The search for new molecules to fight Pseudomonas aeruginosa is of paramount importance. Carbon monoxide (CO) is known to act as an effective inhibitor of the respiratory chain in P. aeruginosa, but the practical use of this gas as an antibacterial molecule is hampered by its toxicity and difficulty to manipulate. Here, we show that a water-soluble CO releaser (CORM-3) possesses bactericidal properties against laboratory and antibiotic-resistant P. aeruginosa. CORM-3 reduced the bacterial count by 4 logs 180 min after in vitro treatment. CORM-3-treated bacteria had a lower O(2) consumption than vehicle-treated bacteria, and the decrease in O(2) consumption temporally preceded the bactericidal action of CORM-3. These results support the hypothesis that the antimicrobial effect of CORM-3 is mediated by an interaction of CO liberated by the carrier with the bacterial respiratory chain. The antibacterial effect occurred at concentrations of CORM-3 that are 50-fold lower than toxic concentrations for eukaryotic cells. CORM-3 treatment compared to vehicle treatment decreased bacterial counts in the spleen and increased survival in immunocompetent and immunosuppressed mice following P. aeruginosa bacteremia. Our results suggest that CORMs could form the basis for developing a new therapeutic strategy against P. aeruginosa-induced infection.

CO carriers inhibit bacterial growth and O(2) consumption in vitro, but transition metal carbonyls appear more powerful than compounds spontaneously liberating CO. The nature of the metal in CO-RMs also modulates the anti-bacterial effect, with ruthenium-based CO-RMs being efficacious both in vitro and in vivo.

Purulent pericarditis (PP) is a potentially life-threatening disease. Reported mortality rates are between 20 and 30%. Constrictive pericarditis occurs over the course of PP in at least 3.5% of cases. The frequency of persistent PP (chronic or recurrent purulent pericardial effusion occurring despite drainage and adequate antibiotherapy) is unknown because this entity was not previously classified as a complication of PP. No consensus exists on the optimal management of PP. Nevertheless, the cornerstone of PP management is complete eradication of the focus of infection. In retrospective studies, compared to simple drainage, systematic pericardiectomy provided a prevention of constrictive pericarditis with better clinical outcome. Because of potential morbidity associated with pericardiectomy, intrapericardial fibrinolysis has been proposed as a less invasive method for prevention of persistent PP and constrictive pericarditis. Experimental data demonstrate that fibrin formation, which occurs during the first week of the disease, is an essential step in the evolution to constrictive pericarditis and persistent PP. We reviewed the literature using the MEDLINE database. We evaluated the clinical efficacy, outcome, and complications of pericardial fibrinolysis. Seventy-four cases of fibrinolysis in PP were analysed. Pericarditis of tuberculous origin were excluded. Among the 40 included cases, only two treated by late fibrinolysis encountered failure requiring pericardiectomy. No patient encountered clinical or echocardiographic features of constriction during follow-up. Only one serious complication was described. Despite the lack of definitive evidence, potential benefits of fibrinolysis as a less invasive alternative to surgery in the management of PP seem promising. Early consideration should be given to fibrinolysis in order to prevent both constrictive and persistent PP. Nevertheless, in case of failure of fibrinolysis, pericardiectomy remains the primary option for complete eradication of infection.

Chronic exposure to particulate air pollution is associated with lung function impairment. To determine the molecular mechanism(s) of this phenomenon, we investigated, in an alveolar human epithelial cell line (A549), whether diesel exhaust particles (DEPs), a main component of particulate air pollution, modulates the expression and activity of the matrix metalloprotease (MMP)-1, a collagenase involved in alveolar wall degradation. Interaction of DEPs with cigarette smoke, which also produces structural and functional lung alterations, was also investigated. A noncytotoxic concentration of DEPs induced an increase in MMP-1 mRNA and protein expression and activity in A549 cells without modifying the expression of the MMP inhibitors TIMP-1 and -2. This effect was not potentiated when cells were coexposed to noncytotoxic concentrations of cigarette smoke condensate. DEP-induced MMP-1 was associated with increased ERK 1/2 phosphorylation and upregulation of expression and activity of the NADPH oxidase analog NOX4. Cell transfection with a NOX4 small interfering RNA prevented these phenomena, showing the critical role of a NOX4 ERK 1/2 pathway in DEP-induced MMP-1 expression and activity. Similar results to those observed in A549 cells were obtained in another human lung epithelial cell line, NCI-H292. Furthermore, experiments in mice intratracheally instilled with DEPs confirmed the in vitro findings, showing the induction of NOX4 and MMP-1 protein expression in alveolar epithelial cells. We conclude that alveolar alterations secondary to MMP-1 induction could explain lung function impairment associated with exposure to particulate pollution.

BackgroundDe-escalation is strongly recommended for antibiotic stewardship. No studies have addressed this issue in the context of health care-associated intra-abdominal infections (HCIAI). We analyzed the factors that could interfere with this process and their clinical consequences in intensive care unit (ICU) patients with HCIAI.MethodsAll consecutive patients admitted for the management of HCIAI who survived more than 3 days following their diagnosis, who remained in the ICU for more than 3 days, and who did not undergo early reoperation during the first 3 days were analyzed prospectively in an observational, single-center study in a tertiary care university hospital.ResultsOverall, 311 patients with HCIAI were admitted to the ICU. De-escalation was applied in 110 patients (53 %), and no de-escalation was reported in 96 patients (47 %) (escalation in 65 [32 %] and unchanged regimen in 31 [15 %]). Lower proportions of Enterococcus faecium, nonfermenting Gram-negative bacilli (NFGNB), and multidrug-resistant (MDR) strains were cultured in the de-escalation group. No clinical difference was observed at day 7 between patients who were de-escalated and those who were not. Determinants of de-escalation in multivariate analysis were adequate empiric therapy (OR 9.60, 95 % CI 4.02–22.97) and empiric use of vancomycin (OR 3.39, 95 % CI 1.46–7.87), carbapenems (OR 2.64, 95 % CI 1.01–6.91), and aminoglycosides (OR 2.31 95 % CI 1.08–4.94). The presence of NFGNB (OR 0.28, 95 % CI 0.09–0.89) and the presence of MDR bacteria (OR 0.21, 95 % CI 0.09–0.52) were risk factors for non-de-escalation. De-escalation did not change the overall duration of therapy. The risk factors for death at day 28 were presence of fungi (HR 2.64, 95 % CI 1.34–5.17), Sequential Organ Failure Assessment score on admission (HR 1.29, 95 % CI 1.16–1.42), and age (HR 1.03, 95 % CI 1.01–1.05). The survival rate expressed by a Kaplan-Meier curve was similar between groups (log-rank test p value 0.176).ConclusionsDe-escalation is a feasible option in patients with polymicrobial infections such as HCIAI, but MDR organisms and NFGNB limit its implementation.

The toxic effect of high concentrations of CO gas in living organisms is coherently typified at biochemical levels by the high affinity of CO for hemoglobin and cytochromes, heme-dependent proteins that are indispensable for oxygen transport and mitochondrial respiration. However, the basal production of CO during heme degradation and the ability of heme oxygenase-1 (HO-1) to increase CO availability pose the question of how this gaseous molecule interacts with metal centers within the intracellular milieu to serve as one of the most unconventional signaling mediators. Emerging evidence indicates that the diverse and multifaceted beneficial effects exerted by "low concentrations" of CO cannot be explained solely by the activation of classic prototypic targets (i.e., guanylate cyclase/potassium channels) but entails the dynamic and concerted activation/inhibition of a group of CO-responsive proteins. As the complexity of the temporal and spatial action of CO is progressively being appreciated, this review aims to (a) highlight the current knowledge on certain metal-containing proteins that interact directly with CO; (b) analyze the latest notions on their functional role in response to CO; and finally (c) propose a rational view on the mode these CO targets may interrelate with and be regulated by the HO/CO pathway.

Metabolic disorders and fluid overload are indications of continuous renal replacement therapy (CRRT) including continuous venovenous hemofiltration in patients on extracorporeal membrane oxygenation (ECMO). Direct connection of CRRT machine to the ECMO circuit provides many advantages. Nevertheless, because pressures in CRRT lines relate to ECMO blood flow, high ECMO blood flow may be associated with high pressures in CRRT lines. Thus, management of CRRT pressure lines becomes challenging. We evaluated a protocol for managing high CRRT pressures. Connections were performed according to a standardized protocol to maintain CRRT lines in the correct pressure ranges without modifying ECMO settings or inhibiting pressure alarms. To achieve this goal, the way of connecting of CRRT lines was adapted following a standardized protocol. Connection was first attempted between pump and oxygenator in the 12 patients. In five cases, high pressures in CRRT lines were successfully managed by changing the connection segment. Continuous renal replacement therapy parameters were within target levels and reduction of serum creatinine was 37%. In conclusion, management of high pressures in CRRT lines induced by ECMO could be achieved without modifying ECMO blood flow or inhibiting CRRT alarms. Iterative stops were avoided allowing efficient procedures.

Introduction: Persistent peritonitis is a frequent complication of secondary peritonitis requiring additional reoperations and antibiotic therapy. This situation raises specific concerns due to microbiological changes in peritoneal samples, especially the emergence of multidrug-resistant (MDR) strains. Although this complication has been extensively studied, the rate and dynamics of MDR strains have rarely been analysed. Methods: We compared the clinical, microbiological and therapeutic data of consecutive ICU patients admitted for postoperative peritonitis either without subsequent reoperation (n = 122) or who underwent repeated surgery for persistent peritonitis with positive peritoneal fluid cultures (n = 98). Data collected on index surgery for the treatment of postoperative peritonitis were compared between these two groups. In the patients with persistent peritonitis, the data obtained at the first, second and third reoperations were compared with those of index surgery. Risk factors for emergence of MDR strains were assessed.