Multidrug-resistant pathogens and ventilator-associated pneumonia in critically ill COVID-19 and non-COVID-19 patients: a prospective observational monocentric comparative study.

BACKGROUND: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking. MATERIAL AND METHODS: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization). RESULTS: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality. CONCLUSION: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes.

Clinical effectiveness of cefiderocol for the treatment of bloodstream infections due to carbapenem-resistant Acinetobacter baumannii during the COVID-19 era: a single center, observational study.

BACKGROUND: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). MATERIALS/METHODS: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). RESULTS: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. CONCLUSIONS: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.

Activity of Meropenem-Vaborbactam against Bacterial Isolates Causing Pneumonia in Patients in U.S. Hospitals during 2014 to 2018.

Meropenem-vaborbactam is approved to treat hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), in Europe. Meropenem-vaborbactam activity was evaluated against 3,193 Pseudomonas aeruginosa and 4,790 Enterobacterales isolates causing pneumonia, including VAP, in hospitalized patients in the United States. Susceptibility testing was performed by using the broth microdilution method, and all carbapenem-resistant isolates were submitted for whole-genome sequencing. Meropenem-vaborbactam exhibited almost complete activity against Enterobacterales (>99.9% susceptible), including carbapenem-resistant Enterobacterales (CRE), and was also very active against P. aeruginosa isolates (89.5% susceptible).

Increased ß-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study.

BACKGROUND: Augmented renal clearance (ARC) is recognized as a leading cause of ß-lactam subexposure when conventional dosing regimens are used. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased ß-lactam dosing regimens for a first episode of hospital or ventilator-acquired pneumonia (HAP-VAP). METHODS: In this single-center, retrospective study, every ARC patient treated by ß-lactam for a first episode of HAP-VAP was included during two 15-month periods, before (Control period) and after (Treatment period) the modification of a local antibiotic therapy protocol. ARC was defined by a 24-h measured creatinine clearance ≥ 150 ml/min. The primary endpoint was defined as a therapeutic failure of the antimicrobial therapy or a HAP-VAP relapse within 28 days. Inverse probability of treatment weight (IPTW) was derived from a propensity score model. Cox proportional hazard models were used to evaluate the association between treatment period and clinical outcome. RESULTS: During the study period, 177 patients were included (control period, N = 88; treatment period, N = 89). Therapeutic failure or HAP-VAP relapse was significantly lower in the treatment period (10 vs. 23%, p = 0.019). The IPTW-adjusted hazard ratio of poor clinical outcome in the treatment period was 0.35 (95% CI 0.15-0.81), p = 0.014. No antibiotic side effect was reported during the treatment period. CONCLUSIONS: Higher than licensed dosing regimens of ß-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill augmented renal clearance (ARC) patients.

Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. METHODS: A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. RESULTS: From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27-100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. CONCLUSION: Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.

Audit of Tracheostomy Care Practices in a Nigerian Tertiary Neurosurgical Intensive Care Unit According to Published Guidelines.

INTRODUCTION: Chest infections are a frequently encountered problem in patients admitted to the intensive care unit (ICU), more so in tracheostomised patients. This study aimed to audit the tracheostomy care practices in patients with neurosurgical pathologies in the ICU of Wellington Clinics Abuja, a tertiary neurosurgical hospital in Nigeria. METHODS: We conducted a closed-loop audit with mixed methods involving analysis of 24 patients who had tracheostomy within the first two weeks of neurosurgical pathology at a tertiary neurosurgical hospital and semi-structured interviews to determine tracheostomy care practices among the primary caregivers - nurses, intensivists, and doctors. RESULTS: Of the 161 ICU admissions in the first cycle, 22 patients received tracheostomy, 16 met the eligibility criteria. At re-audit (second cycle), eight of 40 patients met the criteria. All the patients received open suctioning through a dual cannula-cuffed tracheostomy tube and had independent portable suction units. In the baseline audit (first cycle), suction catheters were reused for 12-24 hours in each patient and were stored in varying combinations of normal saline and Savlon antiseptic (5 mg of cetrimide (0.5% w/w) and 1 mg of chlorhexidine digluconate (0.1% w/w)). The frequency, technique, and assessment of the need for airway suctioning were inconsistent among caregivers interviewed. All 16 patients had at least one episode of pneumonia, 10 patients had a second episode, and two patients had > two episodes. One mortality was recorded directly attributable to the complications of pneumonia. While in the re-audit, with adherence to recommendations, three patients suffered one episode of pneumonia and only one had a second episode. No mortality was recorded. CONCLUSION: A standard practice guideline was necessary for tracheostomy care in our ICU. In low-resource settings, stated recommendations such as single-use suction catheters and improved hygienic practices can reduce rates of pneumonia in tracheostomised patients.

COVID-19 and Pasteurella multocida Pulmonary Coinfection: A Case Series.

OBJECTIVES: In COVID-19 patients, bacterial and fungal pulmonary coinfections, such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, or Aspergillus, have been reported, but to our knowledge, no case has been reported due to Pasteurella multocida. PATIENTS AND METHODS: We describe three cases of Pasteurella multocida coinfections occurring during the 4th wave of COVID-19 in Martinique (French West Indies). RESULTS: All three cases were fatal; thus, Pasteurella multocida has to be considered as a potentially severe coinfection agent. CONCLUSIONS: Alteration of the epithelial-endothelial barrier due to a SARS-CoV-2 infection probably promotes the expression of a Pasteurella infection. In addition, the SARS-CoV-2 infection induced immunosuppression, and an inflammatory cascade could explain the infection's severity. The use of corticosteroids, which are part of the first-line therapeutic arsenal against COVID-19, may also promote the pathogenicity of this agent.

Novel investigational treatments for ventilator-associated pneumonia and critically ill patients in the intensive care unit.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is common; its prevalence has been highlighted by the Covid-19 pandemic. Even young patients can suffer severe nosocomial infection and prolonged mechanical ventilation. Multidrug-resistant bacteria can spread alarmingly fast around the globe and new antimicrobials are struggling to keep pace; hence physicians must stay abreast of new developments in the treatment of nosocomial pneumonia and VAP. AREAS COVERED: This narrative review examines novel antimicrobial investigational drugs and their implementation in the ICU setting for VAP. This paper highlights novel approaches such as monoclonal antibody treatments for P. aeruginosa and S. aureus and phage antibiotic synthesis. This paper also examines mechanisms of resistance in Gram-negative bacteria, virulence factors, and inhaled antibiotics and questions what may be on the horizon in terms of emerging treatment strategies. EXPERT OPINION: The postantibiotic era is rapidly approaching, and the need for personalized medicine, point-of-care microbial sensitivity testing, and development of biomarkers for severe infections is clear. Results from emerging and new antibiotics are encouraging, but infection control measures and de-escalation protocols must be employed to prolong their usefulness in critical illness.

Respiratory tract microbiome and pneumonia.

The respiratory system, like the gut, harbors a vast variety of microorganisms which include bacteria, viruses and fungi. The advent of next generation sequencing and multi-omic approaches has revealed the diversity and functional significances of microorganisms in the respiratory health. It has been identified that there has been a co-evolution of indigenous respiratory microbiota and the human immune system. However, an immune response is usually generated when the homeostasis of the microbiota is disturbed. The respiratory microbiome has been identified to be important in shaping the respiratory immunity. Gut microbiota and oral microbiota are also known to be pivotal in shaping the immune system of the respiratory tract and influence its microbial dynamics. Proteobacteria, Firmicutes, and Bacteroidetes have been identified to be predominant in the respiratory system. While, Streptococcus, Prevotella, Fusobacteria, and Veillonella forms the major part, potential pathogens, such as Haemophilus and Neisseria, also form a small fraction of the healthy lung microbiome. Dysbiosis of respiratory microbiome can lead to increased colonization of opportunistic pathogens that can lead to respiratory infections such as pneumonia. This chapter describes the microbial diversity of respiratory system and the role of respiratory microbiome during respiratory infections like pneumonia. The chapter also discusses few strategies that have been proved effective in preventing pneumonia.

Increased susceptibility to intensive care unit-acquired pneumonia in severe COVID-19 patients: a multicentre retrospective cohort study.

BACKGROUND: The aim of this study is to determine whether severe COVID-19 patients harbour a higher risk of ICU-acquired pneumonia. METHODS: This retrospective multicentre cohort study comprised all consecutive patients admitted to seven ICUs for severe COVID-19 pneumonia during the first COVID-19 surge in France. Inclusion criteria were laboratory-confirmed SARS-CoV-2 infection and requirement for invasive mechanical ventilation for 48 h or more. Control groups were two historical cohorts of mechanically ventilated patients admitted to the ICU for bacterial or non-SARS-CoV-2 viral pneumonia. The outcome of interest was the development of ICU-acquired pneumonia. The determinants of ICU-acquired pneumonia were investigated in a multivariate competing risk analysis. RESULT: One hundred and seventy-six patients with severe SARS-CoV-2 pneumonia admitted to the ICU between March 1st and 30th June of 2020 were included into the study. Historical control groups comprised 435 patients with bacterial pneumonia and 48 ones with viral pneumonia. ICU-acquired pneumonia occurred in 52% of COVID-19 patients, whereas in 26% and 23% of patients with bacterial or viral pneumonia, respectively (p < 0.001). Times from initiation of mechanical ventilation to ICU-acquired pneumonia were similar across the three groups. In multivariate analysis, the risk of ICU-acquired pneumonia remained independently associated with underlying COVID-19 (SHR = 2.18; 95 CI 1.2-3.98, p = 0.011). CONCLUSION: COVID-19 appears an independent risk factor of ICU-acquired pneumonia in mechanically ventilated patients with pneumonia. Whether this is driven by immunomodulatory properties by the SARS-CoV-2 or this is related to particular processes of care remains to be investigated.

Thermosensitive in situ liposomal gels loaded with antimicrobial agent for oral care in critically ill patients.

Aim: A novel thermosensitive in situ gel loaded with meropenem (MP) liposomes was designed to improve retention in the oral cavity as a prophylactic measure to prevent ventilator-acquired pneumonia in critically ill patients. Methodology & results: Meropenem liposomes were incorporated into poloxamer 407 gels and gamma irradiated. Mean size of liposome was 247 nm, polydispersity index < 0.3 and zeta potential >-25 mV; properties remained unaltered even post sterilization. Permeation study revealed that 75.26% and 34% of MPs were released from MP in situ gel and MP in situ liposomal gel, respectively. The relation between viscosity (cp) and shear rate (1/s) indicate that in situ gels exhibited non-Newtonian behavior at 37°C. The study using Pseudomonas aeruginosa confirmed the antimicrobial activity of meropenem. Conclusion: Prolonged in situ residence, because of rapid gelation process enables an easy administration of meropenem as liposomal suspension in critically ill patients.

An overview of ceftolozane sulfate + tazobactam for treating hospital acquired pneumonia.

INTRODUCTION: Ceftolozane-tazobactam is a combination of a new cephalosporin, with activity similar to that of ceftazidime, and a known inhibitor of beta-lactamases. This compound shows excellent activity against most gram-negative organisms causative of hospital-acquired pneumonia (HAP) or ventilator-acquired pneumonia (VAP), including extended spectrum beta-lactamase (ESBL)-producing Enterobacterales and multidrug-resistant (MDR) Pseudomonas aeruginosa. AREAS COVERED: This article reviews the spectrum of activity, the main pharmacokinetic and pharmacodynamic characteristics and the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of HAP/VAP in adult patients. EXPERT OPINION: The results of a randomized clinical trial have demonstrated an efficacy and safety profile of ceftolozane-tazobactam similar to that of its comparator for the treatment of patients with HAP/VAP. Several retrospective studies have shown good efficacy of the drug for the treatment of respiratory infections caused by MDR P. aeruginosa. The use of this drug may be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP in a carbapenem-saving setting or as a therapeutic alternative with a better safety profile than other therapeutic options in patients with infections caused by MDR P. aeruginosa.

Pulmonary infections prime the development of subsequent ICU-acquired pneumonia in septic shock.

PURPOSE: To investigate the determinants and the prognosis of intensive care unit (ICU)-acquired pneumonia in patients with septic shock. METHODS: This single-center retrospective study was conducted in a medical ICU in a tertiary care center from January 2008 to December 2016. All consecutive patients diagnosed for septic shock within the first 48 h of ICU admission were included. Patients were classified in three groups: no ICU-acquired infections (no ICU-AI), ICU-acquired pneumonia and non-pulmonary ICU-AI. The determinants of ICU-acquired pneumonia and death were investigated by multivariate competitive risk analysis. RESULTS: A total of 1021 patients were admitted for septic shock, and 797 patients were alive in the ICU after 48 h of management. The incidence of a first episode of ICU-AI was 31%, distributed into pulmonary (17%) and non-pulmonary ICU-AI (14%). Patients with septic shock caused by pneumonia were at increased risk of further pulmonary ICU-AI with a cumulated incidence of 34.4%. A pulmonary source of the initial septic shock was an independent risk factor for subsequent ICU-acquired pneumonia (cause-specific hazard 2.33, 95% confidence interval [1.55-3.52], p < 0.001). ICU-AI were not associated with a higher risk of ICU mortality after adjustment in a multivariate-adjusted cause-specific proportional hazard model. CONCLUSION: Septic shock of pulmonary origin may represent a risk factor for subsequent ICU-acquired pneumonia without affecting mortality.

Tailoring Empirical Antimicrobial Therapy in Subjects With Ventilator-Associated Pneumonia With a 10-Hour E-Test Approach.

BACKGROUND: In a previous study of subjects suspected of having ventilator-associated pneumonia, a rapid susceptibility testing approach by using ETEST (BioMérieux) strips directly applied to bronchoalveolar lavage samples provided valuable information at hour 24. The primary objective of this study was to assess a new direct specimen testing by using an even more-rapid E-test approach (at hour 10), which could promote an early de-escalation of the antimicrobial therapy. METHODS: Twenty-eight subjects with ventilator-associated pneumonia admitted to a medical ICU were prospectively included. In parallel with standard routine methods, E-test strips were directly applied onto agar plates seeded with bronchoalveolar lavage samples and were analyzed after 10 h of incubation. E-test results were used to identify potential drug choices by simulating clinical decision making if the microscopy results had been available at the point of care. These choices were analyzed for concordance with the narrowest adequate antimicrobial therapy according to the Minimum Inhibitory Concentrations (MICs) provided by the reference method (ie, the laboratory routine diagnostic). RESULTS: At hour 10, direct specimen testing was readable in 18 of 28 bronchoalveolar lavage samples (64%). Total agreement between the 10-h direct specimen testing approach and the laboratory routine diagnostic approach was 90%, with a sensitivity of 83% and a specificity of 95%, with 8% major errors and 3% very major errors. The concordance between the 2 tests was very good (kappa = 0.79). If the 10-h E-test results were taken into account, then an early de-escalation strategy would have been possible in 10 of 18 cases (55%) at hour 10. CONCLUSIONS: This rapid susceptibility testing approach provided early (10 h) and valuable information that could lead to an early adjustment of empirical antimicrobial treatment in a ventilator-associated pneumonia setting. (ClinicalTrials.gov registration NCT01266863.).

Association between augmented renal clearance and clinical failure of antibiotic treatment in brain-injured patients with ventilator-acquired pneumonia: A preliminary study.

OBJECTIVES: This preliminary study aimed to determine whether augmented renal clearance (ARC) impacts negatively on the clinical outcome in traumatic brain-injured patients (TBI) treated for a first episode of ventilator-acquired pneumonia (VAP). METHODS: During a 5-year period, all TBI patients who had developed VAP were retrospectively reviewed to assess variables associated with clinical failure in multivariate analysis. Clinical failure was defined as an impaired clinical response with a need for escalating antibiotics during treatment and/or within 15 days after the end-of-treatment. Recurrence was considered if at least one of the initial causative bacterial strains was growing at a significant concentration from a second sample. Augmented renal clearance (ARC) was defined by an enhanced creatinine clearance exceeding 130mL/min/1.73m2 calculated from a urinary sample during the first three days of antimicrobial therapy. MAIN RESULTS: During the study period, 223 TBI patients with VAP were included and 59 (26%) presented a clinical failure. Factors statistically associated with clinical failure were GSC≤7 (OR=2.2 [1.1-4.4], P=0.03), early VAP (OR=3.9 [1.9-7.8], P=0.0001), bacteraemia (OR=11 [2.2-54], P=0.003) and antimicrobial therapy≤7 days (OR=3.7 [1.8-7.4], P=0.0003). ARC was statistically associated with recurrent infections with an OR of 4.4 [1.2-16], P=0.03. CONCLUSION: ARC was associated with recurrent infection after a first episode of VAP in TBI patients. The optimal administration and dosing of the antimicrobial agents in this context remain to be determined.

Prior antimicrobial therapy duration influences causative pathogens identification in ventilator-associated pneumonia.

OBJECTIVE: To determine whether prior antimicrobial therapy, divided in recent or current antibiotic treatment, influences the identification rate and/or the type of causative pathogens in patients with suspected episodes of ventilator-acquired pneumonia. DESIGN: Monocentric retrospective study. SETTING: Intensive car unit in a universitary hospital. PATIENTS: 230 episodes of ventilator-associated pneumonia with a Clinical Pulmonary Infection Score≥6 were retrospectively evaluated. Based on the antimicrobial treatment regimen, we defined 3 groups: the no antimicrobial treatment group (VAP is suspected in patients that has never received antibiotics during the last 90days), group 2: the current antimicrobial therapy (VAP is suspected under antimicrobial therapy) and group 3: the recent antimicrobial therapy (VAP is suspected whereas an antimicrobial treatment has been used during the last 90days but discontinued for >24h). INTERVENTION: Bacteriologic analysis using a protected distal sampling with microscopic examination, culture and microbial identification using MALDI-TOF. MEASUREMENTS AND MAIN RESULTS: Suspected episodes of VAP were sorted as follow: 70 suspected episodes in the no antimicrobial therapy group, 106 suspected episodes in the current antimicrobial therapy group and 54 suspected episodes in the recent antimicrobial therapy group. The rate of positive culture was significantly lower in the current antimicrobial treatment group (group 2) when compared to the recent (group 3) and to the no antimicrobial treatment groups (group 1) (42%, 68% and 86%, respectively). When compared to the recent antibiotherapy group, we observed that current antibiotherapy was significantly associated with a higher rate of MDR positive culture, mainly due to higher rate of MDR Pseudomonas aeruginosa. CONCLUSION: In patients with a high probability of VAP, current but not recent antibiotic use is associated with a lower rate of positive culture with a higher proportion of MDR pathogens, mostly MDR Pseudomonas aeruginosa.

Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial.

BACKGROUND: Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. METHODS/DESIGN: This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at [≥] 10(4) colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a 'biomarker-guided recommendation on antibiotics' in which BAL fluid is tested for IL-1ß and IL-8 in addition to routine microbiology testing, or to 'routine use of antibiotics' in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. DISCUSSION: This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP. TRIAL REGISTRATION: ISRCTN65937227 . Registered on 22 August 2013. ClinicalTrials.gov, NCT01972425 . Registered on 24 October 2013.

Microbial Biofilms in Pulmonary and Critical Care Diseases.

Microbial biofilms can colonize medical devices and human tissues, and their role in microbial pathogenesis is now well established. Not only are biofilms ubiquitous in natural and human-made environments, but they are also estimated to be associated with approximately two-thirds of nosocomial infections. This multicellular aggregated form of microbial growth confers a remarkable resistance to killing by antimicrobials and host defenses, leading biofilms to cause a wide range of subacute or chronic infections that are difficult to eradicate. We have gained tremendous knowledge on the molecular, genetic, microbiological, and biophysical processes involved in biofilm formation. These insights now shape our understanding, diagnosis, and management of many infectious diseases and direct the development of novel antimicrobial therapies that target biofilms. Bacterial and fungal biofilms play an important role in a range of diseases in pulmonary and critical care medicine, most importantly catheter-associated infections, ventilator-associated pneumonia, chronic Pseudomonas aeruginosa infections in cystic fibrosis lung disease, and Aspergillus fumigatus pulmonary infections.

Spinal Fusion for Scoliosis in Rett Syndrome With an Emphasis on Respiratory Failure and Opioid Usage.

Our objective was to characterize our experience with 8 patients with Rett syndrome undergoing scoliosis surgery in regard to rates of respiratory failure and rates of ventilator-acquired pneumonia in comparison to patients with neurologic scoliosis and adolescent idiopathic scoliosis. This study was a retrospective chart review of patients undergoing scoliosis surgery at a tertiary children's hospital. Patients were divided into 3 groups: (1) adolescent idiopathic scoliosis, (2) neurologic scoliosis, and (3) Rett syndrome. There were 133 patients with adolescent idiopathic scoliosis, 48 patients with neurologic scoliosis, and 8 patients with Rett syndrome. We found that patients with Rett syndrome undergoing scoliosis surgery have higher rates of respiratory failure and longer ventilation times in the postoperative period when compared with both adolescent idiopathic scoliosis and neurologic scoliosis patients. There is insufficient evidence to suggest a difference in the incidence of ventilator-acquired pneumonia between the Rett syndrome and the neurologic scoliosis group. We believe our findings are the first in the literature to show a statistically significant difference between these 3 groups in regard to incidence of respiratory failure.

Multiplex PCR performed of bronchoalveolar lavage fluid increases pathogen identification rate in critically ill patients with pneumonia: a pilot study.

BACKGROUND: In critically ill patients with pneumonia, accurate microorganism identification allows appropriate antibiotic treatment. In patients undergoing bronchoalveolar lavage (BAL), direct examination of the fluid using Gram staining provides prompt information but pathogen identification accuracy is low. Culture of BAL fluid is actually the reference, but it is not available before 24 to 48 h. In addition, pathogen identification rate observed with direct examination and culture is decreased when antibiotic therapy has been given prior to sampling. We therefore assessed, in critically ill patients with suspected pneumonia, the performance of a multiplex PCR (MPCR) to identify pathogens in BAL fluid. This study is a prospective pilot observation. METHODS: We used a MPCR detecting 20 types of microorganisms. Direct examination, culture, and MPCR were performed on BAL fluid of critically ill patients with pneumonia suspicion. The final diagnosis of infective pneumonia was retained after the medical chart was reviewed by two experts. Pathogen identification rate of direct examination, culture, and MPCR in patients with confirmed pneumonia was compared. RESULTS: Among the 65 patients with pneumonia suspicion, the diagnosis of pneumonia was finally retained in 53 cases. Twenty nine (55%) were community-acquired pneumonia and 24 (45%) were hospital acquired. Pathogen identification rate with MPCR (66%) was greater than with culture (40%) and direct examination (23%) (p =0.01 and p <0.001, respectively). When considering only the microorganisms included in the MPCR panel, the pathogen identification rate provided by MPCR reached 82% and was still higher than with culture (35%, p <0.001) and direct examination (21%, p <0.001). Pathogen identification rate provided by MPCR was not modified in the case of previous antibiotic treatment (66% vs. 64%, NS) and was still better than with culture (23%, p <0.001). CONCLUSIONS: The results of this pilot study suggest that in critically ill patients, MPCR performed on BAL fluid could provide higher identification rate of pathogens involved in pneumonia than direct examination and culture, especially in patients having received antimicrobial treatment.