Short-Term Effects of Appropriate Empirical Antimicrobial Treatment with Ceftolozane/Tazobactam in a Swine Model of Nosocomial Pneumonia.

The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1ß (IL-1ß) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.

A real life evaluation of non invasive ventilation in acute cardiogenic pulmonary edema: a multicenter, perspective, observational study for the ACPE SIMEU study group.

BACKGROUND: During the past three decades conflicting evidences have been published on the use of non-invasive ventilation (NIV) in patients with acute cardiogenic pulmonary edema (ACPE). The aim of this study is to describe the management of acute respiratory failure (ARF) due to ACPE in twelve Italian emergency departments (EDs). We evaluated prevalence, characteristics and outcomes of ACPE patients treated with oxygen therapy, continuous positive airway pressure (CPAP) or Bi-level positive airway pressure (BiPAP) on admission to the EDs. METHODS: In this multicenter, prospective, observational study, consecutive adult patients with ACPE were enrolled in 12 EDs in Italy from May 2009 to December 2013. Three study groups were identified according to the initial respiratory treatment: patients receiving oxygen therapy, those treated with CPAP and those treated with BiPAP. Treatment failure was evaluated as study outcome. RESULTS: We enrolled 1293 patients with acute cardiogenic pulmonary edema. 273 (21%) began with oxygen, 788 (61%) with CPAP and 232 (18%) with BiPAP. One out of four patient who began with oxygen was subsequently switched to NIV and initial treatment with oxygen therapy had an odds ratio for treatment failure of 3.65 (95% CI: 2.55-5.23, p < 0.001). CONCLUSIONS: NIV seems to be the first choice for treatment of ARF due to ACPE, showing high clinical effectiveness and representing a rescue option for patients not improving with conventional oxygen therapy.

Development and characterization of a new swine model of invasive pneumococcal pneumonia.

Streptococcus pneumoniae is the most common microbial cause of community-acquired pneumonia. Currently, there are no available models of severe pneumococcal pneumonia in mechanically ventilated animals to mimic clinical conditions of critically ill patients. We studied endogenous pulmonary flora in 4 healthy pigs and in an additional 10 pigs in which we intra-bronchially instilled S. pneumoniae serotype 19 A, characterized by its resistance to penicillin, macrolides and tetracyclines. The pigs underwent ventilation for 72 h. All pigs that were not challenged with S. pneumoniae completed the 72-h study, whereas 30% of infected pigs did not. At 24 h, we clinically confirmed pneumonia in the infected pigs; upon necropsy, we sampled lung tissue for microbiological/histological confirmation of pneumococcal pneumonia. In control pigs, Streptococcus suis and Staphylococcus aureus were the most commonly encountered pathogens, and their lung tissue mean ± s.e.m. concentration was 7.94 ± 20 c.f.u./g. In infected pigs, S. pneumoniae was found in the lungs of all pigs (mean ± s.e.m. pulmonary concentration of 1.26 × 105 ± 2 × 102 c.f.u./g). Bacteremia was found in 50% of infected pigs. Pneumococcal pneumonia was confirmed in all infected pigs at 24 h. Pneumonia was associated with thrombocytopenia, an increase in prothrombin time, cardiac output and vasopressor dependency index and a decrease in systemic vascular resistance. Upon necropsy, microbiological/histological pneumococcal pneumonia was confirmed in 8 of 10 pigs. We have therefore developed a novel model of penicillin- and macrolide-resistant pneumococcal pneumonia in mechanically ventilated pigs with bacteremia and severe hemodynamic compromise. The model could prove valuable for appraising the pathogenesis of pneumococcal pneumonia, the effects associated with macrolide resistance and the outcomes related to the use of new diagnostic strategies and antibiotic or complementary therapies.

Severe community-acquired pneumonia: Characteristics and prognostic factors in ventilated and non-ventilated patients.

BACKGROUND: Patients with severe community-acquired pneumonia (SCAP) and life-threatening acute respiratory failure may require invasive mechanical ventilation (IMV). Since use of IMV is often associated with significant morbidity and mortality, we assessed whether patients invasively ventilated would represent a target population for interventions aimed at reducing mortality of SCAP. METHODS: We prospectively recruited consecutive patients with SCAP for 12 years. We assessed the characteristics and outcomes of patients invasively ventilated at presentation of pneumonia, compared with those without IMV, and determined the influence of risks factors on mortality with a multivariate weighted logistic regression using a propensity score. RESULTS: Among 3,719 patients hospitalized with CAP, 664 (18%) had criteria for SCAP, and 154 (23%) received IMV at presentation of pneumonia; 198 (30%) presented with septic shock. In 370 (56%) cases SCAP was diagnosed based solely on the presence of 3 or more IDSA/ATS minor criteria. Streptococcus pneumoniae was the main pathogen in both groups. The 30-day mortality was higher in the IMV, compared to non-intubated patients (51, 33%, vs. 94, 18% respectively, p<0·001), and higher than that predicted by APACHE-II score (26%). IMV independently predicted 30-day mortality in multivariate analysis (adjusted odds-ratio 3·54, 95% confidence interval 1·45-8·37, p = 0·006). Other independent predictors of mortality were septic shock, worse hypoxemia and increased serum potassium. CONCLUSION: Invasive mechanical ventilation independently predicted 30-day mortality in patients with SCAP. Patients invasively ventilated should be considered a different population with higher mortality for future clinical trials on new interventions addressed to improve mortality of SCAP.

Diagnostic Value of Endotracheal Aspirates Sonication on Ventilator-Associated Pneumonia Microbiologic Diagnosis.

Microorganisms are able to form biofilms within respiratory secretions. Methods to disaggregate such biofilms before utilizing standard, rapid, or high throughput diagnostic technologies may aid in pathogen detection during ventilator associated pneumonia (VAP) diagnosis. Our aim was to determine if sonication of endotracheal aspirates (ETA) would increase the sensitivity of qualitative, semi-quantitative, and quantitative bacterial cultures in an animal model of pneumonia caused by Pseudomonasaeruginosa or by methicillin resistant Staphylococcusaureus (MRSA). MATERIAL AND METHODS: P.aeruginosa or MRSA was instilled into the lungs or the oropharynx of pigs in order to induce severe VAP. Time point assessments for qualitative and quantitative bacterial cultures of ETA and bronchoalveolar lavage (BAL) samples were performed at 24, 48, and 72 h after bacterial instillation. In addition, at 72 h (autopsy), lung tissue was harvested to perform quantitative bacterial cultures. Each ETA sample was microbiologically processed with and without applying sonication for 5 min at 40 KHz before bacterial cultures. Sensitivity and specificity were determined using BAL as a gold-standard. Correlation with BAL and lung bacterial burden was also determined before and after sonication. Assessment of biofilm clusters and planktonic bacteria was performed through both optical microscopy utilizing Gram staining and Confocal Laser Scanning Microscopy utilizing the LIVE/DEAD®BacLight kit. RESULTS: 33 pigs were included, 27 and 6 from P.aeruginosa and MRSA pneumonia models, respectively. Overall, we obtained 85 ETA, 69 (81.2%) from P.aeruginosa and 16 (18.8%) from MRSA challenged pigs. Qualitative cultures did not significantly change after sonication, whereas quantitative ETA cultures did significantly increase bacterial counting. Indeed, sonication consistently increased bacterial burden in ETAs at 24, 48, and 72 h after bacterial challenge. Sonication also improved sensitivity of ETA quantitative cultures and maintained specificity at levels previously reported and accepted for VAP diagnosis. CONCLUSION: The use of sonication in ETA respiratory samples needs to be clinically validated since sonication could potentially improve pathogen detection before standard, rapid, or high throughput diagnostic methods used in routine microbial diagnostics.