Early antibiotic therapy for patients with severe infections is essential to improve outcomes. Conversely, use of overly broad antibiotic therapy for susceptible pathogens or unnecessary antibiotics in patients without bacterial infections is associated with adverse life-threatening events and superinfections. Antibiotics-induced changes in the human microbiota alter both immune and metabolic systems. Uncontrolled antibiotic use encourages emergence of antibiotic-resistant organisms. Around 50

Abstract Background The incidence of Staphylococcus aureus bacteremia (SAB) remains ∼25 cases/100,000 population, and methicillin-resistant S. aureus (MRSA) causes ∼1/2 of all SAB. Historically, mortality has served as the primary gauge for SAB’s outcomes, potentially neglecting other important unfavorable outcomes (UO) that contribute to its morbidity. We developed a multifaceted definition for UOs in SAB and examined their prevalence and early predictors. Methods We included adult hospitalized patients with at least one positive blood culture (BC) for S. aureus in a large US database (∼300 hospitals, 2020-2022). We defined UO as at least one of the following: hospital mortality, antibiotic escalation, persistently positive BCs, prolonged post-infection length of stay (LOS), or readmission within 30 days after discharge. All other outcomes were classified as favorable (FO). We used descriptive statistics to compare patients with UO and FO, and applied multiple regression models to identify factors associated with UOs. Results Among 4,080 patients with SAB, 2,427 (59.5%) suffered an UO. The most common UOs were disease worsening and need for vasopressors (Figure 1). Those with UOs were more likely to be non-White and suffered from a higher co-morbidity burden (Table 1). During hospitalization and prior to the onset of SAB, those with UOs more frequently required an ICU stay and dialysis. The majority of SABs were community-onset, and similarly distributed in the groups. UOs occurred in 66.1% of patients with MRSA vs. 55.2% with MSSA. Vancomycin was the leading empiric drug administered, followed by cefazolin. Daptomycin was used infrequently, and the rate of delayed therapy was low. The unadjusted post-infection hospital LOS and costs were significantly higher with UOs (Table 1). The variables with the highest odds ratios predicting an UO were the presence of septic shock on admission, empiric treatment with daptomycin, and the presence of complicated SAB (Table 3). Conclusion UOs occur frequently in SABs. A broader perspective exploring issues other than mortality demonstrates the substantial implications of SAB both for patients and healthcare systems. Select clinical variables are associated with UOs, some of which may not be modifiable. Disclosures Marya D. Zilberberg, MD, MPH, Basilea Pharmaceutica International Ltd, Allschwil, Switzerland: Grant/Research Support Brian H. Nathanson, Ph.D., MERCK: Advisor/Consultant Rolf J. Wagenaar, MS, Basilea: Advisor/Consultant Jan Posthumus, PhD, MBA, Basilea Pharmaceutica International., Alschwil Ltd: Honoraria|Basilea Pharmaceutica International., Alschwil Ltd: Stocks/Bonds (Public Company) Andrew Shorr, MD, MPH, MBA, Basilea: Advisor/Consultant|Basilea: Grant/Research Support

To combat antimicrobial resistance (AMR), advocates have called for passage of the Pioneering Antimicrobial Subscriptions To End Upsurging Resistance (PASTEUR) Act in the United States, which would appropriate $6 billion in new taxpayer-funded subsidies for antibiotic development. However, the number of antibiotics in clinical development, and US Food and Drug Administration approvals of new antibiotics, have already markedly increased in the last 15 years. Thus, instead of focusing on more economic subsidies, we recommend reducing selective pressure driving AMR by (1) establishing pay-for-performance mechanisms that disincentivize overprescribing of antibiotics, (2) focusing existing research and development funding on strategies that decrease reliance on antibiotics, and (3) changing regulation or law to require specialized training in antibiotic stewardship for a clinician to be able to prescribe new antibiotics that target unmet AMR need. To stabilize the antibiotic market, we recommend (1) establishment of an advisory board of clinical practitioners to more accurately target existing antibiotic incentives and (2) endowment of nonprofit companies that sustainably self-fund antibiotic discovery, creating a bench of molecules that can be partnered with industry at later stages of development.

Background: In the US, 120,000 cases of Staphylococcus aureus bacteremia (SAB) occur annually. Apart from mortality, little is known about other unfavorable outcomes (UOs). We developed a multifaceted definition for UOs in SAB and examined their incidence and predictors. Methods: We conducted a multicenter (~300 hospitals) retrospective cohort study between 2020 and 2022 of adult hospitalized patients with at least one blood culture (BC) positive for S. aureus. UOs were any of the following: hospital mortality, antibiotic escalation, persistently positive BCs, prolonged post-infection length of stay (LOS), 30-day readmission, and disease worsening. We compared the group with UOs to favorable outcomes (FOs). Regression models identified predictors of UOs. Results: Among 4080 patients with SAB, 2427 (59.5%) experienced a UO, most commonly 30-day readmission (42.0%) and antibiotic escalation (37.7%). Those with UOs more frequently had septic shock at admission (5.7% vs. 1.2%), requiring the ICU (18.8% vs. 14.7%) and dialysis (4.4% vs. 1.9%) prior to SAB onset. Community-onset SAB predominated in both groups, with more complicated SAB in the UO group (39.8% vs. 22.3%). Vancomycin use was similar, while daptomycin was more common in the UO group (8.5% vs. 3.0%). Variables with the highest odds ratios predicting a UO were septic shock on admission (3.498, 95% CI 2.145, 5.704), empiric daptomycin (2.723, 95% CI 1.943, 3.821), and complicated SAB (2.476, 95% CI 2.047, 2.994). Conclusions: UOs occur frequently in the setting of SAB. A broader perspective exploring issues other than mortality demonstrates the substantial implications of SAB both for patients and healthcare systems. Select clinical variables are associated with UOs, some of which may not be modifiable.

Background/Objectives: Meropenem-vaborbactam (MEV) and ceftazidime-avibactam (CZA) are active against "urgent threat" pathogens like carbapenem-resistant Enterobacterales (CRE). However, few studies have compared outcomes between them. Methods: To explore comparative outcomes of MEV vs. CZA, we conducted a multicenter retrospective cohort study of all adult hospitalized patients with a serious infection (sepsis, urinary tract infection [UTI], complicated intraabdominal [cIAI] infection, or pneumonia) within the PINC AI Database, 2019-2021. Descriptive statistics compared the two groups along demographic and clinical characteristics, and multiple regression derived adjusted outcomes. Results: Among 1,989,765 patients who met enrollment criteria, 455 received MEV and 2320 CZA. Compared to CZA, patients on MEV were more commonly Caucasian (68.1% vs. 63.6%, p = 0.032) or Hispanic (21.8% vs. 12.8%, p < 0.001). Their mean [SD] Charlson comorbidity scores did not differ (3.6 [2.5] vs. 3.5 [2.5], p = 0.403). The most common index infection in both groups was pneumonia, though it was less prevalent in the MEV- than the CZA-treated group (48.1% vs. 56.8%, p = 0.001). Fewer than one-third of all patients received the respective drug within 2 days of the onset of the index infection (30.6% MEV vs. 33.0% CZA, p = 0.313). Fewer patients on MEV than CZA required mechanical ventilation (35.0% vs. 41.4%, p = 0.010). MEV treatment was associated with lower adjusted mortality (17.0% [95% CI 13.6%, 20.3%] vs. 20.6% [95% CI 19.0%, 22.2%], p = 0.048) relative to CZA. Conclusions: In this cohort of hospitalized patients treated with either MEV or CZA for their infectious syndrome, MEV was associated with lower adjusted hospital mortality, although the confidence intervals around the values overlapped.

Acinetobacter baumannii complex (ABC) can result in a panoply of severe syndromes, including pneumonia and septic shock. Options available for treating infections caused by ABC and, more importantly, by carbapenem-resistant ABC (CRAB) are limited because of the increasing prevalence of antimicrobial resistance. Furthermore, many older agents, such as polymyxin and colistin, have limited lung penetration and are associated with significant toxicities. These factors underscore the urgent need for new paradigms to address ABC and CRAB. Two agents, cefiderocol and sulbactam-durlobactam, are now available to treat CRAB infections. In addition, several anti-infectives that target CRAB are in later-stage clinical trials. In order to place these newer molecules in context and to help clinicians appreciate the emerging potential drug development pipeline, we describe the in vitro activity, mechanisms of action, and clinical trial data not only for the commercially now available alternatives, such as cefiderocol and sulbactam-durlobactam, but also review these topics for molecules undergoing phase II and III clinical trials. Specifically, we discuss and analyze data related to four novel drugs from ABC: BV-100, cefepime-zidebactam, zosurabalpin, and OMN6.

BACKGROUND:Ceftobiprole was non-inferior to comparators for the treatment of Staphylococcus aureus bloodstream infection (bacteraemia) (SAB), acute bacterial skin and skin structure infection (ABSSSI), and community-acquired bacterial pneumonia (CABP), leading to regulatory approval for these indications. Whether dosing should be modified for patients with obesity is unknown. OBJECTIVES:This post hoc analysis evaluated the relationship of obesity and clinical outcomes in patients treated with ceftobiprole for SAB, ABSSSI or CABP. METHODS:Efficacy and safety outcomes were assessed based on BMI from three registrational clinical trials that evaluated ceftobiprole against comparators. RESULTS:Overall, 1641 patients were included from the three Phase 3 clinical trials (802 ceftobiprole; 839 comparators). When stratifying by BMI, ceftobiprole had similar outcomes to the overall ceftobiprole population (80.4%) including patients with obesity (BMI = 30-40 kg/m2) (81.7%). Severe obesity (BMI ≥ 40 kg/m2) was associated with decreased clinical cure rates overall (68.2%) compared with the overall ceftobiprole population, and this was especially noted in the clinically evaluable patient population with CABP receiving ceftobiprole (66.7% in severe obesity versus 86.6% overall). This was also seen in the comparator group (33.3% in severe obesity versus 87.4% overall). However, the number of patients with severe obesity was low in the CABP trial. The safety profile was similar between treatment groups in all studies and not influenced by BMI. CONCLUSIONS:This analysis further supports the efficacy and safety of ceftobiprole at current recommended doses in obese patients with SAB, ABSSSI or CABP.

Background: Community-acquired bacterial pneumonia (CABP) is a common and costly cause of hospitalization. Although severe CABP (sCABP) occurs in 10–25% of all pneumonia hospitalizations, little generalizable data examine its characteristics and outcomes or hospital resource utilization. Methods: We conducted a retrospective single-group cohort study of adults within the IQVIA hospital Charge Data Master, 2018–2022. We identified CABP via an ICD-10 code algorithm and sCABP was defined as an episode requiring ICU care. We examined baseline characteristics and outcomes, including mortality, costs, and readmission rates. We developed models to identify risk factors associated with readmissions. Results: Among 24,149 patients with sCABP, 14,266 (58.4%) were ≥65 years old and 55.2% were male. The majority were hospitalized in large (300+ beds, 50.9%), urban (91.9%) teaching (62.7%) institutions in the US Southern region (52.3%). The mean (SD) Charlson Comorbidity Index was 1.35 (2.33). The most common comorbidities were hypertension (16.7%), diabetes mellitus (15.7%), and chronic obstructive pulmonary disease (COPD) (12.9%). Hospital mortality was 15.9%. The mean (SD) hospital length of stay (LOS) and costs were 13.6 (12.1) and USD 91,965 (USD 133,734), respectively. An amount of 20% required a readmission within 30 days. Readmission was most strongly associated with older age and the presence of select comorbidities (diabetes mellitus, congestive heart failure, and COPD), each with an odds ratio > 1.4 and 95% confidence intervals excluding 1.0. Conclusions: Patients with sCABP comprise a large population with high mortality and 30-day readmissions. The intrinsic factors related to the latter lend themselves to early recognition and aggressive efforts at reducing complications.

BACKGROUND:Ceftobiprole is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus, resistant pneumococci, and Enterobacterales. In a Phase 3 study in community-acquired bacterial pneumonia (CABP) performed prior to the current US Food and Drug Administration (FDA) guidance, clinical cure at the test-of-cure visit (TOC) was the primary endpoint. We present a re-analysis using early clinical success as the primary endpoint per the 2020 FDA CABP Guidance. METHODS:In this multicenter, double-blind study, patients with CABP requiring hospitalization were randomized to intravenous ceftobiprole (500 mg q8h) or ceftriaxone (2000 mg q24h) ± linezolid (600 mg q12h) for 3-14 days. The primary endpoint was clinical success at Day 3 (improvement in ≥2 symptoms of chest pain, cough, productive sputum, difficulty breathing). A 12.5% non-inferiority margin was used. RESULTS:Of the original 638 patients, 618 (97%) had ≥ 2 symptoms and were included in the Day 3 Intent-to-Treat (ITT) population for the re-analysis. The Day 3 modified ITT population consisted of 187 patients (29%) meeting additional FDA Guidance including Patient Outcomes Research Team (PORT) classification ≥III. Ceftobiprole was non-inferior to ceftriaxone for clinical success for Day 3 ITT (71.0% vs 71.1%) and Day 3 modified ITT (71.1% vs 66.7%) populations. The 28-day all-cause mortality was 1.6% (ceftobiprole) vs 2.6% (ceftriaxone) in the Day 3 ITT population and 2.1% vs 7.8% in the Day 3 modified ITT population. CONCLUSION:Ceftobiprole was non-inferior to ceftriaxone ± linezolid for clinical success at Day 3 according to the current 2020 FDA CABP Guidance.

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.

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.

Zilberberg, Marya1; Nathanson, Brian2; Redell, Mark3; Sulham, Kate3; Shorr, Andrew4 Author Information

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.