Optimizing Antimicrobial Stewardship in the Emergency Department.

Antibiotic stewardship is a core component of emergency department (ED) practice and impacts patient safety, clinical outcomes, and public health. The unique characteristics of ED practice, including crowding, time pressure, and diagnostic uncertainty, need to be considered when implementing antibiotic stewardship interventions in this setting. Rapid advances in pathogen detection and host response biomarkers promise to revolutionize the diagnosis of infectious diseases in the ED, but such tests are not yet considered standard of care. Presently, clinical decision support embedded in the electronic health record and pharmacist-led interventions are the most effective ways to improve antibiotic prescribing in the ED.

How New Regulation of Laboratory-Developed Antimicrobial Susceptibility Tests Will Affect Infectious Diseases Clinical Practice.

Antimicrobial resistance (AMR) affects 2.8 million Americans annually. AMR is identified through antimicrobial susceptibility testing (AST), but current and proposed regulatory policies from the United States Food and Drug Administration (FDA) jeopardize the future availability of AST for many microorganisms. Devices that perform AST must be cleared by the FDA using their susceptibility test interpretive criteria, also known as breakpoints. The FDA list of breakpoints is relatively short. Today, laboratories supplement FDA breakpoints using breakpoints published by the Clinical and Laboratory Standards Institute, using legacy devices and laboratory-developed tests (LDTs). FDA proposes to regulate LDTs, and with no FDA breakpoints for many drug-bug combinations, the risk is loss of AST for key clinical indications and stifling innovation in technology development. Effective solutions require collaboration between manufacturers, infectious diseases clinicians, pharmacists, laboratories, and the FDA.

Finding value in novel antibiotics: How can infectious diseases adopt incremental cost-effectiveness to improve new antibiotic utilization?

Research and development of innovative antimicrobials is paramount to addressing the antimicrobial resistance threat. Although antimicrobial discovery and development has increased, difficulties have emerged in the pharmaceutical industry after market approval. In this minireview, we summarize clinical trial data on recently approved antibiotics, calculate incremental cost-effectiveness ratio (ICER) values, and explore ways to adapt ICER calculations to the limitations of antimicrobial clinical trial design. We provide a systematic review and analysis of randomized, controlled studies of antibiotics approved from 2014 - 2022 and extracted the relevant clinical data. Adapted-ICER (aICER) calculations were conducted using the primary condition-specific outcome that was reported in each study (percent mortality or percent cure rate). The literature search identified 18 studies for the 8 total antibiotics which met inclusion criteria and contained data required for aICER calculation. aICER values ranged from -$17,374 to $4,966 per percent mortality and -$43,931 to $2,529 per percent cure rate. With regards to mortality, ceftolozane/tazobactam and imipenem/cilastatin/relebactam proved cost efficacious, with aICER values of $4,965 per percent mortality and $1,955 per percent mortality respectively. Finding value in novel antibiotic agents is imperative to further justifying their development, and aICER values are the most common method of determining value in healthcare. The current outcomes of clinical trials are difficult to translate to aICER, which most effectively use Quality-Adjusted Life Years (QALY) as the quality standard in other fields such as oncology. Future antimicrobial trials should consider introducing methods of assessing measures of health gain such as QALY to better translate the value of novel antimicrobials in healthcare.

Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection.

Parasitic vector-borne diseases (VBDs) represent nearly 20% of the global burden of infectious diseases. Moreover, the spread of VBDs is enhanced by global travel, urbanization, and climate change. Treatment of VBDs faces challenges due to limitations of existing drugs, as the potential for side effects in nontarget species raises significant environmental concerns. Consequently, considering environmental risks early in drug development processes is critically important. Here, we examine the environmental risk assessment process for veterinary medicinal products in the European Union and identify major gaps in the ecotoxicity data of these drugs. By highlighting the scarcity of ecotoxicological data for commonly used antiparasitic drugs, we stress the urgent need for considering the One Health concept. We advocate for employing predictive tools and nonanimal methodologies such as New Approach Methodologies at early stages of antiparasitic drug research and development. Furthermore, adopting progressive approaches to mitigate ecological risks requires the integration of nonstandard tests that account for real-world complexities and use environmentally relevant exposure scenarios. Such a strategy is vital for a sustainable drug development process as it adheres to the principles of One Health, ultimately contributing to a healthier and more sustainable world.

Microbiological Rapid On-Site Evaluation for Pulmonary Infectious Diseases.

The prompt initiation of empirical anti-infective therapy is crucial in patients presenting with unexplained pulmonary infection. Although imaging acquisition is relatively straightforward in clinical practice, its lack of specificity often necessitates additional time-consuming tests such as sputum culture, bronchoalveolar-lavage fluid culture, or genetic sequencing to identify the underlying etiology of the disease accurately. Moreover, the limited efficacy of empirical anti-infective treatment may contribute to antibiotic misuse. Recent advancements in interpreting microbial background on rapid on-site evaluation (ROSE) slides have enabled clinicians to promptly obtain samples through bronchoscopy (e.g., alveolar lavage, mucosal brushing, tissue clamp), facilitating bedside staining and interpretation that provides essential microbial background information. Consequently, this establishes a foundation for developing targeted anti-infection treatment and individualized drug therapy plans. With a better understanding of which pathogens are causing infections in real-time, physicians can avoid unnecessary broad-spectrum antibiotics contributing to antibiotic resistance. Establishing a rapid and standardized M-ROSE workflow within respiratory medicine departments or intensive care units will greatly assist physicians in formulating accurate treatment strategies for patients, which holds significant clinical implications.

Combating Antimicrobial Resistance by Employing Antimicrobial Peptides: Immunomodulators and Therapeutic Agents against Infectious Diseases.

The rising prevalence of multiple-drug-resistant pathogens poses a formidable challenge to conventional antimicrobial treatments. The inability of potent antibiotics to combat these "superbugs" underscores the pressing need for alternative therapeutic agents. Antimicrobial peptides (AMPs) represent an alternative class of antibiotics. AMPs are essential immunomodulatory molecules that are found in various organisms. They play a pivotal role in managing microbial ecosystems and bolstering innate immunity by targeting and eliminating invading microorganisms. AMPs also have applications in the agriculture sector by combating animal as well as plant pathogens. AMPs can be exploited for the targeted therapy of various diseases and can also be used in drug-delivery systems. They can be used in synergy with current treatments like antibiotics and can potentially lead to a lower required dosage. AMPs also have huge potential in wound healing and regenerative medicine. Developing AMP-based strategies with improved safety, specificity, and efficacy is crucial in the battle against alarming global microbial resistance. This review will explore AMPs' increasing applicability, their mode of antimicrobial activity, and various delivery systems enhancing their stability and efficacy.

Antibacterial and anti-coronavirus investigation of selected Senegalese plant species according to an ethnobotanical survey.

ETHNOPHARMACOLOGICAL RELEVANCE: In Senegal, upper and lower respiratory tract infections constitute a real health problem. To manage these disorders, most people rely on the use of local medicinal plants. This is particularly the case for species belonging to the botanical families, Combretaceae, Fabaceae, Myrtaceae and Rubiaceae, which are widely used to treat various respiratory problems such as colds, flu, rhinitis, sinusitis, otitis, angina, bronchitis, bronchiolitis and also pneumonia. AIM OF THE STUDY: The aim of this study was to identify medicinal plants traditionally used for the management of infectious diseases, in particular those of the respiratory tract. On the basis of these ethnopharmacological uses, this study made it possible to highlight the antibacterial, antiviral and cytotoxic activities of selected plant species. MATERIALS AND METHODS: An ethnobotanical survey was conducted in Senegal among informants, including herbalists, traditional healers, and households, using medicinal plants in the management of infectious diseases, with a focus on respiratory tract infections. The most cited plant species were evaluated in vitro on a panel of 18 human pathogenic bacteria may be involved in respiratory infections and against the human coronavirus HCoV-229E in Huh-7 cells. The antiviral activity of the most active extracts against HCoV-229E was also evaluated on COVID-19 causing agent, SARS-CoV-2 in Vero-81 cells. In parallel, cytotoxic activities were evaluated on Huh-7 cells. RESULTS: A total of 127 informants, including 100 men (78.74%) and 27 women (21.26%) participated in this study. The ethnobotanical survey led to the inventory of 41 plant species belonging to 19 botanical families used by herbalists and/or traditional healers and some households to treat infectious diseases, with a specific focus on upper respiratory tract disorders. Among the 41 plant species, the most frequently mentioned in the survey were Guiera senegalensis J.F. Gmel. (95.2%), Combretum glutinosum Perr. Ex DC. (93.9%) and Eucalyptus spp. (82.8%). Combretaceae (30.2%) represented the most cited botanical family with six species, followed by Fabaceae (29.3%, 12 species). A total of 33 crude methanolic extracts of the 24 plant species selected for their number of citations were evaluated in vitro for their antimicrobial and cytotoxic activities. Guiera senegalensis, Combretum glutinosum, Vachellia nilotica subsp. tomentosa (Benth.) Kyal. & Boatwr, Eucalyptus camaldulensis Dehnh., and Terminalia avicennioides Guill. & Perr., showed antibacterial activities. The most active plants against HCoV-229E were: Ficus sycomorus L., Mitragyna inermis (Willd.) Kuntze, Pterocarpus erinaceus Poir., and Spermacoce verticillata L. One of these plants, Mitragyna inermis, was also active against SARS-CoV-2. CONCLUSION: This work confirmed the anti-infective properties of plant species traditionally used in Senegal. Overall, the most frequently cited plant species showed the best antibacterial activities. Moreover, some of the selected plant species could be considered as a potential source for the management of coronavirus infections. This new scientific data justified the use of these plants in the management of some infectious pathologies, especially those of the respiratory tract.

A panel of janus kinase inhibitors identified with anti-inflammatory effects protect mice from lethal influenza virus infection.

Influenza remains a significant threat to public health. In severe cases, excessive inflammation can lead to severe pneumonia or acute respiratory distress syndrome, contributing to patient morbidity and mortality. While antivirals can be effective if administered early, current anti-inflammatory drugs have limited success in treating severe cases. Therefore, discovering new anti-inflammatory agents to inhibit influenza-related inflammatory diseases is crucial. Herein, we screened a drug library with known targets using a human monocyte U937 infected with the influenza virus to identify novel anti-inflammatory agents. We also evaluated the anti-inflammatory effects of the hit compounds in an influenza mouse model. Our research revealed that JAK inhibitors exhibited a higher hit rate and more potent inhibition effect than inhibitors targeting other drug targets in vitro. Of the 22 JAK inhibitors tested, 15 exhibited robust anti-inflammatory activity against influenza virus infection in vitro. Subsequently, we evaluated the efficacy of 10 JAK inhibitors using an influenza mouse model and observed that seven provided protection ranging from 40% to 70% against lethal influenza virus infection. We selected oclacitinib as a representative compound for an extensive study to further investigate the in vivo therapeutic potential of JAK inhibitors for severe influenza-associated inflammation. Our results revealed that oclacitinib effectively suppressed neutrophil and macrophage infiltration, reduced pro-inflammatory cytokine production, and ultimately mitigated lung injury in mice infected with lethal influenza virus without impacting viral titer. These findings suggest that JAK inhibitors can modulate immune responses to influenza virus infection and may serve as potential treatments for influenza.IMPORTANCEAntivirals exhibit limited efficacy in treating severe influenza when not administered promptly during the infection. Current steroidal and nonsteroidal anti-inflammatory drugs demonstrate restricted effectiveness against severe influenza or are associated with significant side effects. Therefore, there is an urgent need for novel anti-inflammatory agents that possess high potency and minimal adverse reactions. In this study, 15 JAK inhibitors were identified through a screening process based on their anti-inflammatory activity against influenza virus infection in vitro. Remarkably, 7 of the 10 selected inhibitors exhibited protective effects against lethal influenza virus infection in mice, thereby highlighting the potential therapeutic value of JAK inhibitors for treating influenza.

Uncovering the secrets of resistance: An introduction to computational methods in infectious disease research.

Antimicrobial resistance (AMR) is a growing global concern with significant implications for infectious disease control and therapeutics development. This chapter presents a comprehensive overview of computational methods in the study of AMR. We explore the prevalence and statistics of AMR, underscoring its alarming impact on public health. The role of AMR in infectious disease outbreaks and its impact on therapeutics development are discussed, emphasizing the need for novel strategies. Resistance mutations are pivotal in AMR, enabling pathogens to evade antimicrobial treatments. We delve into their importance and contribution to the spread of AMR. Experimental methods for quantitatively evaluating resistance mutations are described, along with their limitations. To address these challenges, computational methods provide promising solutions. We highlight the advantages of computational approaches, including rapid analysis of large datasets and prediction of resistance profiles. A comprehensive overview of computational methods for studying AMR is presented, encompassing genomics, proteomics, structural bioinformatics, network analysis, and machine learning algorithms. The strengths and limitations of each method are briefly outlined. Additionally, we introduce ResScan-design, our own computational method, which employs a protein (re)design protocol to identify potential resistance mutations and adaptation signatures in pathogens. Case studies are discussed to showcase the application of ResScan in elucidating hotspot residues, understanding underlying mechanisms, and guiding the design of effective therapies. In conclusion, we emphasize the value of computational methods in understanding and combating AMR. Integration of experimental and computational approaches can expedite the discovery of innovative antimicrobial treatments and mitigate the threat posed by AMR.

Audit of adherence to international guidelines (IDSA) in the treatment of infectious meningitis in pediatric patients in Jordan.

OBJECTIVE: This study aims to audit the adherence of Jordanian medical care staff to the guidelines provided by the Infectious Disease Society of America (IDSA) for managing pediatric patients admitted with suspected cases of meningitis. METHODS: A retrospective observational study was conducted at Jordan University Hospital (JUH). All pediatric patients admitted to JUH with suspected meningitis between January 1, 2019, and September 30, 2022, who underwent Cerebrospinal Fluid (CSF) and blood culture tests were recruited in this study unless there was a reason for exclusion. The study collected data on the empiric antibiotics prescribed prior to diagnostic cultures and susceptibility results. Additionally, the length of hospital stay and all-cause mortality were observed. The appropriateness of antibiotics prescription before culture results was compared to IDSA guidelines, and an overall adherence rate was calculated. RESULTS: A total of 332 pediatric patients were included in this study, of whom 12.3% (n = 41) were diagnosed with bacterial meningitis. Among the enrolled pediatric patients, only 27 patients (8.1%) received appropriate treatment adhering to the IDSA guidelines. The remaining 91.9% (n = 305) showed various forms of non-adherence to recommendations. The highest adherence rate was observed for performing CSF culture (n = 330, 99.4%), while the lowest adherence rate was found in selecting the appropriate dose and duration for empiric antibiotics (n = 107, 41.3% and n = 133, 51.0%, respectively). CONCLUSION: This study revealed a low overall adherence in the management of pediatric patients with meningitis in Jordan. Establishing an antimicrobial stewardship program may improve the outcomes of meningitis infections found in Jordan, and prevent dangerous adverse effects and bacterial resistance.

Improving diagnostic accuracy of blood culture-positive cases in a cancer center via an antimicrobial stewardship program and infectious disease consultations.

The direct impact of antimicrobial stewardship programs (ASP) and infectious disease (ID) consultations on patients' clinical diagnoses remains unknown. We assessed their influence on improving the diagnostic accuracy of blood culture-positive inpatients at a Japanese cancer center. Our single-center, retrospective observational study was conducted from April 1, 2018 to March 31, 2022 to evaluate two phases: pre-intervention (notification of antimicrobials by the infection control team) and post-intervention (ASP implementation and ID consultation service establishment). There were 42,514 inpatients: 22,096 during the pre-intervention and 20,418 during the intervention periods. A total of 939 blood culture-positive episodes (pre-intervention, n = 434; post-intervention, n = 505) were analyzed. During the pre-intervention period, 28.1% of the patients had an unknown diagnosis, which decreased significantly to 1.2% post-intervention. Furthermore, hepatobiliary tract and other infections increased significantly post-intervention, and the mortality rate due to Staphylococcus aureus infection decreased from 28.6% pre-intervention to 10.4% post-intervention. The trend and level of the total number of culture specimens submitted per 1000 patient days for all culture specimens increased significantly post-intervention. Notably, the two-set rate of monthly blood cultures increased significantly. In conclusion, improving the overall diagnostic process with ASP and ID consultations at cancer centers could lead to the optimization of patient care.

Nanotechnology's frontier in combatting infectious and inflammatory diseases: prevention and treatment.

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

Resolution pharmacology and the treatment of infectious diseases.

Inflammation is elicited by the host in response to microbes, and is believed to be essential for protection against infection. However, we have previously hypothesized that excessive or misplaced inflammation may be a major contributor to tissue dysfunction and death associated with viral and bacterial infections. The resolutive phase of inflammation is a necessary condition to achieve homeostasis after acute inflammation. It is possible that targeting inflammation resolution may be beneficial for the host during infection. In this review, we summarize the evidence demonstrating the expression, roles and effects of the best described pro-resolving molecules in the context of bacterial and viral infections. Pro-resolving molecules play a pivotal role in modulating a spectrum of pathways associated with tissue inflammation and damage during both viral and bacterial infections. These molecules offer a blend of anti-inflammatory, pro-resolving and sometimes anti-infective benefits, all the while circumventing the undesired and immune-suppressive unwanted effects associated with glucocorticoids. Whether these beneficial effects will translate into benefits to patients clearly deserve further investigation.

Drug Repurposing in the Chemotherapy of Infectious Diseases.

Repurposing is a universal mechanism for innovation, from the evolution of feathers to the invention of Velcro tape. Repurposing is particularly attractive for drug development, given that it costs more than a billion dollars and takes longer than ten years to make a new drug from scratch. The COVID-19 pandemic has triggered a large number of drug repurposing activities. At the same time, it has highlighted potential pitfalls, in particular when concessions are made to the target product profile. Here, we discuss the pros and cons of drug repurposing for infectious diseases and analyze different ways of repurposing. We distinguish between opportunistic and rational approaches, i.e., just saving time and money by screening compounds that are already approved versus repurposing based on a particular target that is common to different pathogens. The latter can be further distinguished into divergent and convergent: points of attack that are divergent share common ancestry (e.g., prokaryotic targets in the apicoplast of malaria parasites), whereas those that are convergent arise from a shared lifestyle (e.g., the susceptibility of bacteria, parasites, and tumor cells to antifolates due to their high rate of DNA synthesis). We illustrate how such different scenarios can be capitalized on by using examples of drugs that have been repurposed to, from, or within the field of anti-infective chemotherapy.

Mucosal Immunity of Major Gastrointestinal Nematode Infections in Small Ruminants Can Be Harnessed to Develop New Prevention Strategies.

Gastrointestinal parasitic nematode (GIN) infections are the cause of severe losses to farmers in countries where small ruminants such as sheep and goat are the mainstay of livestock holdings. There is a need to develop effective and easy-to-administer anti-parasite vaccines in areas where anthelmintic resistance is rapidly rising due to the inefficient use of drugs currently available. In this review, we describe the most prevalent and economically significant group of GIN infections that infect small ruminants and the immune responses that occur in the host during infection with an emphasis on mucosal immunity. Furthermore, we outline the different prevention strategies that exist with a focus on whole and purified native parasite antigens as vaccine candidates and their possible oral-nasal administration as a part of an integrated parasite control toolbox in areas where drug resistance is on the rise.

Platelet-derived drug delivery systems: Pioneering treatment for cancer, cardiovascular diseases, infectious diseases, and beyond.

Platelets play a critical role as circulating cells in the human body and contribute to essential physiological processes such as blood clotting, hemostasis, vascular repair, and thrombus formation. Currently, platelets are extensively employed in the development of innovative biomimetic drug delivery systems, offering significant enhancements in circulation time, biocompatibility, and targeted delivery efficiency compared to conventional drug delivery approaches. Leveraging the unique physiological functions of platelets, these platelet-derived drug delivery systems (DDSs) hold great promise for the treatment of diverse diseases, including cancer, cardiovascular diseases, infectious diseases, wound healing and other diseases. This review primarily focuses on the design and characteristics of existing platelet-derived DDSs, including their preparation and characterization methods. Furthermore, this review comprehensively outlines the applications of these materials across various diseases, offering a holistic understanding of their therapeutic potential. This study aimed to provide a comprehensive overview of the potential value of these materials in clinical treatment, serving as a valuable reference for the advancement of novel platelet-derived DDSs and their broader utilization in the field of disease treatment.

Infection-related Hospitalizations During Immune Checkpoint Inhibitor Treatment Without Immunosuppressants.

Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.

Rising role of 3D-printing in delivery of therapeutics for infectious disease.

Modern drug delivery to tackle infectious disease has drawn close to personalizing medicine for specific patient populations. Challenges include antibiotic-resistant infections, healthcare associated infections, and customizing treatments for local patient populations. Recently, 3D-printing has become a facilitator for the development of personalized pharmaceutic drug delivery systems. With a variety of manufacturing techniques, 3D-printing offers advantages in drug delivery development for controlled, fine-tuned release and platforms for different routes of administration. This review summarizes 3D-printing techniques in pharmaceutics and drug delivery focusing on treating infectious diseases, and discusses the influence of 3D-printing design considerations on drug delivery platforms targeting these diseases. Additionally, applications of 3D-printing in infectious diseases are summarized, with the goal to provide insight into how future delivery innovations may benefit from 3D-printing to address the global challenges in infectious disease.

What's Hot This Year in Infectious Diseases Clinical Science.

The field of infectious diseases saw numerous exciting advances in 2023. Trials of new antibiotics and treatment regimens sought to address rising rates of antimicrobial resistance. Other studies focused on the most appropriate use of currently available treatments, balancing the dual goals of providing effective treatment and impactful antimicrobial stewardship. Improvements in disease prevention were made through trials of both new vaccines and new chemoprophylaxis approaches. Concerning trends this year included increasing rates of invasive group A streptococcal infections, medical tourism-associated cases of fungal meningitis, and the return of locally acquired malaria to the United States. This review covers some of these notable trials and clinical developments in infectious diseases in the past year.