A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Assessing the academic achievement of United States orthopaedic departments.

BACKGROUND: Assessing academic productivity allows academic departments to identify the strengths of their scholarly contribution and provides an opportunity to evaluate areas for improvement. AIM: To provide objective benchmarks for departments seeking to enhance academic productivity and identify those with significant improvement in recent past. METHODS: Our study retrospectively analyzed a cohort of orthopaedic faculty at United States-based academic orthopaedic programs. 5502 full-time orthopaedic faculty representing 178 programs were included in analysis. Variables included for analysis were National Institutes of Health funding (2014-2018), leadership positions in orthopaedic societies (2018), editorial board positions of top orthopaedic journals (2018), total number of publications and Hirsch-index. A weighted algorithm was used to calculate a cumulative score for each academic program. This study was performed at a large, United States medical school. RESULTS: All 178 programs included in analysis were evaluated using the comprehensive weighted algorithm. The five institutions with the highest cumulative score, in decreasing order, were: Washington University in St. Louis, the Hospital for Special Surgery, Sidney Kimmel Medical College (SKMC) at Thomas Jefferson University, the University of California, San Francisco (UCSF) and Massachusetts General Hospital (MGH)/Brigham and Women's/Harvard. The five institutions with the highest score per capita, in decreasing order, were: Mayo Clinic (Rochester), Washington University in St. Louis, Rush University, Virginia Commonwealth University (VCU) and MGH/Brigham and Women's/Harvard. The five academic programs that had the largest improvement in cumulative score from 2013 to 2018, in decreasing order, were: VCU, SKMC at Thomas Jefferson University, UCSF, MGH/Brigham and Women's/Harvard, and Brown University. CONCLUSION: This algorithm can provide orthopaedic departments a means to assess academic productivity, monitor progress, and identify areas for improvement as they seek to expand their academic contributions to the orthopaedic community.

Evading the host response: Staphylococcus "hiding" in cortical bone canalicular system causes increased bacterial burden.

Extremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss. Debate persists as to the optimal void filler for this "limb salvage" surgery, whether metal or allograft bone. Clinicians focus on optimizing important functional gains for patients, and the risk of devastating implant infection has been thought to be similar regardless of implant material. Recent insights into infection pathophysiology are challenging this equipoise, however, with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus (the most common infecting agent) into the host lacunar-canaliculi network, and also clinical data revealing a higher rate of infection of allograft over metal. The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal. Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal, and both microarchitecture of host implant and presence of host immune response were assessed. An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone. The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection. These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible, contributing to elevated risks of infection in cortical bone. The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

Novel in vivo mouse model of shoulder implant infection.

BACKGROUND: Animal models are used to guide management of periprosthetic implant infections. No adequate model exists for periprosthetic shoulder infections, and clinicians thus have no preclinical tools to assess potential therapeutics. We hypothesize that it is possible to establish a mouse model of shoulder implant infection (SII) that allows noninvasive, longitudinal tracking of biofilm and host response through in vivo optical imaging. The model may then be employed to validate a targeting probe (1D9-680) with clinical translation potential for diagnosing infection and image-guided débridement. METHODS: A surgical implant was press-fit into the proximal humerus of c57BL/6J mice and inoculated with 2 µL of 1 × 103 (e3), or 1 × 104 (e4), colony-forming units (CFUs) of bioluminescent Staphylococcus aureus Xen-36. The control group received 2 µL sterile saline. Bacterial activity was monitored in vivo over 42 days, directly (bioluminescence) and indirectly (targeting probe). Weekly radiographs assessed implant loosening. CFU harvests, confocal microscopy, and histology were performed. RESULTS: Both inoculated groups established chronic infections. CFUs on postoperative day (POD) 42 were increased in the infected groups compared with the sterile group (P < .001). By POD 14, osteolysis was visualized in both infected groups. The e4 group developed catastrophic bone destruction by POD 42. The e3 group maintained a congruent shoulder joint. Targeting probes helped to visualize low-grade infections via fluorescence. DISCUSSION: Given bone destruction in the e4 group, a longitudinal, noninvasive mouse model of SII and chronic osteolysis was produced using e3 of S aureus Xen-36, mimicking clinical presentations of chronic SII. CONCLUSION: The development of this model provides a foundation to study new therapeutics, interventions, and host modifications.

An Early Look at Operative Orthopaedic Injuries Associated with Electric Scooter Accidents: Bringing High-Energy Trauma to a Wider Audience.

BACKGROUND: There is a new method of transportation that started in our community in late 2017- rideshare electric scooters (e-scooters). These scooters have proven immensely popular and can now be found in many cities around the world. Despite the pervasiveness of e-scooters, their associated injury patterns are poorly understood. The purpose of this study was to describe our department's experience at the epicenter of the e-scooter phenomenon that is sweeping the globe and to characterize operative orthopaedic injuries that are related to e-scooter accidents. METHODS: We performed a retrospective chart review of all of the operative orthopaedic cases and trauma consults at 2 trauma centers (a level-I center and a level-II center) between September 2017 and August 2019. We identified all operative injuries in which the cause of injury was an e-scooter accident. Data that included demographics, mechanism of injury, diagnosis, and treatment were collected. RESULTS: Seventy-five operative injuries were identified in 73 patients during the study period. The mean patient age was 35.4 years (range, 14 to 74 years), and the median age was 32 years. There were 4 pediatric patients (14, 15, 15, and 17 years old). Thirty-two patients (43.8%) sustained upper-extremity injuries, and 42 patients (57.5%) sustained lower-extremity injuries; 1 of these patients had both upper and lower-extremity injuries. Nine patients (12.3%) had open fractures. There were 7 hip fractures in patients with an average age of 42.4 years (range, 28 to 68 years). Seventy-one (97.3%) of 73 patients were e-scooter riders, and 2 (2.7%) were pedestrians who were struck by e-scooter riders. CONCLUSIONS: E-scooters can cause serious injury. Seventy-three patients required operative treatment in just the first 2 years of e-scooter use in our community. Operative injuries occurred throughout the skeletal system, and several were injuries that are typically associated with high-energy trauma. Although, as a rule, e-scooter use is limited to adults and banned in high pedestrian-traffic areas in our city, the inclusion of 4 underage riders and 2 pedestrians in our cohort suggests that these rules are not always followed. As e-scooters continue to increase in popularity, additional steps should be taken to regulate their use and protect riders and the public.

Multimodal imaging guides surgical management in a preclinical spinal implant infection model.

Spine implant infections portend disastrous outcomes, as diagnosis is challenging and surgical eradication is at odds with mechanical spinal stability. Current imaging modalities can detect anatomical alterations and anomalies but cannot differentiate between infection and aseptic loosening, diagnose specific pathogens, or delineate the extent of an infection. Herein, a fully human monoclonal antibody 1D9, recognizing the immunodominant staphylococcal antigen A on the surface of Staphylococcus aureus, was assessed as a nuclear and fluorescent imaging probe in a preclinical model of S. aureus spinal implant infection, utilizing bioluminescently labeled bacteria to confirm the specificity and sensitivity of this targeting. Postoperative mice were administered 1D9 probe dual labeled with 89-zirconium (89Zr) and a near infrared dye (NIR680) (89Zr-NIR680-1D9), and PET-CT and in vivo fluorescence and bioluminescence imaging were performed. The 89Zr-NIR680-1D9 probe accurately diagnosed both acute and subacute implant infection and permitted fluorescent image-guided surgery for selective debridement of infected tissue. Therefore, a single probe could noninvasively diagnose an infection and facilitate image-guided surgery to improve the clinical management of implant infections.