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Purpose Carbapenem-resistant Klebsiella pneumoniae (CRKP) is one of the leading causes of healthcare-associated infections (HAIs) and is particularly pervasive in intensive care units (ICUs). This study takes ICU layout as the research object, and integrates clinical data and bacterial genome analysis to clarify the role of separate, small wards within the ICU in controlling the transmission of CRKP. Methods This study prospectively observed the carriage and spread of CRKP from a long-term in-hospital patient (hereafter called the Patient) colonized with CRKP in the gut and located in a separate, small ward within the ICU. The study also retrospectively investigated CRKP-HAIs in the same ICU. The relationship and transmission between CRKP isolates from the Patient and HAI events in the ICU were explored with comparative genomics. Results In this study, 65 CRKP-HAI cases occurred during the investigation period. Seven CRKP-HAI outbreaks were also observed. A total of 95 nonrepetitive CRKP isolates were collected, including 32 strains from the Patient in the separate small ward. Phylogenetic analysis based on core genome single-nucleotide polymorphism (cgSNP) showed that there were five possible CRKP clonal transmission events and two clonal outbreaks (A1, A2) during the study. CRKP strains from the Patient did not cause CRKP between-patient transmission or outbreaks in the ICU during the 5-year study period. Conclusion The presence of a long-term hospitalized patient carrying CRKP and positioned in a separate, small ward did not lead to CRKP transmission or infection outbreaks in the ICU. Combining a small-ward ICU layout with normative HAI control measures for multidrug-resistant pathogen infection was effective in reducing CRKP transmission., Author(s): Xiaohui Chi [sup.1], Xiaohua Meng [sup.1], Luying Xiong [sup.1], Tao Chen [sup.1], Yanzi Zhou [sup.1], Jinru Ji [sup.1], Beiwen Zheng [sup.1] [sup.2] [sup.3], Yonghong Xiao [sup.1] [sup.2] [sup.3] Author [...]

Purpose Transport of secretory immunoglobulin A (SIgA) through the airway epithelial cell barrier into the mucosal lumen by the polymeric immunoglobulin receptor (pIgR) is an important mechanism of respiratory mucosal host defense. Identification of immunomodulating substances that regulate secretory immunity might have therapeutic implications with regard to an improved immune exclusion. Thus, we sought to analyze secretory immunity under homeostatic and immunomodulating conditions in different compartments of the murine upper and lower respiratory tract (URT&LRT). Methods Pigr gene expression in lung, trachea, and nasal-associated lymphoid tissue (NALT) of germ-free mice, specific pathogen-free mice, mice with an undefined microbiome, as well as LPS- and IFN-[gamma]-treated mice was determined by quantitative real-time PCR. IgA levels in bronchoalveolar lavage (BAL), nasal lavage (NAL), and serum were determined by ELISA. LPS- and IFN-[gamma]-treated mice were colonized with Streptococcus pneumoniae and bacterial CFUs were determined in URT and LRT. Results Respiratory Pigr expression and IgA levels were dependent on the degree of exposure to environmental microbial stimuli. While immunostimulation with LPS and IFN-[gamma] differentially impacts respiratory Pigr expression and IgA in URT vs. LRT, only prophylactic IFN-[gamma] treatment reduces nasal colonization with S. pneumoniae. Conclusion Airway-associated secretory immunity can be partly modulated by exposure to microbial ligands and proinflammatory stimuli. Prophylactic IFN-[gamma]-treatment modestly improves antibacterial immunity in the URT, but this does not appear to be mediated by SIgA or pIgR., Author(s): Alexander Pausder [sup.1] [sup.2] [sup.3], Jennifer Fricke [sup.4] [sup.9], Klaus Schughart [sup.4] [sup.5] [sup.6], Jens Schreiber [sup.7], Till Strowig [sup.8], Dunja Bruder [sup.1] [sup.2], Julia D. Boehme [sup.1] [sup.2] [...]

Purpose The life-saving role of oxygen therapy in African children with severe pneumonia is not yet established. Methods The open-label fractional-factorial COAST trial randomised eligible Ugandan and Kenyan children aged > 28 days with severe pneumonia and severe hypoxaemia stratum (SpO.sub.2 3 h receipt of oxygen were excluded. The primary endpoint was 48 h mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. Results The trial was stopped early after enrolling 1852/4200 children, including 388 in the severe hypoxaemia stratum (median 7 months; median SpO.sub.2 75%) randomised to HFNT (n = 194) or LFO (n = 194) and 1454 in the hypoxaemia stratum (median 9 months; median SpO.sub.2 88%) randomised to HFNT (n = 363) vs LFO (n = 364) vs permissive hypoxaemia (n = 727). Per-protocol 15% of patients in the permissive hypoxaemia group received oxygen (when SpO.sub.2 < 80%). In the severe hypoxaemia stratum, 48-h mortality was 9.3% for HFNT vs. 13.4% for LFO groups. In the hypoxaemia stratum, 48-h mortality was 1.1% for HFNT vs. 2.5% LFO and 1.4% for permissive hypoxaemia. In the hypoxaemia stratum, adjusted odds ratio for 48-h mortality in liberal vs permissive comparison was 1.16 (0.49-2.74; p = 0.73); HFNT vs LFO comparison was 0.60 (0.33-1.06; p = 0.08). Strata-specific 28 day mortality rates were, respectively: 18.6, 23.4 and 3.3, 4.1, 3.9%. Neurocognitive sequelae were rare. Conclusions Respiratory support with HFNT showing potential benefit should prompt further trials., Author(s): K. Maitland [sup.1] [sup.4], S. Kiguli [sup.2], P. Olupot-Olupot [sup.3], M. Hamaluba [sup.4], K. Thomas [sup.5], F. Alaroker [sup.6], R. O. Opoka [sup.2] [sup.7], A. Tagoola [sup.7], V. Bandika [...]

Purpose Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics. Methods Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score [less than or equal to] 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement. Results Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days. Conclusions Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy., Author(s): Bruno François [sup.1] [sup.2] [sup.3], Emmanuelle Mercier [sup.4], Céline Gonzalez [sup.1], Karim Asehnoune [sup.5], Saad Nseir [sup.6], Maud Fiancette [sup.7], Arnaud Desachy [sup.8], Gaëtan Plantefève [sup.9], Ferhat Meziani [sup.10] [...]

Background The goal of this study was to assess the impact of prone positioning on the incidence of ventilator-associated pneumonia (VAP) and the role of VAP in mortality in a recent multicenter trial performed on patients with severe ARDS. Methods An ancillary study of a prospective multicenter randomized controlled trial on early prone positioning in patients with severe ARDS. In suspected cases of VAP the diagnosis was based on positive quantitative cultures of bronchoalveolar lavage fluid or tracheal aspirate at the 10.sup.4 and 10.sup.7 CFU/ml thresholds, respectively. The VAP cases were then subject to central, independent adjudication. The cumulative probabilities of VAP were estimated in each position group using the Aalen-Johansen estimator and compared using Gray's test. A univariate and a multivariate Cox model was performed to assess the impact of VAP, used as a time-dependent covariate for mortality hazard during the ICU stay. Results In the supine and prone position groups, the incidence rate for VAP was 1.18 (0.86-1.60) and 1.54 (1.15-2.02) per 100 days of invasive mechanical ventilation (p = 0.10), respectively. The cumulative probability of VAP at 90 days was estimated at 46.5 % (27-66) in the prone group and at 33.5 % (23-44) in the supine group. The difference between the two cumulative probability curves was not statistically significant (p = 0.11). In the univariate Cox model, VAP was associated with an increase in the mortality rate during the ICU stay [HR 1.65 (1.05-2.61), p = 0.03]. HR increased to 2.2 (1.39-3.52) (p < 0.001) after adjustment for position group, age, SOFA score, McCabe score, and immunodeficiency. Conclusions In severe ARDS patients prone positioning did not reduce the incidence of VAP and VAP was associated with higher mortality., Author(s): L. Ayzac [sup.1], R. Girard [sup.2], L. Baboi [sup.3], P. Beuret [sup.4], M. Rabilloud [sup.5] [sup.6] [sup.7] [sup.8], J. C. Richard [sup.3] [sup.6] [sup.7] [sup.9], C. Guérin [sup.3] [sup.6] [...]

Purpose To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis. Methods Random, outcome-stratified case-control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis. Results We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors (p [less than or equal to] 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non-survivors (p [less than or equal to] 0.05). Of these, pseudouridine increased monocyte expression of TNF[alpha] and IL1[beta] versus control (p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham (p < 0.05 for both). Conclusions Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns., Author(s): Christopher W. Seymour [sup.1] [sup.2], Sachin Yende [sup.2] [sup.3], Melanie J. Scott [sup.2] [sup.4], John Pribis [sup.4], Robert P. Mohney [sup.5], Lauren N. Bell [sup.5], Yi-Fan Chen [sup.6], Brian [...]

Purpose To determine the effects of deflating the tracheal cuff during disconnections from mechanical ventilation (MV) in tracheostomized patients. Methods This was a single-center, randomized trial conducted in a general ICU of a tertiary hospital with regional referral for trauma patients. Patients at high risk of aspiration based on the drink test were excluded. Critically ill tracheostomized patients were randomized to have the tracheal cuff deflated or not during spontaneous breathing trials. Weaning was protocolized on progressive T-tube trials, and patients were considered weaned after 24 consecutive hours disconnected from MV. The primary end point was time to definitive withdrawal of MV; secondary end points were ventilator-associated respiratory infection (pneumonia and/or tracheobronchitis) and swallowing function. Statistical analyses included Cox proportional risk models. Results We randomized 195 patients and 181 patients completed the study (94 patients with deflated cuff and 87 with inflated cuff). Variables independently related to weaning time in the multivariate analysis were tracheostomy-to-first MV disconnection time (HR 0.5, 95 % CI 0.3-0.8; p < 0.01) and cuff deflation (HR 2.2, 95 % CI 1.5-3; p < 0.01). Respiratory infection was lower in the deflated group (20 vs. 36 %; p = 0.02). Swallowing function improved more in the deflated group (31 vs. 22 %; p = 0.02). Conclusion Under the conditions of our protocol, deflating the tracheal cuff in tracheostomized patients shortens weaning, reduces respiratory infections, and probably improves swallowing., Author(s): Gonzalo Hernandez [sup.1] [sup.6] [sup.7], Ana Pedrosa [sup.2], Ramon Ortiz [sup.3], Maria del Mar Cruz Accuaroni [sup.2], Rafael Cuena [sup.4], Concepción Vaquero Collado [sup.1], Susana García Plaza [sup.1], Paloma [...]

Purpose The effects of stress-dose corticosteroid therapy were studied in a canine staphylococcal pneumonia model of septic shock. Methods Immediately following intrabronchial bacterial challenge, purpose-bred beagles were treated with stress doses of desoxycorticosterone (DOC), a mineralocorticoid agonist, and dexamethasone (DEX), a glucocorticoid agonist, or with placebo for 96 h. Oxacillin (30 mg/kg every 8 h) was started 4 h after infection onset. Bacterial dose was titrated to achieve 80-90 % lethality (n = 20) using an adaptive design; additional animals (n = 18) were investigated using the highest bacterial dose. Results Initial analysis of all animals (n = 38) demonstrated that the effects of DOC + DEX were significantly altered by bacterial dose (p = 0.04). The treatment effects of DOC + DEX were different in animals administered high or relatively lower bacterial doses in terms of survival (p = 0.05), shock reversal (p = 0.02), interleukin-6 levels (p = 0.02), and temperature (p = 0.01). DOC + DEX significantly improved the above parameters (p [less than or equal to] 0.03 for all) and lung injury scores (p = 0.02) after high-dose bacterial challenges, but not after lower challenges (p = not significant for all). Oxacillin trough levels were below the minimum inhibitory concentration of the infecting organism, and DOC + DEX increased the frequency of persistent staphylococcal bacteremia (odds ratio 3.09; 95 % confidence interval 1.05-9.11; p = 0.04). Conclusions Stress-dose corticosteroids were only beneficial in cases of sepsis with high risk for death and even short courses may interfere with host mechanisms of bacterial clearance., Author(s): Caitlin W. Hicks [sup.1] [sup.2] [sup.3], Daniel A. Sweeney [sup.4], Robert L. Danner [sup.3], Peter Q. Eichacker [sup.3], Anthony F. Suffredini [sup.3], Jing Feng [sup.3], Junfeng Sun [sup.3], Brad [...]

Purpose Pneumonia associated with invasive mechanical ventilation (IMV) is one of the indicator infections of the German Nosocomial Infection Surveillance System. In 2005 surveillance was extended to include pneumonia associated with noninvasive ventilation (NIV). The aim of this study was to determine the utilization of IMV and NIV and the associated incidence densities (IDs) of pneumonia and to compare the characteristics of pneumonia cases and the spectrum of associated pathogens. Methods We analyzed the pooled data of 400 intensive care units (ICUs) with respect to three categories of pneumonia: pneumonia associated with IMV and NIV and pneumonia not associated with ventilation. Pooled ventilation utilization rates and pneumonia IDs were calculated in total and stratified by hospital size, hospital type and ICU type. Results Four hundred ICUs with 779,500 admitted patients, 1,068,472 IMV days and 101,569 NIV days reported 6,869 cases of pneumonia between 2005 and 2007. Of these, 5,811 cases were associated with IMV, 160 with NIV and 898 were not associated with ventilation. The mean pneumonia IDs were 1.58 and 5.44 cases per 1,000 ventilator days for NIV and IMV, respectively. Pneumonia cases associated with IMV were younger, had a longer ICU stay before onset of pneumonia and were more often associated with gram-negative bacteria than cases associated with NIV; however, there were no differences in the proportion of secondary sepsis and death. Conclusions This surveillance study including pneumonia associated with IMV and NIV and pneumonia not associated with ventilation shows significant differences of pneumonia IDs, patient characteristics and the spectrum of associated pathogens., Author(s): Anke Kohlenberg [sup.1] [sup.2] [sup.3], Frank Schwab [sup.1] [sup.2], Michael Behnke [sup.1] [sup.2], Christine Geffers [sup.1] [sup.2], Petra Gastmeier [sup.1] [sup.2] Author Affiliations: (1) grid.6363.0, 0000000122184662, Institute of Hygiene [...]

Purpose Methods for estimating the excess mortality attributable to ventilator-associated pneumonia (VAP) should handle VAP as a time-dependent covariate, since the probability of experiencing VAP increases with the time on mechanical ventilation. VAP-attributable mortality (VAP-AM) varies with definitions, case-mix, causative microorganisms, and treatment adequacy. Our objectives here were to compare VAP-AM estimates obtained using a traditional cohort analysis, a multistate progressive disability model, and a matched-cohort analysis; and to compare VAP-AM estimates according to VAP characteristics. Methods We used data from 2,873 mechanically ventilated patients in the Outcomerea.sup.® database. Among these patients from 12 intensive care units, 434 (15.1%) experienced VAP; of the remaining patients, 1,969 (68.5%) were discharged alive and 470 (16.4%) died. With the multistate model, VAP-AM was 8.1% (95% confidence interval [95%CI], 3.1-13.1%) for 120 days' complete observation, compared to 10.4% (5.6-24.5%) using a matched-cohort approach (2,769 patients) with matching on mechanical ventilation duration followed by conditional logistic regression. VAP-AM was higher in surgical patients and patients with intermediate (but not high) Simplified Acute Physiologic Score II values at ICU admission. VAP-AM was significantly influenced by time to VAP but not by resistance of causative microorganisms. Higher Logistic Organ Dysfunction score at VAP onset dramatically increased VAP-AM (to 31.9% in patients with scores above 7). Conclusion A multistate model that appropriately handled VAP as a time-dependent event produced lower VAP-AM values than conditional logistic regression. VAP-AM varied widely with case-mix. Disease severity at VAP onset markedly influenced VAP-AM; this may contribute to the variability of previous estimates., Author(s): Molière Nguile-Makao [sup.1], Jean-Ralph Zahar [sup.1] [sup.2], Adrien Français [sup.1], Alexis Tabah [sup.1] [sup.3], Maité Garrouste-Orgeas [sup.1] [sup.4], Bernard Allaouchiche [sup.5], Dany Goldgran-Toledano [sup.6], Elie Azoulay [sup.1] [sup.7], Christophe [...]