Clinical and bacterial characteristics of Pseudomonas aeruginosa affecting the outcome of patients with bacteraemic pneumonia.

Few studies have assessed the clinical and bacterial characteristics of Pseudomonas aeruginosa (PA) bacteraemic pneumonia (BP) episodes. This study analysed all non-duplicate PA-BP episodes from a tertiary hospital in 2013-2017. Epidemiology, clinical data, antimicrobial therapy and outcomes were recorded. Whole-genome sequencing was performed on PA blood isolates. The impact on early and late overall mortality of host, antimicrobial treatment and pathogen factors was assessed by multivariate logistic regression analysis. Of 55 PA-BP episodes, 32 (58.2%) were caused by extensively drug-resistant (XDR) PA. ST175 (32.7%) and ST235 (25.5%) were the most frequent high-risk clones. ß-Lactamases/carbapenemases were detected in 29 isolates, including blaVIM-2 (27.2%) and blaGES type (25.5%) [blaGES-5 (20.0%), blaGES-1 (3.6%) and blaGES-20 (1.8%)]. The most prevalent O-antigen serotypes were O4 (34.5%) and O11 (30.9%). Overall, an extensive virulome was identified in all isolates. Early mortality (56.4%) was independently associated with severe neutropenia (aOR = 4.64, 95% CI 1.11-19.33; P = 0.035) and inappropriate empirical antimicrobial therapy (aOR = 5.71, 95% CI 1.41-22.98; P = 0.014). Additionally, late mortality (67.3%) was influenced by septic shock (aOR = 8.85, 95% CI 2.00-39.16; P = 0.004) and XDR phenotype (aOR = 5.46, 95% CI 1.25-23.85; P = 0.024). Moreover, specific genetic backgrounds [ST235, blaGES, gyrA (T83I), parC (S87L), exoU and O11 serotype] showed significant differences in patient outcomes. Our results confirm the high mortality associated with PA-BP. Besides relevant clinical characteristics and inappropriate empirical therapy, bacteria-specific genetics factors, such as XDR phenotype, adversely affect the outcome of PA-BP.

Multicenter study of ceftolozane/tazobactam for treatment of Pseudomonas aeruginosa infections in critically ill patients.

BACKGROUND: This study aimed to assess the efficacy of ceftolozane-tazobactam (C/T) for treating infections due to Pseudomonas aeruginosa (P. aeruginosa) in critically ill patients. PATIENTS AND METHODS: A multicenter, retrospective and observational study was conducted in critically ill patients receiving different C/T dosages and antibiotic combinations for P. aeruginosa infections. Demographic data, localisation and severity of infection, clinical and microbiological outcome, and mortality were evaluated. RESULTS: Ninety-five patients received C/T for P. aeruginosa serious infections. The main infections were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteraemia (10.5%). Forty-six episodes were treated with high-dose C/T (3 g every 8 hours) and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics. Sixty-eight (71.6%) patients presented a favourable clinical response. Microbiological eradication was documented in 42.1% (40/95) of the episodes. The global ICU mortality was 36.5%. Univariate analysis showed that 30-day mortality was significantly associated (P < 0.05) with Charlson Index at ICU admission and the need of life-supporting therapies. CONCLUSIONS: C/T appeared to be an effective therapy for severe infections due to P. aeruginosa in critically ill patients. Mortality was mainly related to the severity of the infection. No benefit was observed with high-dose C/T or combination therapy with other antibiotics.

Zinc oxide nanoparticles inhibits quorum sensing and virulence in Pseudomonas aeruginosa.

BACKGROUND: Quorum sensing inhibitionis an advanced strategy that aims to interfere with bacterial cell-to-cell communication systems (quorum sensing), which regulate virulence factors production in Pseudomonas aeruginosa, in order to overcome the globalcrisis of antimicrobial resistance. OBJECTIVES: Study the potential quorum sensing inhibitory effect of Zinc oxide (ZnO)nanoparticlesin Pseudomonas aeruginosa and the impact on production of virulence factors. METHODS: Quorum sensing inhibitory effect of ZnO was evaluated by assessing its ability to reducePseudomonas aeruginosa virulence factors production; rhamnolipids, pyocyanin, pyoverdin, hemolysins, elastase and proteases. Furthermore, qRT-PCR was performed to determine ZnO inhibitory effect onQS-regulatory geneslasI, lasR, rhlI, rhlR, pqsA and pqsR that control virulence factors secretion. Moreover, mice survival test was conducted to investigate the influence of ZnO on Pseudomonas aeruginosa-induced mortality in vivo. RESULTS: ZnO revealed a statistically significant reduction in the production of QS-controlled virulence factors rhamnolipids, pyocyanin, pyoverdin, hemolysins, elastase and proteases. Furthermore, ZnO exhibited a significant decrease in the relative expression of QS-regulatory geneslasI, lasR, rhlI, rhlR, pqsA and pqsR. Additionally, ZnO significantly reduced the pathogenesis of Pseudomonas aeruginosa in vivo. CONCLUSION: ZnO nanoparticles can be used as a quorum sensing inhibitor in Pseudomonas aeruginosa infections either as an adjuvant or alternative to conventional antimicrobials.

Application of Lactobacillus gasseri 63 AM supernatant to Pseudomonas aeruginosa-infected wounds prevents sepsis in murine models of thermal injury and dorsal excision.

Introduction. Severely burned patients are susceptible to bacterial infection within their burn wounds, which frequently leads to sepsis, multiple organ failure and death. The opportunistic pathogen Pseudomonas aeruginosa, an organism inherently resistant to multiple antibiotics, is a common cause of sepsis in these patients.Aim. Development of a topical treatment unrelated to conventional antibiotics is essential for prevention of P. aeruginosa infection and sepsis, leading to a role for the direct application of probiotics or their by-products.Methodology. We examined the effectiveness of 20× concentrated supernatant from Lactobacillus gasseri strain 63 AM (LgCS) grown in de Man, Rogosa and Sharpe broth in inhibiting P. aeruginosa biofilms in vitro, as well as in reducing wound bioburden and P. aeruginosa sepsis in vivo.Results. LgCS inhibited the growth of P. aeruginosa strain PAO1, prevented its biofilm development and eliminated partially developed PAO1 biofilms. In the murine model of thermal injury, a single injection of LgCS following injury and PAO1 infection reduced mortality to 0 % and prevented systemic spread (sepsis). Furthermore, a second injection of LgCS 24 h after the first eliminated PAO1 from the wound. In the murine dorsal excision infection model, either LgCS or ceftazidime treatment of the PAO1-infected wound significantly reduced the mortality rate among infected mice, while combining LgCS with ceftazidime eliminated mortality.Conclusion. These results suggest the potential of LgCS in preventing sepsis from P. aeruginosa infection in severely burned and other immunocompromised patients.

A retrospective analysis of Pseudomonas aeruginosa bloodstream infections: prevalence, risk factors, and outcome in carbapenem-susceptible and -non-susceptible infections.

Background: Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections, and carbapenem non-susceptible strains are a major threat to patient safety. Methods: A single center, retrospective comparative analysis of carbapenem-non-susceptible PA (CnSPA) and carbapenem-susceptible PA (CSPA) bloodstream infections (BSIs) was conducted between January 1, 2007, and December 31, 2016. Prevalence and risk factors associated with CnSPA BSIs were examined. Results: The study enrolled 340 patients with PA BSIs; 30.0% (N = 101) of patients had CnSPA. High APACHE II scores (≥15), central venous catheterization, and delayed application of appropriate definitive therapy were independently associated with higher risk of mortality in PA BSIs. Multivariate analysis revealed that respiratory disease and exposure to carbapenems within the previous 90 days to onset of BSI were independent risk factors for acquisition of CnSPA BSIs. Overall all-cause 30-day mortality associated with PA BSIs was 26.8% (91/340). In addition, mortality was higher in patients with CnSPA than in those with CSPA (37.6% vs. 22.2%, respectively; P = 0.003). Corticosteroid therapy and delayed receipt of effective definitive therapy were independent risk factors for death from CnSPA BSIs. Conclusion: Increased incidence of CnSPA BSIs was observed during the study period, with higher mortality seen in patients with these infections. Respiratory disease and exposure to carbapenems were independent risk factors for development of CnSPA BSIs. Appropriate definitive therapy reduced mortality rates. BLBLIs were as effective as carbapenems as a treatment for PA BSIs.

A Case-Control Study of Real-Life Experience with Ceftolozane-Tazobactam in Patients with Hematologic Malignancy and Pseudomonas aeruginosa Infection.

We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy. Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 years versus 57.6 years; P = 0.012) and less frequently had bacteremia (52.6% versus 86.8%; P = 0.008). They also had worse Multinational Association for Supportive Care in Cancer (MASCC) scores (10.2 versus 16.1; P = 0.0001), more hospital-acquired infections (78.9% versus 47.4%; P = 0.013), and more extremely drug-resistant (XDR) P. aeruginosa infections (47.4% versus 21.1%; P = 0.015). Cases received a median of 14 days (7 to 18 days) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16 cases; 84.2%) because of resistance (9 cases; 47.4%), failure (4 cases; 21.1%), and toxicity (3 cases; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), and perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue (5.3%) infection. No toxicity was attributed to ceftolozane-tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis. There were no significant differences in clinical cure at day 14 (89.5% versus 71.1%; P = 0.183) or recurrence (15.8% versus 10.5%; P = 0.675). Thirty-day mortality was lower among cases (5.3% versus 28.9%; P = 0.045). Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.

Antibiotic treatment adequacy and death among patients with Pseudomonas aeruginosa airway infection.

OBJECTIVE: The effect of antibiotics on survival in patients with pulmonary Pseudomonas aeruginosa is controversial. The aim of this study is to i) determine the prevalence of adequate antibiotic treatment of P. aeruginosa in an unselected group of adult non-cystic fibrosis patients and ii) to assess the overall mortality in study patients treated with adequate vs. non-adequate antibiotics. METHODS: Prospective, observational study of all adult patients with culture verified P. aeruginosa from 1 January 2010-31 December 2012 in Region Zealand, Denmark. Patients with cystic fibrosis were excluded. Adequate therapy was defined as any antibiotic treatment including at least one antipseudomonal beta-lactam for a duration of at least 10 days. Furthermore, P. aeruginosa had to be tested susceptible to the given antipseudomonal drug and treatment had to be approved by senior clinician to fulfil the adequate-criteria. RESULTS: A total of 250 patients were identified with pulmonary P. aeruginosa. The vast majority (80%) were treated with non-adequate antibiotic therapy. All-cause mortality rate after 12 months was 49% in adequate treatment group vs. 52% in non-adequate treatment group. Cox regression analysis adjusted for age, gender, bacteraemia, comorbidities and bronchiectasis showed no significant difference in mortality between treatment groups (adequate vs. non-adequate: hazard ratio 0.95, 95% CI 0.59-1.52, P = 0.82). CONCLUSION: Adequate antipseudomonal therapy was only provided in a minority of patients with pulmonary P. aeruginosa. Adequate therapy did not independently predict a favourable outcome. New research initiatives are needed to improve the prognosis of this vulnerable group of patients.

Antibiotic-resistant Pseudomonas aeruginosa infection in patients with bronchiectasis: prevalence, risk factors and prognostic implications.

Background and aims: Pseudomonas aeruginosa (PA) is the most common pathogen in bronchiectasis and frequently develops resistance to multiple classes of antibiotics, but little is known about the clinical impacts of PA-resistant (PA-R) isolates on bronchiectasis. We, therefore, investigated the prevalence, risk factors and prognostic implications of PA-R isolates in hospitalized bronchiectasis patients. Patients and methods: Between June 2011 and July 2016, data from adult bronchiectasis patients isolated with PA at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. PA was classified as PA-R in case antibiogram demonstrated resistance on at least one occasion. Results: Seven hundred forty-seven bronchiectasis patients were assessed. Of these, 147 (19.7%) had PA isolate in the sputum or bronchoscopic culture. PA-R and PA-sensitive accounted for 88 (59.9%) and 59 (31.1%) patients, respectively. In multivariate model, factors associated with PA-R isolate in bronchiectasis included prior exposure to antibiotics (odds ratio [OR] =6.18), three or more exacerbations in the previous year (OR =2.81), higher modified Medical Research Council dyspnea scores (OR =1.93) and greater radiologic severity (OR =1.15). During follow-up (median: 26 months; interquartile range: 6-59 months), 36 patients died, of whom 24 (66.7%) had PA-R isolate at baseline. However, PA-R isolate was not associated with greater all-cause mortality in bronchiectasis. Conclusion: PA-R infection is common among bronchiectasis patients, mainly determined by prior exposure to antibiotics, frequent exacerbations, more pronounced dyspnea and more severe radiologic involvement. However, PA-R isolate is not an independent risk factor for all-cause mortality in bronchiectasis.

Clinical experience with ceftazidime/avibactam for treatment of antibiotic-resistant organisms other than Klebsiella pneumoniae.

BACKGROUND: Ceftazidime/avibactam is a newly approved ß-lactam/ß-lactamase inhibitor combination with activity against antibiotic-resistant Gram-negative organisms, including many carbapenem-resistant strains. Although this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant Gram-negative organisms other than Klebsiella pneumoniae is limited. METHODS: A retrospective case series was performed to evaluate patients treated with ceftazidime/avibactam for infections caused by organisms other than K. pneumoniae at our institution over a 1-year period. Patients aged at least 18 years who received at least one dose of ceftazidime/avibactam were eligible for inclusion. Clinical and microbiological data were collected, and investigators assessed adverse effects, microbiological cure, clinical success, and 30-day in-hospital mortality following completion of ceftazidime/avibactam therapy. RESULTS: Ten patients were included. The most common index infection was pneumonia (n = 6/13, 46%) and the most frequently isolated organism was Pseudomonas aeruginosa (n = 8/21, 38%). Fifty percent of patients received ceftazidime/avibactam as monotherapy. Microbiological cure was achieved in 67% (n = 6/9) of patients and 70% (n = 7/10) of patients met criteria for clinical success. The 30-day in-hospital mortality rate was 30%. No patients experienced adverse events because of ceftazidime/avibactam therapy. CONCLUSIONS: For infections caused by antibiotic-resistant Gram-negative organisms other than K. pneumoniae, clinical and microbiological success rates for patients treated with ceftazidime/avibactam were similar to those that have been reported for K. pneumoniae. Ceftazidime/avibactam appears to be a promising treatment option for infections caused by a variety of resistant Gram-negative organisms when limited alternatives exist.

Scaffold of Selenium Nanovectors and Honey Phytochemicals for Inhibition of Pseudomonas aeruginosa Quorum Sensing and Biofilm Formation.

Honey is an excellent source of polyphenolic compounds that are effective in attenuating quorum sensing (QS), a chemical process of cell-to-cell communication system used by the opportunistic pathogen Pseudomonas aeruginosa to regulate virulence and biofilm formation. However, lower water solubility and inadequate bioavailability remains major concerns of these therapeutic polyphenols. Its therapeutic index can be improved by using nano-carrier systems to target QS signaling potently. In the present study, we fabricated a unique drug delivery system comprising selenium nanoparticles (SeNPs; non-viral vectors) and polyphenols of honey (HP) for enhancement of anti-QS activity of HP against P. aeruginosa PAO1. The developed selenium nano-scaffold showed superior anti-QS activity, anti-biofilm efficacy, and anti-virulence potential in both in-vitro and in-vivo over its individual components, SeNPs and HP. LasR is inhibited by selenium nano-scaffold in-vitro. Using computational molecular docking studies, we have also demonstrated that the anti-virulence activity of selenium nano-scaffold is reliant on molecular binding that occurs between HP and the QS receptor LasR through hydrogen bonding and hydrophobic interactions. Our preliminary investigations with selenium-based nano-carriers hold significant promise to improve anti-virulence effectiveness of phytochemicals by enhancing effective intracellular delivery.

Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia: a retrospective cohort study.

Ineffective antimicrobial therapy of Pseudomonas aeruginosa bacteraemia increases mortality. Recent studies have proposed the use of antimicrobial combination therapy composed of a beta-lactam with either ciprofloxacin or tobramycin. To determine if combination therapy correlates to lower mortality and is superior compared to monotherapy, we investigated the effect of antimicrobial treatment regimens on 30-day mortality in a cohort with Pseudomonas aeruginosa bacteraemia. All cases of P. aeruginosa bacteraemia (n = 292) in southwest Skåne County, Sweden (years 2005-2010, adult population 361,112) and the whole county (2011-2012, 966,130) were identified. Available medical and microbiological records for persons aged 18 years or more were reviewed (n = 235). Antimicrobial therapy was defined as empiric at admission or definitive after culture results and was correlated to 30-day mortality in a multivariate regression model. The incidence and mortality rates were 8.0 per 100,000 adults and 22.9% (67/292), respectively. As expected, multiple comorbidities and high age were associated with mortality. Adequate empiric or definitive antipseudomonal treatment was associated with lower mortality than other antimicrobial alternatives (empiric p = 0.02, adj. p = 0.03; definitive p < 0.001, adj. p = 0.007). No difference in mortality was seen between empiric antipseudomonal monotherapy or empiric combination therapy. However, definitive combination therapy including ciprofloxacin correlated to lower mortality than monotherapy (p = 0.006, adj. p = 0.003), whereas combinations including tobramycin did not. Our results underline the importance of adequate antipseudomonal treatment. These data also suggest that P. aeruginosa bacteraemia should be treated with an antimicrobial combination including ciprofloxacin when susceptible.

A propensity score-matched analysis of the impact of minimum inhibitory concentration on mortality in patients with Pseudomonas aeruginosa bacteremia treated with cefepime or ceftazidime.

The United States Clinical and Laboratory Standards Institute recently elected not to revise ceftazidime and cefepime Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints but rather recommended specific dosage regimens to correspond to breakpoints. This study's objective was to examine mortality of low and high MIC P. aeruginosa isolates in bacteremic patients treated with cefepime or ceftazidime. Data were gathered through a Veterans Health Administration national administrative database for veterans with P. aeruginosa blood cultures who received cefepime or ceftazidime. Seventy-four patients in the low MIC (≤2 µg/mL) group and 29 patients in the high (4-8 µg/mL) MIC group were included. Independent baseline variables associated with 30-day all-cause mortality were determined through multivariate analysis to calculate propensity scores and perform matching. All-cause 30-day mortality was not statistically significant between the 2 resultant propensity score-matched groups (17.2% mortality in the low MIC group versus 27.6% in the high MIC group; P=0.34). Data suggested that P. aeruginosa bacteremia episodes where the cephalosporin MIC = 8 µg/mL may have higher mortality, however this may be reflective of higher propensity scores. Our study suggests that it is reasonable to designate a cefepime or ceftazidime MIC ≤8 µg/mL as susceptible for P. aeruginosa bacteremia infections, but potential suboptimal outcomes in episodes for which the P. aeruginosa MIC is 8 µg/mL may need further investigation.

Efficacy of High-Dose Meropenem (Six Grams per Day) in Treatment of Experimental Murine Pneumonia Induced by Meropenem-Resistant Pseudomonas aeruginosa.

High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its in vivo efficacy in refractory lower respiratory tract infections. The purpose of this study was to evaluate the efficacy of MEPM at 6 g/day in a murine model of severe pneumonia caused by MEPM-resistant Pseudomonas aeruginosa Experimental pneumonia induced by MEPM-resistant P. aeruginosa was treated with normal-dose MEPM (150 mg/kg of body weight, simulating a 3-g/day regimen in humans) or high-dose MEPM (500 mg/kg, simulating a 6-g/day regimen in humans). Mice treated with high-dose MEPM showed significantly restored survival relative to that of untreated mice and tended to show a survival rate higher than that of mice treated with normal-dose MEPM. The viable bacterial counts (of two clinical isolates) in the lungs decreased significantly in mice treated with high-dose MEPM from those for untreated mice (P < 0.001) or mice treated with normal-dose MEPM (P, <0.01 and <0.05). The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also significantly lower in mice treated with high-dose MEPM than in untreated mice. The free MEPM concentration in the epithelial lining fluid (ELF) exceeded 16 µg/ml for 85 min in mice treated with high-dose MEPM, but not for mice treated with normal-dose MEPM. Our results demonstrate that high-dose MEPM (6 g/day) might provide better protection against pneumonia caused by MEPM-resistant strains of P. aeruginosa than the dose normally administered (less than 3 g/day).

Salvage Therapy with Ceftolozane-Tazobactam for Multidrug-Resistant Pseudomonas aeruginosa Infections.

Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) present a major problem for therapeutic management. We report here our experience with 12 patients with a severe MDRPA infection (6 of which were pneumonia) who received salvage therapy with ceftolozane-tazobactam after inappropriate empirical treatment and/or suboptimal targeted treatment. Although 10 of the 12 patients (83.3%) experienced septic shock, only 3 patients (25%) died during the follow-up period. Microbiological cure in 7 patients (58.3%) was observed.

Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia.

BACKGROUND: An intervention for Gram-negative bloodstream infections that integrated mass spectrometry technology for rapid diagnosis with antimicrobial stewardship oversight significantly improved patient outcomes and reduced hospital costs. As antibiotic resistance rates continue to grow at an alarming speed, the current study was undertaken to assess the impact of this intervention in a challenging patient population with bloodstream infections caused by antibiotic-resistant Gram-negative bacteria. METHODS: A total of 153 patients with antibiotic-resistant Gram-negative bacteremia hospitalized prior to the study intervention were compared to 112 patients treated post-implementation. Outcomes assessed included time to optimal antibiotic therapy, time to active treatment when inactive, hospital and intensive care unit length of stay, all-cause 30-day mortality, and total hospital expenditures. RESULTS: Integrating rapid diagnostics with antimicrobial stewardship improved time to optimal antibiotic therapy (80.9 h in the pre-intervention period versus 23.2 h in the intervention period, P < 0.001) and effective antibiotic therapy (89.7 h versus 32 h, P < 0.001). Patients in the pre-intervention period had increased duration of hospitalization compared to those in the intervention period (23.3 days versus 15.3 days, P = 0.0001) and longer intensive care unit length of stay (16 days versus 10.7 days, P = 0.008). Mortality among patients during the intervention period was lower (21% versus 8.9%, P = 0.01) and our study intervention remained a significant predictor of survival (OR, 0.3; 95% confidence interval [CI], 0.12-0.79) after multivariate logistic regression. Mean hospital costs for each inpatient survivor were reduced $26,298 in the intervention cohort resulting in an estimated annual cost savings of $2.4 million (P = 0.002). CONCLUSIONS: Integration of rapid identification and susceptibility techniques with antimicrobial stewardship resulted in significant improvements in clinical and financial outcomes for patients with bloodstream infections caused by antibiotic-resistant Gram-negatives. The intervention decreased hospital and intensive care unit length of stay, total hospital costs, and reduced all-cause 30-day mortality.

Epinecidin-1 has immunomodulatory effects, facilitating its therapeutic use in a mouse model of Pseudomonas aeruginosa sepsis.

Antimicrobial peptides (AMPs) are garnering attention as possible alternatives to antibiotics. Here, we describe the antimicrobial properties of epinecidin-1 against a multidrug-resistant clinical isolate of P. aeruginosa (P. aeruginosa R) and a P. aeruginosa strain from ATCC (P. aeruginosa ATCC 19660) in vivo. The MICs of epinecidin-1 against P. aeruginosa R and P. aeruginosa ATCC 19660 were determined and compared with those of imipenem. Epinecidin-1 was found to be highly effective at combating peritonitis infection caused by P. aeruginosa R or P. aeruginosa ATCC 19660 in mouse models, without inducing adverse behavioral effects or liver or kidney toxicity. Taken together, our results indicate that epinecidin-1 enhances the rate of survival of mice infected with the bacterial pathogen P. aeruginosa through both antimicrobial and immunomodulatory effects.

Influence of fish to soybean oil ratio on hepatic mononuclear cell function and survival after intraportal bacterial challenge in parenterally fed mice.

BACKGROUND: Parenteral nutrition (PN) is indispensable for meeting the caloric and substrate needs of patients who cannot receive adequate amounts of enteral nutrition. However, PN decreases hepatic mononuclear cell (MNC) numbers and impairs their functions. We examined the effects of various ratios of ω-3 to ω-6 polyunsaturated fatty acids on hepatic MNC number and function in a murine model. We focused on serum liver enzymes, lipid metabolism, cytokine production, histopathology, and the outcomes of an intraportal bacterial challenge. MATERIAL AND METHODS: In experiment 1, male Institute of Cancer Research mice were randomized to CHOW, 67%, 33%, 16%, 8%, 4%, and 0% fish oil (FO)-PN groups. After receiving their respective diets for 5 days, 1.0 × 10(7) Pseudomonas aeruginosa were delivered by intraportal injection. Survival was observed ≤ 7 days after injection. Liver histologies after intraportal bacterial challenge were examined in the CHOW, 33%, 8%, and 0% FO-PN groups. In experiment 2, the mice were divided into 4 groups: CHOW, 33%, 8%, and 0% FO-PN. After the mice had been fed for 5 days, MNC were isolated. Hepatic MNC were counted and cytokine productions (tumor necrosis factor [TNF]-α and interleukin [IL]-10) by MNC in response to lipopolysaccharide (LPS) were measured. Blood samples were analyzed for lipid metabolism and hepatobiliary biochemical parameters. Liver histologies were also examined. RESULTS: In experiment 1, survival times were significantly shorter in the 4% and 0% FO-PN groups than in the CHOW group. Survival rates at 168 hours were 100%, 64%, 86%, 73%, 67%, 11%, and 13% in the CHOW, 67%, 33%, 16%, 8%, 4%, and 0% FO-PN groups, respectively. At 72 hours after intraportal bacterial challenge, the 0% FO-PN group showed severe tissue damage, whereas such damage was reduced in the 8% and 33% FO-PN groups. In experiment 2, the CHOW, 33%, 8%, and 0% FO-PN groups showed LPS dose-dependent increases in TNF-α levels. IL-10 levels were also LPS dose-dependently increased in the CHOW and 33% FO-PN groups. However, no marked changes were observed in response to LPS stimulation in either the 8% or the 0% FO-PN group. There were no differences in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin among these 4 groups. In the 0% FO-PN group, serum total cholesterol levels were greater than those in the 8% and 33% FO-PN groups. Without bacterial challenge, livers from the 0% FO-PN group showed steatosis, but these changes were attenuated in the 8% and 33% FO-PN groups. CONCLUSION: The 30-40% ratio of FO to soybean oil with 20% of total calories supplied by lipid seems to be the best PN for preservation of hepatic MNC number and function.

Risk of developing pneumonia is enhanced by the combined traits of fluoroquinolone resistance and type III secretion virulence in respiratory isolates of Pseudomonas aeruginosa.

OBJECTIVES: To determine the differential association of host characteristics, antimicrobial resistance, and type III secretion system virulence of Pseudomonas aeruginosa isolates with respiratory syndromes in hospitalized adult patients. DESIGN: Retrospective, cohort study. SETTING: Community teaching hospital. PATIENTS: Two hundred eighteen consecutive adult patients with respiratory culture positive for P. aeruginosa between January 2005 to January 2010. INTERVENTIONS: Medical charts were reviewed to obtain demographic, laboratory, radiographic, and clinical information. Isolates were assayed by polymerase chain reaction for genes encoding the type III secretion system effectors (ExoU, ExoS, and PcrV) and for strain relatedness using randomly amplified polymorphic DNA analysis. Levofloxacin susceptibility was determined by broth microdilution. Patients were grouped by colonization, bronchitis, or pneumonia and were compared for differential risk of developing the clinical syndrome with respect to host and microbial characteristics. MEASUREMENTS AND MAIN RESULTS: Half of the study cohort (54%, 117 of 218) had pneumonia, 32% (70 of 218) had bronchitis, and 14% (31 of 218) had colonization; in-hospital mortality was 35%, 11%, and 0%, respectively. Host factors strongly associated with pneumonia development were residence in long-term care facility, healthcare-associated acquisition of P. aeruginosa, higher Acute Physiology and Chronic Health Evaluation II score, presence of enteral feeding tube, mechanical ventilation, and recent history of pneumonia. Fluoroquinolone-resistant (57% vs 34%, 16%; p < 0.0001) and multidrug-resistant (36% vs 26%, 7%; p = 0.0045) strains were more likely to cause pneumonia than bronchitis or colonization, respectively. Analysis of host and microbial factors in a multivariate regression model yielded the combined traits of fluoroquinolone resistance and gene encoding the type III secretion system ExoU effector in P. aeruginosa as the single most significant predictor of pneumonia development. CONCLUSIONS: These results suggest that fluoroquinolone-resistant phenotype in a type III secretion system exoU strain background contributes toward the pathogenesis of P. aeruginosa in pneumonia.

In vivo efficacy of biapenem with ME1071, a novel metallo-ß-lactamase (MBL) inhibitor, in a murine model mimicking ventilator-associated pneumonia caused by MBL-producing Pseudomonas aeruginosa.

ME1071, a maleic acid derivative, is a novel, specific inhibitor of metallo-ß-lactamases (MBLs). In vitro, ME1071 can potentiate the activity of carbapenems against MBL-producing Pseudomonas aeruginosa. To confirm the clinical efficacy of ME1071 in ventilator-associated pneumonia (VAP) caused by MBL-producing P. aeruginosa, a mouse model that mimics VAP by placement of a plastic tube in the bronchus was used. Biapenem (100 mg/kg) or ME1071 plus biapenem (each 100 mg/kg) was administered intraperitoneally every 12 h beginning at 12 h after inoculation. Survival was evaluated over 7 days. At 30 h post infection, mice were sacrificed and the numbers of viable bacteria in the lungs and bronchoalveolar lavage fluid (BALF) were compared. Histopathological analysis of lung specimens was also performed. The pharmacokinetics of ME1071 was analysed after initial treatment. The ME1071 plus biapenem combination group displayed significantly longer survival compared with the control and biapenem monotherapy groups (P<0.05). Furthermore, the number of viable bacteria in the lungs was significantly lower in the combination group (P<0.05). Histopathological examination of lung specimens indicated that progression of lung inflammation was prevented in the combination group. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in BALF were significantly decreased (P<0.05) in the combination group. The percentage time above the MIC (%T>MIC) for biapenem without ME1071 was 0% in plasma; however, this value was elevated to 10.8% with ME1071. These results suggest that ME1071 is potent and effective for treatment of VAP caused by MBL-producing P. aeruginosa.

KPC presence in Pseudomonas aeruginosa has minimal impact on the in vivo efficacy of carbapenem therapy.

While reports of Klebsiella pneumoniae carbapenemase (KPC) production among Pseudomonas aeruginosa strains have emerged from a number of countries worldwide, outcome data are lacking. This is the first report evaluating how KPC production in P. aeruginosa impacts the efficacy of carbapenems by using the murine thigh infection model. Our findings suggest that the impact of KPC-2 in vivo is less pronounced than would be anticipated based on the in vitro potency.