Jordi Rello

Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients

AbstractPurposenRisk factors for β-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment.MethodsThis analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50xa0% and 100xa0% of the dosing interval respectively (50xa0% and 100xa0% fT>MIC). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure.ResultsA total of 343 critically ill patients receiving eight different β-lactam antibiotics were included. The median (interquartile range) age was 60 (47–73) years, APACHE II score was 18 (13–24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50xa0% and 100xa0% of the dosing interval in 66 (19.2xa0%) and 142 (41.4xa0%) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100xa0% fT>MIC target.ConclusionsThis study found that—in empirical dosing and considering a worst-case scenario—19xa0% and 41xa0% of the patients would not achieve antibiotic concentrations above the MIC during 50xa0% and 100xa0% of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.

Why Mortality Is Increased in Health-Care-Associated Pneumonia: Lessons From Pneumococcal Bacteremic Pneumonia

BACKGROUNDnA cohort of patients with bacteremic Streptococcus pneumoniae pneumonia was reviewed to assess why mortality is higher in health-care-associated pneumonia (HCAP) than in community-acquired pneumonia (CAP).nnnMETHODSnA prospective cohort of all adult patients with bacteremic pneumococcal pneumonia attended at the ED was used.nnnRESULTSnOne hundred eighty-four cases were classified as CAP and 44 (19%) as HCAP. Fifty-two (23%) were admitted to the ICU. Three (1.5%) isolates were resistant to beta-lactams, and only two patients received inappropriate therapy. The CAP cohort was significantly younger (median age 68 years, interquartile range [IQR] 42-78 vs 77 years, IQR 67-82, P < .001). The HCAP cohort presented a higher Charlson index (2.81 +/- 1.9 vs 1.23 +/- 1.42, P < .001) and had higher severity of illness at admission (altered mental status, respiratory rate > 30/min, Pao(2)/Fio(2) < 250, and multilobar involvement). HCAP patients had a lower rate of ICU admission (11.3% vs 25.5%, P < .05), and a trend toward lower mechanical ventilation (9% vs 19%, P = .17) and vasopressor use (9% vs 18.4%, P = .17) were documented. More patients in the HCAP cohort presented with a pneumonia severity index score > 90 (class IV-V, 95% vs 65%, P < .001), and 30-day mortality was significantly higher (29.5% vs 7.6%, P < .001). A multivariable regression logistic analysis adjusting for underlying conditions and variables related to severity of illness confirmed that HCAP is an independent variable associated with increased mortality (odds ratio = 5.56; 95% CI, 1.86-16.5).nnnCONCLUSIONSnPneumococcal HCAP presents excess mortality, which is independent of bacterial susceptibility. Differences in outcomes were probably due to differences in age, comorbidities, and criteria for ICU admission rather than to therapeutic decisions.

Ventilator-Associated Pneumonia: Impact of Organisms on Clinical Resolution and Medical Resources Utilization

BACKGROUNDnClinical resolution of ventilator-associated pneumonia (VAP) determines the duration of treatment and mechanical ventilation. The aim of this study was to evaluate the influence of organisms and their susceptibility to treatment on outcomes.nnnMETHODSnProspective observational study in three teaching ICUs. Sixty episodes of VAP with appropriate therapy (Haemophilus influenzae, 15 episodes; methicillin-sensitive Staphylococcus aureus [MSSA], 15 episodes; Pseudomonas aeruginosa, 15 episodes; and methicillin-resistant S aureus [MRSA], 15 episodes), and 30 episodes with initial inappropriate therapy, all due to P aeruginosa, were compared. The main outcome measures were clinical resolution variables and, in survivors, length of mechanical ventilation after VAP onset.nnnRESULTSnA significant delay in the resolution of hypoxemia was observed in VAP episodes due to MRSA and P aeruginosa with inappropriate antibiotic therapy (IAT) (median time to resolution, 10 and 8 days, respectively) when compared with the remaining pathogens (median time to resolution, 2 days). A multiple regression model, adjusted for disease severity, confirmed the delayed clinical resolution for MRSA and P aeruginosa with IAT. Similar associations were documented for defervescence. Among survivors, the median duration of mechanical ventilation after VAP onset was significantly longer for MRSA (17 days) and P aeruginosa IAT (11 days) when compared with episodes due to H influenzae or MSSA (6 days). Multiple regression analysis, adjusted for disease severity, confirmed that MRSA required significantly (R(2) = 0.132; p < 0.01) longer respiratory support than other organisms.nnnCONCLUSIONSnWhen treated promptly, the resolution of VAP due to MSSA, H influenzae, and P aeruginosa was comparable. The resolution of MRSA VAP, regardless of the appropriateness of initial antibiotic therapy, was associated with longer respiratory support.

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.

Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia

The influence of infecting serotype group on outcome in bacteraemic pneumococcal pneumonia remains unclear. We performed a prospective, 10-yr observational study in an 800-bed teaching hospital. 299 adults diagnosed with pneumonia whose blood cultures showed growth of Streptococcus pneumoniae were included in the study. High invasive disease potential (H) serotypes included serotypes 1, 5 and 7F, which served as a reference category, were compared with low invasive disease potential (L) serotypes (3, 6A, 6B, 8, 19F, and 23F) and other (O) serotypes (non-H, non-L). The influence on outcome was determined for each group of serotypes after adjusting for underlying conditions and severity of illness at admission. Overall, 30-day mortality was 11%. H serotypes (n = 93) infected primarily younger people and presented a higher risk of complicated parapneumonic effusion or empyema (17.2 versus 5.1%; p = 0.01), with lower mortality (3.2%). The isolation of L serotypes (n = 78) was an independent risk factor for 30-day mortality (OR 7.02, 95% CI 1.72–28.61), as were Charlson score (OR 1.30, 95% CI 1.08–1.58), alcohol abuse (OR 3.99, 95% CI 1.39–11.39) and severity of illness measured by American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) criteria (OR 4.80, 95% CI 1.89–12.13). A vaccination strategy including serotypes 3, 6A, 6B, 8, 19F and 23F may improve survival in adults.

Initial management of pneumonia and sepsis: factors associated with improved outcome.

Processes of care and adherence to guidelines have been associated with improved survival in community-acquired pneumonia (CAP). In sepsis, bundles of processes of care have also increased survival. We aimed to audit compliance with guideline-recommended processes of care and its impact on outcome in hospitalised CAP patients with sepsis. We prospectively studied 4,137 patients hospitalised with CAP in 13 hospitals. The processes of care evaluated were adherence to antibiotic prescription guidelines, first dose within 6 h and oxygen assessment. Outcome measures were mortality and length of stay (LOS). Oxygen assessment was measured in 3,745 (90.5%) patients; 3,024 (73.1%) patients received antibiotics according to guidelines and 3,053 (73.8%) received antibiotics within 6 h. In CAP patients with sepsis, the strongest independent factor for survival was antibiotic adherence (OR 0.4). In severe sepsis, only compliance to antibiotic adherence plus first dose within 6 h was associated with lower mortality (OR 0.60), adjusted for fine prognostic scale and hospital. Antibiotic adherence was related to shorter hospital stay. In sepsis, antibiotic adherence is the strongest protective factor of care associated with survival and LOS. In severe sepsis, combined antibiotic adherence and first dose within 6 h may reduce mortality.

Recomendaciones para el diagnóstico de la neumonía asociada a ventilación mecánica

Francisco Alvarez-Lerma, Antonio Torres, Felipe Rodriguez de Castro y la Comision de Expertos del Grupo de Trabajo de Enfermedades Infecciosas de la Sociedad Espanola de Medicina Intensiva, Critica y Unidades Coronarias (GTEI-SEMICYUC ), Area de Trabajo de Tuberculosis e Infecciones Respiratorias de la Sociedad Espanola de Patologia del Aparato Respiratorio (SEPAR) y Grupo de Estudio de Infeccion Hospitalaria de la Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica (GEIH-SEIMC)

Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients

Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this consensus statement of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: Vibrating-mesh nebulizers should be preferred to jet or ultrasonic nebulizers. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (a) the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (b) the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8xa0mL/kg, respiratory frequency 12 to 15 bpm, inspiratory:expiratory ratio 50%, inspiratory pause 20% and positive end-expiratory pressure 5 to 10xa0cm H2O and (c) the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patients flow triggering and episodes of peak decelerating inspiratory flow. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia.

Intubated patients developing tracheobronchitis or pneumonia have distinctive complement system gene expression signatures in the pre-infection period: A pilot study

INTRODUCTIONnIt remains unknown why some intubated patients remain infection-free while others develop tracheobronchitis (VAT) or pneumonia (VAP).nnnOBJECTIVEnTo identify and compare VAP/VAT gene expression signatures using genome-wide oligonucleotide microarrays.nnnMATERIAL AND METHODSnA prospective translational study of gene expression profiles of VAP and VAT groups was carried out, establishing comparisons in both pre-infection and infection phases. Pathway and functional analyses were performed with Ingenuity Pathway Analysis (IPA). Data analysis and hierarchical clustering of the genes involved in the signalling pathways expressed differentially in the two groups were performed with GeneSpring GX 11.0.nnnRESULTSnEight patients developing respiratory infections (3 VAP and 5 VAT) after 4 days of mechanical ventilation were assessed. Comparison of gene expression profiles in the pre-infection period revealed 5595 genes expressed differentially between VAP and VAT (p<0.01, fold change >2). Comparative IPA analysis identified a significant depression of the complement system signalling pathway in the VAP group, affecting the classical pathway along with the final common pathway (p<0.05). In addition, the cAMP and calcium signalling pathways were also significantly depressed in the VAP group during the pre-infection phase also.nnnCONCLUSIONnIntubated patients complicated with pneumonia developed immune impairment in the pre-infection period, manifesting as a relatively lower expression of genes involved in the complement system that differed from patients developing tracheobronchitis. These findings suggest that a significant proportion of VAP episodes cannot be prevented, but might be treatable through pre-emptive therapy.

Sensitivity, Specificity, and Positivity Predictors of the Pneumococcal Urinary Antigen Test in Community-Acquired Pneumonia.

RATIONALEnDetection of the C-polysaccharide of Streptococcus pneumoniae in urine by an immune-chromatographic test is increasingly used to evaluate patients with community-acquired pneumonia.nnnOBJECTIVESnWe assessed the sensitivity and specificity of this test in the largest series of cases to date and used logistic regression models to determine predictors of positivity in patients hospitalized with community-acquired pneumonia.nnnMETHODSnWe performed a multicenter, prospective, observational study of 4,374 patients hospitalized with community-acquired pneumonia.nnnMEASUREMENTS AND MAIN RESULTSnThe urinary antigen test was done in 3,874 cases. Pneumococcal infection was diagnosed in 916 cases (21%); 653 (71%) of these cases were diagnosed exclusively by the urinary antigen test. Sensitivity and specificity were 60 and 99.7%, respectively. Predictors of urinary antigen positivity were female sex; heart rate≥125 bpm, systolic blood pressure<90 mm Hg, and SaO2<90%; absence of antibiotic treatment; pleuritic chest pain; chills; pleural effusion; and blood urea nitrogen≥30 mg/dl. With at least six of all these predictors present, the probability of positivity was 52%. With only one factor present, the probability was only 12%.nnnCONCLUSIONSnThe urinary antigen test is a method with good sensitivity and excellent specificity in diagnosing pneumococcal pneumonia, and its use greatly increased the recognition of community-acquired pneumonia due to S. pneumoniae. With a specificity of 99.7%, this test could be used to direct simplified antibiotic therapy, thereby avoiding excess costs and risk for bacterial resistance that result from broad-spectrum antibiotics. We also identified predictors of positivity that could increase suspicion for pneumococcal infection or avoid the unnecessary use of this test.