Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence.

Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug-drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS-NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE-CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.

A Least Absolute Shrinkage and Selection Operator-Derived Predictive Model for Postoperative Respiratory Failure in a Heterogeneous Adult Elective Surgery Patient Population.

BACKGROUND: Postoperative respiratory failure (PRF) is associated with increased hospital charges and worse patient outcomes. Reliable prediction models can help to guide postoperative planning to optimize care, to guide resource allocation, and to foster shared decision-making with patients. RESEARCH QUESTION: Can a predictive model be developed to accurately identify patients at high risk of PRF? STUDY DESIGN AND METHODS: In this single-site proof-of-concept study, we used structured query language to extract, transform, and load electronic health record data from 23,999 consecutive adult patients admitted for elective surgery (2014-2021). Our primary outcome was PRF, defined as mechanical ventilation after surgery of > 48 h. Predictors of interest included demographics, comorbidities, and intraoperative factors. We used logistic regression to build a predictive model and the least absolute shrinkage and selection operator procedure to select variables and to estimate model coefficients. We evaluated model performance using optimism-corrected area under the receiver operating curve and area under the precision-recall curve and calculated sensitivity, specificity, positive and negative predictive values, and Brier scores. RESULTS: Two hundred twenty-five patients (0.94%) demonstrated PRF. The 18-variable predictive model included: operations on the cardiovascular, nervous, digestive, urinary, or musculoskeletal system; surgical specialty orthopedic (nonspine); Medicare or Medicaid (as the primary payer); race unknown; American Society of Anesthesiologists class ≥ III; BMI of 30 to 34.9 kg/m2; anesthesia duration (per hour); net fluid at end of the operation (per liter); median intraoperative FIO2, end title CO2, heart rate, and tidal volume; and intraoperative vasopressor medications. The optimism-corrected area under the receiver operating curve was 0.835 (95% CI,0.808-0.862) and the area under the precision-recall curve was 0.156 (95% CI, 0.105-0.203). INTERPRETATION: This single-center proof-of-concept study demonstrated that a structured query language extract, transform, and load process, based on readily available patient and intraoperative variables, can be used to develop a prediction model for PRF. This PRF prediction model is scalable for multicenter research. Clinical applications include decision support to guide postoperative level of care admission and treatment decisions.

The pharmacotherapeutic options in patients with catecholamine-resistant vasodilatory shock.

INTRODUCTION: Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure. AREAS COVERED: VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP. EXPERT OPINION: Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

Real-world impact of vaccination on coronavirus disease 2019 (COVID-19) incidence in healthcare personnel at an academic medical center.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) vaccination effectiveness in healthcare personnel (HCP) has been established. However, questions remain regarding its performance in high-risk healthcare occupations and work locations. We describe the effect of a COVID-19 HCP vaccination campaign on SARS-CoV-2 infection by timing of vaccination, job type, and work location. METHODS: We conducted a retrospective review of COVID-19 vaccination acceptance, incidence of postvaccination COVID-19, hospitalization, and mortality among 16,156 faculty, students, and staff at a large academic medical center. Data were collected 8 weeks prior to the start of phase 1a vaccination of frontline employees and ended 11 weeks after campaign onset. RESULTS: The COVID-19 incidence rate among HCP at our institution decreased from 3.2% during the 8 weeks prior to the start of vaccinations to 0.38% by 4 weeks after campaign initiation. COVID-19 risk was reduced among individuals who received a single vaccination (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.40-0.68; P < .0001) and was further reduced with 2 doses of vaccine (HR, 0.17; 95% CI, 0.09-0.32; P < .0001). By 2 weeks after the second dose, the observed case positivity rate was 0.04%. Among phase 1a HCP, we observed a lower risk of COVID-19 among physicians and a trend toward higher risk for respiratory therapists independent of vaccination status. Rates of infection were similar in a subgroup of nurses when examined by work location. CONCLUSIONS: Our findings show the real-world effectiveness of COVID-19 vaccination in HCP. Despite these encouraging results, unvaccinated HCP remain at an elevated risk of infection, highlighting the need for targeted outreach to combat vaccine hesitancy.

Global travel and Gram-negative bacterial resistance; implications on clinical management.

INTRODUCTION: Antimicrobial resistance (AR) is escalating worldwide with the potential for dire consequences, global travel contributes to the dissemination of resistant pathogens from one region to another. The World Health Organization identified the rapid emergence and prevalence of carbapenem-resistant Gram-negative species, including Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa, as an international crisis due to treatment challenges, poor health outcomes, increased mortality, and high economic costs caused by these pathogens. AREAS COVERED: This review describes key carbapenem-resistant (CR) Gram-negative species, changes in current global and regional trends, AR surveillance and reporting, and identifies drivers of change, specifically travel. Finally, we review clinical implications and challenges of treating CR infections which exist due to widespread dissemination of CR bacteria. A literature search was conducted using PubMed, Google Scholar, Ebsco, and ProQuest (from 2000 to December 2019). EXPERT OPINION: The level of global travel is increasing, and antimicrobial resistance continues to disseminate worldwide. Healthcare providers risk assessment for AR needs to consider a patient's recent travel history, including pre-travel and intra-travel antimicrobial prescription, and potential exposure based on geography. Patient education, healthcare provider awareness, and access to data and surveillance resources are critical to inform antimicrobial selection and improve health outcomes.

Community-Acquired Bacterial Pneumonia-Changing Epidemiology, Resistance Patterns, and Newer Antibiotics: Spotlight on Delafloxacin.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality both in the USA and globally. As the burden of CAP continues to increase due to several factors, the advances in its diagnosis, prevention, and treatment have taken on even greater interest and importance. The majority of CAP patients are treated empirically, and selection of appropriate antibiotic treatment is increasingly difficult because the epidemiology of CAP is changing, in part due to antimicrobial resistance, and the causative CAP pathogens differ between countries and regions. There is also an increasing prevalence of chronic co-morbid diseases among CAP patients. Treatment of CAP has become challenging because of these factors along with the varying safety profiles and efficacy of well-established antibiotics, as well as limited new therapeutic options. Recently, however, new antibiotics have been approved, which will expand the treatment options for CAP, particularly in those patients with underlying complications. Recently approved delafloxacin, an anionic fluoroquinolone, has a unique structure and distinct chemical characteristics; it demonstrated non-inferiority to moxifloxacin in a phase III clinical trial, but was shown to be superior to moxifloxacin at early clinical response in CAP patients who also have chronic obstructive pulmonary disease (COPD) or asthma as a co-morbidity, and in CAP patients who may have severe illness. Delafloxacin could offer an additional therapy against resistant isolates and among these difficult-to-treat patients. This review summarizes the development, latest research, and safety profile of the new antibiotic delafloxacin, and its potential future role in the treatment of CAP.

The role of telavancin in hospital-acquired pneumonia and ventilator-associated pneumonia.

Hospital-acquired pneumonia (HAP) due to gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of morbid conditions and death. Telavancin is a lipoglycopeptide antibiotic with potent in vitro activity against a range of gram-positive pathogens, including MRSA, methicillin-susceptible S. aureus, and Streptococcus species. In 2 phase 3 clinical trials, telavancin was noninferior to vancomycin in patients with HAP due to gram-positive pathogens. Clinically evaluable patients with S. aureus as the sole pathogen or S. aureus with a vancomycin minimum inhibitory concentration >1 µg/mL, however, had higher cure rates with telavancin than with vancomycin. In patients with bacteremic HAP, telavancin resulted in clearance of blood cultures. It was associated with increased serum creatinine levels and higher mortality rates in patients with moderate to severe renal impairment at baseline; however, on subsequent analysis, the outcomes seemed to have been at least partially affected by the adequacy of empiric gram-negative antimicrobial therapy. Thus, clinicians need to consider the risk-benefit balance when choosing telavancin in patients with severe renal impairment at baseline. Overall, these data support the use of telavancin in the treatment of HAP due to S. aureus, including MRSA and strains with elevated vancomycin minimum inhibitory concentrations, but clinicians should always weigh the risks and benefits of various treatment options.

Infection in severe asthma exacerbations and critical asthma syndrome.

In chronic persistent asthma and severe acute exacerbations of bronchial asthma, infectious agents are the predominant triggers that drive disease and airway pathobiology. In acute exacerbations of bronchial asthma (AEBA) including near fatal and fatal asthma, viral agents, particularly human rhinovirus-C, respiratory syncytial virus and influenza A appear to be the more prevalent and recurring threats. Both viral, and to a lesser extent bacterial agents, can play a role, and co-infection may also be present and worsen prognosis in hospitalized patients, placing a portion at risk for critical asthma syndrome. During severe acute exacerbations, infectious agents must be treated empirically, but the initial treatment regimens can vary and viral coverage may also vary based on seasonality and patient age. Early treatment with ceftriaxone and azithromycin, along with oseltamivir in winter months, should be initiated with all cases of severe exacerbations where infection is suspected, and definitely in critical asthma syndrome until infection is excluded by appropriate diagnostic testing. In this manuscript we will outline the impact of the major viral agents on severe asthma including the data from the 2009 H1N1 influenza pandemic. The role of bacterial infections in acute exacerbations of asthma will also be reviewed as well as the benefit of empiric antibiotics and the role of macrolides in both acute and chronic asthma.

Cellular scent of influenza virus infection.

Volatile organic compounds (VOCs) emanating from humans have the potential to revolutionize non-invasive diagnostics. Yet, little is known about how these compounds are generated by complex biological systems, and even less is known about how these compounds are reflective of a particular physiological state. In this proof-of-concept study, we examined VOCs produced directly at the cellular level from B lymphoblastoid cells upon infection with three live influenza virus subtypes: H9N2 (avian), H6N2 (avian), and H1N1 (human). Using a single cell line helped to alleviate some of the complexity and variability when studying VOC production by an entire organism, and it allowed us to discern marked differences in VOC production upon infection of the cells. The patterns of VOCs produced in response to infection were unique for each virus subtype, while several other non-specific VOCs were produced after infections with all three strains. Also, there was a specific time course of VOC release post infection. Among emitted VOCs, production of esters and other oxygenated compounds was particularly notable, and these may be attributed to increased oxidative stress resulting from infection. Elucidating VOC signatures that result from the host cells response to infection may yield an avenue for non-invasive diagnostics and therapy of influenza and other viral infections.

Characterization of volatile organic compounds in human leukocyte antigen heterologous expression systems: a cell's "chemical odor fingerprint".

The major histocompatibility complex (MHC), or human leukocyte antigen (HLA) gene-coding region in humans, plays a significant role in infectious disease response, autoimmunity, and cellular recognition. This super locus is essential in mate selection and kin recognition because of the organism-specific odor which can be perceived by other individuals. However, how the unique MHC genetic combination of an organism correlates with generation of the organism-specific odor is not well understood. In the present work, we have shown that human B-cells produce a set of volatile organic compounds (VOCs) that can be measured by GC-MS. More importantly, our results show that specific HLA alleles are related to production of selected VOCs, and that this leads to a cell-specific odor "fingerprint". We used a C1R HLA class I A and B locus negative cell line, along with C1R cell lines that were stably transfected with specific A and B alleles. Our work demonstrates for the first time that HLA alleles can directly influence production of specific odor compounds at the cellular level. Given that the resulting odor fingerprint depends on expression of specific HLA sequences, it may yield information on unique human scent profiles, composition of exhaled breath, as well as immune response states in future studies.

WiFi RFID demonstration for resource tracking in a statewide disaster drill.

OBJECTIVE: To investigate the capabilities of Radio Frequency Identification (RFID) tracking of patients and medical equipment during a simulated disaster response scenario. DESIGN: RFID infrastructure was deployed at two small rural hospitals, in one large academic medical center and in two vehicles. Several item types from the mutual aid equipment list were selected for tracking during the demonstration. A central database server was installed at the UC Davis Medical Center (UCDMC) that collected RFID information from all constituent sites. The system was tested during a statewide disaster drill. During the drill, volunteers at UCDMC were selected to locate assets using the traditional method of locating resources and then using the RFID system. RESULTS: This study demonstrated the effectiveness of RFID infrastructure in real-time resource identification and tracking. Volunteers at UCDMC were able to locate assets substantially faster using RFID, demonstrating that real-time geolocation can be substantially more efficient and accurate than traditional manual methods. A mobile, Global Positioning System (GPS)-enabled RFID system was installed in a pediatric ambulance and connected to the central RFID database via secure cellular communication. This system is unique in that it provides for seamless region-wide tracking that adaptively uses and seamlessly integrates both outdoor cellular-based mobile tracking and indoor WiFi-based tracking. CONCLUSIONS: RFID tracking can provide a real-time picture of the medical situation across medical facilities and other critical locations, leading to a more coordinated deployment of resources. The RFID system deployed during this study demonstrated the potential to improve the ability to locate and track victims, healthcare professionals, and medical equipment during a region-wide disaster.

Zoonotic pathogens isolated from wild animals and environmental samples at two California wildlife hospitals.

OBJECTIVE: To determine types and estimate prevalence of potentially zoonotic enteric pathogens shed by wild animals admitted to either of 2 wildlife hospitals and to characterize distribution of these pathogens and of aerobic bacteria in a hospital environment. DESIGN: Cross-sectional study. SAMPLE: Fecal samples from 338 animals in 2 wildlife hospitals and environmental samples from 1 wildlife hospital. PROCEDURES: Fecal samples were collected within 24 hours of hospital admission. Environmental samples were collected from air and surfaces. Samples were tested for zoonotic pathogens via culture techniques and biochemical analyses. Prevalence of pathogen shedding was compared among species groups, ages, sexes, and seasons. Bacterial counts were determined for environmental samples. RESULTS: Campylobacter spp, Vibrio spp, Salmonella spp, Giardia spp, and Cryptosporidium spp (alone or in combination) were detected in 105 of 338 (31%) fecal samples. Campylobacter spp were isolated only from birds. Juvenile passerines were more likely to shed Campylobacter spp than were adults; prevalence increased among juvenile passerines during summer. Non-O1 serotypes of Vibrio cholerae were isolated from birds; during an oil-spill response, 9 of 10 seabirds screened were shedding this pathogen, which was also detected in environmental samples. Salmonella spp and Giardia spp were isolated from birds and mammals; Cryptosporidium spp were isolated from mammals only. Floors of animal rooms had higher bacterial counts than did floors with only human traffic. CONCLUSIONS AND CLINICAL RELEVANCE: Potentially zoonotic enteric pathogens were identified in samples from several species admitted to wildlife hospitals, indicating potential for transmission if prevention is not practiced.

Controversies in the treatment of sepsis.

Sepsis is a common illness of intensive care unit patients that carries a high morbidity, mortality, and increases hospital cost. Although mortality from sepsis remains high when compared with other critical illnesses, it has declined over the last few decades due to several adjunctive therapies and focused care programs or guidelines. Many interventions, such as early appropriate antibiotic therapy and lung protective, low tidal volume ventilation are commonplace and carry little controversy in their benefit. However, other therapies still have an unclear benefit and remain controversial. This article discusses the controversial roles of intensive insulin therapy, corticosteroids, and activated protein C in the treatment of sepsis.

Avian influenza in birds and mammals.

The disease syndromes caused by avian influenza viruses are highly variable depending on the host species infected, its susceptibility and response to infection and the virulence of the infecting viral strain. Although avian influenza viruses have a broad host range in general, it is rare for an individual strain or subtype to infect more than one species. The H5N1 highly pathogenic avian influenza virus (HPAIV) lineages of viruses that descended from A/goose/Guandong/96 (H5N1 HPAIV) are unusual in the diversity of species they have infected worldwide. Although the species affected by H5N1 HPAI in the field and those that have been experimentally studied are diverse, their associated disease syndromes are remarkably similar across species. In some species, multi-organ failure and death are rapid and no signs of the disease are observed. Most prominently in this category are chickens and other avian species of the order Galliformes. In other species, neurologic signs develop resulting in the death of the host. This is what has been reported in domestic cats (Carnivora), geese (Anseriformes), ratites (Struthioniformes), pigeons inoculated with high doses (Columbiformes) and ducks infected with H5N1 HPAIV isolated since 2002 (Anseriformes). In some other species, the disease is more prolonged and although multi-organ failure and death are the eventual outcomes, the signs of disease are more extensive. Predominantly, these species include humans (Primates) and the laboratory models of human disease, the ferret (Carnivora), mouse (Rodentia) and cynamologous macaques (Primates). Finally, some species are more resistant to infection with H5N1 HPAIV and show few or no signs of disease. These species include pigeons in some studies (Columbiformes), ducks inoculated with pre-2002 isolates (Anseriformes), and pigs (Artiodactyla).

Bench-to-bedside review: the role of nitric oxide in sepsis.

Sepsis is a state of systemic inflammation directed at microbes or their toxins in blood or tissues. Nitric oxide (NO) is one of many vasoactive molecules released from a variety of cell types during sepsis. Almost two decades ago, NO emerged as a potential therapeutic target in sepsis. NO produced by the constitutive NO synthase (NOS) isoform (endothelial NOS and neuronal NOS) in the vascular endothelium and elsewhere acts as a nonadrenergic, noncholinergic neurotransmitter, an inhibitor of platelet aggregation and a vasodilator. During sepsis, activation of inducible NOS (iNOS) in the lung epithelium and other organs occurs, leading to NO overproduction. The result of excessive circulating NO is enhanced bacterial destruction, but also profound vasodilatation, activation of inflammatory cascades and depression of cardiac function. Trials of nonselective NOS inhibitors have shown increased mean arterial pressure, but also increased pulmonary artery pressure and reduced cardiac output. Small animal studies of iNOS selective inhibition have produced dichotomous results, but larger clinical studies assessing mortality are lacking. Inhaled NO has been touted as a therapeutic option to improve systemic oxygenation in the acute lung injury of sepsis (hypoxic pulmonary vasoconstriction and pulmonary hypertension); however, studies of inhaled NO in acute respiratory distress syndrome have not shown survival efficacy. Further investigation into the role of NO in human sepsis, and the development of methods to assess NO balance in patients with sepsis is essential in this field. In this review, we outline the effects of NO in sepsis, and summarize the therapeutic outcomes of NOS inhibitors, and inhaled NO in sepsis and acute respiratory distress syndrome.

Avian flu school: a training approach to prepare for H5N1 highly pathogenic avian influenza.

Since the reemergence of highly pathogenic avian influenza (H5N1 HPAI) in 2003, a panzootic that is historically unprecedented in the number of infected flocks, geographic spread, and economic consequences for agriculture has developed. The epidemic has affected a wide range of birds and mammals, including humans. The ineffective management of outbreaks, mainly due to a lack of knowledge among those involved in detection, prevention, and response, points to the need for training on H5N1 HPAI. The main challenges are the multidisciplinary approach required, the lack of experts, the need to train at all levels, and the diversity of outbreak scenarios. Avian Flu School addresses these challenges through a three-level train-the-trainer program intended to minimize the health and economic impacts of H5N1 HPAI by improving a community's ability to prevent and respond, while protecting themselves and others. The course teaches need-to-know facts using highly flexible, interactive, and relevant materials.

Definitive care for the critically ill during a disaster: a framework for allocation of scarce resources in mass critical care: from a Task Force for Mass Critical Care summit meeting, January 26-27, 2007, Chicago, IL.

BACKGROUND: Anticipated circumstances during the next severe influenza pandemic highlight the insufficiency of staff and equipment to meet the needs of all critically ill victims. It is plausible that an entire country could face simultaneous limitations, resulting in severe shortages of critical care resources to the point where patients could no longer receive all of the care that would usually be required and expected. There may even be such resource shortfalls that some patients would not be able to access even the most basic of life-sustaining interventions. Rationing of critical care in this circumstance would be difficult, yet may be unavoidable. Without planning, the provision of care would assuredly be chaotic, inequitable, and unfair. The Task Force for Mass Critical Care Working Group met in Chicago in January 2007 to proactively suggest guidance for allocating scarce critical care resources. TASK FORCE SUGGESTIONS: In order to allocate critical care resources when systems are overwhelmed, the Task Force for Mass Critical Care Working Group suggests the following: (1) an equitable triage process utilizing the Sequential Organ Failure Assessment scoring system; (2) the concept of triage by a senior clinician(s) without direct clinical obligation, and a support system to implement and manage the triage process; (3) legal and ethical constructs underpinning the allocation of scarce resources; and (4) a mechanism for rapid revision of the triage process as further disaster experiences, research, planning, and modeling come to light.