the prosthesis was the surgical therapy reported in both cases. According to the investigators the hinged TKA was successfully treated with a “3-stage exchange” procedure. This surgical modality included resection arthroplasty, and additional débridement after 2 weeks, 6 weeks of amphotericin B and reimplantation after two months. Fluconazole, an azole not typically thought to have in vitro activity against Aspergillus, was administered for 6 months following reimplantation. The outcome was excellent after 5 years of followup.13 The other case was treated with resection arthroplasty, followed by intravenous administration of amphotericin B for 12 weeks.8

Other unusual cases of fungal PJI caused by Rhodotorula minuta,30 Histoplasma capsulatum,38 and Sporothrix schenckii33 have been reported. Fungi require specialized media for isolation and at most institutions require a separate order by the physician, in addition to aerobic/anaerobic bacterial cultures, when evaluating infected material from cases of PJI.

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Mycobacteria

Mycobacterium tuberculosis

In a retrospective study on 2116 episodes of PJI over a 22-year period, only 7 (0.3%) were due to M. tuberculosis.14 Tuberculous PJI usually involves the hips or the knees and can result most commonly from either local reactivation10,48,54,61,113,124 or occasionally from hematogenous spread.22,75,114 M. tuberculosis TJA infection in patients with no prior history of tuberculosis has been reported.103 The risk of reactivation of M. tuberculosis in patients undergoing THA or TKA for quiescent MTB native septic arthritis varies between 0% to 31%. It is higher for patients receiving a TKA (27%) than for those receiving a THA (6%).14 A decreased risk of reactivation was noted in patients with no evidence of active M. tuberculosis septic arthritis for more than 10 years prior to reimplantation and negative mycobacterial tissue cultures at the time of implantation.59,60 Use of antituberculous therapy at the time of arthroplasty for latent M. tuberculosis septic arthritis may be reasonable for patients who have not received modern antimycobacterial chemotherapy or preoperative isoniazid prophylaxis for their M. tuberculosis septic arthritis.35,59,97 The duration of prophylaxis remains unknown. Patients undergoing a total joint arthroplasty should be asked about a history of M. tuberculosis infection. Obtaining mycobacterial cultures at the time of arthroplasty should be performed in these cases. Like fungi, Mycobacteria spp require specialized media for growth. Administration of a PPD skin testing prior to total joint arthroplasty should be performed in patients who come from an area with high prevalence of tuberculosis, those who have a history of native joint septic arthritis due to an unknown pathogen, or when the underlying joint disease is unknown.14 The majority of patients with M. tuberculosis PJI infection are PPD positive,14 but a negative test has been reported by Tokumoto et al.113

The clinical course of prosthetic joint tuberculous infections can be divided in two patterns: they are either recognized at the time of arthroplasty based on histologic or microbiologic evidence of M. tuberculosis infection, or they may present in the late postoperative phase (> 6 weeks post surgery).103 In the latter situation, M. tuberculosis PJI often presents insidiously, over a period of weeks to months.43 A draining sinus is commonly seen and was present in all cases described by Berbari et al.14 Lusk et al68 reported simultaneous occurrence of two granulomatous processes (foreign body granulomas and necrotizing granulomas due to M. tuberculosis) in a patient with TKA infection.

A coinfecting bacterial pathogen was detected in 5 out of 7 cases reported by Berbari et al14 and has been reported by other investigators.62,113 In vitro susceptibility testing should be performed for all M. tuberculosis isolates, because of the emergence of resistance. Initial therapy should include isoniazid, rifampin and pyrazinamide, with the addition of ethambutol or streptomycin in case of suspected isoniazid resistance.4 Treatment should be continued for 6-9 months in patients with rifampin-susceptible strains.4

The optimal medical and surgical therapy for M. tuberculosis PJI is unknown. Patients with unsuspected M. tuberculosis septic arthritis incidentally discovered at the time of implantation or in the early postoperative period were successfully managed with a nonrifampin antituberculous combination therapy for 12-18 months.14,103 For patients with late onset M. tuberculosis PJI, medical treatment alone is usually unsuccessful and removal of the prosthesis is often required. Two-stage exchange,14,114,124 partial one-stage exchange,14,61,62,114,124 débridement with retention of the prosthesis14,54,75,103,113 and medical management alone have all been utilized. Failure occurred in 3 of 6 (50%) of the patients treated with débridement and retention.14,54,75,103,113

Cases of Mycobacterium bovis THA infection66 and prosthetic knee infection with BCG strain after BCG bladder instillation24 have been reported.

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Rapidly growing mycobacteria

Several articles reported M. fortuitum PJI involving both hips and knees,9,16,24,49,50,80 but very few described M. chelonae PJI.47,93 Most of the PJI caused by M. fortuitum occurred in the early postoperative period. M. chelonae usually causes a late infection. The presentation is usually acute, with drainage, abscess and fistulae formation.16,49,50,80,93

Agents that should be tested against the rapidly growing mycobacteria for clinically important isolates, including bone and joint infections, are amikacin, cefoxitin, ciprofloxacin, clarythromycin, doxycycline, imipenem, sulfamethoxazole, and tobramycin (for M. chelonae only), and linezolid.83 No testing of antituberculous agents such as rifampin, ethambutol or isoniazid should be performed, since most clinically important nontuberculous mycobacteria are resistant to primary antituberculous agents.20,120 M. fortuitum is much more drug susceptible than M. chelonae. Essentially all isolates have in vitro susceptibility to achievable serum levels of amikacin, cefoxitin, imipenem, sulfonamides, fluoroquinolones.21,31,110 Recent studies have shown approximately 80% of isolates of M. fortuitum are susceptible to clarithromycin.19 M. fortuitum isolates may develop resistance in spite of multidrug regimens, therefore repeating susceptibility testing during treatment is important when failure is suspected.72 Only 56% of isolates of M. fortuitum and about 20% to 23% of isolates of M. chelonae were susceptible to clinically achievable levels of doxycycline or minocycline. For M. chelonae, cefoxitin is not used, since isolates of M. chelonae are resistant to this agent (MIC > 128) μg/mL), and tobramycin is preferred to amikacin, because of its greater in vitro activity.21 Linezolid seems to be a promising agent against M. fortuitum, chelonae, and some abscessus isolates. Proposed MIC breakpoints for linezolid are ≤ 8 μg/mL for susceptible strains, 16 μg/mL for moderately susceptible, and 32 μg/mL respectively for resistant strains.20,83,119 Broth microdilution interpretive criteria for amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, sulfamethoxazole, and tobramycin have been published in concordance with Clinical Laboratory Standards Institute (CLSI, formerly National Committee for Clinical Laboratory Standards-NCCLS) guidelines.83

Antimicrobial therapy alone or in combination with débridement and retention of the prosthesis has been proven ineffective in PJI caused by M. fortuitum. Most patients required removal of the prosthesis or arthrodesis.49,50,72 Arthrodesis was the ultimate surgical therapy in 2 cases. One case was treated with amikacin, isoniazid and tetracycline.16 The other case was treated with cefoxitin for 5 weeks, amikacin for 2 weeks and oral doxycycline for one month.49 In one instance, two-stage reimplantation performed 7 weeks after prosthesis removal and a 6 week-course of cefoxitin/amikacin has led to the relapse of M fortuitum infection.49 Prolonged parenteral antimicrobial therapy for 6 weeks, followed by 3 to 6 months of oral therapy with bacteriologic evidence of complete elimination of the infection before reim-plantation has been suggested.49 M. chelonae TKA infection required 6 weeks of cefoxitin and amikacin, followed by administration of trimethoprim-sulfamethoxazole for a total of 3 months of therapy. One-stage exchange arthroplasty and chronic ciprofloxacin suppression had a good outcome after 2 year followup.93 Heathcock et al described a patient treated with a re-section arthroplasty followed by antimicrobial therapy with erythromycin and trimethoprim-sulfamethoxazole for 4 months and late reimplantation after 2 years with no further evidence of infection.47

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Mycobacterium avium complex (MAC)

The importance of Mycobacterium spp as a human pathogen increased with the AIDS epidemic.76 McLaughlin et al described a case of Mycobacterium avium complex THA infection in a 20-year-old man with AIDS who also had MAC bacteremia and histopathological evidence of disseminated M. avium complex infection in both of his THAs.76 Isono et al52 also described a case of a THA infection with M. avium complex in a renal transplant patient who had two sequential positive cultures of periprosthetic tissue.

CSLI (NCCLS) recommendations suggest that macrolide susceptibility testing should be performed for all clinically important isolates.83 McLaughlin76 suggested a prolonged course of at least four antimycobacterials active against M. avium complex with resection of the prosthesis. The author believed MAC PJI has an increased risk of subsequent relapse at the time of reim-plantation. The reported case was treated with five antimycobacterials for 6 months. The patient subsequently died. The incidence, outcome and optimal treatment of M. avium complex PJI in the modern era of highly active antiretroviral therapy (HAART) remain to be determined.

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Other Unusual Microorganisms

Mycoplasma hominis

Mycoplasma hominis was reported as the cause of PJI in 2 patients. One case involved a TKA99 and the other a THA.69 Mycoplasma septic arthritis and osteomyelitis have been described in patients with hypogammaglobulinemia, after urethritis or cervicitis or chronic bronchitis.39 However, both presented cases occurred in women with rheumatoid arthritis and neither of them had evidence of genitourinary or respiratory infections. The infection was acute, with fever and joint pain. M. hominis PJI should be suspected in patients with a clinically infected joint with purulent aspirate, negative gram stain and negative standard bacterial cultures. In these situations, the microbiology laboratory should be asked to look specifically for M. hominis.

Methods available for susceptibility testing of M. hominis are not standardized and do not correlate with the clinical outcome. Many strains are susceptible in vitro to clindamycin and are moderately susceptible to chloramphenicol and rifampin. An increase in tetracycline resistance has been documented for M. hominis in recent years.118 M. hominis is generally resistant to aminoglycosides, β-lactam antibiotics, vancomycin, sulfonamides, trimethoprim and erythromycin. Fluoroquinolones are usually active in vitro against M. hominis, but resistance can be induced in vitro by exposing the microorganism to increasing concentrations of fluoroquinolones. Limited information suggests M. hominis is susceptible in vitro to linezolid and quinupristin-dalfopristin although no clinical trials have been undertaken using these agents in M. hominis infections.57 One of the reported cases required multiple aspirations of the joint and 6 months of doxycycline therapy. The patient developed gastrointestinal side effects leading to discontinuation of doxycycline and relapse of the infection. Subsequently, the patient was treated with ciprofloxacin for 2 weeks with good results.99 The second reported patient improved after repeated aspirations and one month of therapy with clindamycin.69 Cultures of synovial fluid became negative 4 weeks after initiation of antimicrobial therapy in both reported cases.

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Echinococcus

Echinococcus spp infestation is endemic in some sheep-raising areas such as the Asian continent, the Middle East, parts of South America, Iceland and Northern Canada. Bone involvement in echinococcosis occurs in 0.5% to 2% of cases and usually involves the pelvis, spine, humerus and tibia.90 The growth of the cysts in bones is slow, and many years may pass before clinical manifestations become apparent. Although there are no pathognomonic signs of this disease, the most common noted osseous change is a combination of cysts and reactive sclerosis. Echinococcus complicating a THA was reported in a patient with rheumatoid arthritis.117 The patient had cysts present at the time of THA surgery. The patient's serology was positive. Acute signs of local inflammation developed 7 days postoperatively. Sinus tract formation with local cystic and sclerotic changes developed subsequently, ultimately leading to the patient's demise two years later. The laboratory detection of Echinococcus spp requires direct histopathologic inspection of infected material. A positive serology also supports the diagnosis.

The management of bone infestation by echinococcal disease requires complete resection of the involved area. Hemipelvectomy and hindquarter amputation have been advocated for complete eradication of the disease.79 The results have been discouraging. Adjunctive chemotherapy before and after surgery appears to reduce the risk of recurrence by inactivating protoscolices and lessening the tension of the cysts for easier cyst removal.2 Perlick et al90 reported a case of Echinococcus multilocularis THA infestation having a favorable outcome at 36 months after complete surgical removal of the cysts and prolonged treatment with albendazole. Removal of the prosthesis and prolonged treatment with albendazole is required in cases when complete resection of the cysts is not technically feasible.

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Tropheryma whipplei

Tropheryma whipplei involved a TKA two years after the gastrointestinal manifestations of this pathogen causing Whipple's disease resolved after antimicrobial treatment.40 The patient was initially treated with trimethoprim-sulfamethoxazole for 20 months for Whipple's disease. There was no evidence of relapse for 2 years after discontinuation of antimicrobial therapy. He therefore underwent a TKA for osteoarthritis. In the early postoperative period the patient developed low-grade fever, joint pain, swelling and tenderness, and was subsequently diagnosed with T. whipplei PJI.

Débridement with retention of prosthesis and chronic oral antimicrobial suppression (initially with trimethoprimsulfamethoxazole, and later with pristinamycin) controlled the infection after 1 year of followup in the reported case.

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DISCUSSION

We summarized current literature regarding PJI due to zoonotic, fungal, mycobacterial and other selected unusual microorganisms to create a useful reference for the busy clinician. We emphasized the epidemiologic setting associated with these infections, how these infections presented and any available data on the outcome of various medical and surgical treatment strategies used to treat patients with these infections. Our review reveals taking an appropriate exposure history is important when treating PJIs, especially in situations when routine bacterial cultures fail to identify a microorganism in patients with clinical evidence of infection.

Routine bacterial and anaerobic cultures will often fail to yield the pathogens discussed in this review. Furthermore, when an unusual microorganism such as Brucella or Francisella tularensis is suspected, the microbiology laboratory needs to be alerted and special precautions should be used in order to avoid accidental exposure of laboratory personnel handling the specimens. Traditionally, identification of some zoonotic microorganisms (ie, Brucella spp) in blood culture require specialized culture media (ie, brain-heart infusion, trypticase soy broth, chocolate agars) and prolonged incubation (at least 30 days).37,86 However, a more rapid detection of brucellae within the routine 1 week incubation period has been achieved with the use of the BACTEC 9240 blood culture system coupled with the pediatric Peds Plus F (PPF) or adult Plus Aerobic /F (PAF) medium, without the need for subculturing negative blood culture vials.11,96,125-127 Furthermore, the use of serologic tests, such as Brucella or Francisella serology will often help in the final microbiologic diagnosis.

Recent advances in molecular microbiology techniques have lead to a timely and more accurate identification of some of the zoonotic microorganisms presented in this review. Several sensitive and specific polymerase chain-reaction (PCR) assays have been described for the detection of Brucella,3,73,82,84,94 F. tularensis,115 or Tropheryma whipplei.36

While molecular testing is also useful in identification of campylobacters,122 PCR technology appears to be less valuable for routine diagnostic purposes in the case of a rapidly cultivable microorganism such as M. hominis.118 The experience with the use of PCR for detection of Mycobacterium tuberculosis in synovial fluid is limited. Studies suggest a sensitivity of 57.7% of PCR in synovial fluid, lower than the sensitivity in sputum (81%) or pleural fluid,67 and false positive results can occur.112 Another problem is nucleic acid amplification assays have not been yet approved by the FDA for use on nonrespiratory specimens. To our knowledge, no data using nucleic acid amplification techniques are available to address specifically the diagnosis of M. tuberculosis in a large number of samples of synovial fluid surrounding prosthetic joints. When caring for patients with PJIs due zoonotic microorganisms, mycobacteria, fungi, Echinococcus spp, Myco-plasma spp, or Tropheryma whipplei, physicians need to determine quickly and accurately the best medical and surgical treatment strategy leading to a successful outcome. While this article does not provide guidelines for treatment of these infections due to limited experience with each type of infection in the published literature, this article attempts to provide useful information to help the physician make these decisions. Maintaining a high index of suspicion in diagnosing such microorganisms, together with preoperative planning with an infectious disease specialist and the microbiology laboratory, will optimize the orthopaedic surgeon's ability to diagnose and treat these infections. The communication between the microbiolo-gist, orthopaedic surgeon and the infectious disease specialist is essential for final identification and appropriate management of these unusual infections.

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Acknowledgment

We thank Dr. Andrej Trampuz for his help with translation of the articles from German literature.

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