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.

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.

Characteristics of cefazolin inoculum effect-positive methicillin-susceptible staphylococcus aureus infection in a multicentre bacteraemia cohort.

Cefazolin treatment failure has been observed in high-inoculum infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) with a cefazolin inoculum effect (CIE). However, data on the characteristics and risk factors for the acquisition of CIE-positive MSSA infection are scarce. CIE positivity was measured as an MIC ≥ 16 µg/ml with a high inoculum (∼5 × 107 CFU/ml). The blaZ gene type was assessed through sequence analysis. The clinical characteristics and risk factors for the acquisition of CIE-positive MSSA infection were assessed. The association between the antimicrobial susceptibility profile and CIE positivity was evaluated. A total of 303 MSSA bacteraemia cases and their corresponding isolates were collected from ten hospitals: 61 (20.1 %) isolates showed a positive CIE; 254 (83.8 %) were positive for the blaZ gene. No significant association was found between CIE positivity and the site of infection. Metastatic cancer (aOR 2.86, 95 % CI, 1.10-7.48) and recent (≤1 month) close contact with a chronically ill patient (aOR 4.69, 95 % CI, 1.76-12.50) were identified as significant risk factors for CIE-positive MSSA infection through multivariate analyses. Resistances to clindamycin (OR 3.55, 95 % CI, 1.62-7.80) and erythromycin (OR 5.00, 95 % CI, 2.50-9.99) were associated with CIE positivity, presenting high specificity (92.9 %) and a negative predictive value (82.3 %). CIE-positive MSSA constituted approximately one-fifth of MSSA bacteraemia cases. Although CIE positivity was not clinically discernible, CIE positivity was associated with clindamycin or erythromycin susceptibility. Therefore, our findings suggest that cefazolin can be used in the treatment of high-inoculum MSSA infection if the isolates are susceptible to clindamycin or erythromycin.

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.

Pedicle ligation in ovariohysterectomy: an in vitro study of ligation techniques.

OBJECTIVES: Ligature failure is an important complication following ovariohysterectomy in the bitch. The aim of this study was to assess the differences between five individual ligation techniques in their ability to attenuate a bulky vascular model. METHODS: A vascular model was constructed that enabled the occlusive ability of five different ligation techniques to be measured including the square knot, surgeon's knot, slip knot, modified transfixing ligature and the single-double other side knot. Each was constructed using both USP-0 polyglyconate and polyglactin 910 suture material. The extent of attenuation of the vascular model that was achieved by each technique was assessed using pressure transducers. RESULTS: In this model, the slip knot, modified transfixing ligature and the single-double other side knot outperformed the square and surgeon's knots. CLINICAL SIGNIFICANCE: The results of this study suggest that utilising a knot design that has more inherent resistance to slippage of the first throw (e.g. the modified transfixing ligature, slip or single-double other side knots) may be preferable over square and surgeon's knots when tying a ligature on a bulky vascular pedicle like the ovarian stump in a large bitch.

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.

TM-25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co-activator TAZ.

BACKGROUND AND PURPOSE: The transcriptional co-activator with PDZ-binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt-related transcription factor 2 (RUNX2) and PPARγ, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity. EXPERIMENTAL APPROACH: High-throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation. KEY RESULTS: We identified 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine] (TM-25659) as a TAZ modulator. TM-25659 enhanced nuclear TAZ localization in a dose-dependent manner and attenuated PPARγ-mediated adipocyte differentiation by facilitating PPARγ suppression activity of TAZ. In addition, TAZ-induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM-25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM-25659 had a favourable pharmacokinetic profile. CONCLUSION AND IMPLICATIONS: TM-25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARγ-dependent adipogenesis and enhance RUNX2-induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM-25659 could be beneficial in the control of obesity and bone loss.

Frontalis sling operation using silicone rod for the correction of ptosis in chronic progressive external ophthalmoplegia.

AIMS: The aim of the study was to evaluate the results of the frontalis sling operation using silicone rod for the correction of ptosis in chronic progressive external ophthalmoplegia patients. METHODS: Chronic progressive external ophthalmoplegia patients who received the frontalis sling operation using silicone rods from 1999 to 2006 were included in this study. The medical records were retrospectively reviewed and the clinical characteristics and postoperative surgical results of these patients were analysed. This study was a retrospective, non-randomised, interventional case series and the main outcome measures were margin reflex distance, eyelid contour and corneal status. RESULTS: Seven patients were recruited (one male and six female). The mean age at the time of operation was 29.6 (range 15-62) years. Two patients had unilateral ptosis and five patients had bilateral ptosis. The mean follow-up period was 22.7 (range 1-61) months. Satisfactory lid height was achieved in all patients. Although corneal erosions were detected in five patients 1 month after surgery, these findings eventually resolved in three patients 2 months later, after the use of artificial tear eyedrops and ointments. CONCLUSION: The frontalis sling operation using silicone rod can safely and effectively correct ptosis in chronic progressive external ophthalmoplegia patients without serious corneal complications.

Pancreas retransplantation: outcomes of 20 cases.

The objective of this paper was to evaluate our initial experience with pancreas retransplantation. From January 26, 1996 to February 2005, 285 pancreas transplantations were performed, including 20 (7%) retransplants. The causes of primary graft loss were graft thrombosis in 11 (55%, 7 venous and 4 arterial); 4 (20%) chronic rejections; 2 (10%) ischemia/reperfusion injury; 1 severe graft pancreatitis; 1 primary nonfunction; and 1 sepsis. Venous drainage was placed in the iliac vessels in 14 (70%), vena cava in 5 (25%), and portal drainage in 1. The exocrine drainage was vesical in 16 (80%) and enteric in 4 (20%). In 14 cases (70%), the primary graft was removed before and in 6 (30%) at the time of retransplantation. Immunosuppression was based on antilymphocyte induction, tacrolimus, mycophenolate mofetil, and steroids in all patients. One-year patient and graft survivals were 95% and 85%. In conclusion, pancreas retransplants were feasible with results comparable to a primary pancreas transplantation.

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.

Effects of Shikunshito-Kamiho on fecal enzymes and formation of aberrant crypt foci induced by 1,2-dimethylhydrazine.

Shikunshito-Kamiho (SKTK) is a traditional Chinese medicine composed of eight crude drugs (Ginseng Radix, Hoelen, Atractylodis Rhizoma, Glycyrrhizae Radix, Prunellae Spica, Ostreae Testa, Laminaria Thallus, Sargassum). We investigated the effects of SKTK on pH, ammonia, fecal enzymes such as beta-glucuronidase, tryptophanase, urease, and formation aberrant crypt foci in the colon carcinogenesis model induced by 1,2-dimethylhydrazine (DMH). Water extract of SKTK was administered orally for 5 weeks to DMH-treated mice as 0.5% and 1.5% of the diet. Beta-glucuronidase, pH and tryptophanase were significantly inhibited after treatment of 0.5% and 1.5% SKTK, while urease was significantly reduced only during and after treatment of 1.5% SKTK as compared with control data. However, the ammonia concentration wasn't different in SKTK treated groups from control group. The incidence number of aberrant crypts foci (ACF) and aberrant crypts/focus in colon was significantly decreased by 0.5% and 1.5% SKTK mixed diets compared with that in rats treated with DMH alone. These results suggest that SKTK exterts anticarcinogenic activity on experimental murine colorectal cancer.

Comparison of organic and inorganic packing materials in the removal of ammonia gas in biofilters.

Two organic and two inorganic packing materials were compared with regard to the removal of ammonia gas in a biofilter inoculated with night-soil sludge. By gradually increasing the inlet load of ammonia, the complete removal capacity, which was defined as the inlet load of ammonia that was completely removed, and the maximum removal capacity of ammonia, which was the value when the removal capacity leveled off for each packing material, were estimated. Both values which were based on a unit volume of packing material, were higher for organic packing materials than inorganic ones. By using kinetic analysis, the maximum removal rate of ammonia, V(m), and the saturation constant, K(s), were determined for all packing materials and the values of V(m) for organic packing materials were found to be larger. By using the kinetic parameters, the removal rates for ammonia were compared among the four packing materials, and the organic packing materials showed superior performance for the removal of ammonia in the concentration range of 0-300 ppm as compared to inorganic packing materials.

Removal of a high load of ammonia gas by a marine bacterium, Vibrio alginolyticus.

A newly isolated marine bacterium, Vibrio alginolyticus was used to remove a high load of ammonia gas. By a stepwise increase in ammonia supply over the concentration range of 120-2000 ppm (v/v), complete removal of ammonia was observed from the start of the experiment in a suspended culture of the bacterium in basal medium containing 3% NaCl. When cells were inoculated onto an inorganic packing material in a biofilter, and a high load of ammonia was introduced continuously under nonsterile conditions, the average percentage of gas removed exceeded 85% for a 61-d operation. The maximum removal capacity and the complete removal capacity were 22.8 g-N/kg-dry packing material/d and 18.6 g-N/kg-dry packing material/d, respectively, which were about four times larger than those obtained in nitrifying sludge inoculated onto the same packing material. During this operation, the nonsterile air supply had no adverse effect on the removability of ammonia by V. alginolyticus.

Spectrum of opportunistic infections and malignancies in patients with human immunodeficiency virus infection in South Korea.

To determine the frequency and types of major opportunistic diseases in patients with HIV infection in South Korea, we reviewed the medical records of 173 HIV-infected patients. The patients were seen from 1985 to 1998 at a referral hospital for AIDS in South Korea. Most patients (85%) were male, and 107 (62%) were infected by heterosexual contacts. CD4+ lymphocyte counts at presentation were <200/microL in 27% of the patients. Tuberculosis was the most frequent opportunistic infection (25% of patients), followed by candidiasis (21%), herpes zoster (20%), Pneumocystis carinii pneumonia (10%), cytomegalovirus disease (9.8%). There were no cases of toxoplasmosis. Kaposi's sarcoma developed in 3 patients (1.7%), and non-Hodgkin's lymphoma, in 2 (1.2%). Eleven patients (6.4%) developed peripheral neuropathy, and 8 (4.6%) had HIV encephalopathy. Tuberculosis was the single most important HIV-related infection in South Korean patients.

Beta-glucuronidase-inhibitory activity and hepatoprotective effect of Ganoderma lucidum.

To prove the relationship between the fluctuation in serum beta-glucuronidase level and hepatotoxicity, an inhibitor of beta-glucuronidase from G. lucidum was isolated and its hepatoprotective activity was investigated. The ether fraction of G. lucidum, which had potent beta-glucuronidase-inhibitory activity, protected against CCl4-induced liver injury. From this ether fraction, ganoderenic acid A, was isolated as the potent inhibitor of beta-glucuronidase. It had a potent hepatoprotective effect against CCl4-induced liver injury. These results suggest that the beta-glucuronidase seems to be closely related to liver injury, which could be prevented by beta-glucuronidase inhibitors.

A case of Marfan syndrome with acute monoblastic leukemia.

We report on an 18-year-old man who had both acute monoblastic leukemia and Marfan syndrome. A diagnosis of Marfan syndrome was established by those characteristics of arachnodactyly, ectopia lentis, mitral valve prolapse, and mitral regurgitation. Findings on bone marrow examination of the patient showed that most of nucleated cells were monoblasts and immunophenotype of those cells showed CD13+, CD33+, CD56+, and HLA-DR+. To our knowledge, this is the second report of leukemia in Marfan syndrome in the world.

Etiologic considerations of nonspecific pleuritis.

Twenty-three patients with nonspecific pleuritis were studied to determine clinical outcome. After a mean follow-up period of 6 months (1 to 36 months), a diagnosis was reached in 17 patients, while 6 patients remained unknown. The causes of the nonspecific pleuritis diagnosed on initial pleural biopsy were tuberculosis (11 patients, 48%), neoplasm (2 patients, 8.7%), parapneumonic effusion (1 patient), subphrenic abscess (1 patient), congestive heart failure (1 patients), and nephrotic syndrome (1 patient). The diagnosis was made by therapeutic trials (tuberculosis: 11 patients, parapneumonic effusion: 1 patient, congestive heart failure: 1 patient), by repeat pleural biopsy in 1 hepatoma, by open thoractomy in 1 lung cancer, by exploratory laparotomy in 1 subphrenic abscess, and by kidney biopsy in 1 nephrotic syndrome. The WBC counts (more than 2,000/mm3) and lymphocyte percentage (more than 60%) in the pleural fluid were significantly elevated in the patients with tuberculosis compared to those with malignant pleurisy, and other laboratory data were meaningless. As a result of this investigation, we suggest that tuberculous pleurisy is the most common cause of nonspecific pleuritis in Korea and that therapeutic trial with antituberculous medication for patients with high WBC count and lymphocyte percent in pleural fluid can help to locate the nonspecific pleuritis.