Exebacase in Addition to Standard-of-Care Antibiotics for Staphylococcus aureus Bloodstream Infections and Right-Sided Infective Endocarditis: A Phase 3, Superiority-Design, Placebo-Controlled, Randomized Clinical Trial (DISRUPT).

BACKGROUND: Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics. METHODS: In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population. RESULTS: A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported. CONCLUSIONS: Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis. Clinical Trials Registration.NCT04160468.

Liver transplantation from a SARS-COV-2-positive donor: A road ahead or not.

The COVID-19 pandemic has had a remarkable impact on the field of liver transplantation. Increasing evidence demonstrates a minimal risk of transmission of SARS-CoV-2 from non-lung donors who test positive for SARS-CoV-2; however, the risks of donor-derived SARS-CoV-2 from liver donors are unknown. We present our experience with two cases in which a liver was transplanted successfully from a brain-dead donor with incidental SARS-CoV-2 infection. Both donors were asymptomatic SARS-CoV-2-positive with negative bronchoalveolar lavage polymerase chain reaction (BAL PCR) and mechanism of death unrelated to COVID-19. Both the recipients did well after transplant and went home with a well-functioning liver. One patient did get readmitted and was found to be SARS-CoV-2-positive; however, it was probably related to hospital exposure rather than donor-derived. SARS-CoV-2-positive donors in select cases may be used for organ donation and liver transplant is safe for recipients.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Utility of Urine Cultures During Febrile Neutropenia Workup in Hematopoietic Stem Cell Transplantation Recipients Without Urinary Symptoms.

The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.

Evaluation of a COVID-19 convalescent plasma program at a U.S. academic medical center.

Amidst the therapeutic void at the onset of the COVID-19 pandemic, a critical mass of scientific and clinical interest coalesced around COVID-19 convalescent plasma (CCP). To date, the CCP literature has focused largely on safety and efficacy outcomes, but little on implementation outcomes or experience. Expert opinion suggests that if CCP has a role in COVID-19 treatment, it is early in the disease course, and it must deliver a sufficiently high titer of neutralizing antibodies (nAb). Missing in the literature are comprehensive evaluations of how local CCP programs were implemented as part of pandemic preparedness and response, including considerations of the core components and personnel required to meet demand with adequately qualified CCP in a timely and sustained manner. To address this gap, we conducted an evaluation of a local CCP program at a large U.S. academic medical center, the University of North Carolina Medical Center (UNCMC), and patterned our evaluation around the dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to systematically describe key implementation-relevant metrics. We aligned our evaluation with program goals of reaching the target population with severe or critical COVID-19, integrating into the structure of the hospital-wide pandemic response, adapting to shifting landscapes, and sustaining the program over time during a compassionate use expanded access program (EAP) era and a randomized controlled trial (RCT) era. During the EAP era, the UNCMC CCP program was associated with faster CCP infusion after admission compared with contemporaneous affiliate hospitals without a local program: median 29.6 hours (interquartile range, IQR: 21.2-48.1) for the UNCMC CCP program versus 47.6 hours (IQR 32.6-71.6) for affiliate hospitals; (P<0.0001). Sixty-eight of 87 CCP recipients in the EAP (78.2%) received CCP containing the FDA recommended minimum nAb titer of ≥1:160. CCP delivery to hospitalized patients operated with equal efficiency regardless of receiving treatment via a RCT or a compassionate-use mechanism. It was found that in a highly resourced academic medical center, rapid implementation of a local CCP collection, treatment, and clinical trial program could be achieved through re-deployment of highly trained laboratory and clinical personnel. These data provide important pragmatic considerations critical for health systems considering the use of CCP as part of an integrated pandemic response.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study.

COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray's P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher's P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19.

Corrigendum to 'Prosthetic Joint Infection After Dental Work: Is the Correct Prophylaxis Being Prescribed? A Systematic Review' [Arthroplasty Today 7 (2021) 69-75].

[This corrects the article DOI: 10.1016/j.artd.2020.11.007.].

Prioritizing studies of COVID-19 and lessons learned.

INTRODUCTION: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. METHODS: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. RESULTS: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. CONCLUSIONS: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Prosthetic Joint Infection After Dental Work: Is the Correct Prophylaxis Being Prescribed? A Systematic Review.

BACKGROUND: Prosthetic joint infection (PJI) of total hip (THA) or total knee arthroplasty (TKA) after dental procedures is uncommon, and antibiotic prophylaxis remains controversial. For high-risk patients, the American Academy of Orthopedic Surgeons recommends amoxicillin prophylaxis. However, no systematic review of the literature of PJIs associated with dental procedures explores if amoxicillin is suitable for the reported organisms. METHODS: A librarian-assisted search of the major databases (PubMed, Medline, Embase, Scopus) identified 954 articles. Only case reports, case series, and reviews with patient level data were included. After exclusions, 79 articles were fully reviewed. RESULTS: Forty-four PJIs after dental procedures were identified, 22 in primary THA, 20 in primary TKA, one in revision THA, and one in a hip resurfacing procedure. Antibiotic prophylaxis was documented for 5 patients. The dental procedure was invasive in 35 (79.5%). Comorbidities were present in 17 patients (38.7%). The organisms reported were Streptococcus spp. in 44%, other aerobic gram-positives in 27%, anaerobic gram-positives in 18%, and gram-negative organisms in 11%. An estimated 46% of organisms may be resistant to amoxicillin. The outcomes of treatment were reported for 35 patients (79.5%). Twenty-seven patients (61.4%) had no clinical signs of PJI at the final follow-up visit. CONCLUSIONS: Lower extremity PJI associated with dental procedures is often caused by organisms unlikely to be prevented with amoxicillin. Additional studies are warranted to determine the choice and efficacy of antibiotic prophylaxis to prevent dental-associated PJI in the highest risk patients. Insufficient data exist to recommend the optimal treatment for patients with PJI in THA and TKA associated with dental procedures.

Frequency and yield of blood cultures for observation patients with skin and soft tissue infections.

OBJECTIVES: 1) To measure frequency and yield of blood cultures obtained for observation status adult patients with skin and soft tissue infection (SSTI), 2) describe how often blood cultures were performed according to Infectious Diseases Society of America (IDSA) SSTI guideline indications, 3) identify proportion of patients meeting Center for Medicare Services (CMS) sepsis criteria. DESIGN: Retrospective cohort. SETTING: Tertiary academic center. PATIENTS: Consecutive adult observation status patients hospitalized with SSTI between July 2017 and July 2018. METHODS: We measured the proportion and results of blood cultures obtained among the study cohort and proportion of obtained cultures that satisfied IDSA indications. RESULTS: We identified 132 observation status patients with SSTI during the study period; 67 (50.8%) had blood cultures drawn. Only 14 (10.6%) patients met IDSA indications for culture; 51 (38.%) met Center for Medicare Services definition for sepsis. We identified two (3.0%) cases of bacteremia and two (3.0%) cases of skin bacteria contamination. In multivariable analysis, only temperature > 38 °C (OR 3.84, 95%CI 1.09-13.60) and white race (OR 2.71, 95%CI 1.21-6.20) were associated with blood culture obtainment; neither meeting IDSA SSTI guideline indications nor meeting CMS sepsis criteria was associated with culture. CONCLUSIONS: Among observation status patients with SSTI, over half had blood cultures drawn, though 10% satisfied guideline indications for culture. The proportion of cultures with bacterial growth was low and yielded as many skin contaminants as cases of bacteremia. Our study highlights the need for further quality improvement efforts to reduce unnecessary blood cultures in routine SSTI cases.

Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Predictors of multi-drug resistance in burn wound colonization following burn injury in a resource-limited setting.

INTRODUCTION: Bacterial resistance to antibiotics is growing dramatically worldwide due to several contributing factors, including inappropriate antibiotic utilization in the clinical setting and widespread use in the food production industry. Consequently, it is imperative to characterize antibiotic resistance in high-risk populations, such as burn patients, particularly in resource-limited settings where prevention strategies may be high-yield and new antibiotics are not readily available. We therefore sought to characterize and identify predictors of multi-drug resistant (MDR) bacteria colonization in burn patients at our center in Malawi. METHODS: This is a prospective analysis of burn patients presenting to Kamuzu Central Hospital in Lilongwe, Malawi within 72 h of burn injury. A swab of each patient's primary wound was collected at admission and each subsequent week. The primary aim was to determine predictors of colonization in burn wounds with multi-drug resistant bacteria using modified Poisson regression modeling. RESULTS: 99 patients were enrolled and analyzed. The median age was 4 years (IQR 2-12) with a median % total burn surface area (TBSA) of 14% (IQR 9-25). The most common burn injury type was scald (n = 61, 61.6%), followed by flame (n = 37, 37.4%). Overall, 54 patients (54.6%) were colonized with MDR bacteria at some point during their hospitalization, with increases each week. For flame burns, the predictors of MDR bacterial colonization were each 1% increase of %TBSA (RR 1.01, 95% CI 1.00, 1.03, p = 0.038) and the use of operative intervention for burn treatment (RR 1.90, 95% CI 1.17, 3.09, p = 0.010). No variables were predictive of MDR wound colonization in scald burns. CONCLUSION: Our study identified that almost half of the patients in a Malawian burn unit had MDR bacteria colonizing burn wounds after only a week in the hospital. This increased to almost 70% during hospitalization. We also found that for patients with flame burns, increasing %TBSA, and operative intervention put patients at greater risk of MDR colonization. Interventions such as isolation of burn patients, consistent disinfection and sterilization of wards and operating rooms, and optimization of wound care management are imperative to decrease spread of MDR bacteria and to improve burn-associated clinical outcomes in resource-limited environments.

Sulfonamides without trimethoprim in the treatment of Nocardia infections: A case report and literature review.

Sulfonamides are recommended as part of first-line therapy for most Nocardia infections, with trimethoprim-sulfamethoxazole (TMP-SMX) considered the drug of choice for susceptible isolates. However, in the case of central nervous system, disseminated disease, and other serious Nocardia infections, TMP-SMX should not be used as monotherapy. The preferred treatment for a patient unable to take TMP-SMX because of allergy or intolerance remains uncertain. Prior to the availability of TMP-SMX in 1973, other sulfonamides were mainstays of treatment. We describe a Nocardia infection successfully treated with sulfadiazine in a lung transplant recipient who could not tolerate TMP-SMX. A review of similar cases reported in the literature provides insight into the successful treatment of Nocardia infections with sulfonamide regimens not containing trimethoprim in transplant recipients and other immunocompromised hosts.

Loss of daptomycin susceptibility in clinical Staphylococcus epidermidis infection coincided with variants in WalK.

Daptomycin (DAP) is key in treating multidrug-resistant Staphylococcus infections. Diminished susceptibility to DAP is emerging among Staphylococcus epidermidis strains although mechanisms for non-susceptibility (NS) remain poorly understood. We report a case of persistent S. epidermidis bacteremia in which loss of DAP susceptibility arose during prolonged treatment. Whole genome sequencing identified two mutations, Q371del and P415L, in a single-affected gene, WalK, that coincided with the emergence of DAP-NS. Protein modeling of the mutations predicted a disruption of WalK protein configuration. The emergence of mutations in a single-gene during DAP exposure raises concerns in an era of increasingly treatment-resistant infections. Lay summary: Daptomycin is an important antibiotic for fighting Staphylococcus infections. We identified variants in the WalK gene that were coincident with resistance in a clinical Staphylococcus epidermidis infection. Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for the evolution of drug resistance during prolonged daptomycin therapy.

Successful treatment of hepatitis C virus infection with direct-acting antivirals during hematopoietic cell transplant.

Current guidelines recommend that hepatitis C virus (HCV) infection be treated completely prior to hematopoietic cell transplantation or delayed until immune reconstitution after transplantation to avoid drug-drug interactions and treatment interruption. However, these recommendations were informed by outcomes using treatment with ribavirin and pegylated interferon. We report the first case of successful treatment of HCV using direct-acting antivirals during hematopoietic cell transplantation. This case study suggests that treatment of HCV concurrent with hematopoietic cell transplantation for malignancy may be the best option for some patients in whom it is unsafe to delay treatment for either disease.