Improving Outcomes in Nosocomial Pneumonia: Recent Evidence and More Challenges.

Nosocomial pneumonia (NP) represents a leading nosocomial infection and results in substantial morbidity and cost. Over the last several years, the evidence has evolved which directs our approach to NP. Specifically, the definition of NP and classification of its various subtypes has expanded to capture nuances among various phenotypes of this syndrome. For example, segregating those with hospital-acquired pneumonia (HAP) based on whether they subsequently require mechanical ventilation has been shown to be important. Likewise, newer data indicate the true economic cost of NP and underscore the diverse range of pathogens that can cause NP. Moreover, multidrug-resistant (MDR) bacteria have become a major threat in NP. Fortunately, newer simple preventive strategies have been tested and found to be effective at reducing the incidence of NP. Should prevention fail, a range of new antibiotics have been formally studied in NP and found to be effective. Some of these novel agents have relatively broad ranges of activity and are in vitro active against select MDR organisms. Others, however, are narrower in spectrum and directed against specific problem bacteria. In short, the literature in the field of NP has progressed rapidly, and clinicians require a clear appreciation of these changes so as to improve patient outcomes.

At the Intersection of Critical Care and Infectious Diseases: The Year in Review.

Severe infection represents a leading reason for admission to the intensive care unit (ICU) while nosocomial infection can arise as a complication of care in the ICU. The mortality and morbidity of such infections are substantial. These processes also put economic strain on the healthcare system. Additionally, the continued spread of antimicrobial resistance has made it more challenging both to prevent and treat severe infection. Until recently, there were few well-done trials addressing infection among the critically ill. However, over the last year, six important randomized studies have dealt with a range of topics at the intersection of infectious diseases and critical care. Our goal is to review these reports in order to clarify their major findings, significance, strengths, weaknesses, and clinical applications. Specifically, we explore and discuss six trials conducted in the areas of (1) prevention, (2) the present use of standard antimicrobials, and (3) novel adjunctive and antibiotic treatments. Through highlighting these trials, we hope to help clinicians apply their important findings in an evidence-based fashion at the bedside. It is through the application of key evidence that both infectious disease practitioners and intensivists can improve patient outcomes.

Bloodstream Infection in the Intensive Care Unit: Evolving Epidemiology and Microbiology.

Bloodstream infections (BSIs) arising in the intensive care unit (ICUs) present a significant challenge and we completed a narrative review of the emerging literature on this issue. Multiple reports document that these infections are associated with substantial morbidity and mortality. Also, they can be caused by a variety of pathogens. Generally classified as either community or hospital in onset, or as either primary or secondary in origin, the microbiology of ICU BSIs varies across the globe. Gram-positive pathogens predominate in certain regions such as the United States while Gram-negative organisms occur more frequently in Europe, Asia, and Latin America. The incidence of ICU BSIs climbed during the recent pandemic. BSIs complicating the care of persons suffering from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection significantly heighten the risk for death compared to patients who develop ICU BSIs but who are not infected with SARS-CoV-2. Furthermore, rates of antimicrobial resistance are generally increasing in ICU BSIs. This fact complicates attempts to ensure that the patient receives initially appropriate antimicrobial therapy and is of particular concern in Methicillin-resistant Staphylococcus aureus, Carbapenem-resistant Enterobacterales, and Acinetobacter baumannii. Fortunately, with respect to clinical application, preventive measures exist, and recent analyses suggest that increased collaboration between infectious disease specialists and intensivists can improve patient outcomes.

Examining the Burden of Potentially Avoidable Heart Failure Hospitalizations.

Background: Two-thirds of the 1 million annual US CHF hospitalizations are for diuresis only; some may be avoidable. We describe a population of low-severity short-stay (2. We compared baseline characteristics, processes of care, and outcomes in low-severity (CHF-L) to CHF-H. Results: Among 301,672 short-stay CHF patients, 135,304 (44.8%) were CHF-L. Compared to CHF-H, CHF-L was younger (70.5 ± 14.1 vs 72.1 ± 13.6 years, p < 0.001), more commonly female (48.6% vs 45.8%, p < 0.001), and more likely to receive IV ACE-I/ARB agents (0.5% vs 0.4%, p = 0.003). Most other IV medications were more common in CHF-H, and anticoagulation was the most prevalent non-diuretic IV therapy in both groups (23.8% vs 33.3%, p < 0.001). Hospital mortality (0.2% vs 1.5%, p < 0.001) and CHF-related 30-day readmissions (8.1% vs 10.5%, p < 0.001) were lower in CHF-L than CHF-H. Conclusion: Among short-stay CHF patients, nearly ½ meet criteria for CHF-L, and are mainly admitted for fluid management. Avoiding these admissions could result in substantial savings.

Healthcare Trajectories and Outcomes in the First Year After Tracheostomy Based on Patient Characteristics.

OBJECTIVES: To define healthcare trajectories after tracheostomy to inform shared decision-making efforts for critically ill patients. DESIGN: Retrospective epidemiologic cohort study. SETTING: California Patient Discharge Database 2018-2019. PATIENTS: Patients who received a tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tracked 1-year outcomes after tracheostomy, including survival and time alive in and out of a healthcare facility (HCF. Patients were stratified based on surgical status (did the patient require a major operating room procedure or not), age (65 yr old or older and less than 65 yr), pre-ICU comorbid states (frailty, chronic organ dysfunction, cancer, and robustness), and the need for dialysis during the tracheostomy admission. We identified 4,274 nonsurgical adults who received a tracheostomy during the study period with 50.9% being 65 years old or older. Among adults 65 years old or older, median survival after tracheostomy was less than 3 months for individuals with frailty, chronic organ dysfunction, cancer, or dialysis. Median survival was 3 months for adults younger than 65 years with cancer or dialysis. Most patients spent the majority of days alive after a tracheostomy in an HCF in the first 3 months. Older adults had very few days alive and out of an HCF in the first 3 months after tracheostomy. Most patients who ultimately died in the first year after tracheostomy spent almost all days alive in an HCF. CONCLUSIONS: Cumulative mortality and median survival after a tracheostomy were very poor across most ages and groups. Older adults and several subgroups of younger adults experienced high rates of prolonged hospitalization with few days alive and out of an HCF. This information may aid some patients, surrogates, and providers in decision-making.

Respiratory Viruses in Nosocomial Pneumonia: An Evolving Paradigm.

Nosocomial pneumonia (NP) represents a leading cause of morbidity and mortality in hospitalized patients. Historically, clinicians have considered hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), which comprise NP, to be essentially bacterial processes. As such, patients suspected of having either HAP or VAP are initially treated with broad-spectrum antibiotics, and few clinicians search for a possible culprit virus. Recent reports which build on earlier studies, however, indicate that viruses likely play an important role in NP. Studies employing viral diagnostics as part of the evaluation for NP indicate that common respiratory viruses can spread nosocomially and lead to HAP and VAP. Similarly, studies of the general epidemiology of respiratory viral infections, such as influenza, respiratory syncytial virus, adenovirus, and rhinovirus, confirm that these pathogens are important causes of NP, especially among immunosuppressed and pediatric patients. More importantly, these more contemporary analyses reveal that one cannot, based on clinical characteristics, distinguish a viral from a bacterial cause of NP. Additionally, viral HAP and VAP result in crude mortality rates that rival or exceed those reported in bacterial NP. Rigorous prospective, multicenter trials are needed to confirm the significance of respiratory viruses in NP, as are studies of novel therapeutics for these viral infections.

Bloodstream Infection and Gram-Negative Resistance: The Role for Newer Antibiotics.

Gram-negative resistance remains a major challenge. Rates of in vitro resistance to commonly utilized antibiotics have skyrocketed over the last decade. Clinicians now encounter multidrug-resistant organisms routinely. Fortunately, newer agents, such as ceftazidime-avibactam, ceftolozone-tazobactam, meropenem-vaborbactam, and cefiderocol, have been developed and are now available for use against these pathogens. Clinical trials with these novel therapies have focused on multiple infection types ranging from complicated urinary tract infections to nosocomial pneumonia. Nonetheless, there remains little information about the efficacy of these drugs for bacteremia. To better appreciate the types and limitations of the evidence supporting the role for these unique molecules in bloodstream infection, one requires an appreciation of the initial clinical trials supporting the regulatory approval of these antibiotics. Furthermore, physicians must understand the subsequent case series and reports specifically focusing on outcomes for patients with bacteremia treated with these drugs. Despite the limitations of the data and reports relating to treatment for bacteremia with these antibiotics, each agent appears to be efficacious and can provide good outcomes in bloodstream infections due to resistant pathogens.

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis.

Background: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making. Methods: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment. Results: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment. Conclusions: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL. Clinical Trials Registration: NCT02493764.

Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.