Jordi Rello

BACKGROUND: Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. METHODS: This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. RESULTS: We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. CONCLUSIONS: Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

In order to assess potential risk factors for pneumonia within the first 8 d of ventilation, we studied 83 consecutive intubated patients undergoing continuous aspiration of subglottic secretions (CASS). Multivariate analysis showed the protective effect of antibiotic use (relative risk [RR] = 0.10; 95% confidence interval [CI] = 0.01 to 0.71), whereas failure of the CASS technique (RR = 5.29; 95% CI = 1.24 to 22.64) was associated with a greater risk of pneumonia. In addition, there was a trend toward a higher risk of pneumonia (RR = 2.57; 95% CI = 0.78 to 8.03) among patients with persistent intracuff pressures below 20 cm H2O. The remaining factors analyzed were not significant. Failure of CASS did not influence the development of pneumonia among patients undergoing antibiotic treatment (33.0% versus 38.5%, p > 0.20), but was strongly associated with pneumonia (42.1% versus 8.3%, p < 0.01) among intubated patients not receiving antibiotics. When multivariate analysis was repeated in this subpopulation, failure of CASS (RR = 7.52, 95% CI = 1.48 to 38.07) and persistent intracuff pressure below 20 cm H2O (RR = 4.23, 95% CI = 1.12 to 15.92) were factors independently associated with the development of pneumonia. We conclude that leakage of colonized subglottic secretions around the cuff of the endotracheal tube is the most important risk factor for pneumonia within the first 8 d of intubation. This study confirms the importance of maintaining adequate intracuff pressure and effective aspiration of subglottic secretions in preventing pneumonia in intubated patients not receiving antibiotic treatment.

RATIONALE: The clinical relevance of Aspergillus-positive endotracheal aspirates in critically ill patients is difficult to assess. OBJECTIVES: We externally validate a clinical algorithm to discriminate Aspergillus colonization from putative invasive pulmonary aspergillosis in this patient group. METHODS: We performed a multicenter (n = 30) observational study including critically ill patients with one or more Aspergillus-positive endotracheal aspirate cultures (n = 524). The diagnostic accuracy of this algorithm was evaluated using 115 patients with histopathologic data, considered the gold standard. Subsequently, the diagnostic workout of the algorithm was compared on the total cohort (n = 524), with the categorization based on the diagnostic criteria of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group. MEASUREMENTS AND MAIN RESULTS: Among 115 histopathology-controlled patients, 79 had proven aspergillosis. The algorithm judged 86 of 115 cases to have putative aspergillosis. This diagnosis was confirmed in 72 and rejected in 14 patients. The algorithm judged 29 patients to have Aspergillus colonization. This was confirmed in 22 and rejected in 7 patients. The algorithm had a specificity of 61% and a sensitivity of 92%. The positive and negative predictive values were 61 and 92%, respectively. In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%). According to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%). The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%). CONCLUSIONS: The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients.

OBJECTIVE: To assess the effect of baseline variables, including treatment, on outcome in patients with nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: Retrospective analysis of data from two prospective, randomized, double-blind studies. SETTING: Multinational study with 134 sites. PATIENTS: A total of 1,019 patients with suspected Gram-positive nosocomial pneumonia, including 339 patients with documented S aureus pneumonia (S aureus subset) and 160 patients with documented MRSA pneumonia (MRSA subset). INTERVENTIONS: Linezolid, 600 mg, or vancomycin, 1 g, q12h for 7 to 21 days, each with aztreonam. MEASUREMENTS AND RESULTS: Outcome was measured by survival and clinical cure rates (assessed 12 to 28 days after the end of therapy). Logistic regression analysis was used to determine the effect of treatment and other baseline variables on outcome. Kaplan-Meier survival rates for linezolid vs vancomycin were 80.0% (60 of 75 patients) vs 63.5% (54 of 85 patients) for the MRSA subset (p = 0.03). Logistic regression analysis confirmed that the survival difference favoring linezolid remained significant after adjusting for baseline variables (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0 to 4.8; p = 0.05). Other baseline variables associated with significantly higher survival rates in MRSA pneumonia were serum creatinine levels less than or equal to two times the upper limit of normal and absence of cardiac comorbidities. Clinical cure rates for linezolid vs vancomycin (excluding indeterminate or missing outcomes) were 59.0% (36 of 61 patients) vs 35.5% (22 of 62 patients) for the MRSA subset (p < 0.01). Logistic regression analysis confirmed that the difference favoring linezolid remained significant after adjusting for baseline variables (OR, 3.3; 95% CI, 1.3 to 8.3; p = 0.01). Other baseline variables associated with significantly higher clinical cure rates in MRSA pneumonia were single-lobe pneumonia, absence of ventilator-associated pneumonia, and absence of oncologic and renal comorbidities. CONCLUSIONS: In this retrospective analysis, initial therapy with linezolid was associated with significantly better survival and clinical cure rates than was vancomycin in patients with nosocomial pneumonia due to MRSA.