Current Infectious Disease Reports最新文献

Purpose of Review

Antimicrobial resistance is a growing threat to public health, leading to millions of antibiotic-resistant infections and thousands of deaths annually in the USA. One concerning issue is the rise of extended-spectrum beta-lactamase (ESBL)–producing Enterobacterales. Current treatments often involve intravenous carbapenems, leading to prolonged hospital stays and financial burdens.

Recent Findings

To address this, new oral penem agents, tebipenem and sulopenem, are being investigated. They are administered as prodrugs, enhancing bioavailability before becoming active in the gastrointestinal tract, potentially treating multidrug-resistant infections in outpatient settings. Despite promise in clinical trials, challenges exist, such as tebipenem’s renal excretion, requiring dose adjustments for kidney dysfunction. Additionally, sulopenem failed noninferiority margins in trials, and neither drug has established susceptibility testing standards.

Summary

Tebipenem and sulopenem offer potential oral solutions for antimicrobial resistance, especially in urinary tract infections, but further research is needed for optimal dosing and susceptibility testing.

Purpose of Review

Beta-lactam antibiotics are among the most commonly prescribed drug classes in the hospital setting. The pharmacokinetic/pharmacodynamic index correlated with bactericidal activity of beta-lactam antibiotics is the amount of time drug concentrations exceeds the minimum inhibitory concentration over the course of a dosing interval. Standard dosing is based on preclinical trials conducted in healthy volunteers with considerations for renal function and weight to maintain time over minimum inhibitory concentration for an appropriate percentage of the dosing interval. It is commonly accepted that critically ill patients have altered pharmacokinetics which may impact drug efficacy; however, current dosing strategies do not account for these variances. As such, standard dosing delineated in package inserts may not optimize time over the minimum inhibitory concentration. Therapeutic drug monitoring of beta-lactams has been proposed as a possible method to ensure dose optimization in a state of critical illness. To date, there have been limited clinical studies supporting the routine use of therapeutic drug monitoring of beta-lactams, as well as an uncertainty regarding how the process can be applied in the clinical setting. The purpose of this review is to elucidate the current state of therapeutic drug monitoring of beta-lactams and evaluate clinical outcomes of patients who received therapeutic drug monitoring of beta-lactams compared to the standard of care.

Recent Findings

Recent clinical trials suggest there is little demonstrable benefit in patients’ clinical outcomes when therapeutic drug monitoring of beta-lactams is utilized. A number of studies have been performed with variable trial designs. In these studies, there are different pharmacokinetic/pharmacodynamic targets, pathogens, beta-lactams, and primary outcomes. This makes assessment of therapeutic drug monitoring challenging.

Summary

Therapeutic drug monitoring of beta-lactam antibiotics is limited by lack of compelling clinical evidence demonstrating benefit in patient outcomes. Challenges in clinical trial design make patient selection difficult and may underestimate the impact of therapeutic drug monitoring. Widespread availability of assays with on-site testing and validated monitoring software would allow for use in select patients with unpredictable pharmacokinetics.

Purpose of Review

In 2019, a global meta-analysis demonstrated incidence of 3.9% for chorioamnionitis, 1.6% for endometritis, 1.2% for wound infection, 0.05% for sepsis, and 1.1% for maternal peripartum infection (Woodd et al. in PLOS Med 16(12):e1002984, 2019). Antimicrobial regimens for these infections are based on older microbiology profiles and may not account for changes in antimicrobial susceptibility data or the availability more modern antimicrobial therapies.

Recent Findings

Recommendations for treatment of puerperal infection have not changed significantly in recent decades, despite the availability of new antimicrobial therapies with improved safety profiles.

Summary

A consideration should be given to monotherapy or two-drug regimens that have fewer toxicities than older therapeutics and require less monitoring. Obtaining appropriate microbiologic data and antimicrobial susceptibility data is critical to balance broad-spectrum coverage with the threat of antimicrobial resistance.

Purpose of Review

Septic coagulopathy is a complex disorder linked with multiple organ dysfunction and increased mortality, and definitive treatments are still lacking. This review summarizes the current understanding of septic coagulopathy, covering its pathophysiology, diagnosis, and debatable treatment approaches. Additionally, it provides a thorough overview of recent research and emerging trends in this area.

Recent Findings

Recent studies have highlighted the interplay between coagulation mechanisms in sepsis and inflammatory response. Diagnostic tools include the newly published scoring system for sepsis-induced coagulopathy and the existing scoring systems for disseminated intravascular coagulation, enhancing early detection and treatment. Several drugs targeting abnormal clotting have been investigated in septic coagulopathy or wider septic groups, including heparin, antithrombin, activated protein C, and human-soluble thrombomodulin. However, they have not yielded clear survival benefits. Nonetheless, recent studies indicate that some of those therapies may benefit specific groups with septic coagulopathy, emphasizing the growing interest in emerging biomarkers and precision medicine to enhance patient outcomes.

Summary

Despite recent advancements, no pharmaceutical intervention is currently endorsed for septic coagulopathy. However, a noted association exists between disseminated intravascular coagulation and unfavorable prognosis. Future research is imperative, especially in devising individualized treatment strategies tailored to each patient’s condition.

Purpose of Review

Over 50% of the infections in most ICUs in tertiary care centres in India are caused by difficult to treat (DTR) gram-negative bacteria. The options available for the treatment of these infections are quite limited. This review discusses the epidemiology of these DTR infections in India and explores the various treatment strategies for these infections which are relevant in an Indian setting.

Recent Findings

The most common organisms causing DTR infections in India are Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa. The mechanisms of resistance in these organisms are not the same as those in DTR organisms prevalent in the western world. Treatment strategies recommended by western guidelines may not work in India. Management of these DTR organisms needs to be tailored to the situation in India.

Summary

Overuse of antibiotics has led to an alarming rate of DTR infections in Indian ICUs. The polymyxins are often the only drugs which are effective against many of these infections. Physicians in India and the government need to take urgent measures to control the spread of these organisms.

Key points

• Antibiotic overuse has led to a situation where over 50% of infections in Indian ICUs are caused by DTR organisms.

• Carbapenemase production is the primary mechanism of resistance in carbapenem-resistant Enterobacterales (CRE). Efflux pumps, altered outer membrane porin and production of carbapenemases are all implicated in DTR Pseudomonas aeruginosa and Acinetobacter baumannii.

• KPC production is very uncommon in the CRE prevalent in India. Western guidelines may therefore not be relevant in India.

• The polymyxins (in combination) and ceftazidime/avibactam with aztreonam are the drugs most often used to deal with DTR gram-negative bacteria in India.

• Local delivery of antibiotics may be indicated in the management of these DTR infections in special sites like meningitis and pneumonia.

Purpose of Review

Current literature largely suggests that the combination of vancomycin and piperacillin/tazobactam (VPT) is associated with a significantly higher risk of acute kidney injury (AKI) compared to vancomycin alone or in combination with other antipseudomonal beta-lactams. However, the true mechanisms behind this potential nephrotoxic effect remain unclear.

Recent Findings

The majority of studies describing VPT-associated nephrotoxicity are based on potentially flawed surrogates of glomerular function (e.g., serum creatinine). Moreover, the incidence of creatinine-based AKI is dependent on the consensus definition used. In contrast, animal and clinical studies using more reliable kidney damage biomarkers (e.g., cystatin c) and histopathological examinations largely suggest that injury does not occur.

Summary

In the absence of definitive evidence supported by prospective randomized clinical trials specifically designed to address this question and using various GFR markers and AKI biomarkers, the concern of nephrotoxicity should not influence clinical decision-making for patients requiring broad-spectrum antibiotics. Instead, empiric therapy should be guided by the suspected source of infection, local pathogen susceptibility patterns, and adverse effects.

Purpose of Review

Whole genome sequencing is increasingly used in epidemiologic surveillance in healthcare centers, shedding new light on the transmission of healthcare-associated infections. As processing times for these technologies shorten, the ability to use sequencing data for targeted infection prevention is seemingly attainable and of great interest to infection prevention practitioners in an era of limited resources.

Recent Findings

Common healthcare-associated infections such as C. difficile and methicillin-resistant Staphylococcus aureus may be acquired in diverse settings including the community, rather than direct patient-to-patient transmission as previously thought. This along with the emergence of new organisms such as Candida auris may indicate that infection prevention interventions should be all-encompassing rather than organism-specific in focus.

Summary

Whole genome sequencing technologies are providing a level of detail in assessing organism relatedness that is changing our understanding of the transmission of infections in healthcare settings and may impact infection prevention strategies in the future.

Purpose of Review

This review outlines the process of setting and revising Clinical and Laboratory Standards Institute (CLSI) breakpoints and summarizes breakpoints approved in 2023. These breakpoints will be published in the 2024 edition of the CLSI M100 document.

Recent Findings

Over the past decade, new rapid diagnostic tests and antibiotic approvals have led to more frequent updates and revisions to clinical breakpoints—or susceptibility test interpretive criteria (STIC). CLSI is currently the only recognized standards development organization—outside of the FDA—allowed to set or revise STIC. The process of setting breakpoints is not always clear-cut because data evaluation can be limited by a lack of published data in one of three required categories (microbiologic, pharmacokinetic/pharmacodynamics, and clinical outcomes) detailed in the CLSI M23 document.

Summary

Antimicrobial susceptibility testing is a foundation for optimal antimicrobial therapy and plays a critical role in monitoring the spread of antimicrobial resistance.

Purpose of Review

We aim to provide valuable insights into the current state of therapeutic development for the deadly Marburg virus and guide researchers and clinicians to study the emerging therapies and shape future directions against this deadly virus.

Recent Findings

We find considerable progress in understanding the molecular biology and pathogenesis of the Marburg virus, leading to the identification of small-molecule antivirals and host-targeted approaches, including RNA polymerase inhibitors, viral entry inhibitors, and RNA interference therapies. However, there are very few ongoing clinical trials on the therapy/vaccine development against Marburg virus. Some of the potential studied candidates are chimpanzee adenovirus type 3, modified vaccinia Ankara, Marburg DNA plasmid vaccine, antisense phosphorodiamidate morpholino oligomers, and galidesivir. Yet, there are no approved vaccines or drugs against Marburg virus due to the viral genetic variability.

Summary

Extensive efforts and global awareness in the scientific society are requisite to develop preventive and therapeutic measures focusing on combinatorial formulations against Marburg virus.