PHILADELPHIA, PA - Physicians have long speculated at the hard-to-treat nature of joint infection. In an article published in Journal of Infectious Diseases, Thomas Jefferson University scientists, in collaboration with scientists at the National Institutes of Health, come one step closer to understanding why these infections are so tough to tackle. The results could help explain the joint pain caused by different infections, including Lyme disease and why they're so resistant to antibiotic treatment.
"Biofilm formation has been suspected to play a key role during septic arthritis and prosthetic joint infection." said Noreen Hickok, Ph.D., Associate Professor in the Department of Orthopedic Surgery in the Sidney Kimmel Medical College at Thomas Jefferson University. "This study could help explain why these infections have been so difficult to treat and point to therapeutic approaches that could make antibiotics more effective."
Hickok and Michael Otto, Ph.D., a Senior Investigator with the Laboratory of Human Bacterial Pathogenesis National Institute for Allergies and Infectious Diseases, National Institutes of Health, served as co-senior investigators on the study.
"Our goal was to determine why Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus (MRSA), infections of the joint tend to be relatively unresponsive to standard antibiotic treatment," offered Sana Dastgheyb, lead author on the study and student at Jefferson's Graduate School of Biomedical Sciences.
Although many researchers study bacterial growth in standard growth medium, Hickok, Otto, and their teams wanted to know whether the bacteria behaved differently in the liquid that surrounds the joints - the so-called synovial fluid. They grew up several strains of MRSA in human synovial fluid, blood, and typical bacterial growth medium.
The researchers found that the bacteria begin to grow as clumps in the synovial fluid, and that these clumps share many of the same properties as biofilms. For example, the clumped bacteria embed themselves in a protective mesh of proteins that resist the penetration of antibiotics. They also found that the bacteria slow their growth, making them even less susceptible to antibiotics, which are designed to target rapidly growing cells like bacteria.
The collaborators showed that they could inhibit the formation of these biofilm clumps that they called "bio-floaters" by pre-treating the synovial fluid with a plasmin enzyme that degraded the protein matrix. With this pre-treatment, the research team reduced the formation of bio-floater clumps and increased the bacterial susceptibility to antibiotics.
"The study also helps explain why joint infections are so difficult to diagnose, even when there are overt signs of infection," said Dr. Hickok. Current tests for bacterial growth cannot differentiate a single bacterium from a bio-floater clump containing millions of cells, leading to an underestimate of the infection or a lack of detection altogether.
"This study strikes at the heart of one of the most pertinent questions in medicine, namely how the medical community can use antibiotics in the most effective manner to prevent infections." said Javad Parvizi, M.D., the James Edwards Professor of Orthopaedic Surgery in the Sidney Kimmel Medical College at Thomas Jefferson University, Director of Clinical Research at The Rothman Institute, and an author on the study. "Dr. Hickok and her team, by conducting this groundbreaking research, have enhanced our understanding of this phenomenon and opened our eyes to a very novel concept."
Although the pre-treatment appeared to stall growth in the lab, more research is needed before the results can be translated to patient care.
Article Reference: Sana Dastgheyb, Javad Parvizi, Irving M. Shapiro, Noreen J. Hickok, and Michael Otto. Biofilms cause recalcitrance of staphylococcal joint infection to antibiotic treatment J Infect Dis. first published online September 11, 2014 doi:10.1093/infdis/jiu514
This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the U. S. National Institutes of Health under award numbers ZIA AI000904-13, HD06153, DE019901, and T32-AR-052273. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health.
Noreen J. Hickok received funding from the NIH and Synergy Medical. Her husband holds stocks with Pfizer Pharmaceuticals. Javad Parvizi is a board member of 3M and a consultant for Zimmer, Smith & Nephew, ConvaTec, TissueGene, CeramTec, and Medtronic. He holds stocks with Hip Innovation Technologies, CD Diagnostics, and PRN. He received research support from the NIH, OREF, Stryker Orthopedics, Depuy, Zimmer, Baxter, 3M, Biomemetics, Ceramtec, and Smith & Nephew. The authors report no other conflicts of interest.
Thomas Jefferson University (TJU), the largest freestanding academic medical center in Philadelphia, is nationally renowned for medical and health sciences education and innovative research. Founded in 1824, TJU includes the Sidney Kimmel Medical College (SKMC), one of the largest private medical schools in the country and ranked among the nation's best medical schools by U.S. News & World Report, and the Jefferson Schools of Nursing, Pharmacy, Health Professions, Population Health and the Graduate School of Biomedical Sciences. Jefferson University Physicians is TJU's multi-specialty physician practice consisting of the full-time faculty of SKMC. Thomas Jefferson University partners with its clinical affiliate, Thomas Jefferson University Hospitals.