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.

Novel agents in development for multidrug-resistant Gram-negative infections: potential new options facing multiple challenges.

PURPOSE OF REVIEW: To review novel antiinfective agents in development for multidrug-resistant (MDR) Gram-negative bacterial infections. RECENT FINDINGS: Four novel agents are in various phases of development (tebipenem, durlobactam-sulbactam, cefepime-taniborbactam, and xeruborbactam). Tebpipenem is an oral carbapenem with a recently completed phase III trial for complicated urinary tract infections while durlobactam-sulbactam represents a potential alternative for drug-resistant Acinetobacter baumannii . Cefepime-taniborbactam possesses in-vitro potency against a range of troubling pathogens and we await further information on a recently completed study on complicated urinary tract infection. Finally, xeruborbactam is an ultrabroad beta-lactamase inhibitor that can be paired with a range of intravenous and oral agents. It exhibits enhanced in-vitro activity against many MDR pathogens, including those resistant to newer, broader spectrum options. Data in humans with xeruborbactam are limited. SUMMARY: Each of the newer options reviewed possesses a unique range of in-vitro activity against select, challenging pathogens with some narrowly tailored and other broader in activity. Several have both oral and intravenous formulations. Two agents have presented data from recent phase III trials, whereas two are not as advanced in their clinical programs.

Descriptive Epidemiology and Outcomes of Nonventilated Hospital-Acquired, Ventilated Hospital-Acquired, and Ventilator-Associated Bacterial Pneumonia in the United States, 2012-2019.

OBJECTIVES: Multiple randomized controlled trials exploring the outcomes of patients with ventilator-associated bacterial pneumonia and hospital-acquired bacterial pneumonia have noted that hospital-acquired bacterial pneumonia patients who require subsequent ventilated hospital-acquired bacterial pneumonia suffered higher mortality than either those who did not (nonventilated hospital-acquired bacterial pneumonia) or had ventilator-associated bacterial pneumonia. We examined the epidemiology and outcomes of all three conditions in a large U.S. database. DESIGN: Retrospective cohort. SETTING: Two hundred fifty-three acute-care hospitals, United States, contributing data (including microbiology) to Premier database, 2012-2019. PATIENTS: Patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia identified based on a slightly modified previously published International Classification of Diseases, 9th Edition/International Classification of Diseases, 10th Edition-Clinical Modification algorithm. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 17,819 patients who met enrollment criteria, 26.5% had nonventilated hospital-acquired bacterial pneumonia, 25.6% vHAPB, and 47.9% ventilator-associated bacterial pneumonia. Ventilator-associated bacterial pneumonia predominated in the Northeastern United States and in large urban teaching hospitals. Patients with nonventilated hospital-acquired bacterial pneumonia were oldest (mean 66.7 ± 15.1 yr) and most likely White (76.9%), whereas those with ventilator-associated bacterial pneumonia were youngest (59.7 ± 16.6 yr) and least likely White (70.3%). Ventilated hospital-acquired bacterial pneumonia was associated with the highest comorbidity burden (mean Charlson score 4.1 ± 2.8) and ventilator-associated bacterial pneumonia with the lowest (3.2 ± 2.5). Similarly, hospital mortality was highest among patients with ventilated hospital-acquired bacterial pneumonia (29.2%) and lowest in nonventilated hospital-acquired bacterial pneumonia (11.7%), with ventilator-associated bacterial pneumonia in-between (21.3%). Among survivors, 24.5% of nonventilated hospital-acquired bacterial pneumonia required a rehospitalization within 30 days of discharge, compared with 22.5% among ventilated hospital-acquired bacterial pneumonia and 18.8% ventilator-associated bacterial pneumonia. Unadjusted hospital length of stay after infection onset was longest among ventilator-associated bacterial pneumonia and shortest among nonventilated hospital-acquired bacterial pneumonia patients. Median total hospital costs mirrored length of stay: ventilator-associated bacterial pneumonia $77,657, ventilated hospital-acquired bacterial pneumonia $62,464, and nonventilated hospital-acquired bacterial pneumonia $39,911. CONCLUSIONS: Both hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia remain associated with significant mortality and cost in the United States. Our analyses confirm that of all three conditions, ventilated hospital-acquired bacterial pneumonia carries the highest risk of death. In contrast, ventilator-associated bacterial pneumonia remains most costly. Nonventilated hospital-acquired bacterial pneumonia survivors were most likely to require a readmission within 30 days of discharge.

The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012-2019.

BACKGROUND: Inappropriate empiric antimicrobial treatment (IET) contributes to worsened outcomes. While IET's differential impact across types of nosocomial pneumonia (NP: non-ventilated [nvHABP], ventilated [vHABP] hospital-acquired and ventilator-associated [VABP] bacterial pneumonia) is established, its potential interaction with the bacterial etiology is less clear. METHODS: We conducted a multicenter retrospective cohort study in the Premier Healthcare Database using an administrative algorithm to identify NP. We paired respective pathogens with empiric treatments. Antimicrobial coverage was appropriate if a drug administered within 2 days of infection onset covered the recovered organism(s). All other treatment was IET. RESULTS: Among 17,819 patients with NP, 26.5% had nvHABP, 25.6% vHABP, and 47.9% VABP. Gram-negative (GN) organisms accounted for > 50% of all infections. GN pathogens were ~ 2 × as likely (7.4% vHABP to 10.7% nvHABP) to engender IET than Gram-positive (GP, 2.9% vHABP to 4.9% nvHABP) pathogens. Although rare (5.6% nvHABP to 8.3% VABP), GN + GP infections had the highest rates of IET (6.7% vHABP to 12.9% nvHABP). Carbapenem-resistant GNs were highly likely to receive IET (33.8% nvHABP to 40.2% VABP). Hospital mortality trended higher in the IET group, reaching statistical significance in GN + GP vHABP (47.8% IET vs. 29.3% non-IET, p = 0.016). 30-day readmission was more common with IET (16.0%) than non-IET (12.6%, p = 0.024) in GN VABP. Generally post-infection onset hospital length of stay and costs were higher with IET than non-IET. CONCLUSIONS: IET is ~ 2 × more common in GN than GP infections. Although the magnitude of its impact varies by NP type, IET contributes to worsened clinical and economic outcomes.

Sepsis and Septic Shock: Evolving Evidence, Evolving Paradigms.

Sepsis and septic shock represent important infection-related medical emergencies that result in significant morbidity and mortality. The prevalence and microbiology of these processes are evolving. Nonetheless, timely and appropriate antibiotic therapy continues to represent the most important determinant of survival. Recent trials have clarified that crystalloids are preferred for initial resuscitation, and balanced crystalloids appear superior to 0.9% saline. Controversy remains regarding not only the rate and rapidity of fluid resuscitation but also about the timing and use of vasopressors to maintain blood pressure. While some newer alternative vasopressors may have a role in sepsis, more evidence supporting their use is required. Conflicting data exist regarding the impact of corticosteroids on mortality in septic shock. However, these reports indicate that adjunctive hydrocortisone can lead to more rapid shock reversal.

Heparin-induced thrombocytopenia in extra-corporeal membrane oxygenation: epidemiology, outcomes, and diagnostic challenges.

To describe the prevalence of heparin-induced thrombocytopenia (HIT) in patients on extracorporeal membrane oxygenation (ECMO) and to explore ways to improve the diagnostic accuracy of the HIT enzyme-linked immunosorbent assay (ELISA). Retrospective review of all patients needing ECMO between September 2011 and September 2020 who underwent evaluation for HIT while on ECMO. The diagnosis of HIT required a confirmatory serotonin release assay (SRA). Various break points for the optical density (OD) that defines a positive HIT ELISA were examined to estimate their utility as screening tests for HIT. Patient outcomes served as a secondary endpoint. Among 417 ECMO patients, 162 (38.8%) had a HIT ELISA. Of these, 114 (70.4%) had a subsequent SRA. Although the HIT ELISA was positive at an OD ≥ 0.4 in 1/3rd of subjects, only 15 subjects met criteria for HIT by SRA. Hence, the prevalence of HIT equaled 3.6%. At an OD ≥ 0.4 the ELISA had both poor specificity (71.7%) and accuracy (74.6%). Changing the definition of the ELISA to an OD ≥ 1.2 improved both specificity and accuracy with only a limited impact on sensitivity. Nearly 60% of those with HIT developing during ECMO died. HIT is infrequent in persons requiring ECMO. However, HIT remains associated with substantial mortality. The HIT ELISA as currently implemented performs poorly as a screening test and likely results in the unnecessary overuse of alternatives to unfractionated heparin. Altering the definition of a positive OD improves the HIT ELISA's accuracy.

Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections?-No.

In this counterpoint we critically appraise the evidence supporting therapeutic drug monitoring based on the vancomycin 24-hour area under the concentration-time curve (AUC24) for serious methicillin-resistant Staphylococcus aureus infections. We reveal methodologically weaknesses and inconsistencies in the data and suggest that, in the absence of clear and convincing evidence of benefit compared with modestly reducing trough targets, alternative strategies are more likely to result in superior safety and efficacy. These include focusing on fundamental antibiotic stewardship to limit vancomycin exposure overall, achieving earlier and more complete source control, and establishing alternative therapeutic options to vancomycin. Implementation of AUC24-based therapeutic drug monitoring will take resources away from these more promising, alternative solutions.

Novelty and nuance in the intensive care unit: new options to combat multidrug resistant pneumonia.

PURPOSE OF REVIEW: To describe the increasing burden of multidrug resistant (MDR) Gram-negative pathogens in severe pneumonia and to examine the clinical trials supporting a role for novel agents for the treatment of this infection. RECENT FINDINGS: MDR Gram-negative bacteria cause an increasing proportion of severe pneumonias. Although the epidemiology of resistance varies across the globe, all regions have seen an evolution in resistance, especially among Enterobacterales spp, Pseudomonas aeruginosa, and Acinetobacter bumannii. Fortunately, several clinical trials have established the role for multiple new antibiotics in pneumonia. Although these drugs all have different ranges of in vitro activity and potency, each helps to address the problem of MDR. These studies have varied based on the proportion of subjects undergoing mechanical ventilation and the comparator agents employed. Although all these trials have demonstrated noninferiority to the comparator, the mortality rates across the analyses ranged from <% to >20%. None of the recent investigations included immunocompromised subjects. SUMMARY: Multiple new agents exist for treating MDR Gram-negative pneumonia. These agents are not interchangeable. Thus, one must approach their adoption with a nuanced eye.

Nosocomial Infection.

OBJECTIVE: The first 70 years of critical care can be considered a period of "industrial revolution-like" advancement in terms of progressing the understanding and care of critical illness. Unfortunately, like the industrial revolution's impact on the environment, advancing ICU care of increasingly elderly, immunosuppressed, and debilitated individuals has resulted in a greater overall burden and complexity of nosocomial infections within modern ICUs. Given the rapid evolution of nosocomial infections, the authors provide an updated review. DATA SOURCES AND STUDY SELECTION: We searched PubMed and OVID for peer-reviewed literature dealing with nosocomial infections in the critically ill, as well as the websites of government agencies involved with the reporting and prevention of nosocomial infections. Search terms included nosocomial infection, antibiotic resistance, microbiome, antibiotics, and intensive care. DATA EXTRACTION AND DATA SYNTHESIS: Nosocomial infections in the ICU setting are evolving in multiple domains including etiologic pathogens plus novel or emerging pathogens, prevalence, host risk factors, antimicrobial resistance, interactions of the host microbiome with nosocomial infection occurrence, and understanding of pathogenesis and prevention strategies. Increasing virulence and antimicrobial resistance of nosocomial infections mandate increasing efforts toward their prevention. CONCLUSIONS: Nosocomial infections are an important determinant of outcome for patients in the ICU setting. Systematic research aimed at improving the prevention and treatment of nosocomial infections is still needed.

Multiple antimicrobial resistance and outcomes among hospitalized patients with complicated urinary tract infections in the US, 2013-2018: a retrospective cohort study.

BACKGROUND: Complicated urinary tract infection (cUTI) is common among hospitalized patients. Though carbapenems are an effective treatment in the face of rising resistance, overuse drives carbapenem resistance (CR). We hypothesized that resistance to routinely used antimicrobials is common, and, despite frequent use of carbapenems, associated with an increased risk of inappropriate empiric treatment (IET), which in turn worsens clinical outcomes. METHODS: We conducted a retrospective cohort study of patients hospitalized with a culture-positive non-CR cUTI. Triple resistance (TR) was defined as resistance to > 3 of the following: 3rd generation cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole, fosfomycin, and nitrofurantoin. Multivariable models quantified the impact of TR and inappropriate empiric therapy (IET) on mortality, hospital LOS, and costs. RESULTS: Among 23,331 patients with cUTI, 3040 (13.0%) had a TR pathogen. Compared to patients with non-TR, those with TR were more likely male (57.6% vs. 47.7%, p < 0.001), black (17.9% vs. 13.6%, p < 0.001), and in the South (46.3% vs. 41.5%, p < 0.001). Patients with TR had higher chronic (median [IQR] Charlson score 3 [2, 4] vs. 2 [1, 4], p < 0.001) and acute (mechanical ventilation 7.0% vs. 5.0%, p < 0.001; ICU admission 22.3% vs. 18.6%, p < 0.001) disease burden. Despite greater prevalence of empiric carbapenem exposure (43.3% vs. 16.2%, p < 0.001), patient with TR were also more likely to receive IET (19.6% vs. 5.4%, p < 0.001) than those with non-TR. Although mortality was similar between groups, TR added 0.38 (95% CI 0.18, 0.49) days to LOS, and $754 (95% CI $406, $1103) to hospital costs. Both TR and IET impacted the outcomes among cUTI patients whose UTI was not catheter-associated (CAUTI), but had no effect on outcomes in CAUTI. CONCLUSIONS: TR occurs in 1 in 8 patients hospitalized with cUTI. It is associated with an increase in the risk of IET exposure, as well as a modest attributable prolongation of LOS and increase in total costs, particularly in the setting of non-CAUTI.

Timing of antibiotic therapy in the ICU.

Severe or life threatening infections are common among patients in the intensive care unit (ICU). Most infections in the ICU are bacterial or fungal in origin and require antimicrobial therapy for clinical resolution. Antibiotics are the cornerstone of therapy for infected critically ill patients. However, antibiotics are often not optimally administered resulting in less favorable patient outcomes including greater mortality. The timing of antibiotics in patients with life threatening infections including sepsis and septic shock is now recognized as one of the most important determinants of survival for this population. Individuals who have a delay in the administration of antibiotic therapy for serious infections can have a doubling or more in their mortality. Additionally, the timing of an appropriate antibiotic regimen, one that is active against the offending pathogens based on in vitro susceptibility, also influences survival. Thus not only is early empiric antibiotic administration important but the selection of those agents is crucial as well. The duration of antibiotic infusions, especially for ß-lactams, can also influence antibiotic efficacy by increasing antimicrobial drug exposure for the offending pathogen. However, due to mounting antibiotic resistance, aggressive antimicrobial de-escalation based on microbiology results is necessary to counterbalance the pressures of early broad-spectrum antibiotic therapy. In this review, we examine time related variables impacting antibiotic optimization as it relates to the treatment of life threatening infections in the ICU. In addition to highlighting the importance of antibiotic timing in the ICU we hope to provide an approach to antimicrobials that also minimizes the unnecessary use of these agents. Such approaches will increasingly be linked to advances in molecular microbiology testing and artificial intelligence/machine learning. Such advances should help identify patients needing empiric antibiotic therapy at an earlier time point as well as the specific antibiotics required in order to avoid unnecessary administration of broad-spectrum antibiotics.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial.

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Antimicrobial Susceptibility and Cross-Resistance Patterns among Common Complicated Urinary Tract Infections in U.S. Hospitals, 2013 to 2018.

In the face of increasing rates of antimicrobial resistance in complicated urinary tract infections (cUTIs), clinicians need to understand cross-resistance patterns among commonly encountered pathogens. We performed a multicenter, retrospective cohort study in the Premier database of approximately 180 hospitals, from 2013 to 2018. Using an ICD-9/10-based algorithm, we identified all adult patients hospitalized with cUTIs and included those with a positive blood or urine culture. We examined the microbiology and susceptibilities to common cUTI antimicrobials (3rd-generation cephalosporin [C3], fluoroquinolones [FQ], trimethoprim-sulfamethoxazole [TMP/SMZ], fosfomycin [FFM], and nitrofurantoin [NFT]) singly and in groups of two. Among 28,057 organisms from 23,331 patients, the 3 most common pathogens were Escherichia coli (41.0%; C3r, 15.1%), Klebsiella pneumoniae (12.1%; C3r, 13.2%), and Pseudomonas aeruginosa (11.0%; C3r, 12.0%). E. coli was most frequently resistant to FQ (43.5%) and least to NFT (6.7%). K. pneumoniae was most frequently resistant to NFT (60.8%) and least to FFM (0.1%). P. aeruginosa was most frequently resistant to FQ (34.4%) and least to TMP/SMZ (4.2%). Of the C3rE. coli isolates, 87.1% were also FQr, 63.7% were TMP/SMZr, and 13.3% were NFTr C3rK. pneumoniae isolates had a 76.5% chance of being FQr, 78.1% were TMP/SMZr, and 77.6% were NFTr C3rP. aeruginosa coexisted with FQr in 47.3%, TMP/SMZr in 18.9%, and NFTr in 28.7%. Among the most common pathogens isolated from hospitalized patients with cUTIs, the rates of single resistance to common treatments and of cross-resistance to these regimens are substantial. Knowing the patterns of cross-resistance may help clinicians tailor empirical therapy more precisely.

Characteristics, Hospital Course, and Outcomes of Patients Requiring Prolonged Acute Versus Short-Term Mechanical Ventilation in the United States, 2014-2018.

OBJECTIVES: Most patients requiring mechanical ventilation only require it for a short term (< 4 d of mechanical ventilation). Those undergoing prolonged acute mechanical ventilation (≥ 4 d mechanical ventilation) represent a select cohort who face significant morbidity, mortality, and resource utilization. Using administrative codes, we identified prolonged acute mechanical ventilation and short-term mechanical ventilation patients and compared their baseline characteristics, hospital events, and hospital outcomes. DESIGN: Retrospective cohort. SETTING: Seven-hundred eighty-seven acute care hospitals, United States, contributing data to Premier database, 2014-2018. PATIENTS: Patients on mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 691,961 patients meeting the enrollment criteria, 266,374 (38.5%) received prolonged acute mechanical ventilation. At baseline, patients on prolonged acute mechanical ventilation were similar to short-term mechanical ventilation in age (years: 62.0 ± 15.8 prolonged acute mechanical ventilation vs 61.7 ± 17.2 short-term mechanical ventilation), gender (males: 55.6% prolonged acute mechanical ventilation vs 53.9% short-term mechanical ventilation), and race (white: 69.1% prolonged acute mechanical ventilation vs 72.4% short-term mechanical ventilation). The prolonged acute mechanical ventilation group had a higher comorbidity burden than short-term mechanical ventilation (mean Charlson Score 3.5 ± 2.7 vs 3.1 ± 2.7). The prevalence of vasopressors (50.3% vs 36.9%), dialysis (19.4% vs 10.3%), severe sepsis (20.3% vs 10.3%), and septic shock (33.5% vs 15.9%) was higher in prolonged acute mechanical ventilation than short-term mechanical ventilation. Hospital mortality (29.75% vs 21.1%), combined mortality, or discharge to hospice (37.2% vs 25.3%), extubation failure (12.3% vs 6.1%), tracheostomy (21.6% vs 4.5%), development of Clostridium difficile (4.5% vs 1.7%), and incidence density of ventilator-associated pneumonia (2.4/1,000 patient-days vs 0.6/1,000 patient-days) were all higher in the setting of prolonged acute mechanical ventilation than short-term mechanical ventilation. Median (interquartile range) post mechanical ventilation onset length of stay (13 [8-20] vs 4 d [1-8 d]) and hospital costs ($55,014 [$35,051-$88,007] vs $20,120 [$12,071-$34,915] were higher in prolonged acute mechanical ventilation than short-term mechanical ventilation. CONCLUSIONS: Over one-third of all hospitalized patients on mechanical ventilation require it for greater than or equal to 4 days. Prolonged acute mechanical ventilation patients exhibit a higher burden of both chronic and acute illness and experience higher rates than those on short-term mechanical ventilation of hospital-acquired complications and worse clinical and economic outcomes.

Current Epidemiology, Etiology, and Burden of Acute Skin Infections in the United States.

The US burden of acute skin infections is substantial. While Staphylococcus aureus and Streptococcus spp. are the most common causes, gram-negative bacteria and mixed infections can occur in some settings. These mixed infections are more likely to result in inappropriate empiric antibiotic therapy. Important challenges remain in diagnosing and treating acute skin infections.

Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials.

BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

The evolving burden of viruses in pneumonia.

PURPOSE OF REVIEW: To describe the evolving microbiology of various forms of pneumonia and the importance of viruses as etiologic causes of pneumonia. RECENT FINDINGS: Multiple studies utilizing novel diagnostic modalities demonstrate that the prevalence of viruses as causes for pneumonia varies from approximately 10-30% depending on the specific pneumonia type evaluated. Viral pneumonias appear similar in presentation and severity of illness to bacterial causes of pulmonary infection. Clinical criteria do not reliably allow the differentiation of viral from bacterial causes in pneumonia. SUMMARY: Viruses represent a pool of important culprit organisms in pneumonia and identification of a viral pathogen may facilitate attempts at antibiotic stewardship.

Inhaled antibiotics for the treatment of pneumonia.

PURPOSE OF REVIEW: To describe recent developments in trials exploring inhaled antibiotics for treating severe pneumonia. RECENT FINDINGS: Three recent randomized studies investigated the potential role for aerosolized antibiotics for gram-negative pneumonia in ventilated patients. One single center, nonblinded investigation suggested a benefit with inhaled amikacin for resistant gram-negative infections. However, two multicenter, blinded trials found no benefit to adjunctive nebulized amikacin for severe gram-negative pneumonia. SUMMARY: Well done clinical trials do not support the routine use of inhaled amikacin for pneumonia in ventilated patients. There may be a potential role for aerosolized antibiotics when other options are limited.

Burden of hospitalizations over time with invasive aspergillosis in the United States, 2004-2013.

BACKGROUND: Using aggregated data available on the interactive website from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Network (HCUPnet), we examined the annual volume of invasive aspergillosis (IA)-related hospitalizations in the US. METHODS: This was a population study. Age-adjusted volumes were derived through population incidence calculated using year-specific censal and intercensal US population estimates available from the US Census Bureau. We additionally examined IA as the principal diagnosis and its associated outcomes in patients with ICD-9-CM codes 117.3, 117.9 and 484.6. RESULTS: The age-adjusted number of annual hospitalizations with IA grew from 35,968 cases in 2004 to 51,870 in 2013, a 44.2% overall increase, 4.4% per annum. Regionally, the South contributed the plurality of the cases (40%), and the Northeast the fewest (17%). While IA as principal diagnosis dropped, from 14.4 to 9.3%, mortality rose from 10 to 12%. Despite mean hospital length of stay decreasing from 13.3 (standard error [SE] 0.07) to 11.5 (SE 0.6) days, the corresponding mean hospital charges rose from $71,164 (SE $5248) to $123,005 (SE $9738). The aggregate US inflation-adjusted hospital charges for IA principal diagnosis rose from $436,074,445 in 2004 to $592,358,369 in 2013. CONCLUSIONS: Given the substantial volume and rate of growth in IA-related hospitalizations in the US between 2004 and 2013, an increase in mortality and high costs, IA may represent an attractive target for intensive preventive efforts.