Fungal periprosthetic infection: What a bear!

Issue: January 2011

ByJames P. Cashman, MD

ByJavad Parvizi, MD, FRCS

James Cashman

Javad Parvizi

Periprosthetic infection with fungi, although rare, represents a diagnostic and therapeutic challenge for which clear guidelines have not yet been established. It is anticipated, according to Kao and colleagues, that the incidence of fungal infection will increase with the increasing rates of candidemia and the expanding patient population exposed to risk factors such as indwelling central venous catheters, immunosuppressive and corticosteroid therapy during organ transplantation, parenteral nutrition, aggressive cancer chemotherapy and broad-spectrum antibiotics.

Diagnosis

The diagnosis of fungal periprosthetic joint infection can be quite difficult and a high index of suspicion is required. It is common practice to take multiple intraoperative specimens for aerobic and anaerobic culture to diagnose a deep periprosthetic infection. However, the role of routine acid-fast bacilli (AFB) and fungal cultures in this setting remains unclear. If fungi are obtained in tissue or fluid culture, it can be difficult to determine whether this represents true infection or fungal colonization.

While fungal culture remains the mainstay for diagnosis, there are a number of nonculture diagnostic tests. Fungi can be identified under direct microscopic examination by their morphological appearances on a KOH (potassium hydroxide) slide preparation. For example, if yeasts and hyphae are seen in the same microscopic field, the diagnosis is likely to be Candida albicans, whereas if thin septated hyphae which branch acutely appear, the appearance is suggestive of Aspergillus.

The G-test is a diagnostic assay which tests for (1,3)-beta-D-glucan, which is present in most fungal cell walls.This assay is highly sensitive with a detection level of 1 pg/mL, as shown by Obayashi and colleagues in a series that found a sensitivity of 90% with a specificity of 84% to 100%. However, this assay is not useful in the detection of Cryptococcus or Zygomycetes which can give false negatives.

Polymerase chain reaction (PCR) is an emerging technology for the detection of fungal infection. Using the 18s rRNA subunit, investigators have been able to develop a test with a sensitivity of 100%. Specificity is a concern with PCR and all possible contaminants must be eliminated to remove the possibility of contaminants as reported by Einsele and colleagues in 1997. Another exciting technology is the use of multiplex PCR (IBIS) that is available in some institutions. We utilize this technology to determine the pathogen for culture negative cases. Interestingly, a large number of fungi pathogens are identified by this technique when conventional cultures failed to isolate the pathogen.

Treatment

Candida species are the most common fungal infections implicated in periprosthetic infections. This has been demonstrated in a multi-center review by Azzam and colleagues, but also in the majority of published case reports. This review found a total of 46 reports of fungal infections in the English-language literature, the majority of which were candidal infections. Multiple case reports describe a wide variety of treatment methods, both surgical and medical, as well as variable outcomes. This makes direct comparison between studies difficult. Due to the very small number of patients in each report, it is difficult to draw firm conclusions regarding the outcome of treatment for this challenging problem.

The lack of reliable antifungal medications for systemic and, in particular, local delivery poses a real challenge in pathogen-directed treatment. Antifungal agents generally do not penetrate bone tissue to any great extent. Perfusion of tissue does not occur in areas of the body that are not vascularized, like the necrotic tissue. In addition, fungal infections, such as Candida, form biofilm which can further reduce the efficacy of antifungal agents. The Infectious Disease Society of America (IDSA) guidelines for the duration of treatment with antifungal agents in the treatment of native joint arthritis are 6 to 12 months. The challenge to achieve desired drug concentrations at the infection site, coupled with potential patient nonadherence and the overall cost of care, may be best overcome using aggressive surgical debridement with implantation of an antimicrobial impregnated cement spacer. Phelan and colleagues have described their success with a two-stage approach, albeit in a small series.

Elution characteristics of most antifungal agents from bone cement spheres are not optimal for treatment of deep-seated fungal infections, assuming similar antifungal release in vivo. Sealy and colleagues found that only amphotericin B has been found to elute for a prolonged period of time — more than 100 days — from polymethylmethacrylate spheres, with other antifungals such as fluconazole and fluctosine, becoming undetectable after approximately 35 days in vitro. In addition, amphotericin B is a broad-spectrum agent with fungicidal activity, is heat stable to 170°C and is available in a sterile powder dosage form. In sufficient concentrations, amphotericin B exhibits a pH-dependent fungicidal activity against susceptible pathogens. Amphotericin B inhibits the formation of the fungal cell membrane, but toxicity generally limits the systemic dose of amphotericin B to a maximum of 1 mg/kg daily. Cement spacers have been shown to deliver effective antimicrobial levels locally while avoiding systemic levels associated with toxicity. Systemic toxicity has been seen when amphotericin B is delivered locally in a cement spacer, as shown by Marra and colleagues.

The drugs of choice for systemic administration in patients who are infected with Candida species are amphotericin B and fluconazole, according to a report by Rex and colleagues. Recently, new antifungal agents have been introduced to the market that may hold a better promise for oral treatment/suppression of patients with fungal periprosthetic joint infection (PJI). While successful treatment with antifungal agents has been reported in some previous case reports, drug therapy alone will only suppress clinical symptoms of infection at the expense of potential toxic side effects. A further difficulty lies in the potential resistance of Candida species to azole drugs, according to Pfaller and colleagues.

Conclusion

Fungal PJI represents a diagnostic and treatment challenge for the arthroplasty surgeon. A high index of suspicion is necessary for prompt diagnosis. Aggressive surgical debridement and prolonged antimicrobial therapy are necessary to obtain successful outcomes. Selecting the appropriate treatment requires antifungal susceptibility testing and a multidisciplinary approach involving infectious disease specialists, clinical pharmacologists and the treating orthopedic surgeon. Although the exact duration of therapy is not agreed upon, it seems that, on the basis of guidelines for systemic fungal infection, a minimum of 1 year is necessary to ensure resolution of the infection. Further clinical data are necessary to determine optimal treatment strategies.

References:
Azzam K, et al. Microbiological, clinical, and surgical features of fungal prosthetic joint infections: a multi-institutional experience. J Bone Joint Surg (Am). 2009;91 Suppl 6:142-149.
Einsele H, et al. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol. 1997;35(6):1353-1360.
Kao AS, et al. The epidemiology of candidemia in two United States cities: results of a population-based active surveillance. Clin Infect Dis. 1999; 29(5): 1164-1170.
Marra F, et al. Amphotericin B-loaded bone cement to treat osteomyelitis caused by Candida albicans. Can J Surg. 2001;44(5):383-386.
Obayashi T, et al. Plasma (1–>3)-beta-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet. 1995;345(8941): 17-20.
Pappas PG, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503-535.
Pfaller M, et al. Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008-2009). Diagn Microbiol Infect Dis.2010;68(3):278-83.
Phelan DM, et al. Delayed reimplantation arthroplasty for candidal prosthetic joint infection: a report of 4 cases and review of the literature. Clin Infect Dis. 2002;34(7):930-938.
Rex J, et al. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30(4):662-678.
Sealy PI, et al. Delivery of antifungal agents using bioactive and nonbioactive bone cements. Ann Pharmacother.2009;43(10):1606-1615.
Javad Parvizi, MD, FRCS, editor of Infection Watch, can be reached at the Rothman Institute, 925 Chestnut St., 5th Floor, Philadelphia, PA 19107; 267-339-3617; e-mail: parvj@aol.com.
Disclosures: Parvizi is a consultant to Stryker. Cashman has no relevant financial disclosures.