Failure of daptomycin β-Lactam combination therapy to prevent resistance emergence in Enterococcus faecium

Daptomycin β-Lactam combination therapy offers “protection” against daptomycin non-susceptibility (DNS) development in Enterococcus faecium. We report failure of this strategy and the importance of source control. Mutations were detected in the LiaF and cls genes in DNS isolates. A single DNS isolate contained an unrecognized mutation, which requires confirmation.     

Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone

Background

Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear.

Methods

A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50–60 mg/kg 12–24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR.

Results

Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 ± 1.6 ms p = 0.04; and DFO monotherapy +1.9 ± 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group.

Conclusions

Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients.     

Effective Combination Therapy of Deferiprone and deferoxamine for the Rapid Clearance of Excess Cardiac IRON and the Prevention of Heart Disease in Thalassemia. The Protocol of the International Committee on Oral Chelators

The International Committee on Oral Chelators (ICOC) combination therapy protocol involving the administration of deferiprone (L1) during the day (80–110 mg/kg/day) and deferoxamine (DFO) (40–60 mg/kg at least 3 days/week) during the night for 8–12 hours using a pump, or the whole 24 hours using an elastomeric pump infuser, has been tested in 11 thalassemia patients (seven males, four females) over a period of 9–28 months. The patients had variable serum ferritin levels (0.54–4.6 mg/L) and cardiac iron load ranging from normal to severe siderosis levels (MRI T2*: 4.7–45 ms). There was a substantial overall reduction in serum ferritin levels (0.17–2.16 mg/L) and normalization of cardiac iron (MRI T2* >20 ms) in all patients. In two patients with severe and moderate cardiac iron load range levels, cardiac iron normalization was achieved within 9–10 months. Two patients on L1 monotherapy (80–120 mg/kg/day) maintained normal range MRI T2* cardiac iron levels over the same period. The ICOC combination therapy protocol appears to be the most effective and least cumbersome form of chelation treatment for the rapid clearance of excess iron from the heart.     

针药并用治疗输尿管结石的疗效观察

目的　观察针药并用治疗输尿管结石的疗效。方法　采用针刺结合药物治疗输尿管结石 80例 ,并设单纯药物组和针刺组进行疗效比较。结果与结论　针药组痊愈率和总有效率均显著高于药物组和针刺组 (P<0 .0 5 ,P<0 .0 1) ,药物组与针刺组比较 ,两组痊愈率和总有效率无显著性差异     

In vitro biofilm characterization and activity of antifungal agents alone and in combination against sessile and planktonic clinical Candida albicans isolates

Thirty clinical isolates of Candida albicans were collected from blood or other sterile site infections. Biofilm dry weight and metabolic activity were measured for each isolate. Planktonic and sessile antifungal susceptibilities of each isolate were determined for amphotericin B deoxycholate, caspofungin, and voriconazole. Sessile susceptibilities were determined for the combination of caspofungin/voriconazole. No significant differences in biofilm dry weight or metabolic activity were found between bloodstream and other invasive isolates. Planktonic MIC90 values and sessile MIC90 (SMIC90) values were 0.25 and 2, 0.06 and >256, and 0.5 and 2 microg/mL for amphotericin, voriconazole, and caspofungin, respectively. The SMIC90 of the combination of caspofungin/voriconazole against sessile isolates was 0.5/2 microg/mL. Therefore, the source of invasive C. albicans clinical isolates did not affect in vitro biofilm formation. Susceptibility to antifungal agents decreased when C. albicans was associated with biofilm, and the combination of caspofungin/voriconazole did not appear to provide enhanced activity compared with caspofungin alone.     

阿糖胞苷联合光动力疗法对人白血病HL-60细胞作用的研究

目的 探讨阿糖胞苷（Ara-c）在癌光啉（PSD-007）介导的光动力疗法（PDT）杀伤人早幼粒白血病HL-60细胞中的联合作用.方法 实验分为空白对照组、PDT单独作用组（PDT l～4组,为光敏剂剂量（5、7.5μg/ml）和激光能量密度（1.2、2.4 J/cm^2）的两两组合）、Ara-c单独作用组（Ara-c A组和Ara-c B组中Ara-c质量浓度分别为0.3 μg/ml和1.2μg/ml）和联合作用组即上述PDT单独作用组和Ara-c单独作用组的两两组合.所有分组分别按3种时序即P24A时序（PDT作用24h后再加入Ara-c共同作用24h）、A24P时序（Ara-c作用24h后进行PDT再共同作用24h）和PA24时序（PDT作用的同时加入Ara-c再共同作用24h）进行处理.采用CCK-8法检测各组细胞活性,用金氏公式分析联合效应,并用流式细胞术检测细胞周期变化.结果 小剂量PSD-007介导的PDT和Ara-c联合时,3种时序的联合作用均表现为协同效应;而大剂量PSD-007介导的PDT和Ara-c联合时,P24A和A24P 2种时序的联合作用效应为协同或相加,PA24时序则主要为相加或拮抗.流式细胞仪检测细胞周期变化结果显示,Ara-c和PSD介导的PDT均能引起细胞周期G0/G1期阻滞.结论 Ara-c与PSD-007介导的PDT联合作用对HL-60细胞的杀伤有协同作用,其协同作用与剂量和作用时序相关,小剂量比大剂量协同效果明显,且Ara-c和PDT间隔24h作用比2者同时作用于该细胞的协同效果明显.     

Cell-wall-inhibiting antibiotic combinations with activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli

The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied.     

Co-expression of cancer testis antigens and topoisomerase 2-alpha in triple negative breast carcinomas

Triple negative breast cancers (TNBC) are characterized by aggressive tumor biology, lack of targeted treatments and poor prognosis. Anthracyclins were shown to induce immunogenic death in target cells, potentially leading to “endogenous” vaccination. We comparatively assessed expression of cancer testis antigens (CTA) and topoisomerase 2-alpha (TOPO2A), a well defined molecular target of anthracyclins, in TNBC fully characterized for basal-like (BL) immunophenotype, BL morphology and conventional clinicopathological factors. The study included 83 patients undergoing surgery between January 2003 and December 2009. Tissue sections were stained with CK5/6, CK14, EGFR, Ki-67, TOPO2A, MAGE-A1, MAGE-A10, NY-ESO and multi-MAGE-A specific reagents. Of the 83 TNBC, >66.3% had BL immunophenotype and 48.2% had BL morphology. MAGE-A1 specific staining was most frequently detectable (69.2%), followed by multi-MAGE-A (58%), NY-ESO (27.1%) and MAGE-A10 (16%) specific staining. MAGE-A10 expression significantly correlated with tumor size (p = 0.026). Furthermore, MAGE-A1, MAGE-A10 and multi-MAGE-A specific stainings significantly correlated with advanced clinical stage (p = 0.024, p = 0.041, p = 0.031, respectively). We found no significant association between CTA expression and disease free (DFS) or overall survival (OS). Most interestingly, a significant correlation was observed between expression of MAGE-A10 and NY-ESO and expression of TOPO2A (p = 0.005, p = 0.013). Expression of defined CTA and TOPO2A are significantly correlated in TNBC. Considering the limited therapeutic options for TNBC, these findings might suggest novel forms of combination therapies that should be further explored.     

卡培他滨为基础的联合化疗治疗晚期胃癌的临床观察

目的观察卡培他滨(希罗达)为基础的联合化疗治疗晚期胃癌的有效性和安全性。方法 2006年3月～2010年3月,12例晚期胃癌患者接受以希罗达为基础的联合化疗。希罗达2000mg∕m2,分早晚2次口服,连用14d,间隔21d后重复。有4例患者采用HLX方案,3例患者分别采用DOX、POX、DCX方案,2例患者采用EOX方案,3例患者采用XELOX方案。分别按照RECIST标准和NCI-CTC3.0评价疗效和毒性。结果 12例均可评价疗效。6例PR,5例SD,1例PD,总有效率为50%,疾病控制率为91.7%。疾病进展时间(TTP)为2～18个月,总生存时间(OS)为2～29个月。12例患者均可评价毒性,主要毒副反应为骨髓抑制、恶心呕吐、外周神经毒性、色素沉着和手足综合征,主要为Ⅰ～Ⅱ级毒副反应,病人均能耐受。结论以希罗达为基础的联合化疗治疗晚期胃癌疗效确切、毒副反应较低、患者耐受性好,值得临床推广应用。