New Horizon Workshop: Drug Resistance: New Challenges and Opportunities in Biomaterials- Associated Orthopaedic Infection

Antibiotics are critical to the success of surgical procedures including orthopaedic prosthetic surgeries. Unfortunately, there has been a dramatic increase in the emergence of antibiotic resistant bacteria which have led to serious clinical consequences. For instance, in the U.S. alone, antibiotic resistant bacteria have been estimated to cause at least 2 million infections and 23,000 deaths a year. Meanwhile, most clinical cases of orthopaedic surgeries have indicated that patients infected with antibiotic resistant bacteria, such as methicillin resistant Staphylococcus aureus (MRSA), are associated with increased mortality and morbidity. This lecture will review the severity of antibiotic resistance, consequences of antibiotic resistance, and antibiotic resistance mechanisms. This lecture will also highlight the recent development of an innovative immunotherapeutic approach in reducing biomaterial-associated infections. Antibiotic resistance – a serious global problem: The introduction of antibiotics has dramatically improved the fate of infection in patients and has changed the way various diseases and surgical procedures are treated. The ability of antibiotics to treat and cure infection has dramatically reduced the number of incidences of infection, significantly improving the quality of life for numerous patients, reduced childhood mortality, increased life expectancy, and saved numerous lives. Unfortunately, the discovery and increasingly widespread use (especially the misuse) of antibiotics have led to the rapid appearance of antibiotic resistant strains today, and more and more infections are caused by microorganisms that fail to respond to conventional treatments. Meanwhile, the discovery and development of antibiotics have been declining rapidly over the past several decades.(1) This decline was due to decreasing antibiotic research and development in major pharmaceutical companies;(1) investment in new antibiotic development has been hampered by the uncertain lifecycles (associated with antibiotic resistance development) of new antibiotic drugs and the government regulations affecting the pace of translational exploitation. Consequences of antibiotic resistance: The consequences of antibiotic resistance are very serious, and could present a significant impact on morbidity, mortality, and financial burdens for patients and public health systems, as described below:  Antibiotic resistance likely compromises the safety and efficacy of surgical procedures like implantation and transplantation that require the protection of antibiotics. It is estimated that between 38.7% and 50.9% of microorganisms causing surgical site infections are resistant to standard prophylactic antibiotics in the U.S.(2)  Antibiotic resistance has a direct effect on treating infections. Patients with infections caused by multidrug resistant (MDR) microorganisms are generally at increased risk of worse clinical outcomes and death, and consume more health-care resources compared with similar infections caused by antibiotic susceptible strains.(3) Approximately a twofold increase in mortality, morbidity, and cost for patients with resistant versus susceptible infections has been reported.(4) A two-fold higher risk of death was attributed to infections caused by carbapenem-resistant K. pneumoniae compared to infections caused by carbapenem-susceptible strains.(5) Meanwhile, hospitals spend, on average, an additional $10,000-40,000 to treat a patient infected by resistant bacteria versus susceptible strains.(6) According to the Centers for Disease Control and Prevention (CDC), in the U.S. alone, antibiotic resistant bacteria cause at least 2 million infections, 23,000 deaths a year,(7) and $55‐70 billion per year in economic impact.(8, 9) In Europe, approximately 25,000 people die annually due to MDR bacterial infections, along with a €1.5 billion per year cost in the economy.(10, 11)  Antibiotic resistance has led to more death of domesticated animals such as pets and farm animals. Molecular mechanisms of antibiotic resistance: There are two distinct types of antibiotic resistance: intrinsic and acquired. Microorganisms can be intrinsically resistant to certain antibiotics as a result of inherent structural or functional characteristics.(10) For instance, a particular antibiotic may be structurally unable to penetrate the outer membrane of certain microorganisms or the antibiotic entering the membrane is removed by efflux pumps. Meanwhile, microorganisms have also developed, under the selection pressure from antibiotics, various resistance mechanisms to antibiotics that they were originally susceptible to via deactivating, removing, or circumventing the toxicity of antibiotics. These evolved mechanisms are known as acquired resistance and can be acquired via chromosomal mutations or, more commonly, via the acquisition of an antibiotic resistance gene from another bacterium via mobile plasmids or transposons. A variety of factors including human activities may influence the presence of antibiotic resistance and antibiotic resistance genes are omnipresent in natural environments. Antibiotic resistance likely linked to worse clinical outcomes in orthopaedic biomaterial-associated infections: S. aureus is one of the most common causes of orthopaedic implant-associated infections, with both methicillin-susceptible (MSSA) and resistant (MRSA) strains. As shown in the following table, it seems that orthopaedic biomaterial-associated infections caused by microorganisms resistant to antibiotics likely have a less optimal outcome compared to those caused by antibiotic susceptible microorganisms. Table 1. Worse clinical outcomes of patients infected by MRSA compared to those infected by MSSA. Time Patients Worse Outcomes Reference 1995 2004 43 patients with periprosthetic joint infections  Significantly longer hospital durations (median, 15 vs. 10 days)  Significantly higher risk of treatment failure (12) 1997-2001 70 patients with periprosthetic joint infections  Successfully treated only 48% and 18% of hip and knee replacements, respectively, in MRSA infected patients compared to 81% and 89% in MSSA infected cases (13) 1998-2004 31 patients with delayed deep infection after total knee arthroplasty  Significantly higher mean number of surgical procedures per patient  Significantly lower proportion of patients with satisfactory outcomes (14) 2000-2002 59 children with musculoskeletal infections  Significantly longer febrile days and hospital stays. (15) 2004-2008 74 children with bone and joint infections  Significantly longer duration of febrile days, hospital stays, and antibiotic treatment (16) 2005-2011 30 vertebral osteomyelitis patients  Significantly higher co-morbidities  Significantly higher rate of patients to undergo surgical procedure within three months (56.3% vs. 14.3%) (17) Emerging antibiotic alternative: Enhancing host immune response to reduce infections: Innate immunity is the first line of defense against pathogenic organisms and the interface of the interactions between the host and the microbiota. In recent studies, local interleukin 12p70 (IL-12) immunotherapy, which stimulates the host’s immune response, has been shown to be effective in reducing biomaterial-associated infection in animals and to be advantageous over traditional treatments.(18-20)