Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

OBJECTIVES: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. DESIGN: Single-center, prospective, open-label, randomized controlled trial. SETTING: One thousand two hundred-bed academic medical center. PATIENTS: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. INTERVENTIONS: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. MEASUREMENTS AND MAIN RESULTS: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). CONCLUSIONS: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia.

OBJECTIVES: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. METHODS: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population. RESULTS: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable. CONCLUSIONS: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

Clinical Effect of Expedited Pathogen Identification and Susceptibility Testing for Gram-Negative Bacteremia and Candidemia by Use of the Accelerate PhenoTM System.

BACKGROUND: Fast diagnostic tests providing earlier identification (ID) of pathogens, and antimicrobial susceptibility testing (AST) may reduce time to appropriate antimicrobial therapy (AAT), decrease mortality, and facilitate antimicrobial deescalation (ADE). Our objective was to determine the theoretical reduction in time to AAT and opportunities for ADE with Accelerate PhenoTM System (AXDX). METHODS: The prospective cohort (April 14, 2016 through June 1, 2017) was from the Barnes-Jewish Hospital, a 1250-bed academic center. Emergency department (ED) or intensive care unit (ICU) blood cultures Gram-stain positive for gram-negative bacilli (GNB) or yeast. AXDX was used in parallel with standard-of-care (SOC) diagnostics to determine differences in time to pathogen ID and AST. Theoretical opportunities for ADE from AXDX results were determined. RESULTS: In total, 429 blood cultures were screened, 153 meeting inclusion criteria: 110 on-panel GNB, 10 Candida glabrata, and 5 Candida albicans. For GNB SOC, median time from blood culture positivity to ID and AST were 28.2 and 52.1 h. Median time to ID and AST after AXDX initiation was 1.37 and 6.7 h for on-panel organisms. For on-panel Candida, time to ID was approximately 21 h faster with AXDX. ADE or AAT was theoretically possible with AXDX in 48.4%. Of on-panel organisms, 24.0% did not receive initial AAT. In-hospital mortality was 46.7% without initial AAT, and 11.6% with AAT. Coverage of AXDX was 75.3%, specificity 99.7%, positive predictive value (PPV) 96.0%, and negative predictive value (NPV) 97.6%. On-panel sensitivity was 91.5%, specificity 99.6%, PPV 96.0%, and NPV 99.0%. CONCLUSIONS: AXDX provides more rapid ID and AST for GNB and ID for yeast than SOC. AXDX could potentially reduce time to AAT and facilitate ADE.

Acinetobacter Pneumonia: Improving Outcomes With Early Identification and Appropriate Therapy.

In an era of increasing antimicrobial resistance, Acinetobacter distinguishes itself as one of the most resistant Gram-negative bacteria responsible for significant morbidity and mortality. New solutions are needed to combat the detrimental effects of increasing rates of antimicrobial resistance. Using empiric broad-spectrum antibiotics in patients deemed at risk for infections caused by multidrug-resistant pathogens may protect against attributable mortality, but this temporary solution furthers the risk of antimicrobial resistance. In this article we will review relevant strategies to aid with early identification and appropriate treatment of Acinetobacter pneumonia while preserving antibiotic susceptibility.

Secular trends in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: A survey study.

BACKGROUND: Acinetobacter baumannii (AB) has evolved a variety of resistance mechanisms and exhibits unpredictable susceptibility patterns, making it difficult to select empiric therapy. OBJECTIVE: To examine US secular trends in the resistance of AB in respiratory infections and blood stream infections (BSI) to antimicrobial agents whose effectiveness is supported in the literature DESIGN: Survey. METHODS: We analyzed 3 time periods (2003-2005, 2006-2008, 2009-2012) in Eurofins' The Surveillance Network for resistance of AB to the following antimicrobials: carbapenems (imipenem, meropenem, doripenem), aminoglycosides (tobramycin, amikacin), tetracyclines (minocycline, doxycycline), polymyxins (colistin, polymyxin B), ampicillin-sulbactam, and trimethoprim-sulfamethoxazole. Resistance to ≥3 drug classes defined multidrug resistance (MDR). RESULTS: We identified 39,320 AB specimens (81.1% respiratory, 18.9% BSI). The highest prevalence of resistance was to doripenem (90.3%) followed by trimethoprim-sulfamethoxazole (55.3%), and the lowest to colistin (5.3%). Resistance to carbapenems (21.0% in 2003-2005 and 47.9% in 2009-2012) and colistin (2.8% in 2006-2008 to 6.9% in 2009-2012) more than doubled. Prevalence of MDR AB rose from 21.4% in 2003 to 2005 to 33.7% in 2006 to 2008, and remained stable at 35.2% in 2009 to 2012. In contrast, resistance to minocycline diminished from 56.5% (2003-2005) to 30.5% (2009-2012). MDR organisms were most frequent in nursing homes (46.5%), followed by general ward (29.2%), intensive care unit (28.7%), and outpatient setting (26.2%). CONCLUSIONS: Resistance rates among AB to such last-resort antimicrobials as carbapenems and colistin are on the rise, whereas that to minocycline has declined. Nursing homes are a reservoir of resistant AB. These trends should inform not only empiric treatment of serious infections, but also approaches to infection control.

Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.

CONTEXT: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00534287.

A randomized trial of conventional chest physical therapy versus high frequency chest wall compressions in intubated and non-intubated adults.

BACKGROUND: Conventional chest physical therapy (CCPT), applied by therapists using cupped hands to perform percussion, is commonly used in hospitalized adults. However, increased work load demands and occupational health concerns (eg, carpal tunnel syndrome) limit the overall utilization of this therapy. Therefore, we conducted a study to compare the overall effectiveness of CCPT to high-frequency chest wall compressions (HFCWC) applied via a vibratory vest. METHODS: A single-center, randomized trial among hospitalized intubated and non-intubated adult patients requiring chest physical therapy comparing CCPT and HFCWC. The primary outcome measure was hospital stay. RESULTS: A total of 280 per-protocol patients (out of an a priori estimated 320 patients required to demonstrate a 20% relative reduction in hospital stay) were randomly assigned to receive CCPT (no. = 146, 52.1%) or HFCWC (no. = 134, 47.9%). The hospital stay was 12.5 ± 8.8 days for patients randomized to CCPT and 13.0 ± 8.9 days for patients randomized to HFCWC (P = .62). Patient comfort was assessed using a visual analog scale (increasing score reflects greater discomfort) and was statistically greater for patients randomized to CCPT compared to HFCWC (2.2 ± 0.8 vs 1.9 ± 0.8, P = .009). The duration of time until radiographic resolution of lobar atelectasis trended less for CCPT compared to HFCWC (5.2 ± 4.3 d vs 6.5 ± 5.2 d, P = .051). All other secondary outcomes, including hospital mortality and nosocomial pneumonia, were similar for both treatment groups. CONCLUSIONS: This study was inadequately powered for the primary outcome of interest and hence we cannot make recommendations on the preferential use of HFCWC or CCPT for intubated and non-intubated adult patients. HFCWC was associated with statistically better comfort scores. (ClinicalTrials.gov registration NCT00717873.).

Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay.

OBJECTIVES: To describe the impact of initially inappropriate antibiotic therapy on hospital length of stay in Gram-negative severe sepsis and septic shock. DESIGN: Retrospective cohort. SETTING: Academic urban hospital. PATIENTS: Patients with Gram-negative bacteremia (primary or secondary, nosocomial or non-nosocomial) and severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined initially inappropriate antibiotic therapy as occurring when the patient either was not administered an antibiotic within 24 hrs of sepsis onset or was treated with an antibiotic to which the culprit pathogen was resistant in vitro. The cohort included 760 subjects (mean age 59.3 ± 16.3 yrs, mean Acute Physiology and Chronic Health Evaluation II score 23.7 ± 6.7). More than half of infections were nosocomial (55.1%), and Escherichia coli represented the most common pathogen (n = 225). Pseudomonas species were isolated in 17.4% of patients. Nearly one-third of patients (31.3%) received initially inappropriate antibiotic therapy. Patients administered initially inappropriate antibiotic therapy were more likely to have a nosocomial infection, to have underlying cancer or diabetes or both, to require chronic hemodialysis, and to undergo mechanical ventilation. Those administered initially inappropriate antibiotic therapy also faced higher inhospital mortality. The unadjusted median length of stay after sepsis onset in those administered initially inappropriate antibiotic therapy was 11 days compared to 9 days in those treated appropriately (p = .028 by log-rank test). In a Cox model controlling for the multiple confounders noted, initially inappropriate antibiotic therapy independently correlated with continued hospitalization (adjusted hazard ratio 1.19, 95% confidence interval 1.01-1.40, p = .044). Adjusting for these covariates indicated that initially inappropriate antibiotic therapy independently increased the median attributable length of stay by 2 days. CONCLUSIONS: Initially inappropriate antibiotic therapy occurs in one-third of persons with severe sepsis and septic shock attributable to Gram-negative organisms. Beyond its impact on mortality, initially inappropriate antibiotic therapy is significantly associated with length of stay in this population. Efforts to decrease rates of initially inappropriate antibiotic therapy may serve to improve hospital resource use by leading to shorter overall hospital stays.

The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections.

Pseudomonas aeruginosa is an important bacterial pathogen, particularly as a cause of infections in hospitalised patients, immunocompromised hosts and patients with cystic fibrosis. Surveillance of nosocomial P. aeruginosa infections has revealed trends of increasing antimicrobial resistance, including carbapenem resistance and multidrug resistance. Mechanisms of antimicrobial resistance include multidrug efflux pumps, ss-lactamases and downregulation of outer membrane porins. Mechanisms of virulence include secreted toxins and the ability to form biofilms. The effective treatment of infections caused by P. aeruginosa includes prevention when possible, source control measures as necessary and prompt administration of appropriate antibacterial agents. Antibacterial de-escalation should be pursued in patients with an appropriate clinical response, especially when antibacterial susceptibilities are known. Multidrug-resistant P. aeruginosa may require treatment with less commonly used antibacterials (e.g. colistin), but newer anti-pseudomonal antibacterials are expected to be available in the near future.

Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment.

Pseudomonas aeruginosa bloodstream infection is a serious infection with significant patient mortality and health-care costs. Nevertheless, the relationship between initial appropriate antimicrobial treatment and clinical outcomes is not well established. This study was a retrospective cohort analysis employing automated patient medical records and the pharmacy database at Barnes-Jewish Hospital. Three hundred five patients with P. aeruginosa bloodstream infection were identified over a 6-year period (January 1997 through December 2002). Sixty-four (21.0%) patients died during hospitalization. Hospital mortality was statistically greater for patients receiving inappropriate initial antimicrobial treatment (n = 75) compared to appropriate initial treatment (n = 230) (30.7% versus 17.8%; P = 0.018). Multiple logistic regression analysis identified inappropriate initial antimicrobial treatment (adjusted odds ratio [AOR], 2.04; 95% confidence interval [CI], 1.42 to 2.92; P = 0.048), respiratory failure (AOR, 5.18; 95% CI, 3.30 to 8.13; P < 0.001), and circulatory shock (AOR, 4.00; 95% CI, 2.71 to 5.91; P < 0.001) as independent determinants of hospital mortality. Appropriate initial antimicrobial treatment was administered statistically more often among patients receiving empirical combination antimicrobial treatment for gram-negative bacteria compared to empirical monotherapy (79.4% versus 65.5%; P = 0.011). Inappropriate initial empirical antimicrobial treatment is associated with greater hospital mortality among patients with P. aeruginosa bloodstream infection. Inappropriate antimicrobial treatment of P. aeruginosa bloodstream infections may be minimized by increased use of combination antimicrobial treatment until susceptibility results become known.

Quinolones for treatment of nosocomial pneumonia: a meta-analysis.

Although quinolones are often used to treat nosocomial pneumonia (NP), there have been few trials documenting their efficacy in treating NP. Given the growing use of quinolones and issues regarding resistance, we conducted a meta-analysis of all trials of quinolones for treatment of NP. We identified 5 randomized trials comparing quinolones with other agents used to treat NP. The studies varied in both quality and sample size and included a total of nearly 1200 subjects. Four of the 5 trials used ciprofloxacin, administered every 8 h, whereas the fifth used levofloxacin administered daily. In 3 trials, the comparator agent was imipenem-cilistatin, whereas, in 2 trials, ceftazadime was the comparator agent. The efficacy of quinolones and comparator antibiotics was similar, with a pooled odds ratio for clinical cure of 1.12 (95% confidence interval, 0.80-1.55). Neither microbiological eradication rates nor mortality rates varied on the basis of antimicrobial selection.

Gram-negative bacterial resistance: evolving patterns and treatment paradigms.

Successful treatment of patients with nosocomial pneumonia depends primarily on providing adequate initial antibiotic treatment in a timely manner, because an inappropriate course is closely associated with increased mortality. Gram-negative bacteria are commonly responsible for nosocomial pneumonia, and the increasing prevalence of drug resistance among these bacteria complicates decision making with regard to treatment with antibiotics. Infections due to Pseudomonas aeruginosa are particularly problematic because of their intrinsic resistance to multiple classes of antibiotics and their ability to acquire adaptive resistance during a therapeutic course. Numerous strategies, including the use of combination therapy followed by de-escalation of antibiotics, have shown promise in the treatment of these serious infections. However, future success in treating nosocomial infections depends on the appropriate and responsible use of antibiotics in the intensive care unit, to ensure that the antibiotics available today maintain their effectiveness in the future.

Cycling empirical antimicrobial agents to prevent emergence of antimicrobial-resistant Gram-negative bacteria among intensive care unit patients.

OBJECTIVE: To determine the impact of the rotation of antimicrobial agents on the rates of infection, intestinal colonization, and acquisition with antimicrobial-resistant Gram-negative bacteria. DESIGN: Pre- and postintervention design. SETTING: A 19-bed, medical intensive care unit. PATIENTS: Individuals admitted to the study unit for >48 hrs. INTERVENTIONS: After a 5-month baseline observation period, four classes of antimicrobial agents with Gram-negative activity were cycled at 3- to 4-month intervals for 24 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the acquisition rate of antimicrobial resistance among Enterobacteriaceae and Pseudomonas aeruginosa obtained from rectal swab cultures performed on admission, weekly during the patients' stay, and at discharge. Rates and microbiology of nosocomial bloodstream infections and ventilator-associated pneumonia were also compared between baseline and cycling periods. The cycling program resulted in a significant change in prescribing practices; the predominant agent used changed with each cycle. Among study patients who were not already colonized with a resistant organism, the rate of acquisition of enteric colonization with bacteria resistant to any of the target drugs remained stable during the cycling period for P. aeruginosa (relative rate, 0.96; 95% confidence Interval, 0.47-2.16) and Enterobacteriaceae (relative rate, 1.57; 95% confidence interval, 0.80-3.43). Hospital-wide, P. aeruginosa from routine clinical cultures resistant to the target drugs increased during the cycling period. The proportion of Gram-negative bacteria isolated from cases of nosocomial bloodstream infection (29% baseline vs. 26% cycling; p = .11) and ventilator-associated pneumonia (80% vs. 41%; p = .06) did not significantly differ. CONCLUSIONS: In this study, antimicrobial cycling did not result in a significant change in enteric acquisition of resistant Gram-negative bacteria among intensive care unit patients.

An educational intervention to reduce ventilator-associated pneumonia in an integrated health system: a comparison of effects.

STUDY OBJECTIVES: To determine whether an educational initiative could decrease rates of ventilator-associated pneumonia in a regional health-care system. SETTING: Two teaching hospitals (one adult, one pediatric) and two community hospitals in an integrated health system. DESIGN: Preintervention and postintervention observational study. PATIENTS: Patients admitted to the four participating hospitals between January 1, 1999, and June 30, 2002, who acquired ventilator-associated pneumonia. INTERVENTION: An educational program for respiratory care practitioners and ICU nurses emphasizing correct practices for the prevention of ventilator-associated pneumonia. The program included a self-study module on risk factors for, and strategies to prevent, ventilator-associated pneumonia and education-based in-services. Fact sheets and posters reinforcing the information were posted throughout the ICU and respiratory care departments. MEASUREMENTS AND RESULTS: Completion rates for the module were calculated by job title at each hospital. Rates of ventilator-associated pneumonia per 1,000 ventilator days were calculated for all hospitals combined and for each hospital separately. Overall 635 of 792 ICU nurses (80.1%) and 215 of 239 respiratory therapists (89.9%) completed the study module. There were 874 episodes of ventilator-associated pneumonia at the four hospitals during the 3.5-year study period out of 129,527 ventilator days. Ventilator-associated pneumonia rates for all four hospitals combined dropped by 46%, from 8.75/1,000 ventilator days in the year prior to the intervention to 4.74/1,000 ventilator days in the 18 months following the intervention (p < 0.001). Statistically significant decreased rates were observed at the pediatric hospital and at two of the three adult hospitals. No change in rates was seen at the community hospital with the lowest rate of study module completion among respiratory therapists (56%). CONCLUSIONS: Educational interventions can be associated with decreased rates of ventilator-associated pneumonia in the ICU setting. The involvement of respiratory therapy staff in addition to ICU nurses is important for the success of educational programs aimed at the prevention of ventilator-associated pneumonia.