Citations

Abstract Solutions for bone and joint infection (BJI) are needed where conventional treatments are inadequate. Bacteriophages (phages) are naturally occurring viruses that infect bacteria and have been harnessed for refractory bone and joint infections (BJI) in many case reports. Here we examine the safety and efficacy of English-language published cases of BJI since 2010 with phage therapy. From 33 reported cases of BJI treated with phage therapy, 29 (87%) achieved microbiological or clinical success, 2 (5.9%) relapsed with the same organisms, and 2 (5.9%) with a different organism. Of these 4 relapses, all but 1 had eventual clinical resolution with additional surgery or phage treatments. Eight out of 33 cases (24%) reported mild, transient adverse events with no serious events reported. Further work is needed to understand the true efficacy of phages and the role of phages in BJI. Opportunities lay ahead for thoughtfully designed clinical trials adapted to individualized therapies.

Abstract Background Cutibacterium acnes can cause spinal implant infections. However, little is known about the optimal medical management and outcomes of C. acnes spinal implant infections (CSII). Our study aims to describe the management of patients with CSII and evaluate the clinical outcomes. Methods We performed a retrospective cohort study of patients aged 18 years or older who underwent spinal fusion surgery with instrumentation between January 1, 2011, and December 31, 2020, and whose intraoperative cultures were positive for C. acnes. The primary outcome was treatment failure based on subsequent recurrence, infection with another organism, or unplanned surgery secondary to infection. Results There were 55 patients with a median follow-up (interquartile range) of 2 (1.2–2.0) years. Overall, there were 6 treatment failures over 85.8 total person-years, for an annual rate of 7.0% (95% CI, 2.6%–15.2%). Systemic antibiotic treatment was given to 74.5% (n = 41) of patients for a median duration of 352 days. In the subgroup treated with systemic antibiotics, there were 4 treatment failures (annual rate, 6.3%; 95% CI, 1.7%–16.2%), all of which occurred while on antibiotic therapy. Two failures occurred in the subgroup without antibiotic treatment (annual rate, 8.8%; 95% CI, 1.1%–31.8%). Conclusions Our study found that the estimated annual treatment failure rate was slightly higher among patients who did not receive antibiotics. Of the 6 failures observed, 4 had recurrence of C. acnes either on initial or subsequent treatment failures. More studies are warranted to determine the optimal duration of therapy for CSII.

Abstract Background Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. Methods We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration–approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. Results Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. Conclusions Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

Case: A 62-year-old man presented with a 10-year history of isolated melanonychia striata of his dominant thumb. Surgical biopsy ruled out subungual melanoma but revealed foreign plant material causing chronic infectious melanonychia from multiple pathogens, including Pseudomonas aeruginosa , Escherichia coli , and Candida spp. After removal of the nail plate and thorough debridement, the melanonychial streak resolved completely at 12 months of follow-up. Conclusion: Bacterial infection is a rarely reported cause of melanonychia, and in addition to surgical pathologic specimens, intraoperative fungal and bacterial cultures should always be obtained for accurate diagnosis of melanonychia striata.

Mechanical circulatory support is increasingly being used as bridge-to-transplant and destination therapy in patients with advanced heart failure. Technologic improvements have led to increased patient survival and quality of life, but infection remains one of the leading adverse events following ventricular assist device (VAD) implantation. Infections can be classified as VAD-specific, VAD-related, and non-VAD infections. Risk of VAD-specific infections, such as driveline, pump pocket, and pump infections, remains for the duration of implantation. While adverse events are typically most common early (within 90 days of implantation), device-specific infection (primarily driveline) is a notable exception. No diminishment over time is seen, with event rates of 0.16 events per patient-year in both the early and late periods postimplantation. Management of VAD-specific infections requires aggressive treatment and chronic suppressive antimicrobial therapy is indicated when there is concern for seeding of the device. While surgical intervention/hardware removal is often necessary in prosthesis-related infections, this is not so easily accomplished with VADs. This review outlines the current state of infections in patients supported with VAD therapy and discusses future directions, including possibilities with fully implantable devices and novel approaches to treatment.

Introduction: Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty (TJA), with treatment failure occurring in 12% to 28% after 2-stage revision. It is vital to identify diagnostic tools indicative of persistent infection or treatment failure after 2-stage revision for PJI. Methods: The Cochrane Library, PubMed (MEDLINE), and EMBASE were searched for randomized controlled trials and comparative observational studies published before October 3, 2021, which evaluated the utility of serum/plasma biomarkers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], interleukin-6 [IL-6], fibrinogen, D-dimer), synovial biomarkers (white blood cell [WBC] count, neutrophil percentage [PMN %], alpha-defensin [AD], leukocyte esterase [LE]), tissue frozen section, tissue culture, synovial fluid culture, or sonicated spacer fluid culture indicative of persistent infection before the second stage of 2-stage revision for PJI or treatment failure after 2-stage revision for PJI. Results: A total of 47 studies including 6,605 diagnostic tests among 3,781 2-stage revisions for PJI were analyzed. Among those cases, 723 (19.1%) experienced persistent infection or treatment failure. Synovial LE (sensitivity 0.25 [0.10-0.47], specificity 0.99 [0.93-1.00], positive likelihood ratio 14.0 [1.45-135.58]) and serum IL-6 (sensitivity 0.52 [0.33-0.70], specificity 0.92 [0.85-0.96], positive likelihood ratio 7.90 [0.86-72.61]) had the highest diagnostic accuracy. However, no biomarker was associated with a clinically useful negative likelihood ratio. In subgroup analysis, synovial PMN %, synovial fluid culture, serum ESR, and serum CRP had limited utility for detecting persistent infection before reimplantation (positive likelihood ratios ranging 2.33-3.74; negative likelihood ratios ranging 0.31-0.9) and no utility for predicting failure after the second stage of 2-stage revision. Conclusions: Synovial WBC count, synovial PMN %, synovial fluid culture, serum ESR, and serum CRP have modest sensitivity and specificity for predicting persistent infection during the second stage of 2-stage revision, suggesting some combination of these diagnostic tests might be useful before reimplantation. No biomarker or culture accurately predicted treatment failure after reimplantation. Level of Evidence: Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background There are anatomical, pharmacokinetic, and joint biomechanical differences between males and females. Whether these differences result in differing presentation, treatment tolerability and outcomes in periprosthetic joint infection (PJI) has not been widely evaluated. Methods We undertook a retrospective case matched study of patients with staphylococcal PJI managed with two-stage exchange arthroplasty. In order to control for differences other than sex which may influence outcome or presentation, males and females were case-matched for age, causative organism (Coagulase-negative staphylococci vs Staphylococcus aureus) and joint involved. The two matched groups were analyzed for differences in duration of symptoms, inflammatory markers, duration of hospital stay, antimicrobial side effects, post-operative complications and recurrence rate. Recurrence of infection was defined as per Musculoskeletal Infection Society criteria for PJI and included both relapse with original microorganism or with an additional organism. Results 78 pairs of males and females with staphylococcal PJI were successfully matched. There were no significant baseline differences by sex, except for greater use of chronic immunosuppression among females (16.7% vs. 4.1%; p=0.012). Clinical characteristics and outcomes of the patients are summarized in table 1. We did not detect a statistically significant between the outcomes of the two groups. Overall, 16 recurrent infections occurred during a median follow-up time of 2.9 (IQR: 1.5 - 5.3) years. The 3-year cumulative incidence of treatment failure depicted in figure 1 was 16.1% for females, compared with 8.8% for males (p=0.434). Conclusion Success rates for PJI treated with two-stage exchange arthroplasty are high consistent with previously reported literature. A larger cohort of patients may be required to detect differences in relapse rates. This study included only staphylococcal PJI and was thus unable to evaluate the differences in microbiology of PJI between males and females, which could also impact outcomes. This retrospective case-matched study did not detect any significant differences in outcomes between males and females with staphylococcal PJI who underwent two stage exchange arthroplasty. Disclosures Gina A. Suh, M.D., Adaptive Phage Therapeutics (APT): Grant/Research Support|Adaptive Phage Therapeutics (APT): Dr. Suh received grants and has an equity and royalty-bearing know-how agreement with Adaptive Phage Therapeutics but is unrelated to project Aaron J. Tande, M.D., Uptodate: Dr Tande has received an honorarium from Uptodate for medical writing unrelated to this project.

Abstract Background Image-guided biopsies in patients with suspected native vertebral osteomyelitis (NVO) are recommended to establish the microbiological diagnosis and guide antibiotic therapy. Despite recent advances, the microbiological yield of this procedure remains between 48% and 52%. A better understanding of factors associated with this low yield may lead to improved microbiological diagnosis. Methods We retrospectively identified patients with suspected NVO undergoing image-guided biopsies from January 2011 to June 2021 at our institution. Two hundred nine patients undergoing 248 percutaneous biopsies were included. Demographic data, biopsy and microbiologic techniques, clinical characteristics, and antibiotic use were collected. Multivariable logistic regression analysis was conducted to determine factors associated with microbiological yield. Results A total of 110 of 209 (52.6%) initial image-guided biopsies revealed positive microbiological results. This number increased to 121 of 209 (57.9%) when repeat image-guided biopsies were included. In multivariable analysis, aspiration of fluid was associated with a 3-fold increased odds of yielding a positive result (odds ratio [OR], 3.13; 95% confidence interval [CI], 1.39–7.04; P = .006), whereas prior antibiotic use was associated with a 3-fold decreased yield (OR, 0.32; 95% CI, .16–.65; P = .002). A univariate subgroup analysis revealed a significant association between the length of the antibiotic-free period and microbiological yield, with the lowest rates of pathogen detection at 0–3 days and higher rates as duration increased (P = .017). Conclusions Prior antibiotic use in patients with suspected NVO was associated with a decrease in the microbiological yield of image-guided biopsies. An antibiotic-free period of at least 4 days is suggested to maximize yield. Successful fluid aspiration during the procedure also increases microbiological yield.

Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad–generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

The precision health era is likely to reduce and respond to antimicrobial resistance (AMR). Our stewardship and precision efforts share terminology, seeking to deliver the “right drug, at the right dose, at the right time.” Already, rapid diagnostic testing, phylogenetic surveillance, and real-time outbreak response provide just a few examples of molecular advances we dub “precision stewardship.” However, the AMR causal factors range from the molecular to that of global health policy. Mirroring the cross-sectoral nature of AMR science, the research addressing the ethical, legal and social implications (ELSI) of AMR ranges across academic scholarship. As the rise of AMR is accompanied by an escalating sense of its moral and social significance, what is needed is a parallel field of study. In this paper, we offer a gap analysis of this terrain, or an agenda for “the ELSI of precision stewardship.” In the first section, we discuss the accomplishments of a multi-decade U.S. national investment in ELSI research attending to the advances in human genetics. In the next section, we provide an overview of distinct ELSI topics pertinent to AMR. The distinctiveness of an ELSI agenda for precision stewardship suggests new opportunities for collaboration to build the stewardship teams of the future.