Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial.

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. Design, Setting, and Participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). Main Outcomes and Measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. Conclusions and Relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Septic arthritis due to Nocardia brasiliensis and a review of nocardiosis as a cause of arthritis.

Bacteria of the genus Nocardia are implicated in several disease processes but are a rare cause of septic arthritis. Typically, the cause of Nocardia septic arthritis is dissemination from a pulmonary infection in an immunocompromised host. Herein we present a case of a 64-year-old male who had received a long course of prednisone for membranous nephropathy and developed a septic arthritis due to Nocardia brasiliensis. He was treated sequentially with trimethoprim-sulfamethoxazole and amoxicillin-clavulanate, linezolid and amoxicillin-clavulanate, tigecycline and amoxicillin-clavulanate, and omadacycline and amoxicillin-clavulanate. To our knowledge, only two prior cases of Nocardia brasiliensis septic arthritis without antecedent trauma to the joint or local skin breakdown have been reported. A review of the literature identified 19 other cases of Nocardia septic arthritis. This case reinforces the need to consider Nocardia infection in the differential diagnosis in the immunocompromised patient with concurrent pulmonary infection and septic arthritis.

Personal Protective Equipment and Donning and Doffing Techniques in the Cardiac Catheterization Laboratory During the COVID-19 Pandemic: Insights From an Internet Search for Protocols.

Background: Due to the ongoing coronavirus disease 2019 (COVID-19) pandemic, a need for precise donning and doffing protocols for personal protective equipment (PPE) among healthcare infrastructures is paramount. Procedures involving the cardiac catheterization laboratory (CCL) are routinely non-aerosolizing but have the potential for rapid patient deterioration, creating the need for aerosolizing generating procedures. Multiple societal and governmental guidelines on the use of PPE during medical procedures are available on Internet websites; however, there is limited literature available in peer-reviewed formats in this context. This study aims to provide an overview of current PPE donning and doffing protocols specific to the catheterization laboratory. Methods: A series of internet searches regarding donning and doffing of PPE in the CCL including published articles and internet protocols were compiled and compared using Pubmed.gov, Google.com, www.twitter.com, and www.youtube.com. Results: Most institutions used N95 masks, shoe covers, at least one head covering, face shield or goggles, two pairs of gloves, and inner and outer gowns. Doffing variation was greater than donning. Doffing has the potential to contaminate the healthcare worker (HCW), and therefore, this step of PPE management requires further study. Common steps in temporal priority included cleaning of gloved hands, removal of outer (or only) gown, removal of outer gloves, repeat gloved hand cleaning, removal of facial PPE last, and a final non-gloved hand cleaning. Conclusions: This analysis provides a summary of commonly used practices that may be considered when designing CCL-specific PPE protocols. Analysis of consistent steps from the literature led the authors to formulate a suggested protocol for CCL HCWs when performing procedures on patients with confirmed or suspected/unknown COVID-19.

Tuberculosis Patients Who Are A Potential Source for Unprotected Exposure in Health Care Systems: A Multicenter Case Control Study.

SETTING: Five health care systems in Texas. OBJECTIVE: To describe the epidemiology of inadequate isolation for pulmonary tuberculosis leading to tuberculosis (TB) exposures from confirmed TB patients and the patient factors that led to the exposures. DESIGN: A retrospective cohort and case-control study of adult patients with TB resulting in exposures (cases) vs those TB patients who did not result in exposures (controls) during January 2005 to December 2012. RESULTS: There were 335 patients with pulmonary TB disease, 199 cases and 136 controls. There was no difference between groups in age (46 ± 14.6 vs 45 ± 17 years; P > .05), race, or substance abuse. Cases were more likely to be transplant recipients (adjusted odds ratio [AOR], 18.90; 95% CI, 1.9-187.76), have typical TB chest radiograph (AOR, 2.23; 95% CI, 1.1-4.51), and have positive acid-fast bacilli stains (AOR, 2.36; 95% CI, 1.31-4.27). Cases were less likely to have extrapulmonary disease (AOR, 0.47; 95% CI, 0.24-0.95). CONCLUSIONS: TB exposure resulting from inadequate isolation is frequent in health care settings. Extrapulmonary involvement resulted in earlier airborne isolation. Being a transplant recipient, having chest radiograph findings typical for TB, and sputum positivity acid-fast bacilli upon staining were associated with increased risk of inadequate isolation.

Treatment of infections due to resistant Staphylococcus aureus.

This chapter reviews data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). This review covers findings reported in the English language medical literature up to January of 2013. Despite the emergence of resistant and multidrug-resistant S. aureus, we have seven effective drugs in clinical use for which little resistance has been observed: vancomycin, quinupristin-dalfopristin, linezolid, tigecycline, telavancin, ceftaroline, and daptomycin. However, vancomycin is less effective for infections with MRSA isolates that have a higher MIC within the susceptible range. Linezolid is probably the drug of choice for the treatment of complicated MRSA skin and soft tissue infections (SSTIs); whether it is drug of choice in pneumonia remains debatable. Daptomycin has shown to be non-inferior to either vancomycin or ß-lactams in the treatment of staphylococcal SSTIs, bacteremia, and right-sided endocarditis. Tigecycline was also non-inferior to comparator drugs in the treatment of SSTIs, but there is controversy about whether it is less effective than other therapeutic options in the treatment of more serious infections. Telavancin has been shown to be non-inferior to vancomycin in the treatment of SSTIs and pneumonia, but has greater nephrotoxicity. Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA; it is non-inferior to vancomycin in the treatment of SSTIs. Clindamycin, trimethoprim-sulfamethoxazole, doxycycline, rifampin, moxifloxacin, and minocycline are oral anti-staphylococcal agents that may have utility in the treatment of SSTIs and osteomyelitis, but the clinical data for their efficacy is limited. There are also several drugs with broad-spectrum activity against Gm-positive organisms that have reached the phase II and III stages of clinical testing that will hopefully be approved for clinical use in the upcoming years: oritavancin, dalbavancin, omadacycline, tedizolid, delafloxacin, and JNJ-Q2. Thus, there are currently many effective drugs to treat resistant S. aureus infections and many promising agents in the pipeline. Nevertheless, S. aureus remains a formidable adversary, and despite our deep bullpen of potential therapies, there are still frequent treatment failures and unfortunate clinical outcomes. The following discussion summarizes the clinical challenges presented by MRSA, the clinical experience with our current anti-MRSA antibiotics, and the gaps in our knowledge on how to use these agents to most effectively combat MRSA infections.

The higher the decrease in the standardized uptake value of positron emission tomography after chemoradiation, the better the survival of patients with gastroesophageal adenocarcinoma.

BACKGROUND: Postchemoradiation percentage decrease in standardized uptake value (SUV) of positron emission tomography (PET) from baseline correlates with overall survival (OS) and pathologic response. Analyses of dichotomized data are commonly reported. The authors analyzed percentage SUV decrease as both dichotomized and continuous variables. METHODS: The authors assessed 151 consecutive patients with gastroesophageal adenocarcinoma who had chemoradiation and surgery. Baseline and postchemoradiation PET/computed tomography imaging was performed. The log-rank test and Cox proportional hazards models were used to associate percentage SUV changes and OS, and logistic regression models were used to detect the association between percentage SUV changes and pathologic response. RESULTS: A >52% SUV decrease (dichotomized analysis) was associated with a longer OS (log-rank test, P = .023). The univariate Cox proportional hazards model indicated that greater percentage SUV decrease (as a continuous variable) was associated with a lower risk of death (hazard ratio [HR], 0.99; P = .01). Pathologic response (< or =50% residual cancer) was associated with longer OS (P = .003). Patients with chemoradiation resistance (>50% residual cancer) tended to have a higher risk of death than those with chemoradiation sensitivity (0-50% residual cancer; HR, 2.12; P = .099). In the multivariate model, the percentage SUV decrease (as a continuous variable) was the only prognosticator of OS (P = .01). The percentage SUV decrease was nonsignificantly associated with pathologic complete response (univariate odds ratio [OR], 1.01; P = .06 and multivariate OR, 1.03; P = .07). CONCLUSIONS: The greater the decline in SUV after chemoradiation, the longer is the OS of gastroesophageal adenocarcinoma patients. The percentage SUV decrease as a continuous variable is a better prognosticator of OS than its dichotomized assessments.

Influence of the baseline 18F-fluoro-2-deoxy-D-glucose positron emission tomography results on survival and pathologic response in patients with gastroesophageal cancer undergoing chemoradiation.

BACKGROUND: In patients with esophageal cancer who receive chemoradiation, tools to predict/prognosticate outcome before administering therapy are lacking. The authors evaluated initial standardized unit value (iSUV) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography and its association with overall survival and the degree of pathologic response after surgery. METHODS: The authors analyzed 161 patients with esophageal adenocarcinoma who had chemoradiation followed by surgery. The log-rank test, univariate Cox proportional hazards model, Kaplan-Meier survival plot, and Fisher exact test were used to analyze dichotomized iSUV and its association with overall survival and pathologic response. RESULTS: The median age of 161 patients was 61 years (range, 26-80 years) and the majority of patients had lower esophageal or gastroesophageal junction involvement. All patients received fluoropyrimidine and, most commonly, a taxane or platinum compound with concomitant radiation. The median radiation dose was 45 grays (Gy) (range, 45 Gy-50.4 Gy). The median iSUV for all patients was 10.1 (range, 0-58). Using the Fisher exact test, iSUV was not found to be associated with the location of the primary cancer. iSUV higher than the median (10.1) was associated with a better pathologic response (P = .06). Patients with primary cancer with iSUV >10.1 had a lower risk for death (hazards ratio of 0.56) compared with those with iSUV < or = 10.1. Higher iSUV was nonsignificantly associated with improved survival (P = .07). CONCLUSIONS: Data from the current study suggest that lower iSUV is associated with poor survival and lower probability of response to chemoradiation. iSUV needs to be further evaluated because it may be used to complement other imaging or biomarker assessments to individualize therapy.

Influence of induction chemotherapy and class of cytotoxics on pathologic response and survival after preoperative chemoradiation in patients with carcinoma of the esophagus.

BACKGROUND: Patients with localized esophageal cancer (LEC) have diverse outcomes (post-therapy pathologic response, disease-free survival [DFS], and overall survival [OS]) after preoperative chemoradiation (P-CTRT), dictated also by inherent molecular heterogeneity. Whether the type of therapy influences the outcomes remains largely unanswered. It is hypothesized that induction chemotherapy (IC) or the type of cytotoxics used would not influence patient outcomes. METHODS: In this retrospective analysis, consecutive patients with LEC who had P-CTRT were analyzed. Data were collected regarding age, sex, baseline clinical stage, location, type of cytotoxics, post-therapy pathology, DFS, and OS. IC and the type of cytotoxics used were found to be correlated with DFS, OS, and post-therapy pathologic response. RESULTS: A total of 180 patients with LEC (119 had IC before P-CTRT, all had received 5-fluorouracil, 87 had received a taxane, and 57 had received a platinol) were analyzed. The median survival (MS) of all patients was 57.7 months and the 3-year and 5-year OS rates were 65.4% and 46.5%, respectively. The type of therapy appeared to have no influence on the outcome: IC versus no IC (P = .58) or platinol versus taxane versus platinol plus taxane (P = .63). Similarly, the type of pathologic response was not found to be influenced by IC (P = .18) or the type of cytotoxics used (P = .42). The data were similar for DFS. CONCLUSIONS: IC or the type of cytotoxics used with radiation for patients with LEC does not appear to influence OS, DFS, or the type of pathologic response after therapy, suggesting that a plateau has been reached. It remains to be seen whether the use of biochemoradiotherapy can provide an advantage in outcome.