Citations

Abstract Background Minocycline is a second-generation tetracycline with a broad antimicrobial spectrum. It is often used in chronic suppression of musculoskeletal infections, given activity against gram positive organisms. Efficacy of Minocycline against gram negative skin and soft tissue infection has not previously been defined. In this study, we review in vitro minocycline efficacy against isolates from skin, muscle, and bone sources.Fig 1.Organisms isolated Methods We conducted a retrospective review of all minocycline susceptibility testing performed on musculoskeletal GNB isolates performed at the Mayo Clinic reference lab between 2013-2022. We describe the isolates broken down by site of culture and organism isolated. Then, we calculated the overall susceptibility of these isolates to Minocycline and susceptibility of the most common 6 organisms isolated.Fig 2.Sites of gram negative isolation Results During the study timeframe, we identified 13,567 gram negative isolates from musculoskeletal sites. Of 330 species identified, 19 were identified in at least 100 isolates (fig 1). Of 36 unique sites, 19 sites were each identified in at least 100 isolates (fig 2). 1920 isolates were tested for susceptibility to minocycline. Of these, 1584 (82.5%) were susceptible to minocycline. Of the most common organisms identified and tested for minocycline susceptibility, 99% of Stenotrophomonas maltophilia, 83% of Enterobacter cloacae, 80% of Escherichia coli, 68% of Acinetobacter baumanii, 1% of Proteus mirabilis, 53% of Klebsiella pneumoniae, 65% of Serratia marcescens isolates were susceptible to minocycline (fig 3). Pseudomonas aeruginosa isolates were not tested, due to innate resistance.Fig 3.Minocycline susceptibility compared to key organisms Conclusion A majority of skin and soft tissue cultures positive for Gram negative isolates were below the waist line. Of these, we reported organisms most commonly found. Minocycline showed in vitro activity against some commonly isolated gram negative organisms, especially E.coli, Acinetobacter, and Stenotrophomonas. Further research is needed into the efficacy of minocycline in gram negative skin and soft tissue infections, but it may represent a viable oral option, especially in the end of life. Disclosures All Authors: No reported disclosures

Abstract Background The introduction of shotgun metagenomic sequencing (sMGS) methods that identify the presence of microbial cell-free DNA (mcfDNA) in peripheral blood have shown promising results in various populations of patients. There is a pressing need to evaluate its application for osteoarticular infections (OAIs) in real-world setting. Baseline characteristics of the patients with suspected osteo-articular infections, including demographics, clinical characteristics, diagnosis, and KT results. Methods We retrospectively collected data on 73 adult patients who presented to the Mayo Clinic with suspected OAIs between 2019 and 2023, and for whom mcfDNA sMGS (Karius®, KT) testing was part of their diagnostic workup. We collected data on comorbidities, diagnostics, microbiological workout and its concordance with the KT. The primary objective was to evaluate its clinical impact on OAI diagnoses and management distinguishing into four categories: (1) KT was able to confirm an established diagnosis, (2) KT supported non-ID diagnosis, (3) KT established an unsuspected diagnosis, (4) KT did not add relevant information. Relevant microbiologic studies of patients with unsuspected diagnoses established by the KT (N=5) Results In our cohort KT was performed in 73 patients (Table 1). Among the infected individuals, KT yielded positive results in 22/43 (51.2%) cases. Out of these 22 cases, 11 (50%) showed agreement with conventional diagnostic workup, while in five (22.7%) cases, the KT established an unsuspected diagnosis, improving the diagnostic power from 11/43 (25.6%) to 16/43 (37.2%) (Table 2). Moreover, yielded a negative result in 19/26 (73.1%) patients with non-infectious diagnosis (Figure 1). Native Vertebral Osteomyelitis (NVO) diagnosis (p < 0.001) or OAIs with concomitant presence of endocarditis or endovascular infection (p = 0.005) were statistically associated with a definite, probable, or possible diagnostic certainty of KT result (Table 3). Overall, KT influenced antibiotic therapy in six cases (8.2%). Table 3 Factors associated with diagnostic certainty categories Conclusion This is the first retrospective study aiming to assess the real-world usefulness of the KT on the clinical management of patients with OAIs, with a special focus on NVO. It underscores KT's real-world application in cases where traditional diagnostic methods fall short. In highly complex OAIs cases, KT added 11.6% to the diagnostic power by establishing unsuspected diagnosis in 5 of 43 infective patients. Patients with NVO or OAIs with concomitant endocarditis or endovascular infections particularly benefited from KT testing. Figure 1 Distribution of KT results and their respective outcome according to the final diagnosis of suspected OAIs cases. Disclosures All Authors: No reported disclosures

Abstract Background Gram-negative bacteria (GNB) account for 5-23% of all periprosthetic joint infections (PJI), following total knee or hip arthroplasties (TKA, THA). Literature on the management of Gram-negative PJI is limited. This study aimed to describe our experience with the presentation, management, and outcomes of Gram-negative PJI.Table 1:Baseline characteristics (N = 126 cases)Data are N (%) unless otherwise specified. Abbreviations: BMT; Bone-marrow transplant, CCI; Charlson comorbidity index, CPPD; Calcium pyrophosphate crystal deposition, CRP; C-reactive protein, DMARDs; Disease-modifying antirheumatic drugs, ESR; Erythrocyte sedimentation rate, GERD; Gastroesophageal reflux disease, IQR; Inter-quartile range, PJI; prosthetic joint infection, SD; Standard deviation, TNF; Tumor necrotic factor, WBC; white blood cell Methods A retrospective review of our infected institutional total joint registry from 2012-2023 identified 125 patients with 126 GNB PJI (60 THA and 66 TKA) according to MSIS criteria for PJI. Seventy-two cases (57%) of GNB PJI in this series were classified as acute based on the duration of symptoms of less than 4 weeks. Treatment failure was defined as reoperation for any reason, persistent infection, or reinfection post-surgery. Baseline demographics, presenting symptoms, microbiological data, and treatment outcomes were reviewed.Table 2:Therapies (N = 126 joints)Data are N (%) unless otherwise specified. Abbreviations: DAIR; Debridement, antibiotics, and implant retention, IQR; Inter-quartile range Results For baseline demographics, see Table 1. Notably, 10% of patients included in the study were immunosuppressed. Fifty-five cases (43.6%) had a history of revision prior to the diagnosis of PJI, including 44 cases with history of prior PJI. Pseudomonas aeruginosa was the most commonly isolated pathogen (31.7%). Wound drainage was associated with polymicrobial growth (40.8%). Debridement, antibiotics, and implant retention (DAIR) was utilized in 42 cases with 9.8% failure rate. History of revision arthroplasty, chronic PJI and the presence of sinus tract were associated with higher odds of reoperation within 1 year. Eighty-four cases underwent resection arthroplasty (RA), 73 had antimicrobial spacer, of those, 60 patients completed two-stage revision (TSR). At the time of reimplantation, 45/60 (75%) of cases had negative cultures (Table 2). The overall failure rate in resection group failure rate was 45.2%. Wound drainage was associated with higher odds of reoperation in this group (Table 3). The Failure rate in this cohort was 33%. Fluoroquinolones had a 90% susceptibility rate but were used infrequently for chronic suppression (25%).Table 3:Predictor factors with reoperation for any reason within 1 yearData are N (%) unless otherwise specified.Abbreviations: DAIR; Debridement, antibiotics, and implant retention, PJI; Prosthetic joint infection Conclusion Pseudomonas aeruginosa was the predominant pathogen in GNB PJI, with a high failure rate observed in the resection group. History of revision arthroplasty, chronic PJI, sinus tracts and wound drainage were associated with increased risk of reoperation within 1 year.Figure 1:Distribution of failure events across the study Disclosures Nicholas Bedard, MD, Stryker: Advisor/Consultant

Abstract Background The underlying cause of fever of unknown origin (FUO) remains unidentified in up to 51% of cases despite systematic evaluation. Microbial cell-free DNA next-generation sequencing (mcfDNA-NGS) offers an agnostic, noninvasive approach to pathogen identification, but the utility and clinical impact of this assay in FUO remain unknown. Methods This retrospective cohort study evaluated adult patients referred for FUO evaluation at a tertiary medical center between November 2019 and November 2023. Patients underwent both standard microbiologic testing (ST) and mcfDNA-NGS. Diagnostic impact was assessed in 4 domains: new diagnoses, earlier time to diagnosis, avoidance of invasive procedures, and non-hypothesis-driven diagnoses. Logistic regression was used to identify predictors of positive mcfDNA-NGS testing. Results Among 176 patients, mcfDNA-NGS was positive in 44.3%, with 49% of these cases considered clinically significant. Infectious cause of FUO was identified in 39% of patients, noninfectious in 35%, and unknown in 26%. mcfDNA-NGS contributed to a positive diagnostic impact in 30% of cases, mainly by earlier diagnosis (16%) and potential for avoidance of invasive procedures (10%). Positive mcfDNA-NGS was significantly associated with higher Charlson comorbidity index score (odds ratio [OR], 1.22; P < .001) and white blood cell (WBC) count ≤4.5 × 109 cells/L (OR, 8.61; P < .001). Conversely, FUO without localization was associated with a decreased likelihood of positive mcfNDA testing (OR, 0.18; P < .001). Conclusions mcfDNA-NGS effectively complements ST in diagnosing FUO, providing earlier detection and minimizing invasive testing. Clinical predictors such as high comorbidity and low WBC count may guide the optimal use of mcfDNA-NGS in FUO. Prospective evaluation of optimal timing and use of mcfDNA-NGS and cost-benefit analysis in FUO is needed.

ABSTRACT A total of 1,925 Corynebacterium isolates were tested for antimicrobial susceptibility at the Mayo Clinic Microbiology laboratory (Rochester, Minnesota) from January 2012 to March 2023, with C. striatum (35.6%) and C. amycolatum (24.4%) identified as the predominant species. Species known to potentially carry diphtheria toxin were excluded. Common sources of isolation included skin and soft tissue (56.8%), bone and/or native joint synovial fluid (14.2%), urine (13.1%), sputum (6.1%), and blood (5.9%). For penicillin, susceptibility decreased from 47.5% (58 of 122) in 2012 to 20.6% (14 of 68) in 2023. Isolates also showed a decrease in susceptibility to erythromycin from 22.4% (26 of 116) in 2012 to 13.2% (9 of 68) in 2023. Susceptibility to trimethoprim-sulfamethoxazole averaged around 50% throughout the period. Notably, linezolid and vancomycin were universally effective in vitro against all species. The highest susceptibility rates among tested oral agents were to linezolid and doxycycline for non- C . striatum species. Daptomycin minimal inhibitory concentrations (MICs) of >256 µg/mL were observed for one C. amycolatum isolate, one C. tuberculostearicum isolate, and for seven C. striatum isolates, all from patients with prior daptomycin exposure. Daptomycin MICs of 2 µg/mL (nonsusceptible) were observed in one C. striatum isolate recovered from a daptomycin-naïve patient and in six C. jeikeium isolates, from both daptomycin-exposed and non-exposed patients. Significant variation in susceptibility profiles across different Corynebacterium species underscores the importance of performing antimicrobial susceptibility testing to guide effective treatment. Moreover, multidrug resistance observed in C. striatum poses substantial therapeutic challenges especially in patients requiring prolonged or chronic antibiotic suppression.

Background: Isavuconazole (ISA) has a favorable side effect profile that makes it attractive for treatment of invasive fungal infections (IFI). It carries FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data for other organisms and non-pulmonary infections. We conducted this review to investigate how ISA performed at treating IFI, with an especial interest in these non-approved indications. Methods: We retrospectively identified and reviewed 131 patients who received ISA as treatment for IFI at our institution, some of whom received ISA as their first anti-fungal therapy and others who received ISA as either step-down therapy or salvage therapy. We identified the microbiologic cause of infection as well as the anatomic site involved for each patient. We then classified patients according to their response to ISA: namely cured, partially responded, or stabilized. Results: The majority of patients were immunocompromised (n = 76, 58%). ISA was used primarily as a secondary therapy (n = 116, 89%); either as a step-down/switching from other agents, or as salvage therapy. The most common reasons for switching to ISA were toxicities with prior agents followed by QT prolongation. Although pulmonary aspergillosis and mucormycosis were represented in more than half of the cohort, ISA was also used off-label for treatment of other organisms such as endemic fungi (n = 19, 15%) as well as central nervous system (CNS) infections (n = 15, 11%). We have described the detailed clinical characteristics of these CNS infections cases. The overall clinical response rate varied by type of infection and site involved (57–73% response rate). Conclusions: We demonstrated encouraging clinical responses, particularly outside the FDA-approved indications, as well as good tolerability. This report highlights the critical need for expanded scope of prospective studies to delineate the efficacy of this better-tolerated agent, especially in central nervous system infections.

Abstract We examined the effect of preoperative antibiotic exposure and duration on synovial fluid samples from patients with native joint septic arthritis of the hip/knee. While exposure before diagnostic arthrocentesis did not affect fluid parameters, increased duration was associated with a decreased total nucleated cell count, underscoring the complex antibiotic effects on synovial fluid parameters.

Abstract Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and be administered at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework. A multidisciplinary steering committee was formed, which completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention that included bundled education with the use of therapeutic drug monitoring (TDM; i.e. drug-level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. The education and TDM intervention were deployed through a Plan, Do, Study, Act cycle. In the 3 months after “go-live,” 54 episodes of beta-lactam TDM occurred in 41 unique intensive care unit patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. Ninety-four percent of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; P = .73). Application of the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

Abstract Background Recent advances in shotgun metagenomic sequencing (sMGS) for detecting microbial cell-free DNA (mcfDNA) in peripheral blood have shown promise across various patient populations. This study evaluates the application of sMGS for diagnosing osteoarticular infections (OAIs), a condition with significant diagnostic challenges. Methods We conducted a retrospective analysis on 73 patients suspected of OAIs at the Mayo Clinic from 2019 to 2023, incorporating mcfDNA sMGS (Karius test [KT]) into their diagnostic evaluation. We categorized the clinical impact of KT on OAI diagnoses and management into 4 distinct outcomes. (1) KT was able to confirm an established diagnosis, (2) KT supported noninfectious diseases diagnosis, (3) KT established an unsuspected diagnosis, (4) KT did not add relevant information. Results In our cohort, KT was performed in 73 patients. Among the infected individuals, KT yielded positive results in 22 of 43 (51.2%) cases. Of these 22 cases, 11 (50%) showed agreement with conventional diagnostic workup, whereas in 5 (22.7%) cases, the KT established an unsuspected diagnosis. Native vertebral osteomyelitis diagnosis (P < .001) or OAIs with concomitant presence of endocarditis or endovascular infection (P = .005) were statistically associated with a definite, probable, or possible diagnostic certainty of KT result. Conclusions In complex OAIs, KT enhanced diagnostic accuracy by 11.6%, proving especially beneficial in diagnosing native vertebral osteomyelitis and infections with concurrent endocarditis or endovascular complications. Our findings underscore the utility of KT in the diagnostic workflow for challenging OAI cases, potentially altering clinical management for a significant subset of patients.

Abstract Background Identifying and treating patients with acute Q fever who are at an increased risk of progressing to persistent disease is crucial for preventing future complications. In this study, we share our decade-long clinical experience with acute Q fever, highlighting the challenges that clinicians encounter from making an initial diagnosis and performing risk stratification to determining the appropriate prophylaxis regimen and duration. Methods We retrieved records of adult Mayo Clinic patients (≥18 years) with positive Coxiella burnetii serology results between 1 January 2012 and 31 March 2022. Patients with Q fever anti–phase II immunoglobulin G ≥1:256 by indirect immunofluorescence were further analyzed. Results Thirty-one patients were included. Their median age was 58 years (IQR, 50–64), and the majority were men (84%). Acute hepatitis (29%), flu-like illness (25.8%), and pneumonia (16%) were the most common presentations. Thirteen patients (42%) received antibiotic prophylaxis to prevent disease progression, with significant variation in the indications and duration across physicians. The combination of doxycycline and hydroxychloroquine was the preferred regimen. Prophylaxis was administered for a median 333 days (IQR, 168–414). Four patients (13%) progressed to Q fever native valve infective endocarditis, with elevated anticardiolipin immunoglobulin G levels being the sole risk factor in 2 cases. The small sample size precluded drawing conclusions on the impact of prophylaxis in preventing disease progression. Conclusions Management of acute Q fever is complicated by the lack of comprehensive clinical guidelines leading to varied clinical practices. There is a critical need for randomized trials to establish robust evidence-based protocols for management.