Despoina Koulenti

Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.

Objectives:Information on clinical practice regarding the diagnosis of pneumonia in European intensive care units is limited. The aim of this study was to describe the spectrum of actual diagnostic practices in a large sample of European intensive care units. Design:Prospective, observational, multicenter study. Setting:Twenty-seven intensive care units of nine European countries. Patients:Consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or receiving mechanical ventilation for >48 hrs irrespective of admission diagnosis. Interventions:None. Measurements and Main Results:A total of 2,436 patients were evaluated; 827 were admitted with or developed nosocomial pneumonia (hospital-acquired pneumonia [HAP], 27.1%; ventilator-associated pneumonia [VAP], 56.2%; very early onset VAP, 16.7%). Mean age was 59.4 ± 18.1 yrs, 65.0% were men, and mean admission Simplified Acute Physiology Score II was 46.7 ± 17.1. Worsening oxygenation (76.8%), purulent/changing respiratory secretions (72.1%), and new temperature elevation (69.2%) were the most frequent clinical signs of nosocomial pneumonia. Etiological diagnosis was based on noninvasive respiratory specimens in 74.8% of episodes. Bronchoscopy was performed in 23.3% of episodes. Bronchoscopy performance, after adjustment by severity of illness, age, and type of hospital, were predicted by worsening oxygenation (odds ratio 2.03; 95% confidence interval, 1.27–3.24) and male sex (odds ratio 1.77; 95% confidence interval, 1.19–2.65). Definite cause was documented in 69.5% of nosocomial pneumonia cases. The most common isolates were Staphylococcus aureus (16.3% methicillin-sensitive S. aureus and 16.0% methicillin-resistant S. aureus), Pseudomonas aeruginosa (23.1%), and Acinetobacter baumannii (19.1%). Presence of nosocomial pneumonia significantly prolonged mean length of mechanical ventilation (10.3 days, p < .05) and mean intensive care unit length of stay (12.2 days, p < .05) in intensive care unit survivors. Mortality rate was 37.7% for nosocomial pneumonia vs. 31.6% for patients without pneumonia (p < .05). Conclusions:Etiological diagnosis of nosocomial pneumonia in a large sample of European intensive care units was based mainly on noninvasive techniques. However, there was high variability in bronchoscopy use between the participating intensive care units.

Prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients

Objective:We investigated the epidemiology of ventilator-associated pneumonia in elderly ICU patients. More precisely, we assessed prevalence, risk factors, signs and symptoms, causative bacterial pathogens, and associated outcomes. Design:Secondary analysis of a multicenter prospective cohort (EU-VAP project). Setting:Twenty-seven European ICUs. Patients:Patients who were mechanically ventilated for greater than or equal to 48 hours. We compared middle-aged (45–64 yr; n = 670), old (65–74 yr; n = 549), and very old patients (≥ 75 yr; n= 516). Measurements and Main Results:Ventilator-associated pneumonia occurred in 103 middle-aged (14.6%), 104 old (17.0%), and 73 very old patients (12.8%). The prevalence (n ventilator-associated pneumonia/1,000 ventilation days) was 13.7 in middle-aged patients, 16.6 in old patients, and 13.0 in very old patients. Logistic regression analysis could not demonstrate older age as a risk factor for ventilator-associated pneumonia. Ventilator-associated pneumonia in elderly patients was more frequently caused by Enterobacteriaceae (24% in middle-aged, 32% in old, and 43% in very old patients; p = 0.042). Regarding clinical signs and symptoms at ventilator-associated pneumonia onset, new temperature rise was less frequent among very old patients (59% vs 76% and 74% for middle-aged and old patients, respectively; p = 0.035). Mortality among patients with ventilator-associated pneumonia was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients (p = 0.036). Logistic regression analysis confirmed the importance of older age in the risk of death (adjusted odds ratio for old age, 2.1; 95% CI, 1.2–3.9 and adjusted odds ratio for very old age, 2.3; 95% CI, 1.2–4.4). Other risk factors for mortality in ventilator-associated pneumonia were diabetes mellitus, septic shock, and a high-risk pathogen as causative agent. Conclusions:In this multicenter cohort study, ventilator-associated pneumonia did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with ventilator-associated pneumonia, whereas more episodes among elderly patients were caused by Enterobacteriaceae.

Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia

The objectives of this study were to assess the determinants of empirical antibiotic choice, prescription patterns and outcomes in patients with hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in Europe. We performed a prospective, observational cohort study in 27 intensive care units (ICUs) from nine European countries. 100 consecutive patients on mechanical ventilation for HAP, on mechanical ventilation >48 h or with VAP were enrolled per ICU. Admission category, sickness severity and Acinetobacter spp. prevalence >10% in pneumonia episodes determined antibiotic empirical choice. Trauma patients were more often prescribed non-anti-Pseudomonas cephalosporins (OR 2.68, 95% CI 1.50–4.78). Surgical patients received less aminoglycosides (OR 0.26, 95% CI 0.14–0.49). A significant correlation (p<0.01) was found between Simplified Acute Physiology Score II score and carbapenem prescription. Basal Acinetobacter spp. prevalence >10% dramatically increased the prescription of carbapenems (OR 3.5, 95% CI 2.0–6.1) and colistin (OR 115.7, 95% CI 6.9–1,930.9). Appropriate empirical antibiotics decreased ICU length of stay by 6 days (26.3±19.8 days versus 32.8±29.4 days; p = 0.04). The antibiotics that were prescribed most were carbapenems, piperacillin/tazobactam and quinolones. Median (interquartile range) duration of antibiotic therapy was 9 (6–12) days. Anti-methicillin-resistant Staphylococcus aureus agents were prescribed in 38.4% of VAP episodes. Admission category, sickness severity and basal Acinetobacter prevalence >10% in pneumonia episodes were the major determinants of antibiotic choice at the bedside. Across Europe, carbapenems were the antibiotic most prescribed for HAP/VAP.

What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review

As treatment options for critically ill patients with multidrug-resistant bacteria diminish, older antibiotics such as fosfomycin are being investigated for use as last-resort drugs. Fosfomycin is a broad-spectrum antibiotic with activity both against Gram-positive and Gram-negative bacteria. The aim of this review was to examine the effectiveness of current fosfomycin dosing strategies in critically ill patients. These patients can be subject to pathophysiology that can impact antibiotic pharmacokinetic (PK) profiles and potentially the effectiveness of their treatment. As a hydrophilic drug with negligible protein binding, fosfomycin is eliminated almost entirely by glomerular filtration and is subject to patient renal function. If altered as seen in augmented renal clearance, renal function in a critically ill patient may lead to low blood concentrations and predispose patients to the risk of treatment failure. If altered as seen in acute kidney injury, toxic blood concentrations may develop. Fosfomycin has a volume of distribution comparable with β-lactams and aminoglycosides and may therefore increase in critically ill patients. Altered dosing strategies may be required to optimise dosing given these PK changes, although the current paucity of data on fosfomycin in critically ill patients prevents accurate dosing guidance being recommended at this time.

Patient to Nurse Ratio and Risk of Ventilator-Associated Pneumonia in Critically Ill Patients

OBJECTIVE To determine how the patient to nurse ratio affects risk for ventilator-associated pneumonia. METHODS Data from an earlier study in 27 intensive care units in 9 European countries were examined in a secondary analysis. The initial cohort included 2585 consecutive patients who had mechanical ventilation (1) after admission for treatment of pneumonia or (2) for more than 48 hours irrespective of the diagnosis at admission. In units with variable staffing levels, the highest patient to nurse ratio in a 24-hour period was considered. Patients from 6 units that did not provide data on nurse staffing levels were excluded from the analysis. RESULTS Ventilator-associated pneumonia developed in 393 of the 1658 patients (23.7%) in the secondary cohort. In units with patient to nurse ratios of 1 to 1, 2 to 1, 2.5 to 1, and 3 to 1, rates were 9.3%, 25.7%, 18.7%, and 24.2%, respectively (P = .003). Rates were significantly lower (P = .002) in units with a ratio of 1 to 1 (9.3%) than in units with a ratio of more than 1 patient to 1 nurse (24.4%). After adjustments for confounding covariates, ratios of more than 1 patient to 1 nurse were no longer associated with increased risk for ventilator-associated pneumonia. CONCLUSIONS A patient to nurse ratio of 1 to 1 appears to be associated with a lower risk for ventilator-associated pneumonia, but after adjustments for confounding covariates, the difference is not significant.

Approach to invasive pulmonary aspergillosis in critically ill patients

Purpose of review Apparently immunocompetent critically ill patients represent an increasing population at risk for invasive pulmonary aspergillosis (IPA). The current review gives an update on the epidemiology, diagnosis, and management of IPA in the ICU. Recent findings Patients without apparent severe immunosuppression (e.g. chronic obstructive pulmonary disease, decompensated liver disease, etc.) represent the majority of ICU IPA cases. IPA diagnosis is problematic and the true incidence of IPA is difficult to be estimated because of the nonspecific clinical presentation. A user-friendly clinical diagnostic algorithm for IPA is valuable, particularly through a high negative predictive value. IPA carries a poor prognosis and has an important impact on hospital costs. Timely diagnosis and prompt administration of appropriate treatment may improve the outcomes. Intravenous voriconazole is the recommended primary IPA treatment, but liposomal amphotericin B also has clinical utility. Voriconazole presents bioavailability and toxicity issues, and drug level monitoring is advocated. Caspofungin or antifungal combinations are recommended as salvage therapy. Summary A high level of suspicion in critically ill patients presenting with Aspergillus-positive respiratory tract cultures or nonresolving pulmonary infection may lead to earlier IPA diagnosis. Dosage individualization may decrease treatment discontinuation and improve clinical efficacy.

Gram-negative bacterial pneumonia : aetiology and management

Purpose of review Recent articles of clinical and investigational interest on Gram-negative pneumonia, particularly hospital-acquired and ventilator-associated pneumonia, are reviewed. Recent findings The high rate of respiratory infections due to Gram-negative bacteria in late-onset ventilator-associated pneumonia has been repeatedly documented. The predominant pathogens are Pseudomonas aeruginosa and Acinetobacter baumannii. On the other hand, the frequency of Gram-negative bacteria in community-acquired pneumonia and in early-onset ventilator-associated pneumonia is increasing. Patients with risk factors for infection with resistant pathogens should initially receive a combination therapy that covers a broad spectrum, and, as soon as the pathogen and the susceptibilities are available, treatment should be simplified to a more targeted one (with the possible exception of P. aeruginosa pneumonia). Adequate dosing is of great importance and the use of pharmacodynamic/pharmacokinetic principles when prescribing antibiotics increases effectiveness. The optimal duration of therapy remains unknown; several studies have supported the use of shorter courses of treatment. Alternative treatment approaches (e.g. vaccines) are under investigation. Summary The increasing frequency of resistant Gram-negative bacteria and the shortage of newer antibiotics in the pipeline with activity against Gram-negative bacteria is of concern. Early effective antimicrobial treatment is a key for the resolution of infection and improved survival.

Respiratory infections in patients undergoing mechanical ventilation

Lower respiratory tract infections in mechanically ventilated patients are a frequent cause of antibiotic treatment in intensive-care units. These infections present as severe sepsis or septic shock with respiratory dysfunction in intubated patients. Purulent respiratory secretions are needed for diagnosis, but distinguishing between pneumonia and tracheobronchitis is not easy. Both presentations are associated with longlasting mechanical ventilation and extended intensive-care unit stay, providing a rationale for antibiotic treatment initiation. Differentiation of colonisers from true pathogens is difficult, and microbiological data show Staphylococcus aureus and Pseudomonas aeruginosa to be of great concern because of clinical outcomes and therapeutic challenges. Key management issues include identification of the pathogen, choice of initial empirical antibiotic, and decisions with regard to the resolution pattern.

Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: Lessons from the DALI Study

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic

BackgroundThe clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals) on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study) is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol.MethodsDALI will recruit over 500 patients administered a wide range of either beta-lactam or glycopeptide antibiotics or triazole or echinocandin antifungals in a pharmacokinetic point-prevalence study. It is anticipated that over 60 European intensive care units (ICUs) will participate. The primary aim will be to determine whether contemporary antibiotic dosing for critically ill patients achieves plasma concentrations associated with maximal activity. Secondary aims will compare antibiotic pharmacokinetic exposures with patient outcome and will describe the population pharmacokinetics of the antibiotics included. Various subgroup analyses will be conducted to determine patient groups that may be at risk of very low or very high concentrations of antibiotics.DiscussionThe DALI study should inform clinicians of the potential clinical advantages of achieving certain antibiotic pharmacokinetic exposures in infected critically ill patients.