Development and validation of a high performance liquid chromatography method to determine linezolid concentrations in pig pulmonary tissue.

BACKGROUND: Linezolid is the first synthetic compound of a new group of antimicrobials, the oxazolidinones, which inhibit protein synthesis. It shows a broad spectrum of activity against Gram positive organisms. With respect to its pharmacokinetics, linezolid shows a relatively high volume of distribution and good penetration into inflammatory fluids, bone, fat and muscle. METHODS: A reversed-phase isocratic high-performance liquid chromatographic method for linezolid analysis in piglet pulmonary tissue is described. Tissue samples and controls were prepared in 1 x TBE (1 M Tris, 0.9 M boric acid, 0.01 M EDTA). The mobile phase consisted of 20% ultrafiltered water and 80% of (A) 15 mM potassium monohydrogen phosphate buffer (pH = 5) with (B) acetonitrile (80%/20%; v/v). Samples were homogenized and precipitated with HClO(4) 3% (1/1, v/v). The injection volume was 100 microL. Ofloxacin was used as an internal standard. RESULTS: The assay was linear over a linezolid concentration range: 1.6-100 microg/mL. The method provided good validation data (n = 15): inaccuracy (3.6%), intra and inter-day variability (4.2% and 5.2%, respectively), recovery (91.8%), limit of detection (0.8 microg/mL) and quantitation (1.6 microg/mL) and acceptable stability within 24 h in the auto-sampler. CONCLUSIONS: The method offers a fast and simple approach to determine linezolid in pulmonary tissue which could be of use in pharmacokinetic studies.

Severe community-acquired pneumonia: validation of the Infectious Diseases Society of America/American Thoracic Society guidelines to predict an intensive care unit admission.

BACKGROUND: The recent Infectious Disease Society of America/American Thoracic Society guidelines for the management of community-acquired pneumonia (CAP) in adults defined a predictive rule to identify patients with severe CAP to determine the need for intensive care unit (ICU) admission. We clinically validated this rule. METHODS: We analyzed 2102 episodes of CAP in consecutively hospitalized patients over a 7-year period. The predictive rule consists of at least 1 of 2 major severity criteria (septic shock and invasive mechanical ventilation) or at least 3 of 9 minor severity criteria. We assessed the association of the predictive rule with ICU admission and mortality. RESULTS: A total of 235 episodes of CAP (11%) occurred in patients who were admitted to the ICU, whereas the predictive rule identified 397 (19%) of 2102 episodes as severe CAP. The predictive rule and the decision for ICU admission agreed in 1804 (86%) of the episodes (kappa coefficient, 0.45), with a sensitivity of 71% and a specificity of 88%, similar to the 2001 American Thoracic Society guidelines (sensitivity, 66%; specificity, 90%) in predicting ICU admission. Severe CAP criteria had higher sensitivity (58% vs. 46%) and similar specificity (88% vs. 90%), compared with the 2001 American Thoracic Society guidelines in predicting hospital mortality. Invasive mechanical ventilation was the main determinant for ICU admission, followed by septic shock. In the absence of major criteria, ICU admission was not related to survival of patients with minor severity criteria. CONCLUSIONS: The predictive rule to identify severe CAP is accurate for ICU admission and improved the prediction of mortality, compared with the previous American Thoracic Society guidelines. The need for ICU admission derived from minor severity criteria alone is uncertain and deserves further investigation.

Systemic inflammatory response and increased risk for ventilator-associated pneumonia: a preliminary study.

OBJECTIVE: Inflammatory markers have been assessed for the diagnosis and follow-up of ventilator-associated pneumonia (VAP), but their potential role in predicting the risk for VAP is unknown. We prospectively assessed the evolution of cytokines in mechanically ventilated patients and their predictive and diagnostic role for VAP. DESIGN: Prospective observational study. SETTING: Medical intensive care unit. PATIENTS: Mechanically ventilated patients. Exclusion criteria were active infection at admission and subsequent extrapulmonary infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sequential measurements of interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha were done in 44 ventilated patients. VAP was suspected in 20 cases and microbiologically confirmed in nine. At admission, demographics, severity scores, and clinical and standard laboratory values did not discriminate patients with and without VAP, but the median (interquartile range) serum levels of IL-6 were higher in patients who subsequently developed VAP, compared with those without VAP (235 [141-803] vs. 113 [60-170] pg/mL, p = 0.015). The sensitivity and specificity of IL-6 to predict VAP was 71% and 78%, respectively, using 198 pg/mL as optimal cutoff, with relative risk (95% confidence interval) 8.9 (1.4-56.3). When VAP was suspected, serum levels of IL-6 were higher in patients with confirmed compared with nonconfirmed VAP (1131 [496-1987] vs. 236 [115-357] pg/mL, p = 0.016). The sensitivity and specificity to discriminate between confirmed and nonconfirmed VAP was 71% and 89%, respectively, using 620 pg/mL as optimal cutoff, with relative risk (95% confidence interval) 15.0 (1.2-185.2). CONCLUSIONS: IL-6 at admission is an early and accurate indicator of patients at increased risk for VAP. IL-6 is also accurate in discriminating patients with VAP from other causes of pulmonary infiltrates. Extrapolation of these results to the overall population of critically ill patients is limited by the small number of patients.

Hospitalized community-acquired pneumonia due to Streptococcus pneumoniae: Has resistance to antibiotics decreased?

STUDY OBJECTIVES: To determine the incidence and trends of pneumococcal community-acquired pneumonia (CAP) resistant to antibiotics, to describe clinical and microbiological features of pneumococcal CAP, and to ascertain prognostic risk factors in a third-level hospital. DESIGN AND SETTING: We performed a prospective study of all well-defined pneumococcal CAP hospitalizations in the Hospital Clínic de Barcelona (Spain) over 2 years of follow-up, and results were compared with a previous study. MEASUREMENTS AND RESULTS: One hundred twenty-five patients were included (mean age, 59.6 years; 71.2% male and 28.8% female). Mortality was 7% (n = 9). Twenty-four percent were HIV-1 seropositive (n = 30), and 53% had at least one comorbidity (n = 65). Nonsusceptibility to penicillin, ceftriaxone, and erythromycin accounted for 34%, 9%, and 33%, respectively. A decrease in penicillin (p = 0.01) and cephalosporin (p < 0.001) resistance was observed on comparison with a previous study, while macrolide resistance remained unchanged. Serotype 1 infection was overrepresented (8%, n = 10). A bad outcome was related to female gender (relative risk [RR], 9.1; confidence interval [CI], 1.3 to 61.3), pleural effusion (RR, 13.35; CI, 1.9 to 93.1), and prior oral corticoid intake (RR, 10.59; CI, 1.2 to 91.2), whereas drug-resistant strains were not. CONCLUSIONS: We found a decrease in drug resistance compared with a previous report and a relatively high incidence of serotype 1 pneumococcal CAP. We also observed a high prevalence of HIV-1 infection among individuals with pneumococcal pneumonia. We confirm the lack of association of drug resistance with mortality and length of hospitalization. Mortality was associated with female gender, pleural effusion, and previous oral corticoid treatment. These results should be better ascertained in further studies.