Petri, Francesco

Abstract Background Culture-negative native vertebral osteomyelitis (CN-NVO) is increasingly common, rising from 0.3 to 1.8 cases per 100,000 between 1995 and 2008. The lack of microbial identification complicates optimal treatment and creates prognostic uncertainties. We describe our decade-long clinical experience with CN-NVO, focusing on patient characteristics, treatment, and outcomes. Patient Characteristics Methods We retrospectively analyzed adult patients with radiographic evidence of NVO between January 1, 2011, and July 31, 2021. CN-NVO required clinical indicators such as back pain and fever, elevated inflammatory markers, and negative cultures from at least one spine biopsy. Patients with infected instrumentation were excluded. Diagnostic Evaluation Values represent median, lower quartile, and upper quartile for continuous variables unless otherwise specified, 2 whereas frequencies and percentages are presented for categorical variables. ^ All results returned negative *Biopsies number two and three did not result in additional findings or change clinical management. Results Seventy-two patients were included. Their characteristics are presented in Table 1. Most (77.8%) had received antibiotics within the 4 weeks preceding the biopsy. Disc space enhancement on MRI was the primary finding, with the lumbar spine being the most frequently involved (Table 2). Blood cultures were positive in 39.4% of the patients within 3 months of symptom onset. Streptococcus spp. (n=9, median time between positive culture and diagnosis: 6.5 days [IQR 2.25, 26.75]) and Staphylococcus aureus (n=7, 40 days [IQR 37.5, 51.5]) were most common. Definitive antibiotics were administered in 98.6% of the cases, primarily IV β-lactam + vancomycin. Oral antibiotics (PO) were used in 46.5% of the patients, primarily as step-down therapy (91%) (Table 3). Surgery was required in 8.5% of the patients for abscess drainage or relief of spinal cord compression. Treatment failure occurred in 9.4% of patients, and 37.5% died during the median follow-up of 568.5 days, with two deaths related to the infection. Treatment and Outcomes ^ defined as requiring another course of antibiotics and/or surgery for suspected ongoing infection ¶ Clinical findings include back pain or fevers; laboratory findings indicate abnormal or uptrend in inflammatory marker values # Defined as MRI findings concerning ongoing or worsening infection as per the interpretation of the Radiologist, Infectious Disease physician, and/or Orthopedic Surgeon Conclusion Patients with CN-NVO often require prolonged antibiotic therapy, typically combination regimens, with favorable treatment outcomes. Our treatment failure rate is similar to other studies, although comparability may be limited by heterogeneity in definitions. Mortality rates in the range of 6 and 36% have been reported, with the higher end driven mostly by comorbidities. Enhanced diagnostics and standardized treatment protocols are needed to further improve patient outcomes. Disclosures All Authors: No reported disclosures

Background Identifying a microorganism in patients with native vertebral osteomyelitis presents diagnostic challenges. Microorganism identification through culture-based methods is constrained by prolonged processing times and sensitivity limitations. Despite the availability of molecular diagnostic techniques for identifying microorganisms in native vertebral osteomyelitis, there is considerable variability in reported sensitivity and specificity across studies, leading to uncertainty in their clinical utility. Questions/purposes What are the sensitivity, specificity, and diagnostic odds ratios for 16S broad-range PCR followed by Sanger sequencing (16S) and metagenomic next-generation sequencing (NGS) for detecting bacteria in native vertebral osteomyelitis? Methods On June 29, 2023, we searched Cochrane, Embase, Medline, and Scopus for results from January 1970 to June 2023. Included studies involved adult patients with suspected native vertebral osteomyelitis undergoing molecular diagnostics—16S bacterial broad-range PCR followed by Sanger sequencing and shotgun or targeted metagenomic NGS—for bacteria detection. Studies involving nonnative vertebral osteomyelitis and cases of brucellar, tubercular, or fungal etiology were excluded. The reference standard for the diagnosis of native vertebral osteomyelitis was a composite clinical- and investigator-defined native vertebral osteomyelitis diagnosis. Diagnostic performance was assessed using a bivariate random-effects model. Risk of bias and diagnostic applicability were evaluated using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. After a manual screening of 3403 studies, 10 studies (5 on 16S, 5 on NGS) were included in the present analysis, from which 391 patients were included from a total of 958 patients overall. Quality assessment via QUADAS-2 criteria showed moderate risk of bias and good applicability. Results 16S showed 78% (95% confidence interval [CI] 95% CI 31% to 96%) sensitivity and 94% (95% CI 73% to 99%) specificity, whereas NGS demonstrated 82% (95% CI 63% to 93%) sensitivity and 71% (95% CI 37% to 91%) specificity. In addition, the diagnostic ORs were 59 (95% CI 9 to 388) and 11 (95% CI 4 to 35) for 16S and NGS, respectively. Summary receiver operating characteristic curves showed high test performance for 16S (area under the curve for 16S 95% [95% CI 93% to 97%] and for NGS 89% [95% CI 86% to 92%]). Certainty in estimates was moderate because of sample size limitations. Conclusion This meta-analysis found moderate-to-high diagnostic performance of molecular methods on direct patient specimens for the diagnosis of native vertebral osteomyelitis. When used as a complementary test to microbiological analyses, a positive 16S result rules in the diagnosis of native vertebral osteomyelitis, while further studies are needed to understand the role of NGS in the diagnosis of native vertebral osteomyelitis. When available, these tests should be used in addition to conventional microbiology, especially in complex cases with extensively negative standard microbiological test results, to detect fastidious bacteria or to confirm the causative bacteria when their isolation and pathogenicity are unclear. A large sample size is needed in future research to understand the use of these techniques as standalone tests for diagnosis. Level of Evidence Level III, diagnostic study.

The incidence of culture-negative NVO (CN-NVO) cases is increasing, presenting significant diagnostic and therapeutic challenges due to the inability to isolate causative organisms with conventional microbiological methods. Factors influencing the diagnosis of CN-NVO include prior antimicrobial therapy, low pathogen burden, fastidious or intracellular organisms, technical issues, and non-infectious mimickers. Diagnosis often relies on imaging modalities like magnetic resonance imaging (MRI) and computed tomography (CT)-guided biopsy, though these methods can sometimes fail to yield positive microbiological results. Advanced diagnostic tools, such as polymerase chain reaction (PCR), metagenomic next-generation sequencing (mNGS), and cell-free DNA analysis, may be necessary to identify the pathogen. The causative pathogen cannot be isolated in some patients, among which an empirical antimicrobial therapy should be initiated. This narrative review discusses the management, monitoring, surgical indications, and outcomes for patients with CN-NVO.

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.

Infections of cardiac implantable electronic devices (CIEDs) and vascular grafts are some of the most dreaded complications of these otherwise life-saving devices. Many of these infections are not responsive to conventional treatment, such as systemic antibiotics and surgical irrigation and debridement. Therefore, innovative strategies to prevent and manage these conditions are warranted. Among these, there is an increasing interest in phages as a therapeutical option. In this review, we aim to collect the available evidence for the clinical application of phage therapy for CIED and vascular graft infections through literature research. We found 17 studies for a total of 34 patients. Most of the indications were left ventricular assist device (LVAD) (n = 20) and vascular graft infections (n = 7). The bacteria most often encountered were Staphylococcus aureus (n = 18) and Pseudomonas aeruginosa (n = 16). Clinical improvements were observed in 21/34 (61.8%) patients, with microbiological eradication in 18/21 (85.7%) of them. In eight cases, an adverse event related to phage therapy was reported. Phage therapy is a promising option for difficult-to-treat CIED and vascular graft infections by means of an individualized approach. Clinical trials and expanded access programs for compassionate use are needed to further unveil the role of phage therapy in clinical application.

Abstract Background Native vertebral osteomyelitis (NVO) caused by Staphylococcus aureus is associated with high risk of treatment failure and increased morbidity. The role of rifampin-based therapy for the treatment of this condition is controversial. The goal of this systematic review and meta-analysis is to explore the efficacy and safety of rifampin-based therapy for the treatment of S. aureus NVO. Methods We searched Cochrane, Embase, Medline, Scopus, and Web of Science databases for studies published up to May 2023, focusing on adults with NVO treated with or without rifampin-containing regimens. A random-effects model meta-analysis estimated relative risks and risk difference with 95% confidence intervals (CI). Results Thirteen studies (2 randomized controlled trials and 11 comparative cohort studies), comprising 244 patients with S. aureus NVO who received rifampin and 435 who did not, were analyzed. Meta-analysis showed that rifampin-based regimens were associated with lower risk of clinical failure (risk difference, −14%; 95% CI, −19% to −8%; P < .001; I 2 = 0%; relative risk, 0.58; 95% CI, .37–.92, P = .02, I 2 = 21%). Only 1 study reported on adverse events. All studies had a high or uncertain risk of bias, and the certainty of evidence was rated as very low. Conclusions Adjunctive rifampin therapy might be associated with lower risk of S. aureus NVO treatment failure; however, the low certainty of evidence precludes drawing definitive conclusions that would alter clinical practice. A randomized trial is necessary to corroborate these findings.