Plasmon-Enhanced Digital Fluoroimmunoassay for Subfemtomolar Detection of Protein Biomarkers.

Rapid and accurate quantification of low-abundance protein biomarkers in biofluids can transform the diagnosis of a range of pathologies, including infectious diseases. Here, we harness ultrabright plasmonic fluors as "digital nanolabels" and demonstrate the detection and quantification of subfemtomolar concentrations of human IL-6 and SARS-CoV-2 alpha and variant proteins in clinical nasopharyngeal swab and saliva samples from COVID-19 patients. The resulting digital plasmonic fluor-linked immunosorbent assay (digital p-FLISA) enables detection of SARS-CoV-2 nucleocapsid protein, both in solution and in live virions. Digital p-FLISA outperforms the "gold standard" enzyme-linked immunosorbent assay (ELISA), having a nearly 7000-fold lower limit-of-detection, and outperforms a commercial antigen test, having over 5000-fold improvement in analytical sensitivity. Detection and quantification of very low concentrations of target proteins holds potential for early detection of pathological conditions, treatment monitoring, and personalized medicine.

Prevalence and risk factors associated with readmission with acute kidney injury in patients receiving vancomycin outpatient parenteral antimicrobial therapy.

INTRODUCTION: Vancomycin is commonly used during outpatient parenteral antimicrobial therapy (OPAT). Therapeutic drug monitoring (TDM) of vancomycin is recommended to ensure effective and safe therapy, as use has been associated with acute kidney injury (AKI). METHODS: The MarketScan® Commercial Database was queried from 2010 to 2016 to identify patients aged 18-64 years discharged from an inpatient hospitalization on vancomycin OPAT. The primary endpoint was hospital readmission with AKI within 6 weeks of index hospital discharge. TDM was defined as at least one vancomycin level obtained during outpatient therapy. Bivariate analysis was used to examine associations with outcomes; significant factors were incorporated into a multivariable logistic regression model. RESULTS: A total of 14,196 patients were included in the study; median age was 54 years and 53.8% were male. Readmission with AKI occurred in 385 (2.7%) and was independently associated with chronic kidney disease (aOR 2.63 [95%CI 1.96-3.52]), congestive heart failure (1.81 [1.34-2.44]), chronic liver disease (1.74 [1.17-2.59]), hypertension (1.73 [1.39-2.17]), septicemia (1.61 [1.30-2.00]), and concomitant OPAT with IV penicillins (1.73 [1.21-2.49]) while skin and soft tissue infection (0.67 [0.54-0.83]) and surgical site infection (0.74 [0.59-0.93]) were associated with lower risk of readmission with AKI. TDM was not associated with lower risk of readmission with AKI. CONCLUSION: Chronic kidney disease, congestive heart failure, hypertension, chronic liver disease, septicemia, and concomitant OPAT with IV penicillins were significantly associated with higher risk of readmission with AKI during vancomycin OPAT.

Novel agents in the treatment of invasive fungal infections in solid organ transplant recipients.

PURPOSE OF REVIEW: Recipients of solid organ transplants (SOTs) suffer a significant burden of invasive fungal infections (IFIs). The emergence of drug-resistant fungi and toxicities of currently used antifungal agents as well as drug-drug interactions with immunosuppressants make their treatment challenging. This review discusses selected novel antifungal agents in the development pipeline that can currently be used through clinical trials or may be commercially available in the near future. RECENT FINDINGS: These agents in development have novel pharmacokinetics and pharmacodynamics, expanded spectra of activity and excellent safety profiles. SUMMARY: The properties of novel antifungal agents have the potential to expand the therapeutic options for IFIs in recipients of SOTs.

Performance of the Lateral Flow Assay and the Latex Agglutination Serum Cryptococcal Antigen Test in Cryptococcal Disease in Patients with and without HIV.

Cryptococcal epidemiology is shifting toward HIV-negative populations who have diverse presentations. Cryptococcal antigen (CrAg) testing is also changing, with development of the lateral flow assay (LFA) having reported increased sensitivity and specificity, but with minimal knowledge in the HIV-negative population. In this study, we evaluate the real-life performance of CrAg testing in patients with cryptococcal disease. We conducted a retrospective review of patients with cryptococcosis from 2002 to 2019 at Barnes-Jewish Hospital. Latex agglutination (LA) was used exclusively until April 2016, at which point LFA was used exclusively. Demographics, presentations, and testing outcomes were evaluated. Serum CrAg testing was completed in 227 patients with cryptococcosis. Of 141 HIV-negative patients, 107 had LA testing and 34 had LFA testing. In patients with disseminated disease, serum CrAg sensitivity by LA was 78.1% compared to 82.6% for LFA. In patients with localized pulmonary disease, serum CrAg sensitivity was 23.5% compared to 90.9% for LFA. Of 86 people living with HIV (PLWH), 76 had LA testing, and 10 had LFA testing. Serum CrAg sensitivity for LA was 94.7% compared to 100% for LFA in patients with disseminated disease. We noted a significant improvement in sensitivity from LA testing to LFA testing, predominantly in those with localized pulmonary disease. However, both LFA and LA appear to be less sensitive in HIV-negative patients than previously described in PLWH.

Comparative Epidemiology and Outcomes of Human Immunodeficiency virus (HIV), Non-HIV Non-transplant, and Solid Organ Transplant Associated Cryptococcosis: A Population-Based Study.

In this population-based study in the contemporary era in the United States, the proportion of human immunodeficiency virus (HIV)-negative patients with cryptococcosis approaches that in HIV-infected patients. Cryptococcosis is associated with higher mortality rates in HIV-negative patients (including organ transplant recipients).

Delayed infection with Parvimonas micra following spinal instrumentation.

BACKGROUND CONTEXT: Delayed-onset surgical site infections following spinal instrumentation are uncommon and often present with chronic pain and implant failure. Anaerobic organisms are rarely implicated and identified with difficulty in these infections. PURPOSE: We report a case of vertebral osteomyelitis and epidural abscess due to Parvimonas micra, an anaerobic bacterium, six months following spinal instrumentation. STUDY DESIGN/SETTING: Case Report. RESULTS: P. micra was identified from multiple intraoperative tissue and hardware specimens. With hardware explant and antibiotic therapy, the patient had a successful outcome. CONCLUSIONS: To our knowledge, this is the first report of a P. micra hardware-associated spinal infection.

Outcomes of Ceftriaxone Compared With Cefazolin or Nafcillin/Oxacillin for Outpatient Therapy for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infections: Results From a Large United States Claims Database.

Background: Ceftriaxone is a convenient option for methicillin-sensitive Staphylococcus aureus (MSSA) outpatient parenteral antimicrobial therapy (OPAT), but population-based studies for its effectiveness are lacking. Methods: In this retrospective cohort, a large insurance claims database was queried from 2010 to 2018 for adults with MSSA bloodstream infection (BSI). Patients discharged on OPAT on cefazolin or oxacillin/nafcillin were compared with ceftriaxone with respect to 90-day hospital readmission with the same infection category and 90-day all-cause readmission using logistic regression models. Results: Of 1895 patients with MSSA BSI, 1435 (75.7%) patients received cefazolin, oxacillin, or nafcillin and 460 (24.3%) ceftriaxone. Readmission due to the same infection category occurred in 366 (19.3%), and all-cause readmission occurred in 535 (28.3%) within 90 days. Risk factors significantly associated with readmission with the same infection category were the oldest sampled age group (61-64 years: adjusted odds ratio [aOR], 1.47 [95% confidence interval {CI}, 1.01-2.14]), intensive care unit stay during index admission (aOR, 2.33 [95% CI, 1.81-3.01]), prosthetic joint infection (aOR, 1.96 [95% CI, 1.18-2.23]), central line-associated BSI (aOR, 1.72 [95% CI, 1.33-2.94]), and endocarditis (aOR, 1.63 [95% CI, 1.18-2.23]). Ceftriaxone was not associated with increased risk of readmission with the same infection category (aOR, 0.89 [95% CI, .67-1.18]), or 90-day all-cause readmission (aOR, 0.86 [95% CI, .66-1.10]) when compared with oxacillin/nafcillin/cefazolin. Conclusions: In this cohort of MSSA BSI patients discharged on OPAT, there were no differences in outcomes of readmission with the same infection and 90-day all-cause readmission in patients treated with ceftriaxone compared to oxacillin/nafcillin or cefazolin. Patients with complicated BSIs such as endocarditis and epidural abscess were more likely to be prescribed cefazolin or oxacillin/nafcillin.

Diagnostic efficacy and clinical impact of image-guided core needle biopsy of suspected vertebral osteomyelitis.

OBJECTIVES: The diagnostic yield and clinical impact of image-guided core needle biopsy (ICNB) of suspected vertebral osteomyelitis in adults is heterogenous in published studies owing to small sample sizes, indicating the need for large cohort studies. METHODS: A retrospective analysis of ICNBs was performed from 2010 to 2021 for patients with imaging findings consistent with vertebral osteomyelitis. For each biopsy, a series of factors were analyzed, as well as if histopathology was diagnostic of osteomyelitis and if microbiological cultures were positive. In addition, it was recorded in what way biopsy influenced clinical management regarding antimicrobial treatment. A multivariate statistical analysis was performed to evaluate the factors associated with yield. RESULTS: A total of 570 biopsies performed on 527 patients were included. A histopathologic diagnosis of osteomyelitis was made in 68.4% (359 of 525) of biopsies, and microbiological cultures were positive in 29.6% (169 of 570). Elevated erythrocyte sedimentation rate was positively associated with a histopathologic diagnosis of osteomyelitis (odds ratio [OR] =1.96, P = 0.007) and positive cultures from bone cores (OR = 1.02, P ≤0.001) and aspirate (OR = 1.02, P ≤0.001). Increased total core length was positively associated with a histopathologic diagnosis of osteomyelitis (OR = 1.81, P = 0.013) and positive cultures from bone cores (OR = 1.65, P = 0.049). Clinical management was affected by ICNB in 37.5% (214 of 570) of cases. CONCLUSIONS: In this large cohort, ICNB yielded approximately 30% positive cultures and changed clinical management in over one-third of the patients.

Outcomes of Outpatient Parenteral Antimicrobial Therapy With Ceftriaxone for Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections-A Single-Center Observational Study.

BACKGROUND: Staphylococcus aureus bloodstream infections (BSIs) are associated with significant morbidity and mortality. Ceftriaxone is convenient for outpatient parenteral antimicrobial therapy (OPAT), but data for this indication are limited. METHODS: Adult patients with methicillin-susceptible Staphylococcus aureus (MSSA) BSI discharged on OPAT with cefazolin, oxacillin, or ceftriaxone for at least 7 days were included. We compared outcomes of ceftriaxone vs either oxacillin or cefazolin. Ninety-day all-cause mortality, readmission due to MSSA infection, and microbiological failure were examined as a composite outcome and compared among groups. Rates of antibiotic switches due to intolerance were assessed. RESULTS: Of 243 patients included, 148 (61%) were discharged on ceftriaxone and 95 (39%) were discharged on either oxacillin or cefazolin. The ceftriaxone group had lower rates of intensive care unit care, endocarditis, and shorter duration of bacteremia, but higher rates of cancer diagnoses. There was no significant difference in the composite adverse outcome in the oxacillin or cefazolin group vs the ceftriaxone group (18 [19%] vs 31 [21%]; P = .70), comprising microbiological failure (6 [6.3%] vs 9 [6.1%]; P = .94), 90-day all-cause mortality (7 [7.4%] vs 15 [10.1%]; P = .46), and readmission due to MSSA infection (10 [10.5%] vs 13 [8.8%]; P = .65). Antibiotic intolerance necessitating a change was similar between the 2 groups (4 [4.2%] vs 6 [4.1%]; P = .95). CONCLUSIONS: For patients with MSSA BSI discharged on OPAT, within the limitations of the small numbers and retrospective design we did not find a significant difference in outcomes for ceftriaxone therapy when compared with oxacillin or cefazolin therapy.

Potential missed opportunities for diagnosis of cryptococcosis and the association with mortality: A cohort study.

BACKGROUND: Cryptococcosis is one of the most common life-threatening opportunistic mycoses worldwide. Insidious presentation and slow onset of symptoms make it difficult to recognize, complicating the diagnostic process. Delays in diagnosis may lead to increased mortality. We aim to determine the frequency of missed opportunities for diagnosis of cryptococcosis and its effects on mortality. METHODS: To estimate the proportion of individuals with a potentially missed diagnosis for cryptococcosis in hospitalized patients, we conducted a retrospective cohort study using the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2015 from eight states. All hospitalized adult patients diagnosed with cryptococcal infection or cryptococcal meningitis were included. Potentially missed diagnoses were defined as admissions coded for a procedure or diagnosis suggestive of cryptococcosis in the 90-days prior to the initial cryptococcosis admission. Generalized estimating equations models were used to evaluate the association between underlying comorbidities and potential missed diagnosis of cryptococcosis and 90-day all-cause in-hospital mortality. FINDINGS: Of 5,354 patients with cryptococcosis, 2,445 (45·7%) were people living with HIV (PLWH). Among PLWH, 493/2,445 (20·2%) had a potentially missed diagnosis, of which 83/493 (16·8%) died while hospitalized compared with 265/1,952 (13·6%) of those without a potentially missed diagnosis (relative risk [RR] 1·04, 95% CI 0·99-1·09). Among HIV-negative patients, 977/2,909 (33·6%) had a potentially missed diagnosis, of which 236/977 (24·2%) died while hospitalized compared with 298/1,932 (15·4%) of those not missed (RR 1·12, 95% CI 1·07-1·16). INTERPRETATION: Missed opportunities to diagnose cryptococcosis are common despite highly efficacious diagnostic tests and are associated with increased risk of 90-day mortality in HIV-negative patients. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality. FUNDING: National Center for Advancing Translational Sciences, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.

Presentation and Mortality of Cryptococcal Infection Varies by Predisposing Illness: A Retrospective Cohort Study.

BACKGROUND: Cryptococcal epidemiology is changing in the modern antiretroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by immune status in the antiretroviral therapy era. METHODS: We conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality. RESULTS: We identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with human immunodeficiency virus (HIV), 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV nontransplant (NHNT). Age analysis showed that people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (P < .001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (P = .003 and P = .001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, P < .001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared with transplant (66%) or NHNT (73%) (P < .001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, interquartile range [IQR] ± 9 days) and NHNT patients (median 2 days, IQR ± 7 days) as compared with people living with HIV (median 1 day, IQR ± 2 days) (P = .003). NHNT patients had a higher risk of 90-day mortality (hazard ratio 3.3; 95% confidence interval, 1.9-5.8) as compared with people living with HIV. CONCLUSIONS: The majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher level of clinical suspicion than it currently receives.

Epidemiology of Cryptococcosis and Cryptococcal Meningitis in a Large Retrospective Cohort of Patients After Solid Organ Transplantation.

BACKGROUND: Cryptococcosis is the third most common invasive fungal infection in solid organ transplant (SOT) recipients. There are no nationally representative data describing the incidence, risk factors, and outcomes of cryptococcosis after SOT. METHODS: We assembled a large cohort of adult SOT recipients using Classification of Diseases, Ninth Revision, Clinical Modification billing data from Healthcare Cost and Utilization Project State Inpatient Databases of Florida (2006-2012), New York (2006-2011), and California (2004-2010). Demographics, comorbidities, death, and cryptococcal infections coded during hospitalization were identified. RESULTS: A total of 42634 adults with SOT were identified during the study period. Cryptococcal disease was identified in 0.37% (n = 158), 44% of which had meningitis (n = 69). Median time to diagnosis of cryptococcosis was 464 days (range, 4-2393). The median time to onset of cryptococcosis was earlier for lung (191 days; range, 7.5-1816), heart (195 days; range, 4-1061), and liver (200 days; range, 4-1581) compared with kidney transplant recipients (616 days; range, 12-2393; P < .001, log rank test). Very early-onset disease (<30 days after transplantation) more frequently occurred in liver and lung transplant recipients. Lung transplant recipients had the highest risk of cryptococcosis (hazard ratio [HR], 2.10; 95% confidence interval [CI], 1.21-3.60). Cryptococcosis was associated with death (HR, 2.29; 95% CI, 1.68-3.11), after adjusting for age, type of SOT, and other comorbidities. CONCLUSIONS: Cryptococcosis is rare after SOT, but it is associated with significantly increased risk of death. Lung transplant recipients are at highest risk for cryptococcosis among SOTs. Nonkidney transplants have earlier onset of cryptococcosis and higher risk of death compared with kidney transplant recipients.

Epidemiology and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients at a Midwestern Center.

BACKGROUND: Nontuberculous mycobacterial (NTM) infections have the potential to affect outcomes in solid organ transplant (SOT) recipients. METHODS: Retrospective cohort of adults who underwent SOT at a Midwestern hospital between January 1, 2004, and December 31, 2013. NTM-infected patients had at least 1 positive culture for NTM posttransplant. NTM disease was defined by 1) American Thoracic Society/Infectious Disease Society of America criteria for respiratory specimens or 2) NTM cultured from a sterile site with a compatible clinical syndrome. The remaining NTM infected patients were classified as colonized. Cox regression analysis was used to determine the association of NTM with mortality among lung transplant recipients. RESULTS: Of 3338 SOT recipients, 50 (1.5%) had NTM infection during a median 1038 days (range, 165-3706) follow-up posttransplant. Forty-three patients (86%) with NTM infection were lung transplant recipients; 18 of 43 (41.8%) were treated for NTM and 6 (13.9%) met disease criteria. Isolation of the same species on multiple occasions was associated with treatment among the colonized lung transplant recipients (8/12 [67%] vs 3/25 [12%] who were not treated, P = 0.014). NTM infection was not associated with increased mortality in lung transplant recipients (9/43 [20.9%] in infected died versus 161/510 [31.6%] in uninfected, age-adjusted hazard ratio, 0.56; 95% confidence interval, 0.2-1.1; P = 0.091). Three of 6 lung transplant recipients with NTM disease died compared with 6 of 37 colonized (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.003). CONCLUSIONS: Among SOT patients, NTM were most frequently identified from lung transplant recipients. NTM infection was not associated with increased mortality, although NTM disease was associated with increased mortality compared with colonization in lung transplant recipients.