First case report of Solobacterium moorei bacteremia due to acute cholangitis in South Korea.

Solobacterium moorei is an anaerobic gram-positive bacillus that rarely causes bacteremia. Herein, we report a case of S. moorei bacteremia associated with acute cholangitis in a patient without malignancy. The patient had a history of chronic pancreatitis with pancreaticogastrostomy and presented with fever and abdominal pain. Computed tomography scans showed acute cholangitis and S. moorei identified in blood cultures were confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and 16S rRNA sequencing. The patient was successfully treated with endoscopic retrograde biliary drainage and antibiotics including meropenem and piperacillin-tazobactam.

Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes.

BACKGROUND: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. METHODS: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6-16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. RESULTS: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. CONCLUSION: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.

In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease.

Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of ≥8 µg/ml. Treatment success rate was significantly different between MAC isolates with MICs of ≥8 µg/ml for rifampin and ethambutol and those with MICs of <8 µg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of ≥8 µg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of ≥8 µg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

Vancomycin AUC24 /MIC Ratio in Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia.

BACKGROUND: Vancomycin is the treatment of choice for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. The area under the concentration-time curve from 0 to 24 hr (AUC24 )/minimum inhibitory concentration (MIC) ratio was recently introduced as a parameter for assessing clinical outcome by S. aureus. This study was purposed to apply the vancomycin AUC24 /MIC in patients with MRSA pneumonia. METHODS: Forty-seven patients with confirmed lower respiratory infection caused by MRSA during 2011 were enrolled. All patients were treated with vancomycin. Clinical characteristics and laboratory data were collected. AUC24 /MIC values were calculated as previously reported and patients were divided into two groups based on the bacteriologic response, which was eradicated or not, and an AUC24 /MIC value (above or below 400). RESULTS: MRSA infections were eradicated in 39 patients but 8 patients had persistent MSRA infection in the following cultures. The mean AUC24 /MIC values and vancomycin concentrations were not statistically different between patients with and without MRSA eradication. All 13 patients with a vancomycin MIC of 2 mg/L had an AUC24 /MIC below 400. CONCLUSION: AUC24 /MIC might not be a reliable indicator for assessing treatment response of vancomycin in MRSA pneumonia. Relationship between vancomycin AUC24 /MIC and therapeutic outcome needs to undergo further studies, including sufficiently large sample size.

Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma.

PURPOSE: Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC. METHODS: The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival. RESULTS: Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase. CONCLUSIONS: The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.

Nocardioides endophyticus sp. nov. and Nocardioides conyzicola sp. nov., isolated from herbaceous plant roots.

Two Gram-stain-positive, non-motile, non-spore-forming, rod-shaped actinobacterial strains were isolated from the surface-sterilized roots of mugwort (Artemisia princeps) and horse-weed (Conyza canadensis), and subjected to taxonomic characterization. 16S rRNA gene sequence analysis indicated that the isolates, designated MWE 3-5(T) and HWE 2-02(T), should be placed in the genus Nocardioides of the family Nocardioidaceae. The strains were closely related to Nocardioides hankookensis DS-30(T), which exhibited 16S rRNA gene sequence similarity values of 97.99 and 99.09 % with strains MWE 3-5(T) and HWE 2-02(T), respectively. The genome relatedness of N. hankookensis DS-30(T) with strain MWE 3-5(T) was 35.8 %, and that with strain HWE 2-02(T) was 36.4 %, whereas that between the two isolates was 43.2 %. Strains MWE 3-5(T) and HWE 2-02(T) possessed MK-8(H4) as the major isoprenoid quinone, and ll-diaminopimelic acid in the cell-wall peptidoglycan. The main fatty acids were iso-C16 : 0, iso-C17 : 0 and C18 : 1ω9c for strain MWE 3-5(T) and iso-C16 : 0, 10-methyl C18 : 0 and C18 : 1ω9c for strain HWE 2-02(T). Based on phenotypic, genotypic and phylogenetic studies, the following two novel species are proposed: Nocardioides endophyticus sp. nov. (type strain, MWE 3-5(T) = KCTC 29122(T) = JCM 18532(T)) and Nocardioides conyzicola sp. nov. (type strain, HWE 2-02(T) = KCTC 29121(T) = JCM 18531(T)).

Impact of reduced vancomycin MIC on clinical outcomes of methicillin-resistant Staphylococcus aureus bacteremia.

Vancomycin has been a key antibiotic agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. However, little is known about the relationship between vancomycin MIC values at the higher end of the susceptibility range and clinical outcomes. The aim of this study was to determine the impact of MRSA bacteremia on clinical outcomes in patients with a vancomycin MIC near the upper limit of the susceptible range. Patients with MRSA bacteremia were divided into a high-vancomycin-MIC group (2 µg/ml) and a low-vancomycin-MIC group (≤1.0 µg/ml). We examined the relationship between MIC, genotype, primary source of bacteremia, and mortality. Ninety-four patients with MRSA bacteremia, including 31 with a high vancomycin MIC and 63 with a low MIC were analyzed. There was no significant difference between the presence of agr dysfunction and SCCmec type between the two groups. A higher vancomycin MIC was not found to be associated with mortality. In contrast, high-risk bloodstream infection sources (hazard ratio [HR], 4.63; 95% confidence interval [CI] = 1.24 to 17.33) and bacterial eradication after treatment (HR, 0.06; 95% CI = 0.02 to 0.17), irrespective of vancomycin MIC, were predictors of all-cause 30-day mortality. Our study suggests that a high-risk source of bacteremia is likely to be associated with unfavorable clinical outcomes, but a high vancomycin MIC in a susceptible range, as well as genotype characteristics, are not associated with mortality.

Emergence of antibiotic resistance during therapy for infections caused by Enterobacteriaceae producing AmpC beta-lactamase: implications for antibiotic use.

Enterobacter spp., Serratia marcescens, Citrobacter freundii, and Morganella morganii are characterized by chromosomally encoded AmpC beta-lactamases and possess the ability to develop resistance upon exposure to broad-spectrum cephalosporins. To determine the incidences of the emergence of resistance during antimicrobial therapy for infections caused by these organisms and the effect of the emergence of resistance on patient outcomes, all patients who were admitted to the Asan Medical Center (Seoul, Republic of Korea) from January 2005 to June 2006 and whose clinical specimens yielded Enterobacter spp., S. marcescens, C. freundii, or M. morganii were monitored prospectively. The main end point was the emergence of resistance during antimicrobial therapy. A total of 732 patients with infections were included for analysis. The overall incidence of the emergence of antimicrobial resistance during antimicrobial therapy was 1.9% (14/732). Resistance to broad-spectrum cephalosporins, cefepime, extended-spectrum penicillin, carbapenem, fluoroquinolones, and aminoglycosides emerged during treatment in 5.0% (11/218), 0% (0/20), 2.0% (2/100), 0% (0/226), 0% (0/153), and 1.1% (1/89) of patients, respectively. The emergence of resistance to broad-spectrum cephalosporins occurred more often in Enterobacter spp. (8.3%, 10/121) than in C. freundii (2.6%, 1/39), S. marcescens (0%, 0/37), or M. morganii (0%, 0/21). Biliary tract infection associated with malignant bile duct invasion was significantly associated with the emergence of resistance to broad-spectrum cephalosporins (P = 0.024 at a significance level of 0.042, by use of the Bonferroni correction). Only 1 of the 14 patients whose isolates developed resistance during antimicrobial therapy died. The emergence of resistance was more frequently associated with broad-spectrum cephalosporins than with the other antimicrobial agents tested, especially in Enterobacter spp. However, the emergence of resistance was associated with a low risk of mortality.

[Emergence of beta-lactam-dependent Bacillus cereus associated with prolonged treatment with cefepime in a neutropenic patient].

Antibiotic dependence in clinical isolates has been reported, albeit rarely, such as vancomycin-dependent enterococcus and beta-lactam-dependent Staphylococcus saprophyticus. We report herein a clinical isolate of beta-lactam-dependent Bacillus cereus. A 16-yr-old female was admitted on 8 September 2005 with neutropenic fever during chemotherapy following surgical removal of peripheral neuroectodermal tumor. She had had an indwelling chemoport since August 2004 and experienced B. cereus bacteremia three times during the recent 3-month period prior to the admission; the bacteremias were treated with cefepime-based chemotherapy. On hospital days 1 and 3, B. cereus was isolated from blood drawn through the chemoport. The isolates were resistant to penicillin, ceftriaxone, and erythromycin, and susceptible to vancomycin and ciprofloxacin. The isolate of hospital day 3 grew only nearby the beta-lactam disks including penicillin and ceftriaxone on disk diffusion testing. The beta-lactam-dependent isolate required a minimum of 0.064 microg/mL of penicillin or 0.023 microgram/mL of cefotaxime for growth, which was demonstrated by E test (AB Biodisk, Sweden). Light microscopy and transmission electron microscopy revealed a marked elongation of the dependent strain compared with the non-dependent strain. Prolonged therapy with beta-lactams in the patient with an indwelling intravenous catheter seemed to be a risk factor for the emergence of beta-lactam-dependence in B. cereus.