Enhanced antimicrobial stewardship based on rapid phenotypic antimicrobial susceptibility testing for bacteraemia in patients with haematological malignancies: a randomized controlled trial.

OBJECTIVES: Recently, rapid phenotypic antimicrobial susceptibility testing (AST) based on microscopic imaging analysis has been developed. The aim of this study was to determine whether implementation of antimicrobial stewardship programmes (ASP) based on rapid phenotypic AST can increase the proportion of patients with haematological malignancies who receive optimal targeted antibiotics during early periods of bacteraemia. METHODS: This randomized controlled trial enrolled patients with haematological malignancies and at least one positive blood culture. Patients were randomly assigned 1:1 to conventional (n = 60) or rapid phenotypic (n = 56) AST. The primary outcome was the proportion of patients receiving optimal targeted antibiotics 72 hr after blood collection for culture. RESULTS: The percentage receiving optimal targeted antibiotics at 72 hr was significantly higher in the rapid phenotypic AST group (45/56, 80.4%) than in conventional AST group (34/60, 56.7%) (relative risk (RR) 1.42, 95% confidence interval (CI) 1.09-1.83). The percentage receiving unnecessary broad-spectrum antibiotics at 72 hr was significantly lower (7/26, 12.5% vs 18/60, 30.0%; RR 0.42, 95% CI 0.19-0.92) and the mean time to optimal targeted antibiotic treatment was significantly shorter (38.1, standard deviation (SD) 38.2 vs 72.8, SD 93.0 hr; p < 0.001) in the rapid phenotypic AST group. The mean time from blood collection to the AST result was significantly shorter in the rapid phenotypic AST group (48.3, SD 17.6 vs 83.1, SD 22.2 hr). DISCUSSION: ASP based on rapid phenotypic AST can rapidly optimize antibiotic treatment for bacteraemia in patients with haematological malignancy. Rapid phenotypic AST can improve antimicrobial stewardship in immunocompromised patients.

One-step lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation without bone grafts: a retrospective study.

The aim of this study was to evaluate the clinical and radiographic outcomes of a lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation. From 2014 to 2018, all patients who received sinus pathology removal via a lateral window approach combined with transcrestal sinus floor elevation were screened. The serous exudate or minor sinus pathology was drained or removed via lateral window approach. Subsequently, transcrestal sinus floor elevation without grafting and simultaneous implant placement were performed. Panoramic radiographs and cone-beam computed tomography were taken preoperatively, immediately after surgery, and after prosthesis delivery. Twelve patients were included in this study. The decrease in Schneiderian membrane thickness was statistically significant (P<0.001). Endo-sinus bone formation was observed on the buccal (1.35±2.31mm) and palatal (1.61±2.65mm) sites of the implant. The implant survival rate was 100%. All implants survived for an average of 21.83±11.11 months. Within the limitations of this study, we suggest that the lateral window approach for minor sinus pathology removal combined with transcrestal sinus floor elevation has several advantages including endo-sinus bone gain without bone graft, minimal patient discomfort, reduced postoperative complications and shorter treatment period.

Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy.

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

Which tissues are best for microbiological diagnosis in patients with pyogenic vertebral osteomyelitis undergoing needle biopsy?

Identification of the causative microorganism is important in the management of pyogenic vertebral osteomyelitis (PVO). The aim of this study was to investigate whether culture positive rates differ between needle biopsy sites in patients with PVO, and which tissues are best for microbiological diagnosis. Between January 2005 and December 2013, we conducted a retrospective cohort study of PVO patients who had soft-tissue abscesses (paraspinal or psoas abscesses) and who received needle biopsy for microbiological diagnosis. Needle biopsy sites were classified into two anatomical categories: vertebral bodies, or soft tissues (intervertebral discs, paraspinal abscesses, or psoas abscesses). A generalized estimating equation model was developed to identify factors associated with tissue-culture positivity. During the study period a total of 136 tissues were obtained by needle biopsy from 128 PVO patients with soft-tissue abscesses. The culture positive rates of vertebral bodies and soft tissues were 39.7% (29/73), and 63.5% (40/63), respectively (p < 0.05). In a multivariate analysis, male gender (adjusted odds ratio (aOR) 2.24, 95% CI 1.00-5.02), higher C-reactive protein (aOR 1.07, 95% CI 1.01-1.15), positive blood culture (aOR 2.57, 95% CI 1.01-6.59), and soft tissues as biopsy site compared with vertebral bodies (aOR 2.28, 95% CI 1.08-4.78) were independent factors associated with tissue culture positivity. Soft tissues were the best sites for microbiological diagnosis in PVO patients undergoing needle biopsy.

Korean mistletoe lectin regulates self-renewal of placenta-derived mesenchymal stem cells via autophagic mechanisms.

OBJECTIVES: The balance between survival and death is a key point for regulation of physiology of stem cells. Recently, applications of natural products to enhance efficiencies in culturing and differentiation of stem cells are increasing. Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) has been known to be toxic to some cancer cells, but it is still unclear whether VCA has a cytotoxic or indeed a proliferative effect on mesenchymal stem cells (MSCs). Here, we have compared effects of VCA in naïve placenta-derived stem cells (PDSCs), immortalized PDSCs and cancer cells (HepG2), and analysed their mechanisms. MATERIALS AND METHODS: MTT assay was performed to analyse effects of VCA on naïve PDSCs, immortalized PDSCs and HepG2. FACS, ROS, caspase-3 assay, western blotting and immunofluorescence were performed to detect signalling events involved in self-renewal of the above cell types. RESULTS: VCA had cancer cell-specific toxicity to HepG2 cells even with low concentrations of VCA (1-5 pg/ml), toxicity was observed to immortalized PDSCs and HepG2s, while proliferation of naïve PDSCs was significantly increased (P < 0.05). ROS production by VCA treatment in naïve PDSCs was significantly lower compared to controls (P < 0.05). Furthermore, autophagy was activated in naïve PDSCs treated with VCA through increase in type II LC3 and decrease in phosphorylated mTOR. CONCLUSIONS: VCA can promote MSC proliferation through an activated autophagic mechanism.

Risk factors for 30-day mortality in adult patients with pneumococcal bacteraemia, and the impact of antimicrobial resistance on clinical outcomes.

The clinical impact of antimicrobial resistance on the outcome of pneumococcal bacteraemia has remained unclear. This study aimed to evaluate risk factors for mortality and determine the impact of antimicrobial resistance on clinical outcomes. A total of 150 adult patients with pneumococcal bacteraemia were identified over a period of 11 years at Seoul National University Hospital. Of the 150 patients, 122 (81.3%) had penicillin-susceptible (Pen-S) strains and 28 (18.7%) penicillin-non-susceptible (Pen-NS) strains; 43 (28.7%) had erythromycin-susceptible (EM-S) strains and 107 (71.3%) erythromycin-non-susceptible (EM-NS) strains. On multivariate analysis, elevated APACHE II score [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.14-1.34, P<0.001) and presence of solid organ tumour (OR 2.99, 95% CI 1.15-7.80, P=0.025) were independent risk factors for mortality. Neither erythromycin resistance nor penicillin resistance had a significant effect on clinical outcomes. However, for the 76 patients with pneumococcal pneumonia, the time required for defervescence was significantly longer in the EM-NS group than in the EM-S group (5.45 ± 4.39 vs. 2.93 ± 2.56, P=0.03 by log rank test). In conclusion, antimicrobial resistance does not have an effect on mortality in adult patients with pneumococcal bacteraemia.

Outcome of inappropriate empirical antibiotic therapy in patients with Staphylococcus aureus bacteraemia: analytical strategy using propensity scores.

Patients with Staphylococcus aureus bacteraemia (SAB) who received either inappropriate or appropriate empirical therapy were compared by using two risk stratification models: (1) a cohort study using a propensity score to adjust for confounding by empirical treatment assignment; and (2) a propensity-matched case-control study. Inappropriate empirical therapy was modelled on the basis of patient characteristics, and included in the multivariate model to adjust for confounding. For case-matching analysis, patients with inappropriate empirical therapy (cases) were matched to those with appropriate empirical therapy (controls) on the basis of the propensity score (within 0.03 on a scale of 0-1). In total, 238 patients with SAB were enrolled in the cohort study. Characteristics associated with inappropriate empirical therapy were methicillin resistance, underlying haematological malignancy, no history of colonisation with methicillin-resistant S. aureus, and a long hospital stay before SAB. These variables were included in the propensity score, which had an area under the receiver operating characteristics curve of 85%. In the cohort study, SAB-related mortality was 39% (45/117) for inappropriate empirical therapy vs. 28% (34/121) for appropriate empirical therapy (odds ratio (OR) 1.60; 95% CI 0.93-2.76). After adjustment for independent predictors for mortality and the propensity score, inappropriate empirical therapy was not associated with mortality (adjusted OR 1.39; 95% CI 0.62-3.15). In the matched case-control study (50 pairs), SAB-related mortality was 32% (16/50) for inappropriate empirical therapy and 28% (14/50) for appropriate empirical therapy (McNemar's test; p 0.85; OR 1.15; 95% CI 0.51-2.64). In conclusion, inappropriate empirical therapy resulted in only a slight tendency towards increased mortality in patients with SAB.

Clinical features and outcome of patients with community-acquired Pseudomonas aeruginosa bacteraemia.

Cases of community-acquired Pseudomonas aeruginosa bacteraemia (n = 39) that occurred at a tertiary-care hospital during a 5-year period were analysed retrospectively. The commonest underlying diseases were solid tumour (41%) and haematological malignancy (18%). Most (44%) of the patients were neutropenic, and 39% had septic shock at initial presentation. The 30-day attributable mortality rate was 39%. Two previously healthy patients were identified with fatal P. aeruginosa pneumonia with bacteraemia. P. aeruginosa bacteraemia is a fatal infection that should be considered in the differential diagnosis of patients presenting from the community with rapidly progressive sepsis.

Involvement of caspase-3 in apoptosis induced by Viscum album var. coloratum agglutinin in HL-60 cells.

A cytotoxic lectin (Viscum album L. coloratum agglutinin, VCA) from Korean mistletoe was isolated by affinity chromatography on Sepharose 4B immobilized with asialofetuin. In HL-60 cells, addition of VCA resulted in a dose- and time-dependent growth suppression, morphological changes of apoptotic nuclei, and DNA fragmentation characteristics of apoptosis. To investigate how caspase-3 activation during VCA-induced apoptosis induces cleavages of PARP, the expression of PARP and the pattern of caspase-3 activation in HL-60 cells were investigated. The native and processed PARP forms typically seen in apoptotic cells were observed, and a decrease in expression of the 32-kDa form of caspase-3 in a dose-dependent manner was observed. The VCA-induced apoptosis was significantly inhibited by a caspase-3 specific inhibitor, z-DEVD-FMK, and the PARP processing and caspase-3 activation were also inhibited by the inhibitor. A possible involvement of cell cycle arrest in VCA-induced apoptosis was investigated by flow cytometry and the results suggested that the apoptotic effect of VCA is not involved in the induction of cell cycle arrest.

Reoperation of Recurrent Gastric Cancer.

PURPOSE: The aim of this study was to evaluate the outcome of reoperation in recurrent gastric cancers. MATERIALS AND METHODS: We conducted a retrospective analysis of 86 patients who underwent reoperation for recurrent gastric cancer. We reviewed the time interval between first operation and reoperation, as well as the recurrence pattern, type of reoperation, and survival following reoperation. RESULTS: the average time to reoperation following curative resection was 27.8+/-25.9 months (median 18.4 months). Fifty-three cases (61.6%) of reoperation were performed within 2 years follwoing the first operation. The most common reason for reoperation was intestinal obstruction followed by gastric remnant recurrence and intra-abdominal mass. Complete resection was possible in 14 cases (16.3%) and a palliative procedure such as partial resection or bypass procedures was performed in 54 cases. In 18 cases (20.9%), simple lapalotomy was done without any aid. The most common site of recurrence was the peritoneum followed by the gastric remnant, distant lymph node and hematogenous liver metastasis. Operative mortality was 10.5%. Excluding the 9 cases of operative mortality, the mean survival time after reoperation was 15.4+/-2.5 months (mean 8.6 months). Survival following complete resection was much longer than palliative procedure and exploration only (37.9+/-8.7 vs 10.9+/-1.5 vs 4.7+/-0.8 months, p=0.000). CONCLUSION: The complete resection of recurrent gastric cancer can prolong survival. Early detection of localized recurrence is important in order to increase the chance of complete resection.

Inhibition of tumor growth and metastasis by Korean mistletoe lectin is associated with apoptosis and antiangiogenesis.

The mistletoe lectins are major active components in the extract of European mistletoes that have been widely used in adjuvant chemotherapy of cancer. This study was performed to investigate the mechanism of anticancer and antimetastatic activity of the purified Korean mistletoe lectin (Viscum album L. coloratum agglutinin, VCA). C57BL6 mice inoculated with B16-BL6 melanoma cells and treated with VCA were assessed for survival and metastasis. The induction of apoptosis of B16-BL6 cells by VCA was investigated by morphological changes, DNA fragmentation characteristics, and cell cycle analysis. The antiangiogenic activity of VCA was also measured by the CAM (choriallantoic membrane) assay. Length of survival of mice was increased and lung metastasis was inhibited by VCA. Treatment of cells with VCA resulted in growth suppression, nuclear morphological changes, DNA fragmentation, and an increased fraction of cells in sub-G1 consistent with apoptosis. Antiangiogenesis of VCA was assessed by CAM assay, where vessel growth induced by fat emulsion was decreased. These results suggest that VCA inhibits tumor growth and metastasis by increasing apoptosis and inhibiting angiogenesis.

Comparative study of Korean (Viscum album var. coloratum) and European mistletoes (Viscum album).

A lectin (agglutinin, VCA) from Korean mistletoe (Viscum album L. coloratum) was isolated by affinity chromatograpy on a asialofetuin-Sepharose 4B. The molecular weights of A- and B-chains of VCA were differenf from those of VAAS. The VCA recognized the antibody of VAAs in the Western blot analysis and ELLA system. We also investigated the synergistic effects of the components in mistletoe by dividing the extract into different molecular weight fractions.