Infection: Periprosthetic infection

Antibacterial implant coatings may better adhere to devices using a polymer layer

A research group at the University of South Australia has worked on developing techniques to permanently bind antibacterial coatings to medical devices - from orthopedic implants and catheters to contact lenses - by first binding them to a polymer layer, according to a press release from the American Institute of Physics.
The researchers presented their results using a novel diterpene compound at the American Vacuum Society (AVS) 57th International Symposium and Exhibition. Their overall approach is aimed at preventing biofilm formation on implants, which can increase the risk of infection.

“We believe that no solution will be universal so we want to establish an array of approaches,” Hans Griesser of the University of South Australia stated in the release. “The new diterpene compounds that we are testing are structurally quite different from established antibacterial compounds, and they are effective against methicillin-resistant Staphylococcus aureus (MRSA). That is what got us excited about them.”

The researchers started by applying a plasma polymer coating, which is an ultra-thin film. This technique works on different base materials, including glass, metal and many polymers used in manufacturing devices, according to the release. The ultra-thin polymer film then acts as a scaffold that materials bind to and either signal the bacteria to not attach to the surface or prevent the bacteria from multiplying once they are attached to it.

In their presentation, the researchers discussed and compared how several antibiotics work when they were applied to the polymer film, including silver nanoparticles and novel diterpene compounds. The latter are derived from Australian plants used in traditional medicine. Each approach has its pros and cons, which must be carefully weighed before ever using them on devices implanted in humans, according to the release.


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Fungal periprosthetic infection

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.

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.

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.


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Antimicrobial agents helpful in preventing biofilm infections, study finds

Antimicrobial peptides may prevent cement colonization, indicating they could be useful in preventing bacterial growth and subsequent biofilm formation, according to investigators from the United Kingdom.

As Staphylococcus epidermidis is a major cause of biofilm infections associated with indwelling medical devices and most prosthetic joint infections (PJI), increasing resistances among these isolates means new therapies are needed to prevent the initial adhesion of bacteria to biomaterial surfaces, study investigator Mathew Upton, PhD, said during his presentation at the 2010 Meeting of the Combined Orthopaedic Associations.

“[S. epidermidis] has only recently been recognized as a real cause of significant infection,” Upton said.

“It is now widely recognized that more than 80% of infections — and certainly the majority of those involving medical devices — have a biofilm element to their development,” he added, noting that his group was approaching the issue “from a different angle.”

This new angle, Upton reported, involves the incorporation of antimicrobial peptides directly into medical devices and materials to prevent the development of potentially dangerous biofilm.

Incorporating the peptides

His group incorporated lantibiotic gallidermin and NI01 with respective inhibitory activities of more than 5120 AU/mL and 2560 AU/mL into polymethylmethacrylate (PMMA) bone cement. Columns of bone cement with a diameter of 4 mm and a height of 7 mm were attached to the lid of a microtitre plate, then incubated with clinical biofilm forming S. epidermidis strain 156 for 1 hour.

These columns were then rinsed in phosphate-buffered saline (PBS) and immersed in PBS containing 0.25% glucose, ammonium sulfate and 1% tryptic soy broth. The growth of adhered bacteria was then monitored in real time using a kinetic plate reader for more than 48 hours, producing a time proliferation curve.

Further investigation is necessary

The investigators found that gallidermin and NI01, when incorporated into columns of PMMA cement, resulted in a significant decrease in the growth of clinical S. epidermidis isolate 156. This included a significant reduction in the growth of PJI-associated strains during the course of 96 hours.

According to Upton, the use of peptides could represent “a potential novel therapy” for preventing bacterial growth, and the incorporation of these materials into clinical use should be investigated.

“We are very interested in incorporating these into a number of areas, to be used in things like prosthetic joint infections,” Upton said. — by Robert Press

Reference:
Sandiford SK, Tagg J, Kay P, Upton M. Effectiveness of antimicrobial peptides against biofilm forming Staphylococcus epidermidis strains associated with orthopaedic infection. Presented at the 2010 Meeting of the Combined Orthopaedic Associations. Sept. 13-17. Glasgow.
Mathew Upton, PhD, can be reached at m.upton@manchester.ac.uk


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