Shyh-Ren Chiang

In vitro efficacy of fosfomycin-containing regimens against methicillin-resistant Staphylococcus aureus in biofilms

OBJECTIVES To compare the in vitro antibacterial efficacy of antistaphylococcal antibiotics in combination with fosfomycin or rifampicin, using a biofilm model. METHODS The antibacterial activities of fusidic acid, linezolid, vancomycin, teicoplanin, rifampicin, minocycline, fosfomycin and tigecycline, individually and in fosfomycin or rifampicin combinations, were measured against planktonic or biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) with susceptible and resistant breakpoint concentrations (SBCs and RBCs, respectively), using the MTT-staining method and by counting the number of cfu in the biofilms. RESULTS Linezolid alone at its SBC, and fosfomycin, linezolid, minocycline and tigecycline at their RBCs, exhibited killing effects on biofilm-embedded MRSA (P < 0.0001). Of the eight fosfomycin combinations studied, fosfomycin combined with linezolid, minocycline, vancomycin or teicoplanin at their respective SBCs, exhibited enhanced antibacterial activities (P < 0.0001) when compared with the control group, and outperformed rifampicin combinations (P < 0.01). The killing effects of fosfomycin combinations at their respective RBCs were better than those at their respective SBCs (P < 0.05). Significantly enhanced killing effects were observed with fosfomycin in combination with vancomycin or teicoplanin, compared with vancomycin or teicoplanin alone. For 10 randomly selected MRSA isolates, the results of colony counting in biofilms were comparable with those of the MTT-staining method. CONCLUSIONS Fosfomycin enhanced the activities of linezolid, minocycline, vancomycin and teicoplanin. These combinatorial treatments were even better than rifampicin combination regimens, and may provide therapeutic advantages in catheter-related or prosthetic joint infections.

In Vitro and In Vivo Activities of Fluoroquinolones against Aeromonas hydrophila

ABSTRACT Aeromonas hydrophila, an uncommon human pathogen, can cause invasive infections in immunocompromised individuals. As the fluoroquinolones have been shown to be active in vitro against mesophilic aeromonads and clinical experience with the use of fluoroquinolones to treat aeromonads infections is limited, the antimicrobial activities of five selected drugs (ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, and moxifloxacin) against A. hydrophila were studied in vitro and in mice. The MICs of the fluoroquinolones (except lomefloxacin), cefotaxime, and minocycline for 90% of 64 clinical isolates of A. hydrophila tested by the agar dilution method were ≤1 μg/ml. With a clinical cefotaxime-resistant strain, Ah 2743, in an in vitro time-kill study, at an inoculum of 7 × 105 CFU/ml incubated with fluoroquinolones, cefotaxime, or minocycline at concentrations equal to twice the MICs, the inhibitory effect lasted for less than 6 h and regrowth occurred thereafter. In an animal model with female BALB/c mice intraperitoneally infected with an inoculum of 1.1 × 107 CFU of Ah 2743, more mice in the ciprofloxacin-treated group survived (72.2%) than in the cefotaxime-, minocycline-, or cefotaxime-minocycline-treated group (P < 0.00001, log rank test). However, there were similar fatality rates, ranging from 71.4 to 87.5%, among mice treated with any of five fluoroquinolones. With a larger inoculum, 4.9 × 107 CFU, mice in the ciprofloxacin-treated group survived longer than those in the minocycline-, cefotaxime-, or cefotaxime-minocycline-treated group (30 h versus 18, 12, and 12 h, respectively [P < 0.002, log rank test]). However, in mice infected with cefotaxime-susceptible Ah 2556, ciprofloxacin was as effective as cefotaxime-minocycline. Thus, our results suggest that ciprofloxacin is at least as effective as cefotaxime-minocycline against murine A. hydrophila infections, which warrants clinical studies to delineate its role in human infections.

Intratracheal colistin sulfate for BALB/c mice with early pneumonia caused by carbapenem-resistant Acinetobacter baumannii

Objectives:To study the efficacy of intratracheal colistin sulfate therapy in a murine model of acute pneumonia caused by a clinical CRAB strain, Ab396. Colistin therapy has currently achieved a favorable outcome in patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections, but parenteral colistin may have limited therapeutic efficacy for CRAB pneumonia. Design:A controlled, in vivo experimental study. Setting:Research laboratory of a medical center. Subjects:Female BALB/c mice. Interventions:The minimal inhibitory concentrations of antibiotics were measured. Acute pneumonia was established by intratracheal inoculation with an inoculum size of 2.5 × 107 colony-forming units Ab396 plus 10% porcine mucin into the lungs of mice, verified by histopathological examinations, and then treated with or without antibiotics. Mice received intratracheal saline treatment as a control group, intraperitoneal administration (IP) imipenem/cilastatin plus sulbactam (IP IS group, 80/80 mg/kg and 40 mg/kg every 8 hrs, n = 30), IP colistin sulfate (IP CS group, 150,000 U/kg every 8 hrs, n = 30), and intratracheal colistin sulfate (intratracheal CS group, 75,000 U/kg every 8 hrs, n = 30) at 2 hrs after intratracheal inoculation of Ab396. Measurements and Main Results:The minimal inhibitory concentrations of colistin sulfate, imipenem/cilastatin, or sulbactam for Ab396 were 2 μg/mL, 128 μg/mL, or 32 μg/mL, respectively. Compared with the mice in the control, IP IS, and IP CS groups, those in intratracheal CS group had a significantly favorable outcome at 72 hrs after infection (survival rate = 0%, 10%, 0% and 100%, respectively; all p < .001, log-rank test). Furthermore, intratracheal therapy decreased significantly the bacterial loads in the lungs and normalized the wet lung/body weight ratios in mice with acute pneumonia. Conclusions:The intratracheal colistin sulfate therapy led to more favorable outcomes than therapies by IP colistin sulfate or imipenem/cilastatin plus sulbactam in mice with early CRAB pneumonia.

In vitro efficacy of fosfomycin-based combinations against clinical vancomycin-resistant Enterococcus isolates

Vancomycin-resistant (VR) enterococci (VRE) are increasingly important nosocomial pathogens, commonly causing catheter-related urinary tract infections or vascular catheter-related bloodstream infections. In this study, 10 Enterococcus faecium and 9 Enterococcus faecalis different pulsed-field gel electrophoresis genome-type VR clinical isolates were detected. The potential role of fosfomycin-based combination regimens for biofilm-related VRE infection is in vitro evaluated. Anti-VRE activities of fosfomycin, ampicillin, linezolid, minocycline, rifampicin, tigecycline, teicoplanin, vancomycin alone, or fosfomycin-based combinations were studied by time-kill method and a biofilm model. Of the fosfomycin-based combinations, a synergistic effect was particularly noted for teicoplanin against 89% of the VR E. faecalis isolates. In a biofilm model, only linezolid alone was able to reduce the bacterial loads, and the use of fosfomycin-based combinations, excluding rifampicin (40%), failed to enhance antibacterial activity against VR E. faecium. For E. faecalis, an inhibitory effect was evident using ampicillin alone or fosfomycin plus rifampicin (100%), tigecycline (56%), or teicoplanin (44%). However, an antagonistic effect was found for ampicillin plus fosfomycin against 2 of 3 of the VR E. faecalis isolates. The antibacterial activities of the drugs tested against VRE in vitro varied by species. Ampicillin exhibited potential activity against planktonic- and biofilm-embedded VR E. faecalis. Fosfomycin-based combinations may have enhanced antibacterial effects against VRE even in the biofilm model, and this observation warrants further clinical studies.

The outcomes and prognostic factors of patients requiring prolonged mechanical ventilation

The aims of this study were to investigate the outcomes of patients requiring prolonged mechanical ventilation (PMV) and to identify risk factors associated with its mortality rate. All patients admitted to the respiratory care centre (RCC) who required PMV (the use of MV ≥21 days) between January 2006 and December 2014 were enrolled. A total of 1,821 patients were identified; their mean age was 69.8 ± 14.2 years, and 521 patients (28.6%) were aged >80 years. Upon RCC admission, the APACHE II scores were 16.5 ± 6.3, and 1,311 (72.0%) patients had at least one comorbidity. Pulmonary infection was the most common diagnosis (n = 770, 42.3%). A total of 320 patients died during hospitalization, and the in-hospital mortality rate was 17.6%. A multivariate stepwise logistic regression analysis indicated that patients were more likely to die if they who were >80 years of age, had lower albumin levels (<2 g/dl) and higher APACHE II scores (≥15), required haemodialysis, or had a comorbidity. In conclusion, the in-hospital mortality for patients requiring PMV in our study was 17%, and mortality was associated with disease severity, hypoalbuminaemia, haemodialysis, and an older age.

The Ratio of Partial Pressure Arterial Oxygen and Fraction of Inspired Oxygen 1 Day After Acute Respiratory Distress Syndrome Onset Can Predict the Outcomes of Involving Patients.

AbstractThe initial hypoxemic level of acute respiratory distress syndrome (ARDS) defined according to Berlin definition might not be the optimal predictor for prognosis. We aimed to determine the predictive validity of the stabilized ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2 ratio) following standard ventilator setting in the prognosis of patients with ARDS.This prospective observational study was conducted in a single tertiary medical center in Taiwan and compared the stabilized PaO2/FiO2 ratio (Day 1) following standard ventilator settings and the PaO2/FiO2 ratio on the day patients met ARDS Berlin criteria (Day 0). Patients admitted to intensive care units and in accordance with the Berlin criteria for ARDS were collected between December 1, 2012 and May 31, 2015. Main outcome was 28-day mortality. Arterial blood gas and ventilator setting on Days 0 and 1 were obtained.A total of 238 patients met the Berlin criteria for ARDS were enrolled, and they were classified as mild (n = 50), moderate (n = 125), and severe (n = 63) ARDS, respectively. Twelve (5%) patients who originally were classified as ARDS did not continually meet the Berlin definition, and a total of 134 (56%) patients had the changes regarding the severity of ARDS from Day 0 to Day 1. The 28-day mortality rate was 49.1%, and multivariate analysis identified age, PaO2/FiO2 on Day 1, number of organ failures, and positive fluid balance within 5 days as significant risk factors of death. Moreover, the area under receiver-operating curve for mortality prediction using PaO2/FiO2 on Day 1 was significant higher than that on Day 0 (P = 0.016).PaO2/FiO2 ratio on Day 1 after applying mechanical ventilator is a better predictor of outcomes in patients with ARDS than those on Day 0.

LIGHT Is a Crucial Mediator of Airway Remodeling

Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease are major health problems globally. Airway epithelial cells play important role in airway remodeling, which is a critical process in the pathogenesis of diseases. This study aimed to demonstrate that LIGHT, an inflammatory factor secreted by T cells after allergen exposure, is responsible for promoting airway remodeling. LIGHT increased primary human bronchial epithelial cells (HBECs) undergoing epithelial‐mesenchymal transition (EMT) and expressing MMP‐9. The induction of EMT was associated with increased NF‐κB activation and p300/NF‐κB association. The interaction of NF‐κB with p300 facilitated NF‐κB acetylation, which in turn, was bound to the promoter of ZEB1, resulting in E‐cadherin downregulation. LIGHT also stimulated HBECs to produce numerous cytokines/chemokines that could worsen airway inflammation. Furthermore, LIGHT enhanced HBECs to secrete activin A, which increased bronchial smooth muscle cell (BSMC) migration. In contrast, depletion of activin A decreased such migration. The findings suggest a new molecular determinant of LIGHT‐mediated pathogenic changes in HBECs and that the LIGHT‐related vicious cycle involving HBECs and BSMCs may be a potential target for the treatment of chronic inflammation airway diseases with airway remodeling. J. Cell. Physiol. 230: 1042–1053, 2015.

Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results from In Vitro and In Vivo Animal Studies

ABSTRACT The emergence of multidrug-resistant Salmonella isolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoid Salmonella (NTS) isolates in vitro and ex vivo. Subsequently, the efficacy of carbapenem treatment against selected Salmonella isolates in vivo was assessed using a murine peritonitis model. The MIC50 and MIC90 for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directly ex vivo from mice with Salmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 102- to 104-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 105 and 106 CFU of a ceftriaxone-susceptible Salmonella isolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 104 and 105 CFU of a ceftriaxone-resistant and ciprofloxacin-resistant Salmonella isolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively; P < 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murine Salmonella infections and show that further clinical investigations on the potential use of ertapenem in treatment of human Salmonella infections are warranted.

Establishing predictors for successfully planned endotracheal extubation

Abstract The aim of this study was to establish predictors for successfully planned extubation, which can be followed by medical personnel. The patients who were admitted to the adult intensive care unit of a tertiary hospital and met the following criteria between January 2005 and December 2014 were collected retrospectively: intubation > 48 hours; and candidate for extubation. The patient characteristics, including disease severity, rapid shallow breath index (RSBI), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), cuff leak test (CLT) before extubation, and outcome, were recorded. The CLT was classified as 2+ with audible flow without a stethoscope, 1+ with audible flow using a stethoscope, and negative (N) with no audible flow, even with a stethoscope. Failure to extubate was defined as reintubation within 48 hours. In total, 6583 patients were enrolled and 403 patients (6.1%) had extubation failures. Male patients dominated the patient cohort (4261 [64.7%]). The mean age was 64.5±16.3 years. The overall in-hospital mortality rate was 11.3%. The extubation failure rate for females was greater than males (7.7% vs 5.3%, P < 0.001). The group of patients who failed extubation were older (66.7 ± 14.4 vs 64.3 ± 16.4, P = 0.002), had higher APACHE II scores (16.8 ± 7.6 vs 15.9 ± 7.8, P = 0.023), lower coma scales (10.3 ± 3.7 vs 10.8 ± 3.7, P = 0.07), a higher RSBI (69.9 ± 37.3 vs 58.6 ± 30.3, P < 0.001), a lower MIP, and MEP (−35.6 ± 15.3 vs −37.8 ± 14.6, P = 0.0001 and 49.6 ± 28.4 vs 58.6 ± 30.2, P < 0.001, respectively), and a higher mortality rate (25.6% vs 10.5%, P < 0.001) compared to the successful extubation group. Based on multivariate logistic regression, a CLT of 2+ (odds ratio [OR] = 2.07, P < 0.001), a MEP ≥ 55 cmH2O (OR = 1.73, P < 0.001), and a RSBI < 68 breath/min/ml (OR = 1.57, P < 0.001) were independent predictors for successful extubation. This study identified 3 independent risk factors for successful extubation after a successful breathing trial, including a CLT of 2+, a MEP ≥ 55 cmH2O, and a RSBI < 68 breath/min/ml. Furthermore, a nomogram integrating these 3 parameters, which represented the combined consideration of the upper airway patentency, cough strength, and respiratory capacity, was developed to better predict extubation success.

The prognostic value of N-terminal proB-type natriuretic peptide in patients with acute respiratory distress syndrome

We investigated whether N-terminal proB-type natriuretic peptide (NT-proBNP) predicts the prognosis of patients with acute respiratory distress syndrome (ARDS). Between December 1, 2012, and May 31, 2015, this observational study recruited patients admitted to our tertiary medical center who met the Berlin criteria for ARDS and who had their NT-proBNP measured. The main outcome was 28-day mortality. We enrolled 61 patients who met the Berlin criteria for ARDS: 7 were classified as mild, 29 as moderate, and 25 as severe. The median APACHE II scores were 23 (interquartile range [IQR], 18–28), and SOFA scores were 11 (IQR, 8–13). The median lung injury score was 3.0 (IQR, 2.50–3.25), and the median level of NT-proBNP was 2011 pg/ml (IQR, 579–7216). Thirty-four patients died during this study, and the 28-day mortality rate was 55.7%. Patients who die were older and had significantly (all p < 0.05) higher APACHE II scores and NT-proBNP levels than did patients who survived. Multivariate analysis identified age (HR: 1.546, 95% CI: 1.174–2.035, p = 0.0019) and NT-proBNP (HR: 1.009, 95% CI: 1.004–1.013, p = 0.0001) as significant risk factors of death. NT-proBNP was associated with poor outcomes for patients with ARDS, and its level predicted mortality.