GAT107-mediated α7 nicotinic acetylcholine receptor signaling attenuates inflammatory lung injury and mortality in a mouse model of ventilator-associated pneumonia by alleviating macrophage mitochondrial oxidative stress via reducing MnSOD-S-glutathionylation.

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). Compromised host defense and inflammatory lung injury are mediated, in part, by high extracellular concentrations of HMGB1, which can be decreased by GTS-21, a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). Here, we report that a novel α7nAChR agonistic positive allosteric modulator (ago-PAM), GAT107, at 3.3 mg/kg, i.p., significantly decreased animal mortality and markers of inflammatory injury in mice exposed to hyperoxia and subsequently infected with Pseudomonas aeruginosa. The incubation of macrophages with 3.3 µM of GAT107 significantly decreased hyperoxia-induced extracellular HMGB1 accumulation and HMGB1-induced macrophage phagocytic dysfunction. Hyperoxia-compromised macrophage function was correlated with impaired mitochondrial membrane integrity, increased superoxide levels, and decreased manganese superoxide dismutase (MnSOD) activity. This compromised MnSOD activity is due to a significant increase in its level of glutathionylation. The incubation of hyperoxic macrophages with 3.3 µM of GAT107 significantly decreases the levels of glutathionylated MnSOD, and restores MnSOD activity and mitochondrial membrane integrity. Thus, GAT107 restored hyperoxia-compromised phagocytic functions by decreasing HMGB1 release, most likely via a mitochondrial-directed pathway. Overall, our results suggest that GAT107 may be a potential treatment to decrease acute inflammatory lung injury by increasing host defense in patients with VAP.

The importance of viruses in ventilator-associated pneumonia.

OBJECTIVE: Ventilator-associated pneumonia (VAP) remains a challenge. The importance of viruses in VAP is not established. We sought to determine the prevalence of viruses in VAP and the outcomes of viral VAP. DESIGN: Retrospective study of VAP over 3 years. The frequency of a viral process represented the primary endpoint. Clinical outcomes served as secondary endpoints. We identified variables independently associated with a virus and conducted sensitivity analyses to assess the interaction between type of infection and patient characteristics. SETTING: Tertiary-care referral center. PATIENTS: The final cohort consisted of 710 patients and a virus was isolated in 5.1%. INTERVENTIONS: None. RESULTS: The most common viruses included: rhinovirus, influenza A, and cytomegalovirus. Baseline characteristics were similar between those with and without viral infections. In logistic regression, immunosuppression (adjusted odds ratio [aOR], 2.97; 95% confidence interval [CI], 1.44-6.14) and stem-cell transplantation (SCT, aOR, 3.58; 95% CI, 1.17-10.99) were independently associated with a virus. The presence of either variable performed poorly as a screening test for a virus. In-hospital (22.4% vs 21.6%; P = .869) and 30-day (32.8% vs 27.9%; P = .448) mortality rates were similar between the cohorts, respectively. Sensitivity analyses restricted to patients without a mixed viral and bacterial infection or those who were immunocompetent yielded similar results. CONCLUSION: Although infrequent, a range of viruses may cause VAP. Viruses more often complicate SCT and immunosuppression, but one can isolate viruses in immunocompetent subjects. Viral VAP produces severe infection and results in high mortality rates. Clinical features do not differentiate viral from nonviral VAP.

Neumonía asociada a ventilación mecánica en pacientes con neumonía grave por SARS-CoV-2 / Ventilation associated pneumonia in patients with severe SARS-CoV-2 pneumonia

Introducción: Los pacientes con COVID-19 pueden evolucionar hacia una falla respiratoria aguda grave y requerir ventilación mecánica invasiva (VMI). La complicación más frecuente en estos pacientes es la neumonía asociada a ventilación mecánica (NAVM), con incidencias reportadas más altas que en la época pre-COVID. El objetivo de este estudio es reportar la incidencia, tasa de incidencia y microbiología de la NAVM en pacientes en VMI con COVID-19. Métodos: Se incluyeron a todos los pacientes con neumonía grave y PCR (+) para SARS-CoV-2 que ingresaron y requirieron VMI entre marzo y julio del 2021 en el Instituto Nacional del Tórax (INT). Se recolectaron datos demográficos, clínicos y de laboratorio de la ficha electrónica. Se registraron y caracterizaron los casos de neumonía asociado a la ventilación mecánica. Resultados: Se incluyeron 112 pacientes de los cuales el 42,8% presentó NAVM, con una tasa de incidencia de 28,8/1.000 días de VMI. Los microorganismos aislados más frecuentes fueron Klebsiella pneumoniae (29,6%), Staphylococcus aureus (21,8%) y Pseudomonas aeruginosa (12,5%). Los pacientes que cursaron NAVM estuvieron casi el doble de tiempo en VMI, pero sin presentar aumento de la mortalidad. Conclusión: La NAVM es una complicación frecuente en los pacientes con neumonía grave asociada a COVID-19. La microbiología de estas entidades no ha cambiado respecto a la era pre-pandémica. Estos resultados cobran relevancia en el inicio y suspensión de antibióticos en este grupo de pacientes.

Introduction: Patients with COVID-19 can progress to severe acute respiratory failure and require invasive mechanical ventilation (IMV). The most frequent complication in these patients is ventilator-associated pneumonia (VAP), with higher reported incidences than in the pre-COVID era. The objective of this study is to report the prevalence, incidence rate and microbiology of VAP in patients on IMV with COVID-19. Methods: Patients with severe pneumonia and PCR (+) for SARS-CoV-2 who were admitted to IMV between march and july 2021 at the Instituto Nacional del Tórax (Chile) were included. Demographic, clinical and laboratory data from electronic records were collected. Cases of pneumonia associated with mechanical ventilation were recorded and characterized. Results: 112 patients were included, 42.8% of them presented VAP with an incidence rate of 28.8/1,000 IMV days. The most frequent isolated microorganisms were Klebsiella pneumoniae (29.6%), Staphylococcus aureus (21.8%) and Pseudomonas aeruginosa (12.5%). Patients who underwent VAP spent almost twice as long on IMV, although they had not increase in mortality. Conclusion: VAP is a common complication in patients with severe pneumonia associated with COVID-19. The microbiology of these entities has not changed from the pre-pandemic era. These results become relevant in the initiation and suspension of antibiotics in this group of patients.

Lipid kinetics in patients with non-fermenting Gram-negative bacterial ventilator-associated pneumonia.

OBJECTIVES: In non-fermenting Gram-negative bacilli (NFGNB) infections, the interaction between the immune system of the host and the bacteria plays a more important role in determining the pathogenesis than the virulence factors of bacteria per se. We aimed to evaluate the sequential changes in the inflammatory response, including the lipid profile, antimicrobial susceptibility, and outcomes in NFGNB ventilator-associated pneumonia (VAP). METHODS: A total of 81 patients who developed NFGNB VAP were divided into two groups, namely multi-drug resistant (MDR) (n=51) and non-MDR (n=30) groups. RESULTS: When compared with the control group, the cholesterol levels of VAP patients decreased, while the levels of C-reactive protein and procalcitonin (PCT) levels significantly increased (p<0.05). The best sensitivity (93 %) corresponds to PCT levels on day 4, and the best specificity (89 %) corresponds to the levels of high-density lipoprotein (HDL) on day 4, which makes the latter parameters suitable candidates for predicting the 30-day mortality. The impact of resistant NFGNB isolates on early and late mortality rates was similar. CONCLUSION: In NFGNB VAP patients, the change relative to antimicrobial resistance was not appreciated in either the systemic inflammatory response or disease severity. MDR NFGNB isolates were not associated with greater mortality in VAP patients. The decrease in serum HDL and increase in PCT on day 4 indicated a poor prognosis (Tab. 5, Fig. 2, Ref. 30).

Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel ß-lactam ß-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Ventilator-associated pneumonia: incidence, microbial etiology and antimicrobial resistance profile / Pneumonia associada à ventilação mecânica: incidência, etiologia microbiana e perfil de resistência antimicrobiana / Neumonía asociada a ventilador: incidencia, etiología microbiana y perfil de resistencia antimicrobiana

Background and Objectives: Infections caused by multi-drug resistant microorganisms have a great clinical and economic impact. The present study proposed to determine and assess ventilator-associated pneumonia (VAP) incidence in an Intensive Care Unit (ICU), to establish the profile of hospitalized patients and to determine the frequency of microorganisms isolated as well as their antimicrobial resistance profile. Methods: A descriptive, documental study, with a quantitative approach, carried out at a teaching hospital. Participants were all individuals admitted to the General ICU who developed VAP in 2018 and 2019. Results: During the study, 146 patients were diagnosed with VAP, with an incidence of 23.66/1000 patient-days on mechanical ventilation. The median age of patients was 52.5 years and most of them were man. One hundred and eight microorganisms were isolated in cultures, the majority being gram-negative bacteria. Non-fermenting bacteria were the most frequent (n=46; 42.6%), followed by enterobacteria (n=42; 38.9%). Staphylococcus aureus was the most frequent microorganism among gram-positive (n=17; 15.7%). The most frequent multi-drug resistant bacteria were Acinetobacter baumannii and Enterobacter spp. No microorganism showed colistin and vancomycin resistance. Patients infected with multi-drug resistant bacteria were hospitalized longer when compared to other patients. Conclusions: VAP incidence was high. The knowledge of the etiologic agents of VAP and their antimicrobial resistance profile is fundamental to support the elaboration of institutional treatment protocols as well as assist in empirical antibiotic therapy.(AU)

Justificativa e Objetivos: As infecções causadas por microrganismos multirresistentes têm grande impacto clínico e econômico. O presente estudo propôs determinar e avaliar a incidência de pneumonia associada à ventilação mecânica (PAV) em uma Unidade de Terapia Intensiva (UTI), estabelecer o perfil dos pacientes internados e determinar a frequência de microrganismos isolados, bem como seu perfil de resistência antimicrobiana. Métodos: Estudo descritivo, documental, com abordagem quantitativa, realizado em um hospital universitário. Participaram todos os indivíduos admitidos na UTI Geral que desenvolveram PAV em 2018 e 2019. Resultados: Durante o estudo, 146 pacientes foram diagnosticados com PAV, com incidência de 23,66/1000 pacientes-dia em ventilação mecânica. A idade mediana dos pacientes foi de 52,5 anos e a maioria era do sexo masculino. Cento e oito microrganismos foram isolados em culturas, sendo a maioria bactérias gram-negativas. As bactérias não fermentadoras foram as mais frequentes (n=46; 42,6%), seguidas das enterobactérias (n=42; 38,9%). Staphylococcus aureus foi o microrganismo mais frequente entre os Gram-positivos (n=17; 15,7%). As bactérias multirresistentes mais frequentes foram Acinetobacter baumannii e Enterobacter spp. Nenhum microrganismo apresentou resistência à colistina e vancomicina. Pacientes infectados com bactérias multirresistentes ficaram mais tempo internados quando comparados a outros pacientes. Conclusões: A incidência de PAV foi alta. O conhecimento dos agentes etiológicos da PAV e seu perfil de resistência antimicrobiana é fundamental para subsidiar a elaboração de protocolos institucionais de tratamento, bem como auxiliar na antibioticoterapia empírica.(AU)

Justificación y Objetivos: Las infecciones causadas por microorganismos multirresistentes tienen un gran impacto clínico y económico. El presente estudio se propuso determinar y evaluar la incidencia de neumonía asociada a ventilación mecánica (NAV) en una Unidad de Cuidados Intensivos (UCI), establecer el perfil de pacientes hospitalizados y determinar la frecuencia de microorganismos aislados así como su perfil de resistencia antimicrobiana. Métodos: Estudio descriptivo, documental, con abordaje cuantitativo, realizado en un hospital escuela. Participaron todas las personas ingresadas en UCI General que desarrollaron NAV en 2018 y 2019. Resultados: Durante el estudio, 146 pacientes fueron diagnosticados con NAV, con una incidencia de 23,66/1000 pacientes-día en ventilación mecánica. La mediana de edad de los pacientes fue de 52,5 años y la mayoría eran hombres. Se aislaron 108 microorganismos en cultivos, siendo la mayoría bacterias gramnegativas. Las bacterias no fermentadoras fueron las más frecuentes (n=46; 42,6%), seguidas de las enterobacterias (n=42; 38,9%). Staphylococcus aureus fue el microorganismo más frecuente entre los grampositivos (n=17; 15,7%). Las bacterias multirresistentes más frecuentes fueron Acinetobacter baumannii y Enterobacter spp. Ningún microorganismo mostró resistencia a colistina y vancomicina. Los pacientes infectados con bacterias multirresistentes fueron hospitalizados por más tiempo en comparación con otros pacientes. Conclusiones: La incidencia de NAV fue alta. El conocimiento de los agentes etiológicos de la VAP y su perfil de resistencia a los antimicrobianos es fundamental para apoyar la elaboración de protocolos de tratamiento institucionales, así como para ayudar en la terapia antibiótica empírica.(AU)

Emergence of blaNDM-1 and blaVIM producing Gram-negative bacilli in ventilator-associated pneumonia at AMR Surveillance Regional Reference Laboratory in India.

INTRODUCTION: Ventilator-associated pneumonia (VAP) may be a life threatening nosocomial infection encountered in intensive care units. Currently the emergence of carbapenem-resistant Gram-negative pathogens has become worrisome threat worldwide. MATERIAL AND METHODS: Endotracheal aspirates samples were collected from patients who were under mechanical ventilation for > 48 h. The bacterial isolates were identified by MALDI-TOF-MS and antibiotic susceptibility testing performed. All carbapenem resistant isolates were tested by Modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM) and PCR were performed to detect blaIMP, blaVIM and blaNDM producing MBL genes. RESULTS: VAP occurred in 172/353(48.7%), 23.3% had early-onset VAP and 76.7% had late-onset VAP. Males (69.2%) were found to suffer more from VAP. Prior antibiotic therapy, CPI>6, prior surgery and tracheostomy were associated with VAP. The mortality in VAP (58.1%) contrasted with non-VAP (40%). 99/169 (58.6%) Gram-negative isolates were resistant to carbapenems. Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were common pathogens found in late onset VAP, whereas K. pneumoniae, A. baumannii and Staphylococcus aureus were common in early onset VAP. The PCR results detected blaNDM in 37/172(21.5%) and blaVIM in 30/172(17.4%); 15/172(8.7%) isolates carried both genes. CONCLUSION: The blaNDM-1 and blaVIM genes are the main antibiotic-resistance genes that induce resistance patterns to carbapenems in VAP, highlighting CRE strains of potential public health concern and therapeutic challenge. Diagnostic laboratories in India must get on high caution for early MBL detection as it may limit the wide dispersal of MBL genes.

Mechanical ventilation enhances Acinetobacter baumannii-induced lung injury through JNK pathways.

BACKGROUND: Patients in intensive care units (ICUs) often received broad-spectrum antibiotic treatment and Acinetobacter baumannii (A.b.) and Pseudomonas aeruginosa (P.a.) were the most common pathogens causing ventilator-associated pneumonia (VAP). This study aimed to examine the effects and mechanism of mechanical ventilation (MV) on A.b.-induced lung injury and the involvement of alveolar macrophages (AMs). METHODS: C57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1-/-) mice received MV for 3 h at 2 days after nasal instillation of A.b., P.a. (1 × 106 colony-forming unit, CFU), or normal saline. RESULTS: Intranasal instillation of 106 CFU A.b. in C57BL/6 mice induced a significant increase in total cells and protein levels in the bronchoalveolar lavage fluid (BALF) and neutrophil infiltration in the lungs. MV after A.b. instillation increases neutrophil infiltration, interleukin (IL)-6 and vascular cell adhesion molecule (VCAM) mRNA expression in the lungs and total cells, IL-6 levels, and nitrite levels in the BALF. The killing activity of AMs against A.b. was lower than against P.a. The diminished killing activity was parallel with decreased tumor necrosis factor-α production by AMs compared with A.b. Inducible nitric oxide synthase inhibitor, S-methylisothiourea, decreased the total cell number in BALF on mice receiving A.b. instillation and ventilation. Moreover, MV decreased the A.b. and P.a. killing activity of AMs. MV after A.b. instillation induced less total cells in the BALF and nitrite production in the serum of JNK1-/- mice than those of WT mice. CONCLUSION: A.b. is potent in inducing neutrophil infiltration in the lungs and total protein in the BALF. MV enhances A.b.-induced lung injury through an increase in the expression of VCAM and IL-6 levels in the BALF and a decrease in the bacteria-killing activity of AMs. A lower inflammation level in JNK1-/- mice indicates that A.b.-induced VAP causes lung injury through JNK signaling pathway in the lungs.

Epidemiology and clinical outcome of ventilator-associated events at a tertiary care hospital from North India.

The aim of our study was to determine the incidence, microbiological profile, risk factors and outcomes of patients diagnosed with ventilator-associated events in our tertiary care hospital. In this prospective study, intensive care patients put on mechanical ventilation for >48 h were enrolled and monitored daily for ventilator-associated event according to Disease Centre Control guidelines. A ventilator-associated event developed in 33/250 (13.2%); its incidence was 3.5/100 mechanical ventilation days. The device utilisation rate was 0.86, 36.4% of patients had early and 63.6% late-onset ventilator-associated pneumonia whose most common causative pathogen was Acinetobacter sp. (63.6%). Various factors were significantly associated with a ventilator-associated event: male gender, COPD, smoking, >2 underlying diseases, chronic kidney disease and elevated acute physiological and chronic health evaluation II scores. Therefore, stringent implementation of infection control measures is necessary to control ventilator-associated pneumonia in critical care units.

Antibiotic Exposure Is Not Associated With Clearance of Bronchoalveolar Growth: Results From a Prospective Ventilator-Associated Pneumonia Study.

BACKGROUND: Ventilator-associated pneumonia is poorly understood in trauma. Ventilated trauma patients can develop bacterial burden without symptoms; the factors that influence this are unknown. METHODS: Injured adults ventilated for > 2 days were enrolled. Mini-bronchoalveolar lavage was performed for 14 days or until extubation. Semi-quantitative cultures were blinded from clinicians. All cultures with > 104 colony forming units (CFU) were assessed for antibiotic exposure (ABXE) and spectrum of coverage. mBAL CFU was assessed daily. RESULTS: 60 patients were ventilated for 9 days (median). There were 75 with > 104 CFU. 46 had > 104 CFU and no ABXE on the sample day. 74% had clearance or a decrease (CoD) in CFU without ABXE. 29 had > 104 CFU and ABXE on the sample day. 19 had ABXE with pathogen coverage. 84% had CoD in CFU. 10 had ABXE with no spectrum of coverage. 1/10 had increased CFU and the remaining 9/10 CoD in CFU. The three groups were not statistically different on chi-squared analysis. CONCLUSION: Clearance of pathogens on surveillance cultures was unaffected by ABXE.

A Minority of Patients on Mechanical Ventilation Consume Disproportionate Resources: A Retrospective Cohort Study.

BACKGROUND: The Pareto principle states that the majority of any effect comes from a minority of the causes. This property is widely used in quality improvement science. RESEARCH QUESTION: Among patients requiring mechanical ventilation (MV), are there subgroups according to MV duration that may serve as potential nodes for high-value interventions aimed at reducing costs without compromising quality? STUDY DESIGN AND METHODS: This multicenter retrospective cohort study included approximately 780 hospitals in the Premier Research Database (2014-2018). Patients receiving MV were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification, and International Classification of Diseases, Tenth Revision, codes. They were then divided into quintiles according to MV duration; their hospital costs, post-MV onset length of stay (LOS), ICU LOS, and cumulative post-MV onset hospital days per quintile were compared. RESULTS: A total of 691,961 patients were included in the analysis. Median [interquartile range] duration of MV in days by quintile was as follows: quintile 1 (Q1), 1 [1, 1]; Q2, 2 [2, 2]; Q3, 3 [3, 3]; Q4, 6 [6, 7]; and Q5, 13 [10, 19]. Median [interquartile range] post-MV onset LOS (Q1, 2 [0, 5]; Q5, 17 [12, 26]) and hospital costs (Q1, $15,671 [$9,180, $27,901]; Q5, $70,133 [$47,136, $108,032]) rose from Q1 through Q5. Patients in Q5 consumed 47.7% of all post-MV initiation hospital days among all patients requiring MV, and the mean per-patient hospital costs in Q5 exceeded the sum of costs incurred by Q1 to Q3. Adjusted marginal mean (95% CI) hospital costs rose exponentially from Q1 through Q5: Q2 vs Q1, $3,976 ($3,354, $4,598); Q3 vs Q2, $5,532 ($5,103, $5,961); Q4 vs Q3, $11,705 ($11,071, $12,339); and Q5 vs Q4, $26,416 ($25,215, $27,616). INTERPRETATION: Patients undergoing MV in the highest quintiles according to duration of MV consume a disproportionate amount of resources, as evidenced by MV duration, hospital LOS, and costs, making them a potential target for streamlining MV care.

Epidemiological and clinical characteristics of healthcare-associated infection in elderly patients in a large Chinese tertiary hospital: a 3-year surveillance study.

BACKGROUND: We analyzed the results of a 3-year surveillance study on the epidemiological and clinical characteristics of healthcare associated-infections (HAIs) in elderly inpatients in a large tertiary hospital in China. METHODS: Real-time surveillance was performed from January 1, 2015 to December 31, 2017. All HAIs were identified by infection control practitioners and doctors. Inpatient data were collected with an automatic surveillance system. RESULTS: A total of 134,637 inpatients including 60,332 (44.8%) elderly ≥60 years were included. The overall incidence of HAI was 2.0%. The incidence of HAI in elderly patients was significantly higher than that in non-elderly patients (2.6% vs. 1.5%, χ2 = 202.421, P < 0.01) and increased with age. The top five sites of HAIs in the elderly were the lower respiratory tract, urinary tract, blood stream, antibiotic-associated diarrhea, and surgical site. The five most common pathogens detected in elderly HAI patients were Candida albicans, Klebsiella pneumonia, Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa. The incidence of ventilator-associated pneumonia in the elderly was lower than in the non-elderly, catheter-associated urinary tract infections were more common in elderly patients, and the rate of central line-associated bloodstream infection was similar between groups. The numbers of male patients and patients with comorbidities and special medical procedures (e.g., intensive care unit admission, cerebrovascular disease, brain neoplasms, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, chronic obstructive pulmonary disease, malignant tumor, malignant hematonosis, and osteoarthropathy) were significantly higher in the elderly group, but the number of patients who underwent surgery was lower. CONCLUSION: We observed a significantly higher overall incidence of HAI in elderly inpatients ≥60 compared to non-elderly inpatients < 60 years, but the trend was different for device-associated HAIs, which was attributed to the higher rates of comorbidities and special medical procedures in the elderly group. The main HAI sites in elderly inpatients were the lower respiratory tract, urinary tract, and bloodstream, and the main pathogens were gram-negative bacilli and Candida albicans.

The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.

Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O2) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O2) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM-800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.

Treatment of ventilator-associated pneumonia (VAP) caused by Acinetobacter: results of prospective and multicenter ID-IRI study.

Ventilator-associated pneumonia (VAP) due to Acinetobacter spp. is one of the most common infections in the intensive care unit. Hence, we performed this prospective-observational multicenter study, and described the course and outcome of the disease. This study was performed in 24 centers between January 06, 2014, and December 02, 2016. The patients were evaluated at time of pneumonia diagnosis, when culture results were available, and at 72 h, at the 7th day, and finally at the 28th day of follow-up. Patients with coexistent infections were excluded and only those with a first VAP episode were enrolled. Logistic regression analysis was performed. A total of 177 patients were included; empiric antimicrobial therapy was appropriate (when the patient received at least one antibiotic that the infecting strain was ultimately shown to be susceptible) in only 69 (39%) patients. During the 28-day period, antibiotics were modified for side effects in 27 (15.2%) patients and renal dose adjustment was made in 38 (21.5%). Ultimately, 89 (50.3%) patients died. Predictors of mortality were creatinine level (OR, 1.84 (95% CI 1.279-2.657); p = 0.001), fever (OR, 0.663 (95% CI 0.454-0.967); p = 0.033), malignancy (OR, 7.095 (95% CI 2.142-23.500); p = 0.001), congestive heart failure (OR, 2.341 (95% CI 1.046-5.239); p = 0.038), appropriate empiric antimicrobial treatment (OR, 0.445 (95% CI 0.216-0.914); p = 0.027), and surgery in the last month (OR, 0.137 (95% CI 0.037-0.499); p = 0.003). Appropriate empiric antimicrobial treatment in VAP due to Acinetobacter spp. was associated with survival while renal injury and comorbid conditions increased mortality. Hence, early diagnosis and appropriate antibiotic therapy remain crucial to improve outcomes.

Antimicrobial-resistant pathogens associated with pediatric healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015-2017.

OBJECTIVE: To describe common pathogens and antimicrobial resistance patterns for healthcare-associated infections (HAIs) among pediatric patients that occurred in 2015-2017 and were reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). METHODS: Antimicrobial resistance data were analyzed for pathogens implicated in central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonias (VAPs), and surgical site infections (SSIs). This analysis was restricted to device-associated HAIs reported from pediatric patient care locations and SSIs among patients <18 years old. Percentages of pathogens with nonsusceptibility (%NS) to selected antimicrobials were calculated by HAI type, location type, and surgical category. RESULTS: Overall, 2,545 facilities performed surveillance of pediatric HAIs in the NHSN during this period. Staphylococcus aureus (15%), Escherichia coli (12%), and coagulase-negative staphylococci (12%) were the 3 most commonly reported pathogens associated with pediatric HAIs. Pathogens and the %NS varied by HAI type, location type, and/or surgical category. Among CLABSIs, the %NS was generally lowest in neonatal intensive care units and highest in pediatric oncology units. Staphylococcus spp were particularly common among orthopedic, neurosurgical, and cardiac SSIs; however, E. coli was more common in abdominal SSIs. Overall, antimicrobial nonsusceptibility was less prevalent in pediatric HAIs than in adult HAIs. CONCLUSION: This report provides an updated national summary of pathogen distributions and antimicrobial resistance patterns among pediatric HAIs. These data highlight the need for continued antimicrobial resistance tracking among pediatric patients and should encourage the pediatric healthcare community to use such data when establishing policies for infection prevention and antimicrobial stewardship.

The etiology of neonatal pneumonia, complicated by bronchopulmonary dysplasia.

BACKGROUND: The frequency of bronchopulmonary dysplasia (BPD) in preterm infants with a "ventilator-associated" pneumonia (VAP) ranges between 7 to 50%. OBJECTIVE: To investigate the features of the etiological structure of neonatal pneumonia complicated by BPD, and to determine the sensitivity of pathogens to antibiotics. METHODS: A retrospective chart review of 194 preterm infants with VAP, birth weight from 780 to 2820 g and gestational age from 27 to 37 weeks was conducted. A microbiological study of washings from the respiratory tract was conducted by standard qualitative and quantitative methods. RESULTS: Respiratory tract infections caused by E. coli (with hemolytic properties), Enterococcus spp. (with hemolytic properties), Pseudomonas aeruginosa, Stenotrophomonas maltophilia, various types of mycoplasmas, Staphylococcus aureus, and Candida krusei were found 4- 13 times more frequent in preterm infants with BPD than in preterm infants without BPD and more mature infants with or without this complication. BPD developed 7- 11 times more frequent in preterm infants with prolonged VAP and change in pathogens than in preterm infants with VAP without change of agent. BPD developed 5- 7 times more frequent in preterm infants with the association of pathogens than in preterm infants with a monoinfection. Massive colonization of respiratory tract pathogens by 1- 3 days of life (lg4 colony forming units in 1 ml and above) was an unfavorable prognostic factor for the development of VAP, complicated by BPD. CONCLUSION: The reduction in the frequency of BPD is might be possible with timeous and adequate antibacterial therapy of VAP.

Comparative efficacy of doripenem versus meropenem for hospital-acquired and ventilator-associated pneumonia.

BACKGROUND: Doripenem shows good in vitro activity against common nosocomial pathogens, such as extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. However, the use of doripenem for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remains controversial. The aim of this study was to compare the efficacy and safety between doripenem and meropenem for patients with HAP or VAP. METHODS: Adult patients diagnosed with HAP and VAP at National Taiwan University Hospital, who received doripenem or meropenem for more than 48 h between January 2015 and November 2017, were retrospectively reviewed. All-cause mortality on the 30th day was used as the primary outcome measurements. RESULTS: Fifty-seven patients with doripenem and 252 patients with meropenem were analyzed. Compared to the meropenem group, the doripenem group was younger and had a higher Sequential Organ Failure Assessment (SOFA) score. Multivariable Cox regression analysis revealed that presence of solid organ malignancies (adjusted hazard ratio [AHR], 1.82; 95% CI, 1.04-3.19, p = 0.003) and SOFA score (AHR, 1.10; 95% CI, 1.03-1.17, p = 0.003) were independent factors associated with mortality. There was no survival difference of 30-day mortality between patients receiving doripenem and meropenem for HAP or VAP (log-rank p = 0.113). However, a poorer outcome was observed among patients with hematological disease in the doripenem group (log-rank p = 0.012). CONCLUSION: Our results demonstrate that doripenem has similar efficacy as meropenem in HAP or VAP patients. With an aim to enhance antibiotic diversity, doripenem could be an alternative choice for patients with HAP or VAP, except for those with hematological malignancies.

Help, hinder, hide and harm: what can we learn from the interactions between Pseudomonas aeruginosa and Staphylococcus aureus during respiratory infections?

Recent studies of human respiratory secretions using culture-independent techniques have found a surprisingly diverse array of microbes. Interactions among these community members can profoundly impact microbial survival, persistence and antibiotic susceptibility and, consequently, disease progression. Studies of polymicrobial interactions in the human microbiota have shown that the taxonomic and structural compositions, and resulting behaviours, of microbial communities differ substantially from those of the individual constituent species and in ways of clinical importance. These studies primarily involved oral and gastrointestinal microbiomes. While the field of polymicrobial respiratory disease is relatively young, early findings suggest that respiratory tract microbiota members also compete and cooperate in ways that may influence disease outcomes. Ongoing efforts therefore focus on how these findings can inform more 'enlightened', rational approaches to combat respiratory infections. Among the most common respiratory diseases involving polymicrobial infections are cystic fibrosis (CF), non-CF bronchiectasis, COPD and ventilator-associated pneumonia. While respiratory microbiota can be diverse, two of the most common and best-studied members are Staphylococcus aureus and Pseudomonas aeruginosa, which exhibit a range of competitive and cooperative interactions. Here, we review the state of research on pulmonary coinfection with these pathogens, including their prevalence, combined and independent associations with patient outcomes, and mechanisms of those interactions that could influence lung health. Because P. aeruginosa-S. aureus coinfection is common and well studied in CF, this disease serves as the paradigm for our discussions on these two organisms and inform our recommendations for future studies of polymicrobial interactions in pulmonary disease.

Hospital-Acquired Infections in Critically Ill Patients With Cancer.

Hospital-acquired infections are a common and costly problem facing critically ill patients in the intensive care unit (ICU). Critically ill patients with cancer are a particularly vulnerable subpopulation who possesses additional, nonmodifiable risk factors for developing these infections and, in many cases, are at increased risk of death as a result. This review will describe the most common nosocomial infections patients with cancer acquire while in the ICU: ventilator-associated events, central line-associated bloodstream infection, catheter-associated urinary tract infections, and Clostridium difficile infection.

Microorganismos causales de neumonía asociada a la ventilación mecánica, Guantánamo 2014-2018 / Microrganismos causais de pneumonia associados à ventilação mecânica, Guantanamo 2014-2018 / Causal microorganisms of pneumonia associated with mechanical ventilation, Guantanamo 2014-2018

Introducción: en la Unidad de Cuidados Intensivos (UCI) del Hospital Dr. Agostinho Neto no se ha precisado cuálesgérmenes causan la neumonía asociada a la ventilación mecánica. Objetivo: precisar los gérmenes causales de este tipo de neumonía en la citada unidad durante los años 2014-2018. Método: se realizó un estudio observacional, retrospectivo y longitudinal. El universo fueron todos los pacientes con diagnóstico de este tipo de neumonía (N=561), de estos se seleccionó una muestra aleatoria de 200 pacientes. Se estudiaron las siguientes variables: total de pacientes ingresados en la UCI y los que se trataron con ventilación mecánica y tiempo de aplicación de ésta, características de los pacientes (edad, sexo, tipo de paciente y diagnóstico al ingreso), caracterización de esta neumonía (tipo, nivel de gravedad y etiología). Resultados: el 46,8 por ciento de los pacientes que se trató con ventilación mecánica presentó este tipo de neumonía, y de estos el 94,0 por ciento presentó una neumonía detipo tardía. Su edad fue de 56,1 ± 12,4 años y la mayoría fueron varones (n=59). El 65,5 por ciento presentó una enfermedad clínica, y la más común fue la enfermedad cerebrovascular (24,5 por ciento). El 73,5 por ciento se ventiló por más de cinco días. El principal germen causal fue la Klebsiella (24,5 por ciento). Conclusión: la Klebsiella y el Streptococcus pneumoniae son los gérmenes causales más comunes de esta neumonía y esta fue más común en los pacientes con formas clínicas de enfermedad cerebrovascular(AU)

Introduction: in the intensive care unit of the Dr. Agostinho Neto Hospital it has not been specified which germs cause pneumonia associated with mechanical ventilation. Objective: to specify the causal germs of this type of pneumonia in the aforementioned unit during the years 2014-2018. Method: an observational, retrospective and longitudinal study was carried out. The universe was all patients diagnosed with this type of pneumonia (N=561), from these a random sample of 200 patients was selected. The following variables were studied: total of patients admitted to the ICU and those treated with mechanical ventilation and its application time, characteristics of the patients (age, sex, type of patient and diagnosis at admission), characterization of this pneumonia (type, severity level and etiology). Results: 46.8 percent of the patients who were treated with echanical ventilation presented this type of pneumonia, and of these 94.0 percent presented late pneumonia. Their age was 56.1 ± 12.4 years and the majority were male (n=59). 65.5 percent presented a clinical disease, and the most common was cerebrovascular disease (24.5 percent). 73.5 percent was ventilated for more than five days. The main causal germ was Klebsiella (24.5 percent). Conclusion: Klebsiella and Streptococcus pneumoneae are the most common causative germs of this pneumonia and this was more common in patients with clinical forms of cerebrovascular disease(AU)

Introdução: na unidade de terapia intensiva do Hospital Dr. Agostinho Neto no foi especificado quais germes causam pneumonia associada à ventilação mecânica. Objetivo: especificar os germes causais desse tipo de pneumonia na unidade citada nos anos de 2014 a 2018. Método: estudo observacional, retrospectivo e longitudinal. O universo foi constituído por todos os pacientes diagnosticados com esse tipo de pneumonia (N=561), dos quais foi selecionada uma amostra aleatória de 200 pacientes. Foram estudadas as seguintes variáveis: total de pacientes admitidos na UTI e tratados com ventilação mecânica e seu tempo de aplicação, características dos pacientes (idade, sexo, tipo de paciente e diagnóstico na admissão), caracterização dessa pneumonia (tipo, nível de gravidade e etiologia). Resultados: 46,8 por cento dos pacientes tratados com ventilação mecânica apresentaram esse tipo de pneumonia e desses 94,0 por cento apresentaram pneumonia tardia. A idade era de 56,1 ± 12,4 anos e a maioria era do sexo masculino (n=59). 65,5 por cento apresentaram doença clínica e a mais comum foi doença cerebrovascular (24,5 por cento). 73,5 por cento foram ventilados por mais de cinco dias. O principal germe causal foi Klebsiella (24,5 por cento). Conclusão: Klebsiella e streptococcus pneumoneae são os germes causadores mais comuns dessa pneumonia, sendo mais comum em pacientes com formas clínicas de doença cerebrovascular(AU)