Search

As the third year of the SARS-CoV-2 pandemic approaches, COVID-19 continues to cause substantial morbidity and mortality due to waning vaccine efficacy and the emergence of new, highly contagious subvariants and better therapies are urgently needed.Hospitalized patients who develop hypoxia due to SARS-CoV-2 infection are typically treated with an antiviral agent, remdesivir, as well as an immunomodulator, dexamethasone, but mortality rates for severe COVID-19 remain unacceptably high. Mounting evidence suggests a second immunomodulator added to the standard of care may benefit some hospitalized patients; however, the optimal treatment remains controversial.On 2 June 2022, the United States National Institutes of Health reported results from a large, randomized placebo-controlled clinical trial known as ACTIV-1. The study found a mortality benefit and substantially improved clinical status for adults hospitalized with COVID-19 who were treated with infliximab, a chimeric monoclonal antibody that binds to and inhibits TNF-α, and is widely used to treat a variety of autoimmune conditions, including rheumatoid arthritis, Crohn's disease, and ulcerative colitis. This manuscript reviews what is known about infliximab as an immunomodulator for patients with COVID-19 and explores how this agent may be used in the future to address the SARS-CoV-2 pandemic.

Monkeypox virus is a zoonotic double-stranded DNA poxvirus in the genusOn 6 May 2022, monkeypox was detected in the United Kingdom and the virus has now been detected in every continent except Antarctica. The current outbreak represents the first documentation of widespread community transmission outside of Africa.On 23 July 2022, the World Health Organization declared monkeypox a public health emergency of international concern and issued a series of guidance and recommendations for governments, health professionals and the public. This manuscript reviews what is known about monkeypox virus, with a focus on recent diagnostics and epidemiologic advances, and explores how recent advances in our understanding of the virus will be used to combat the expanding outbreak.

On 26 November 2021, the World Health Organization's Technical Advisory Group on SARS-CoV-2 Virus Evolution designated PANGO lineage B.1.1.529 a variant of concern and gave it the designation Omicron. The following day, the United Kingdom reported its first two cases of Omicron, a novel variant that was thought to be more transmissible than other variants such as Delta, Beta, and Alpha.Omicron has since become the dominant variant around the world, accounting for unprecedented case counts and hospitalizations. Omicron's high rate of spread has been attributed to a variety of factors, including enhanced replication in the upper airways (bronchi) as well as immune evasion.These intrinsic factors have implications for the approach to treatment. Monoclonal antibody therapies, which were highly effective against prior SARS-CoV-2 variants, were rendered largely ineffective against Omicron, and other antiviral options remain severely limited due to supply issues. This manuscript reviews the landscape of Omicron therapeutics and looks ahead to examine how these treatments and others may be used in the future to address the expanding threat of the Omicron variant.

SARS-CoV-2, the virus that causes COVID-19, elicits a variety of host responses ranging from asymptomatic or mild illness in most people, to severe disease and critical illness in a subset of patients with systemic inflammation and hypoxemic respiratory failure.Heterogeneous clinical presentations are often driven by disparate responses of the host immune system, with severe disease associated with aberrant interferon signaling or cytokine storm syndrome. This manuscript examines current therapeutic approaches, including the use of immunomodulators such as corticosteroids, interleukin inhibitors, kinase inhibitors, fluvoxamine, and ivermectin, and also explores the ways that these therapies and others may be used to treat COVID-19 in the future.Modulation of the immune response has become a mainstay of treatment of COVID-19, although the optimal mechanism has not yet been defined and there is considerable controversy regarding clinical management. As time progresses, the therapeutic approach to COVID-19 will undoubtedly change, particularly as we learn more about the pathophysiology of SARS-CoV-2 infection.

Background The diagnosis of urinary tract infection (UTI) is challenging among hospitalized older adults, particularly among those with altered mental status. Objective To determine the diagnostic accuracy of procalcitonin (PCT) for UTI in hospitalized older adults. Design We performed a prospective cohort study of older adults (≥65 years old) admitted to a single hospital with evidence of pyuria on urinalysis. PCT was tested on initial blood samples. The reference standard was a clinical definition that included the presence of a positive urine culture and any symptom or sign of infection referable to the genitourinary tract. We also surveyed the treating physicians for their clinical judgment and performed expert adjudication of cases for the determination of UTI. Participants Two hundred twenty-nine study participants at a major academic medical center. Main Measures We calculated the area under the receiver operating characteristic curve (AUC) of PCT for the diagnosis of UTI. Key Results In this study cohort, 61 (27%) participants met clinical criteria for UTI. The median age of the overall cohort was 82.6 (IQR 74.9–89.7) years. The AUC of PCT for the diagnosis of UTI was 0.56 (95% CI, 0.46–0.65). A series of sensitivity analyses on UTI definition, which included using a decreased threshold for bacteriuria, the treating physicians’ clinical judgment, and independent infectious disease specialist adjudication, confirmed the negative result. Conclusions Our findings demonstrate that PCT has limited value in the diagnosis of UTI among hospitalized older adults. Clinicians should be cautious using PCT for the diagnosis of UTI in hospitalized older adults. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07265-8.

Introduction The COVID-19 pandemic has created an unprecedented opportunity to reimagine clinical research. While much has been written about the challenges associated with generating real-world evidence during the COVID-19 pandemic, comparatively little attention has been paid to the ethical challenges facing patients, clinicians, researchers, and regulatory bodies. Areas covered In this manuscript, we examine these challenges through the lens of informed consent and explore how the consenting process changes as our understanding of the disease is altered. Expert opinion We also suggest ways to limit these ethical hurdles through the use of embedded pragmatic clinical trials, which generate real-world data without the limitations associated with observational trials or the resources and lack of generalizability that are obstacles to conducting conventional randomized clinical trials. We argue that clinical research must become more nimble, and must include embedded researchers to ensure that relevant questions and ethical issues are properly addressed.

Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. Among the etiologies of osteoarticular mycoses are Candida spp., Aspergillus spp., Mucorales, dematiaceous fungi, non-Aspergillus hyaline molds, and endemic mycoses, including those caused by Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides species. This review analyzes the history, epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, inflammatory biomarkers, diagnostic imaging modalities, treatments, and outcomes of osteomyelitis and septic arthritis caused by these organisms. Candida osteomyelitis and Candida arthritis are associated with greater events of hematogenous dissemination than those of most other osteoarticular mycoses. Traumatic inoculation is more commonly associated with osteoarticular mycoses caused by Aspergillus and non-Aspergillus molds. Synovial fluid cultures are highly sensitive in the detection of Candida and Aspergillus arthritis. Relapsed infection, particularly in Candida arthritis, may develop in relation to an inadequate duration of therapy. Overall mortality reflects survival from disseminated infection and underlying host factors.

Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis may be caused by bacterial, fungal, or viral pathogens. The clinical manifestations exhibited by patients with severe coronavirus disease 2019 (COVID-19)-related sepsis overlap with those exhibited by patients with sepsis from secondary bacterial or fungal infections and can include an altered mental status, dyspnea, reduced urine output, tachycardia, and hypotension. Critically ill patients hospitalized with severe acute respiratory syndrome coronavirus 2 infections have increased risk for secondary bacterial and fungal infections. The same risk factors that may predispose to sepsis and poor outcome from bloodstream infections (BSIs) converge in patients with severe COVID-19. Current diagnostic standards for distinguishing between (1) patients who are critically ill, septic, and have COVID-19 and (2) patients with sepsis from other causes leave healthcare providers with 2 suboptimal choices. The first choice is to empirically administer broad-spectrum, antimicrobial therapy for what may or may not be sepsis. Such treatment may not only be ineffective and inappropriate, but it also has the potential to cause harm. The development of better methods to identify and characterize antimicrobial susceptibility will guide more accurate therapeutic interventions and reduce the evolution of new antibiotic-resistant strains. The ideal diagnostic test should (1) be rapid and reliable, (2) have a lower limit of detection than blood culture, and (3) be able to detect a specific organism and drug sensitivity directly from a clinical specimen. Rapid direct detection of antimicrobial-resistant pathogens would allow targeted therapy and result in improved outcomes in patients with severe COVID-19 and sepsis.

Background The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild-to-moderate coronavirus 2019 (COVID-19) is unclear. Tolerability has also been identified as a potential limiting factor for 100 mg twice daily of fluvoxamine. We evaluated the efficacy of low-dose fluvoxamine 50 mg twice daily for 10 days compared with placebo for the treatment of early mild-to-moderate COVID-19. Methods ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with confirmed SARS-CoV-2 infection. Non-hospitalized adults aged ≥ 30 years, experiencing ≥ 2 symptoms of acute infection for ≤ 7 days were randomized to fluvoxamine 50 mg twice daily for 10 days or placebo. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent care or emergency department visit by day 28. Results Of those eligible for the fluvoxamine arm, 675 were randomized to and received fluvoxamine; 619 received concurrent placebo. Sixty-six percent of the study population reported at least 2 doses of a COVID-19 vaccine. There was no evidence of improvement in time to recovery with fluvoxamine compared with placebo (hazard ratio [HR] 0.96, 95% credible interval [CrI] 0.86–1.06; posterior probability for benefit [HR > 1]=0.2). Sixteen participants (2.4%) in the fluvoxamine arm had urgent care or emergency department visits or were hospitalized compared with 11 (1.8%) in the pooled, concurrent placebo arm (HR 1.5, 95% CrI 0.5–3.0; posterior probability for benefit [HR < 1]=0.1725). No participant in either arm was hospitalized, and no deaths occurred. Adverse events were uncommon in both arms. Conclusion Treatment with low-dose fluvoxamine 50 mg dosed twice daily for 10 days did not result in improved time to recovery among outpatients with COVID-19 in the United States during the delta and omicron variant surges. Disclosures All Authors: No reported disclosures.

Background The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild-to-moderate coronavirus 2019 (COVID-19) is unclear. Tolerability has also been identified as a potential limiting factor for 100 mg twice daily of fluvoxamine. We evaluated the efficacy of low-dose fluvoxamine 50 mg twice daily for 10 days compared with placebo for the treatment of early mild-to-moderate COVID-19. Methods ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial testing repurposed medications in outpatients with confirmed SARS-CoV-2 infection. Non-hospitalized adults aged ≥ 30 years, experiencing ≥ 2 symptoms of acute infection for ≤ 7 days were randomized to fluvoxamine 50 mg twice daily for 10 days or placebo. The primary outcome was time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Secondary outcomes included composites of hospitalization or death with or without urgent care or emergency department visit by day 28. Results Of those eligible for the fluvoxamine arm, 675 were randomized to and received fluvoxamine; 619 received concurrent placebo. Sixty-six percent of the study population reported at least 2 doses of a COVID-19 vaccine. There was no evidence of improvement in time to recovery with fluvoxamine compared with placebo (hazard ratio [HR] 0.96, 95% credible interval [CrI] 0.86–1.06; posterior probability for benefit [HR > 1]=0.2). Sixteen participants (2.4%) in the fluvoxamine arm had urgent care or emergency department visits or were hospitalized compared with 11 (1.8%) in the pooled, concurrent placebo arm (HR 1.5, 95% CrI 0.5–3.0; posterior probability for benefit [HR < 1]=0.1725). No participant in either arm was hospitalized, and no deaths occurred. Adverse events were uncommon in both arms. Conclusion Treatment with low-dose fluvoxamine 50 mg dosed twice daily for 10 days did not result in improved time to recovery among outpatients with COVID-19 in the United States during the delta and omicron variant surges. Disclosures All Authors: No reported disclosures.

First-generation therapeutics have improved clinical outcomes in patients infected with SARS-CoV-2. However, viral evolution has produced variants and subvariants capable of resisting many of these drugs and novel treatment strategies are urgently needed.A corporate compound library screen identified ensitrelvir (formerly S-217622), a non-covalent, non-peptidic, orally bioavailable small-molecule protease inhibitor as a potential treatment for SARS-CoV-2. Ensitrelvir cleaves the active site of the 3C-like protease (3CLEnsitrelvir demonstrates strong

The pathogenesis of severe COVID-19 is due, in part, to dysregulation of the human immune system in response to SARS-CoV-2 infection. Immune cells infected with SARS-CoV-2 can trigger a hyperinflammatory response of both the adaptive and innate immune system that has been associated with severe disease, hospitalization, and death, and better treatment options are urgently needed.A mainstay of therapy for COVID-19 involves an antiviral agent, remdesivir, in combination with a systemic corticosteroid, dexamethasone.The addition of a second immunomodulator, such as an interleukin-6 inhibitor or a Janus kinase inhibitor, has been associated with clinical benefit in a subset of patients with moderate-to-severe disease, but their use remains controversial. This manuscript reviews what is known about the approach to treatment of severe COVID-19 and examines how immunomodulators such as infliximab and abatacept may alter clinical management and COVID-19 research in the years ahead based on the results of randomized, controlled trials.

Lefamulin (Xenleta) has been approved by the US FDA for the treatment of community-acquired bacterial pneumonia (CABP). It may be taken intravenously or orally and has activity against a broad range of pulmonary pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumonia, as well as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Lefamulin has an adverse effect profile that is similar to other antimicrobial agents commonly used to treat CABP. Despite these promising features, the use of lefamulin remains limited in clinical practice. However, given the rise of antibiotic-resistant organisms, this may soon change. This review examines what is known about the pharmacokinetics and pharmacodynamics of lefamulin and looks ahead to its potential applications in clinical practice, including the treatment of sexually transmitted infections such as multidrug-resistant Mycoplasma genitalium, as well as its role as a synergistic agent used in combination with other antimicrobials in the treatment of drug-resistant organisms.

BackgroundImmune 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.MethodsWe 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.ResultsA 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.ConclusionsInfliximab 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 registrationClinicalTrials.gov (NCT04593940).

Monkeypox is a viral zoonosis, with symptoms similar to those seen in smallpox patients, although the clinical presentation may be less severe. Until recently, human monkeypox infection was rare, and primarily occurred in Central and West Africa.An international outbreak began in May 2022, and monkeypox has now been detected on every continent except Antarctica. The first recognized case from the current outbreak was confirmed in the United Kingdom on 6 May 2022, in an adult with travel links to Nigeria, but it has been suggested that cases had been spreading in Europe for months. On 23 July 2022 the Director-General of the World Health Organization declared the monkeypox outbreak a public health emergency of international concern.There are no treatments specifically for monkeypox virus infections. However, monkeypox and smallpox viruses are genetically similar, and therapeutics developed to combat smallpox may be used to treat monkeypox. This manuscripts reviews what is known about these potential treatments, including tecovirimat and brincidofovir, based on a literature search of PubMed through 9 August 2022, and explores how these therapeutics may be used in the future to address the expanding monkeypox pandemic.

On 4 September, 2020, the US National Institutes of Health launched a new clinical trial, "A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults with COVID-19." This open-label, placebo-controlled, multicenter, adaptive platform study was designed to evaluate therapeutic options for patients hospitalized with mild, moderate, or severe COVID-19. A variety of drugs and drug classes were selected, including heparin, the monoclonal antibody crizanlizumab, sodium-glucose cotransporter-2 inhibitors, and purinergic signaling receptor Y

Purpose To investigate the antimycotic activity of amphotericin B deoxycholate that has been previously frozen for 28 days before supplementation of Optisol-GS. Methods Triplicate Optisol-GS samples were inoculated with 10 colony-forming units (CFU) of Candida albicans. Each set of triplicate cultures was supplemented with 2.5 μg/mL of amphotericin B that was either freshly resuspended and never frozen, frozen overnight at -20°C and thawed, or frozen at -20°C for 4 weeks and thawed. The cultures were stored at 4°C, with aliquots taken at 0, 6, 24, and 72 hours for quantification. The efficacy of each preparation of amphotericin B in reducing C. albicans growth was assessed at these time points. Results Six hours after antifungal supplementation, there was a 1.33 log10 CFU reduction with freshly resuspended amphotericin B, compared with a 1.31 log10 reduction with amphotericin B that was frozen overnight (P = 0.20) and a 1.18 log10 reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). After 72 hours, there was a 2.72 log10 CFU reduction with freshly resuspended amphotericin B, a 2.64 log10 CFU reduction with amphotericin B that was frozen overnight (P = 0.45), and a 2.18 log10 CFU reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). Conclusions Previously frozen amphotericin B remains highly effective against C. albicans. Optisol-GS supplemented with 2.5 μg/mL amphotericin B that was frozen for 4 weeks at -20°C resulted in >90% CFU reduction by 6 hours and >99% reduction by 72 hours.

Introduction: Clustered regularly interspaced short palindromic repeats (CRISPR) are segments of nucleic acid that play a role in prokaryotic defense and form the basis of a genome editing technology that allows permanent alteration of genetic material. This methodology, known as CRISPR-Cas9, is poised to revolutionize molecular biology, but no literature yet exists on how these advances will affect hospitalists. Areas covered: These specialists in inpatient medicine care for a wide variety of hospitalized patients, including those with infectious disease, cancer, cardiovascular disease, autoimmune disease, hematologic disease, and a variety of other conditions that may soon be impacted by advances in gene-modifying technology provided by CRISPR-Cas9. A Literature search was performed using PubMed [1 December 2019–17 April 2020]. Expert opinion: This paper reviews the remarkable diagnostic and therapeutic potential of the CRISPR-Cas9 platform and concludes with a look at ethical issues and technical hurdles pertaining to the implementation of permanent gene modification in the practice of Hospital Medicine.

Lysins are bacteriophage-derived enzymes that degrade essential components of bacteria. Exebacase (Lysin CF-301) is an attractive antimicrobial agent because it demonstrates rapid bacteriolytic activity against staphylococcal species, including Staphylococcus aureus, has a low resistance profile, eradicates biofilms, and acts synergistically with other antibiotics. Combinations including exebacase and standard of care antibiotics represent an alternative to antibiotic monotherapies currently used to treat invasive staphylococcal infections. This manuscript reviews what is known about exebacase and explores how this novel agent may be used in the future to treat human bacterial pathogens.

On 17 November 2020, the United States Food and Drug Administration (FDA) authorized the first rapid SARS-CoV-2 assay that can be run entirely at home [1]. Created by Lucira Health, the All-In-One ...

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a powerful new tool to identify human fungal pathogens and has radically altered the diagnostic mycology workflow at many medical centers around the world. Areas covered: While most experience is with the identification of yeasts, including species of Candida and Cryptococcus, there is ongoing work investigating the role of MALDI-TOF MS to detect molds, including species of Aspergillus, Fusarium, Scedosporium, and Mucormyctes as well as thermally dimorphic fungi. Expert commentary: In this paper, we review the current knowledge about this important new platform and examine how its expanding use may impact molecular diagnostics and patient care in the years ahead.

On November 14, 2019, the U.S. Food and Drug Administration (FDA) approved cefiderocol, a siderophore-cephalosporin conjugate antibiotic, for the treatment of adults with complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options. The approval was based on substantial preclinical and clinical data, including in vitro and in vivo work, as well as pharmacokinetic and pharmacodynamic studies that established cefiderocol as an effective agent for the treatment of cUTI. This paper reviews that work and looks ahead to determine how cefiderocol might be used by clinicians in the future.

Introduction: Clinical trials for invasive pulmonary aspergillosis, a potentially lethal mold infection, are complex investigations that require protracted time and extensive resources, delaying the development of new antifungal agents for this important disease.Areas covered: In this paper, the authors examine a novel approach to study invasive pulmonary aspergillosis in humans, with a focus on the potentials and pitfalls of surrogate end points such as galactomannan antigenemia to evaluate therapeutic response to novel compounds.Expert commentary: The authors believe the use of serum galactomannan as a primary end point in clinical trials may allow for development studies that could be accomplished with fewer resources. It is widely appreciated that serum galactomannan values strongly correlate with outcome of invasive aspergillosis in patients with hematologic cancer and may be applicable to other at-risk patient populations.

In March 2015, the extended-spectrum triazole antifungal isavuconazole was granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. Isavuconaozle has activity against a broad range of yeasts, dimorphic fungi, and molds and is associated with fewer toxicities than voriconazole. It also has predictable pharmacokinetics in adults, fewer drug-drug interactions than many existing antifungal agents, and is available in both oral and β-cyclodextrin-free intravenous formulations. In this review, we explore what is known about the pharmacokinetics and pharmacodynamics of isavuconazole and look ahead to its expanding applications in clinical practice.

Despite the essential role played by infectious diseases specialists in patient care, public health, cost-containment, and biomedical research, the field has a substantially higher percentage of vacant positions than other medicine sub-specialties. While much has been written about what this disturbing trend means for patient care, comparatively little attention has been focused on the dire implications for clinical research and the development of novel anti-infective therapy. Areas covered: We examine the ways that hospitalists and infectious disease specialists might collaborate to study emerging diagnostic platforms, novel antimicrobial agents, and strengthen antimicrobial stewardship programs to improve the delivery of high-quality health care. Through the use of PubMed, the manuscript reviews existing collaborations as well as those that might develop in the years to come. Expert commentary: In this paper, we propose potential strategies to confront this emerging problem, focusing on novel collaborations with the hospitalist - the specialist in inpatient medicine - to bolster the pipeline of funding for clinical infectious diseases investigators.

Outpatient treatment options for mild to moderate COVID-19 are severely limited. While many therapeutic options have been proposed, very few have demonstrated the appropriate safety and efficacy to warrant approval by national or international regulatory bodies. Monoclonal antibodies have been shown to decrease hospitalization in high-risk patients, but use remains limited due to challenges associated with both production and administration, and other treatment options are urgently needed. The anti-inflammatory drug fluticasone propionate has recently emerged as a potential outpatient treatment option, especially for those with newly diagnosed disease. This manuscript reviews what is known about fluticasone and looks ahead to examine how the drug may be used in the future to address the COVID-19 pandemic.

The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms.This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms. We also explore the pharmacokinetics of this new compound as well as results from preclinical and clinical studies.There is an urgent need for novel antimicrobial agents to address the emergence of multidrug-resistant pathogens, which are an increasing cause of morbidity and mortality worldwide. Our understanding of multidrug-resistance and bacterial biochemical pathways continues to expand, and the development of cefiderocol specifically targeting siderophore-mediated iron transport shows potential in escaping mechanisms of drug resistance. Cefiderocol, which demonstrates a favorable side effect profile, has the potential to become first-line therapy for our most aggressive and lethal multidrug-resistant Gram-negative pathogens.

Acute dyspnea is a common chief complaint among patients who visit an emergency room and presents diagnostic challenges for clinicians in both identifying the etiology and determining the clinical severity. The study of biomarkers in the prognostication and risk stratification of these patients has been increasing, including the investigation of the prognostic value for mid-regional pro-adrenomedullin (MR-proADM). Areas covered: In this review, the authors cover what is known about MR-proADM testing in patients presenting with acute dyspnea and the supporting evidence of its prognostic value in common conditions in medical patients with acute dyspnea, including acute heart failure, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute pulmonary embolism. Expert commentary: Numerous studies have proposed MR-proADM as a more accurate, prognostic tool in the evaluation of acute dyspnea than other biomarkers and consensus risk scores such as Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA). The authors review recent prospective studies, systematic reviews, and meta-analyses that demonstrate its prognostic value and role in risk stratification, including its use in biomarker-based triage algorithms as part of the diagnostic evaluation of the acutely dyspneic patient.

A growing demand for transparency in medicine has the potential to strain the doctor-patient relationship. While information can empower patients, unrestricted patient access to the electronic medical record may have unintended consequences. Medical documentation is often written in language that is inaccessible to people without medical training, and without guidance, patients have no way to interpret the constellation of acronyms, diagnoses, treatments, impressions, and arguments that appear throughout their own chart. Additionally, full transparency may not allow physicians the intellectual or clinical freedom they need to authentically express questions, problematic impressions, and concerns about the patient's clinical and psychosocial issues. This article examines the ethical challenges of transparency in the digital era and suggests that selective redaction may serve as a means to maintain transparency, affirm physician's discretion, and uphold the core values of the doctor-patient relationship amidst disruptive technological change.

IMPACT: This work seeks to improve the diagnostic accuracy of urinary tract infection among hospitalized older adults and mitigate antibiotic overuse in this population. OBJECTIVES/GOALS: Primary objective: To determine the diagnostic accuracy of serum procalcitonin (PCT) for the diagnosis of symptomatic urinary tract infection (UTI) in hospitalized older adults. Secondary objectives: (1) To develop a predictive model for the diagnosis of UTI; (2) To determine the ability of PCT in discriminating between lower and upper UTI. METHODS/STUDY POPULATION: We performed a prospective observational cohort study of 228 participants from a single institution. The study population included older adults (age 65 or older) who were hospitalized on the general medicine wards with a possible or suspected urinary tract infection (UTI). Upon obtaining informed consent, serum procalcitonin (PCT) was processed on remnant blood samples collected from the emergency department. We performed additional data collection through the electronic health record to obtain demographic information, clinical characteristics, and other laboratory and imaging results. Clinicians were surveyed for the diagnosis of UTI and charts were adjudicated by independent reviews of the medical record by infectious diseases experts to determine the primary endpoint of symptomatic UTI. RESULTS/ANTICIPATED RESULTS: We anticipate that serum procalcitonin predicts the presence of symptomatic urinary tract infection (UTI) by demonstrating an area under the receiver operating characteristic curve of at least 0.85. A predictive model developed in our cohort for the diagnosis of symptomatic UTI will be improved by the addition of serum PCT to the prediction model. Finally, we anticipate the serum PCT will accurately discriminate between upper and lower UTI. DISCUSSION/SIGNIFICANCE OF FINDINGS: Diagnosis of symptomatic UTI in hospitalized older adults is challenging and may lead to overuse of antibiotics and the development of antibiotic resistance in this vulnerable patient population. Serum procalcitonin offers a novel diagnostic strategy in the diagnosis of symptomatic UTI to enable more appropriate antibiotic therapy.

Procalcitonin has emerged as a reliable marker of acute bacterial infection in hospitalized patients and the assay has recently been incorporated into several clinical algorithms to reduce antimicrobial overuse, but its use in patients with end-organ dysfunction is controversial. Areas covered: In this review, the authors examine what is known about procalcitonin testing in patients with organ dysfunction, including those with end-stage renal disease, congestive heart failure, chronic obstructive pulmonary disease, and cirrhosis, and explore how the assay is now being used in the management of non-infectious diseases. Expert commentary: Procalcitonin holds tremendous promise to identify a diverse set of medical conditions beyond those associated with acute bacterial infection, including post-surgical anastomotic leaks, acute kidney injury, and complications after intracerebral hemorrhage. The authors review recent studies examining procalcitonin in these areas and explore how the assay might be used to guide diagnosis and prognosis of non-infectious diseases in the near future.

Candida auris is an emerging multidrug resistant human yeast pathogen associated with nosocomial transmission and high mortality. The organism can be a challenge to diagnose, may be even more difficult to treat, and continues to pose an expanding threat to patients. Areas covered: Our medical center and others in the surrounding area have seen a concerning rise in confirmed cases of C. auris infection and substantial resources have been dedicated to containment measures. We draw on our in vitro and in vivo work with this organism to examine the most effective ways to curb the current outbreak. Expert commentary: We explore novel strategies to halt the spread C. auris, including enhanced molecular diagnostics, novel therapeutics, and epidemiologic studies to determine risk factors for infection and transmission.

Introduction: On 18 September 2012, United States health officials began to react to a large outbreak of fungal meningitis traceable to methylprednisolone from a compounding pharmacy in Framingham, Massachusetts. Although the index case was attributed to the opportunistic mold Aspergillus fumigatus, all subsequent cases were due to the dematiaceous mold Exserohilum rostratum, which had previously been an uncommon cause of disease in humans.Areas covered: In this paper, the authors examine recent advances in the diagnosis and treatment of Exserohilum infection and provide updates on how the innate and acquire immune responses enable clearance of human fungal pathogens.Expert commentary: The fungal meningitis outbreak of 2012 stretched across 20 states and resulted in 753 cases of central nervous system infection and 64 deaths. In this paper, the authors examine how the outbreak prompted investigators to develop novel diagnostic and therapeutic options that have advanced the study of human fungal pa...

Introduction: CRISPR-Cas9 has emerged as an important new tool for genetic engineering. While much has been written about the potential of this technology to treat human disease, relatively little has attention has been paid to the ways in which it might further the study of human fungal pathogens.Areas covered: In this paper, the authors review what is known about the role of CRISPR-Cas9 in the study of invasive mycoses, including species of Candida, Cryptococcus, and Aspergillus, and explore how this platform might be used to identify novel drug targets.Expert commentary: The authors investigate the ways CRISPR might be utilized to modify human diseases that predispose patients to invasive fungal infections, including human immunodeficiency virus, chronic granulomatous disease, and CARD9 deficiency, and highlight the substantial controversy regarding its application in clinical practice.

Introduction: Immune checkpoint inhibition has emerged as an important new approach to the treatment of cancer. Agents targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and PD-1 ligand (PD-L1) have shown remarkable promise as anti-neoplastic drugs, but they are also associated with unique set of toxicities termed immune-related adverse events (IRAEs) that differ from toxicities observed with conventional cytotoxic chemotherapy.Areas covered: A burgeoning body of literature suggests that patients who are treated with a checkpoint inhibitor are at increased risk for infection, either from immune dysregulation, medication-induced neutropenia, or from immunosuppression associated with the management of IRAEs. In this paper, we examine these phenomena and explore how the risk of infectious might be mitigated through the use of antimicrobial prophylaxis in high-risk patients.Expert commentary: There is no prospective data on thee toxicities associated with c...

The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.

Introduction: Invasive fungal infections represent an expanding threat to public health. The recent emergence of Candida auris, which is often resistant to existing antifungal agents and is associated with a high mortality rate, underscores the urgent need for novel drug development strategies.Areas covered: In this paper, we examine both challenges and opportunities associated with antifungal drug development and explore potential avenues to accelerate the development pipeline, including data sharing, surrogate endpoints, and the role of historical controls in clinical trials.Expert commentary: We review important lessons learned from the study of other rare diseases, including mitochondrial storage diseases and certain forms of cancer that may inform strategies to develop new antifungal agents while highlighting promising new compounds such as SCY-078 for the treatment of invasive fungal infections.

On 16 July, 2019, the US Food and Drug Administration approved imipenem–cilastatin/relebactam (Recarbrio™) for the treatment of adults with complicated urinary tract infections and complicated intra-abdominal infections. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work, and is an important step forward in the management of these debilitating conditions. This article provides an overview of the body of research associated with imipenem–cilastatin/relebactam, beginning with an examination of the fundamental underpinnings of the pharmacokinetic/pharmacodynamic index. This is followed by the pharmacokinetic/pharmacodynamic work that led to the approval of this novel drug combination, including data derived from checkerboard and hollow fiber infection studies, as well as large, multi-center, phase III clinical trials known as RESTORE-IMI 1 and RESTORE-IMI 2. The article also explores how this important new antibiotic may be used to treat other infections in the years to come, including hospital-acquired bacterial pneumonia and ventilator-associated pneumonia attributed to imipenem-non-susceptible pathogens and certain atypical mycobacterial infections.

In 2015, a screen of bacterial strains produced a novel antibiotic with broad antimicrobial activity known as teixobactin [1]. The compound was identified using a new method to grow uncultured orga...

OBJECTIVES This study aims to better understand and describe antibiotic prescribing practices and adherence to a procalcitonin (PCT)-guided algorithm in patients undergoing serum PCT testing in adult hospitalized patients. METHODS We performed an observational, retrospective study of 201 randomly selected patients who are aged ≥18 years, admitted to the general medicine floors or step-down unit between 1 January 2017 and 31 December 2017, and had serum PCT testing. Physician adherence to a PCT-guided algorithm was assessed through chart review. RESULTS We found an overall adherence of 64.7%. Adherence was highest for PCT values above 0.25 ng/mL (82.8% for 0.25-0.50 ng/mL and 83.6% for >0.50 ng/mL). Adherence was lower for PCT values less than 0.25 ng/mL (59% for

On 27 August, 2018, the US Food and Drug Administration approved eravacycline, a fluorocycline antimicrobial agent within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections in patients aged 18 years and older. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work. This paper examines the in-vivo pharmacokinetic/pharmacodynamic work that led to the approval of eravacycline and explores how this important new antibiotic may be used to treat aggressive multidrug-resistant infections in the years ahead.