Therapeutic monoclonal antibodies with a focus on hereditary angioedema.

Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.

Harvesting the low-hanging fruit? Comparative assessment of intravenous to oral route antimicrobial conversion policy implementation.

Policies that promote conversion of antibiotics from intravenous to oral route administration are considered "low hanging fruit" for hospital antimicrobial stewardship programs. We developed a simple metric based on digestive days of therapy divided by total days of therapy for targeted agents and a method for hospital comparisons. External comparisons may help identify opportunities for improving prospective implementation.

Impact of Oral Metronidazole, Vancomycin, and Fidaxomicin on Host Shedding and Environmental Contamination With Clostridioides difficile.

BACKGROUND: Shedding of Clostridioides difficile spores from infected individuals contaminates the hospital environment and contributes to infection transmission. We assessed whether antibiotic selection affects C. difficile shedding and contamination of the hospital environment. METHODS: In this prospective, unblinded, randomized controlled trial of hospitalized adults with C. difficile infection, patients were randomized 1:1:1 to receive fidaxomicin, oral vancomycin, or metronidazole. The primary outcome was change in environmental contamination rate during treatment. Secondary outcomes included stool shedding, total burden of contamination, and molecular relatedness of stool versus environmental C. difficile isolates. RESULTS: Of 33 patients enrolled, 31 (94%) completed the study. Fidaxomicin (-0.36 log10 colony-forming units [CFUs]/d [95% confidence interval (CI), -.52 to -.19]; P < .01) and vancomycin (-0.17 log10 CFUs/d [-.34 to -.01]; P = .05) were associated with more rapid decline in C. difficile shedding than metronidazole (-0.01 log10 CFUs/d [95% CI, -.10 to .08). Both vancomycin (6.3% [95% CI, 4.7-8.3) and fidaxomicin (13.1% [10.7-15.9]) were associated with lower rates of environmental contamination than metronidazole (21.4% [18.0-25.2]). With specific modeling of within-subject change over time, fidaxomicin (adjusted odds ratio, 0.83 [95% CI, .70-.99]; P = .04) was associated with more rapid decline in environmental contamination than vancomycin or metronidazole. Overall, 207 of 233 environmental C. difficile isolates (88.8%) matched patient stool isolates by ribotyping, without significant difference by treatment. CONCLUSIONS: Fidaxomicin, and to a lesser extent vancomycin, reduces C. difficile shedding and contamination of the hospital environment relative to metronidazole. Treatment choice may play a role in reducing healthcare-associated C. difficile transmission. CLINICAL TRIALS REGISTRATION: NCT02057198.

Impact of Antibiotic Stewardship Rounds in the Intensive Care Setting: A Prospective Cluster-Randomized Crossover Study.

BACKGROUND: Few groups have formally studied the effect of dedicated antibiotic stewardship rounds (ASRs) on antibiotic use (AU) in intensive care units (ICUs). METHODS: We implemented weekly ASRs using a 2-arm, cluster-randomized, crossover study in 5 ICUs at Duke University Hospital from November 2017 to June 2018. We excluded patients without an active antibiotic order, or if they had a marker of high complexity including an existing infectious disease consult, transplantation, ventricular assist device, or extracorporeal membrane oxygenation. AU during and following ICU stay for patients with ASRs was compared to the controls. We recorded the number of reviews, recommendations delivered, and responses. We evaluated change in ICU-specific AU during and after the study. RESULTS: Our analysis included 4683 patients: 2330 intervention and 2353 controls. Teams performed 761 reviews during ASRs, which excluded 1569 patients: 60% of patients off antibiotics, and 8% complex patients. Exclusions affected 88% of cardiothoracic ICU (CTICU) patients. The AU rate ratio (RR) was 0.97 (95% confidence interval [CI], .91-1.04). When CTICU was removed, the RR was 0.93 (95% CI, .89-.98). AU in the poststudy period decreased by 16% (95% CI, 11%-24%) compared to AU in the baseline period. Change in AU was differential among units: largest in the neurology ICU (-28%) and smallest in the CTICU (-2%). CONCLUSIONS: Weekly multidisciplinary ASRs was a high-resource intervention associated with a small AU reduction. The noticeable ICU AU decline over time is possibly due to indirect effects of ASRs. Effects differed among specialty ICUs, emphasizing the importance of customizing ASRs to match unit-specific population, workflow, and culture.

Ehrlichiosis and anaplasmosis subcommittee report to the Tick-borne Disease Working Group.

Ehrlichioses and anaplasmosis have undergone dramatic increases in incidence, and the geographic ranges of their occurrence and vectors have also expanded. There is marked underreporting of these diseases owing to deficient physician awareness and knowledge of the illnesses as well as limited access to appropriate diagnostic tests. Human monocytic ehrlichiosis and anaplasmosis are life threatening diseases with estimated case fatality rates of 2.7 and 0.3%, respectively. However, knowledge of their full range of signs and symptoms is incomplete, and the incidence of subclinical infections is unknown. Currently available laboratory diagnostic methods are poorly utilized, and with the exception of nucleic acid amplification tests are not useful for diagnosis during the acute stage of illness when timely treatment is needed. The Ehrlichiosis and Anaplasmosis Subcommittee of the Tick-Borne Disease Working Group recommended active clinical surveillance to determine the true incidence, full clinical spectrum, and risk factors for severe illness, as well as standardized surveillance of ticks for these pathogens, and enhanced education of primary medical caregivers and the public regarding these diseases. The subcommittee identified the needs to develop sensitive, specific acute stage diagnostic tests for local clinical laboratories and point-of-care testing, to develop approaches for utilizing electronic medical records, data mining, and artificial intelligence for assisting early diagnosis and treatment, and to develop adjunctive therapies for severe disease.

Effects of a Collaborative, Community Hospital Network for Antimicrobial Stewardship Program Implementation.

BACKGROUND: Individual hospitals may lack expertise, data resources, and educational tools to support antimicrobial stewardship programs (ASP). METHODS: We established a collaborative, consultative network focused on hospital ASP implementation. Services included on-site expert consultation, shared database for routine feedback and benchmarking, and educational programs. We performed a retrospective, longitudinal analysis of antimicrobial use (AU) in 17 hospitals that participated for at least 36 months during 2013-2018. ASP practice was assessed using structured interviews. Segmented regression estimated change in facility-wide AU after a 1-year assessment, planning, and intervention initiation period. Year 1 AU trend (1-12 months) and AU trend following the first year (13-42 months) were compared using relative rates (RR). Monthly AU rates were measured in days of therapy (DOT) per 1000 patient days for overall AU, specific agents, and agent groups. RESULTS: Analyzed data included over 2.5 million DOT and almost 3 million patient-days. Participating hospitals increased ASP-focused activities over time. Network-wide overall AU trends were flat during the first 12 months after network entry but decreased thereafter (RR month 42 vs month 13, 0.95, 95% confidence interval [CI]: .91-.99). Large variation was seen in hospital-specific AU. Fluoroquinolone use was stable during year 1 and then dropped significantly. Other agent groups demonstrated a nonsignificant downward trajectory after year 1. CONCLUSIONS: Network hospitals increased ASP activities and demonstrated decline in AU over a 42-month period. A collaborative, consultative network is a unique model in which hospitals can access ASP implementation expertise to support long-term program growth.

Kallikrein-1 Blockade Inhibits Aortic Expansion in a Mouse Model and Reduces Prostaglandin E2 Secretion From Human Aortic Aneurysm Explants.

Background Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high- and low-molecular-weight kininogen by the serine protease kallikrein-1. The aims of this study were first to examine the effect of neutralizing kallikrein-1 on AAA development in a mouse model and second to test how blocking kallikrein-1 affected cyclooxygenase-2 and prostaglandin E2 in human AAA explants. Methods and Results Neutralization of kallikrein-1 in apolipoprotein E-deficient (ApoE-/-) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein-1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2 and reduced cyclooxygenase-2 activity. Kallikrein-1 neutralization also decreased protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein-1 blocking antibody reduced levels of cyclooxygenase-2 and secretion of prostaglandin E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions These findings suggest that kallikrein-1 neutralization could be a treatment target for AAA.

Microbial Assessment of Health Care-Associated Pathogens on Various Environmental Sites in Patient Rooms After Terminal Room Disinfection.

We examined the microbial burden on hospital room environmental sites after standard (quaternary ammonium [Quat]) or enhanced disinfection (quat/ultraviolet light [UV-C], bleach, or bleach/UV-C). An enhanced terminal room disinfection reduced the microbial burden of epidemiologically important pathogens on high-touch surfaces in patient rooms, especially sites around the bed, better than standard room disinfection.

Invasive Mycobacterium abscessus Complex Infection After Cardiac Surgery: Epidemiology, Management, and Clinical Outcomes.

BACKGROUND: We recently mitigated a clonal outbreak of hospital-acquired Mycobacterium abscessus complex (MABC), which included a large cluster of adult patients who developed invasive infection after exposure to heater-cooler units during cardiac surgery. Recent studies have detailed Mycobacterium chimaera infections acquired during cardiac surgery; however, little is known about the epidemiology and clinical courses of cardiac surgery patients with invasive MABC infection. METHODS: We retrospectively collected clinical data on all patients who underwent cardiac surgery at our hospital and subsequently had positive cultures for MABC from 2013 through 2016. Patients with ventricular assist devices or heart transplants were excluded. We analyzed patient characteristics, antimicrobial therapy, surgical interventions, and clinical outcomes. RESULTS: Ten cardiac surgery patients developed invasive, extrapulmonary infection from M. abscessus subspecies abscessus in an outbreak setting. Median time from presumed inoculation in the operating room to first positive culture was 53 days (interquartile range [IQR], 38-139 days). Disseminated infection was common, and the most frequent culture-positive sites were mediastinum (n = 7) and blood (n = 7). Patients received a median of 24 weeks (IQR, 5-33 weeks) of combination antimicrobial therapy that included multiple intravenous agents. Six patients required antibiotic changes due to adverse events attributed to amikacin, linezolid, or tigecycline. Eight patients underwent surgical management, and 6 patients required multiple sternal debridements. Eight patients died within 2 years of diagnosis, including 4 deaths directly attributable to MABC infection. CONCLUSIONS: Despite aggressive medical and surgical management, invasive MABC infection after cardiac surgery caused substantial morbidity and mortality. New treatment strategies are needed, and compliance with infection prevention guidelines remains critical.

Tap Water Avoidance Decreases Rates of Hospital-onset Pulmonary Nontuberculous Mycobacteria.

We analyzed the impact of a hospital tap water avoidance protocol on respiratory isolation of nontuberculous mycobacteria (NTM). After protocol implementation, hospital-onset episodes of respiratory NTM isolation on high-risk units decreased from 41.0 to 9.9 episodes per 10 000 patient-days (incidence rate ratio, 0.24; 95% confidence interval, .17-.34; P < .0001).

Assessing severe acute respiratory coronavirus virus 2 (SARS-CoV-2) preparedness in US community hospitals: A forgotten entity.

We performed a cross-sectional survey of infection preventionists in 60 US community hospitals between April 22 and May 8, 2020. Several differences in hospital preparedness for SARS-CoV-2 emerged with respect to personal protective equipment conservation strategies, protocols related to testing, universal masking, and restarting elective procedures.

Universal masking in hospitals in the COVID-19 era: Is it time to consider shielding?

With concerns for presymptomatic transmission of COVID-19 and increasing burden of contact tracing and employee furloughs, several hospitals have supplemented pre-existing infection prevention measures with universal masking of all personnel in hospitals. Other hospitals are currently faced with the dilemma of whether or not to proceed with universal masking in a time of critical mask shortages. We summarize the rationale behind a universal masking policy in healthcare settings, important considerations before implementing such a policy and the challenges with universal masking. We also discusses proposed solutions such as universal face shields.

Practical Guidance for Clinical Microbiology Laboratories: A Comprehensive Update on the Problem of Blood Culture Contamination and a Discussion of Methods for Addressing the Problem

In this review, we present a comprehensive discussion of matters related to the problem of blood culture contamination. Issues addressed include the scope and magnitude of the problem, the bacteria most often recognized as contaminants, the impact of blood culture contamination on clinical microbiology laboratory function, the economic and clinical ramifications of contamination, and, perhaps most importantly, a systematic discussion of solutions to the problem. We conclude by providing a series of unanswered questions that pertain to this important issue.